JTCS KCI
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Benedetto Marino
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sugimoto, S.
Right arrow Articles by Marino, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sugimoto, S.
Right arrow Articles by Marino, B.

J Thorac Cardiovasc Surg 1994;108:455-466
© 1994 Mosby, Inc.

CARDIOPULMONARY BYPASS,
MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES

Pretreatment with the adenosine triphosphate–sensitive potassium channel opener nicorandil and improved myocardial protection during high-potassium cardioplegic hypoxia

Satoru Sugimoto, MD, Paolo Emilio Puddu, MD, FESC, FACC, Francesco Monti, MD, Michele Schiariti, MD, Pietro Paolo Campa, MD, Benedetto Marino, MD


Rome, Italy

Supported in part by a grant from the Ministry of Foreign Affairs of Italy and by a grant-in-aid from Chugai Pharmaceutical Co., Tokyo, Japan, to Satoru Sugimoto, on leave from the Department of Surgery, Section 2, Sapporo Medical College, Sapporo, Japan.

Received for publication April 13, 1993. Accepted for publication Feb. 4, 1994. Address for reprints: P. E. Puddu, MD, Istituto di Chirurgia del Cuore e Grossi Vasi, II Cattedra di Cardiologia, Università degli Studi di Roma "La Sapienza," Viale del Policlinico, 155, Rome 00161, Italy.

Abstract

We hypothesized that pretreatment with the potassium channel opener nicorandil might enhance myocardial protection achieved by cold (20°C) high-potassium (16 mmol/L) cardioplegia (5 ml/min) during long-duration (120 minutes) myocardial hypoxia (average oxygen content 5.4 ml/dl). We tested a 15-minute infusion of nicorandil (1 mmol/L) given only before (group A, n = 8) or before and during cardioplegia (group B, n = 8) in guinea pig papillary muscle preparations contracting isometrically while stimulated (4 mA, 2 msec) at 1600 msec cycle length. Nicorandil was significantly negative inotropic before cardioplegia and shortened significantly action potential duration. During cardioplegia, time to arrest of contraction was shortened from 145±28 seconds (mean±standard error) in the vehicle group (dimethyl sulfoxide 1:100; n = 8) to 56±10 seconds (p < 0.02) and 68±5 seconds (p < 0.05) in groups A and B, respectively. Recovery of developed tension at 60 minutes of normothermic reoxygenation (expressed as percent of prehypoxia basal value) was ameliorated from 54%±6% (vehicle group) to 92%±4% (group A, p < 0.01) and to 119%±19% (group B, p< 0.01). The specific potassium channel blocker glibenclamide (glib: 1µmol/L, n = 8) prolonged action potential duration and was without effect on time to arrest. On reoxygenation, the glib group had prolonged time to half relaxation (versus group A, p < 0.02) and the worst percent developed tension at 60 minutes (40%±4%). In the overall study, time to arrest and percent developed tension at 60 minutes were inversely correlated (r = -0.45, p < 0.01). Arrhythmias were never observed. Multivariate analysis showed that pretreatment with nicorandil (with or without drug adjunct to cardioplegic solution) was a significant factor (r 2= 0.65, p = 0.0001) to influence reoxygenation-mediated recovery of mechanical function. Neither the negative inotropic effect of nicorandil before cardioplegia nor its abbreviating action on time to arrest during cardioplegia was contributory to explain recovery of function on reoxygenation. In subgroup analysis, negative inotropism and the shortening of action potential duration were contributory factors. These data suggest that nicorandil pretreatment activates potassium channels and enhances the myocardial protection provided by cold cardioplegia an effect, which is evident after a long hypoxic period, late on reoxygenation. (J THORAC CARDIOVASC SURG 1994;108:455-66)

After postulation by Noma Go 1 that adenosine triphosphate–sensitive potassium (KATP) channels might open during ischemia and be instrumental to reduced action potential plateau phase, reduced calcium current, and therefore reduction of calcium-related energy cost of contraction, Go 2 it was shown that hypoxia activates these channels and produces early contractile failure. Go 3 These events are counteracted by the sulfonylurea glibenclamide, Go 4 a specific blocker of KATP channels in the heart. Go 5 Therefore, during an ischemic insult, a decrease in hypoxia-mediated myocardial [ATP]i, Go 6 KATP channel opening, and loss of contraction Go 3 might represent a teleologic cell response to energy deprivation, forming a "natural" cell protection by a negative feedback mechanism Go 7 that counteracts further ATP consumption. Drug-induced KATP channel opening afforded myocardial protection in investigations Go Go 8-12 in which models of either global or regional ischemia Go 8 were used, whereas pretreatment with glibenclamide prevented this effect. Go Go Go 8,10-13 However, only the hybrid compound 2-nicotinamidoethyl nitrate (nicorandil), a KATP channel opener Go 14 developed in Japan, Go 15 has been approved for clinical use in ischemic heart disease. Go 16

Whether drug-induced KATP channel opening modifies myocardial contractility at induction of cold potassium cardioplegia or whether ensuing contractility changes might relate to subsequent functional recovery after a long period of cold cardioplegia arrest is not known. Levcromakalim, the pure levoisomer of the KATP channel opener cromakalim, was investigated by Galiñanes, Shattock, and Hearse Go 17 in isolated Langendorff-perfused rat hearts during 20 minutes of normothermic global ischemia. However, although significant antiischemic effects and acceleration of contractile arrest were observed with levcromakalim, when it was used in combination with high-potassium cardioplegia these effects were lost. Go 17 On the other hand, ischemic preconditioning, that is, a brief period of myocardial ischemia followed by short-lived reperfusion (and thus reoxygenation), increases resistance to subsequent long-duration myocardial ischemia. Go Go 18,19Activation of adenosine A1 receptor or KATP channels, or both, have been mechanistically implicated. Go Go 20-23

The hypothesis on which the present investigation is based is that KATP channel activation by nicorandil given before rapid induction of contraction arrest with high-potassium cold crystalloid cardioplegia might enhance myocardial protection over a long, clinically meaningful period of cold cardioplegic perfusion. To do so, we have adapted a widely known method described by Bing, Brooks, and Messer Go 24 to investigate mechanical and electrophysiologic correlates of myocardial hypoxia and reoxygenation. Go Go 25,26 We used St. Thomas' Hospital solution as the cardioplegic solution (CPS). Go Go 27,28 Implications for clinicians and surgeons recently raised by Fox Go 29 were considered to secure differentiation between interventions made during the ischemic (or hypoxic) interval versus those performed at the time of reperfusion/reoxygenation.

MATERIAL AND METHODS

Preparation
Forty female guinea pigs (300 to 350 gm) were used. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resource and published by the National Institutes of Health (NIH Publication No. 86-23, revised 1985). They were killed by cervical dislocation and exsanguinated. The hearts were quickly removed and placed in a dish containing oxygenated Tyrode's solution at room temperature. The composition of Tyrode's solution was the following (millimoles per liter): NaCl, 108.2; KCl, 4.0; CaCl2, 1.8; MgCl2, 1.0; NaHCO3, 25.0; NaHPO4, 1.8; and glucose, 5.5. The pH was adjusted to 7.35 ± 0.02 with hydrochloric acid. The solution was gassed with 95% oxygen and 5% carbon dioxide. Papillary muscle preparation was obtained with ophthalmologist's scissors. In brief, the atria were removed, and the right ventricle was opened by an incision in its posterior wall along the septal border. The anterior papillary muscle was recognized, carefully dissected from its base and from tricuspid attachment, and placed within 1 minute in an immersion chamber (5 ml in capacity).

The immersion chamber received incoming fluid at a rate of 5 ml/min by a single-headed peristaltic pump (Masterflex 7013-21, Cole-Parmer Instrument Co., Chicago, Ill.). A vacuum-water pump controlled the outflow of the chamber. The transit time of the incoming fluid, as measured in each experiment, varied from 30 to 40 seconds depending on Tygon tubing length (Norton Plastics, Akron, Ohio) passing through the peristaltic pump. Temperature was controlled by a circulating thermostat-regulated bath (Polystat 86602, Bioblock Scientific, Illkirch, France). The lower end of the papillary muscle was fixed to the chamber floor with fine stainless steel pins and the tendinous upper end was connected to a force transducer (Gould RC 369500-8641, Gould Inc., Recording System Division, Cleveland, Ohio) via a stainless steel hook. The muscle was stimulated by 2 msec square pulses delivered from an orthorhythmic stimulator (Explorer 1000, VPA Medical, Paris, France) at 4 mA after the diastolic threshold intensity was measured (0.5 to 1 mA) by a bipolar Teflon-coated 99.99% silver wire electrode (AG-15T, 0.375 mm in diameter, PHYMEP sarl, Paris, France) placed on the lower end of the muscle surface. During a 30-minute equilibration period, the muscle shortened while carrying a light load. The preparation was then made to contract isometrically and lengthened to the apex of its length-tension curve (Lmax) while immersed in circulating oxygenated Tyrode's solution at 5 ml/min (37° C). After a subsequent 15-minute period, muscle length was carefully readjusted for optimum force production by means of a micrometer screw that controlled the position of the force transducer, and the preparation then remained at Lmax throughout the experiment. Unstable or poor preparations were discarded.

Baseline force development at Lmax in oxygenated and thermostat-controlled Tyrode's solution at 37° C was obtained after muscle tension was stabilized (total equilibration time 60 minutes or more) at 1600 msec cycle length. At baseline, pH, oxygen tension, and carbon dioxide tension were measured from samples obtained from the immersion chamber (BG Electrolytes, Instrumentation Laboratory SpA, Milan, Italy, at 755 mm Hg barometric pressure) and found to be 7.4 ± 0.2, 510 ± 20 mm Hg, and 14 ± 3 mm Hg, respectively. Basal temperature was continuously measured in the immersion chamber (Bat 10 thermometer, Physitemp Inc., Clifton, N.J.). The difference among experimental groups was not in excess of 0.1° C. Temperature measurements were continued during all successive phases of the protocol. Papillary muscle isometric tension was continuously recorded on a multichannel polygraph (Gould RS 3400, Gould Inc. Recording System Division, Cleveland, Ohio) at both low and high speed. Measurements of muscle tension included the following: time to peak tension, developed tension, and time to half relaxation. These measurements were performed according to the methods illustrated by Bing, Brooks, and Messer. Go 24 At baseline, data were expressed in these units: milliseconds, millinewtons, and milliseconds, respectively (GoTable I). Moreover, developed tension divided by time to peak tension (micronewtons/microseconds) was calculated. The rationale for selecting developed tension/time to peak tension is based on its mathematical (derivative) and physiological significance because developed tension/time to peak tension represents dP/dt Go 25 and therefore might be considered to index contractility of isometrically contracting papillary muscle. For the successive calculations, percent time to peak tension, percent developed tension, percent time to half relaxation, and percent developed tension/time to peak tension were obtained by this equation: Percent value = (Value at time of interest/basal value) x 100. Cross-sectional areas at Lmax were not considered in order to prevent assumptions as to uniform cylindrical geometry of papillary muscles and possible visual errors during telemicroscope measurements in either length or width of these muscles that might concur to macroscopic calculation errors of normalized force. However, if differences in cycle length, temperature, [Ca ++]0, and flow rate of circulating solutions are taken into account, our baseline values were similar to those observed in guinea pig, Go Go 26,30 kitten, Go 31 or rat Go Go 26,32 papillary muscle preparations from animals whose body weight was in the weight range of our guinea pigs.


View this table:
[in this window]
[in a new window]
  		Table I. Absolute basal parameters of isometric contractility and changes resulting from120 minutes of cold hypoxic cardioplegia in guinea pig right ventricular papillary muscle (n = 40)
 
After basal measurements, drugs were started. At the end of the drug pretreatment (or at corresponding points in time in control groups), that is, immediately before induction of cardioplegia, the effect of drug pretreatment on contraction parameters was assessed. Then oxygenated normothermic Tyrode's solution with or without drugs was switched to room-temperature nonoxygenated hyperkalemic CPS (5 ml/min), previously described as St. Thomas' Hospital CPS. Go Go 27,28 The composition of the CPS was the following (millimoles per liter): NaCl, 110.0; KCl, 16.0; CaCl2, 1.2; MgCl2, 16.0; NaHCO3, 10.0. The measured pH of this solution was 7.8. The temperature of incoming CPS was gradually reduced with a heat exchanger (Cryothermostat compact Variostat, model C85107, Bioblock, Illkirch, France) until 20° C was reached, within about 8 minutes. Hypothermia was maintained at 20° C until the end of the experimental hypothermic hypoxic period, namely, until 120 minutes after induction of cardioplegia. While the preparation was stimulated at 1600 msec cycle length, time to arrest of mechanical activity was measured in each experiment, with transit time (as previously defined) being taken into account. This interval was considered as the time between the start of hypothermic immersion (as the arrival of CPS into the chamber) and the cessation of mechanical activity of the papillary muscle. Cessation of mechanical activity was recognized by complete stoppage of tension development on paper recording. Throughout the experiments, electrical stimulation was continued to confirm that no contraction occurred during hypothermic immersion. At several intervals during hypothermic immersion with CPS, pH, oxygen tension, and carbon dioxide tension were measured, as described earlier. Mean values at 30 (n = 10) and 110 (n = 20) minutes of hypothermic superfusion were 7.55 ± 0.02, 180 ± 1.15 mm Hg, and 15 ± 1.23 mm Hg, respectively (values referred to 37° C for comparison). After 120 minutes of hypothermic hypoxic cardioplegia (average oxygen content 5.44 ml/dl), Go 33 oxygenated Tyrode's solution was reinfused and the heat exchanger used to stabilize temperature of incoming fluid at 37° C within about 8 minutes.

To control for hypoxia-related mechanical failure independent of the CPS, we performed experiments in a parallel series of animals (n = 4), and cold (20° C) nonoxygenated Tyrode's solution for 120 minutes was used in place of cold CPS. Tyrode's solution used in these latter experiments contained glucose 5.5 mmol/L as described earlier. We chose not to test substrate-free Tyrode's solution because it has been demonstrated previously that in preparations of left ventricular trabecular muscle in the rat, 15 minutes of hypoxia (<10 mm Hg with nitrogen gassing) in a 5 mmol/L dose as compared with a 50 mmol/L dose of glucose Krebs-Henseleit solution is followed by identical tension decrease (averaging 30% of prehypoxia control). Go 26 Measurements in this series were obtained similar to those in the experimental series. After 30 (n = 2) and 110 (n = 2) minutes, pH, oxygen tension, and carbon dioxide tension were 7.65 ± 0.01, 186 ± 1.5 mm Hg, and 23 ± 0.45 mm Hg, respectively (values referred to 37° C for comparison).

Experimental protocol
Fig. 1 illustrates the groups included in this investigation. There were 40 preparations randomized into five groups, each composed of eight preparations, based on interventions added to the CPS (during 120 minutes: treatment) or administered for 15 minutes in Tyrode's solution immediately before initiation of circulating immersion with CPS (pretreatment). Groups were as follows: (1) control group (controls), with CPS without either drugs or vehicle; (2) vehicle control group (vehicle group), with CPS containing dimethyl sulfoxide (DMSO) (Sigma Chemical Co., St. Louis, Mo.) (1:100); (3) pretreatment alone group (group A), with KATP channel opener nicorandil (Chugai, Tokyo Japan) 1 mmol/L in DMSO (1:100) as vehicle, only in Tyrode's solution for 15 minutes before infusion of CPS; (4) pretreatment plus treatment group (group B), with nicorandil 1 mmol/L in DMSO (1:100), in Tyrode's solution for 15 minutes before cardioplegia, and later at the same drug and vehicle concentrations in the CPS; (5) glibenclamide pretreatment plus treatment group (glib group), 1 µmol/L in DMSO (1:10000) in Tyrode's solution, and later 1 µmol/L in DMSO (1:10000) plus DMSO (1:100) in the CPS. Nicorandil and glibenclamide solutions were freshly prepared for each experiment by dilution from 100 mmol/L and 10 mmol/L stock solutions in DMSO, respectively. All chemicals used to prepare solutions were of analytical grade (Merck, Darmstadt, Germany) and dissolved in distilled water.



View larger version (30K):
[in this window]
[in a new window]
  		Fig. 1. Experimental protocol and grouping. GP, Guinea pig; RV, right ventricle.

 
The high concentration of nicorandil tested in this investigation was chosen on the basis of the following: First, preliminary results obtained in our laboratory, with normally oxygenated right ventricular anterior papillary muscle from guinea pig, showed that, over the wide range of concentrations from 1 nmol/L to 1 mmol/L, peak effect was observed at a nicorandil concentration of 1 mmol/L. In that study, performed in seven animals at 1600 msec cycle length, the logarithm of percent developed tension was negatively correlated with the coded (1 to 7) negative logarithm of nicorandil concentration (Y = 1.9354 - 0.02691X, n = 48 data sets, r = -0.249, p = 0.088). Second, data obtained by Orita and associates Go 34 in the dog showed that orthotopically transplanted hearts might receive a solution containing 8 mg/L (approximately 40 µmol/ L) nicorandil without any adverse effect. Third, Although 1 mmol/L nicorandil might be considered an excessively high concentration as compared with those generally observed clinically after oral administration (maximum plasma concentration was reportedly 770 ± 70 nmol/L at 23 minutes after 10 mg nicorandil orally in healthy young male volunteers Go 35), we did choose it to minimize ß-error of the effectiveness hypothesis raised in the present investigation. Also, in the context of adjunct interventions tested previously during surgical cardiac arrest, the case of adenosine was explored in the range of 1 to 10 mmol/L. Go Go 36,37

Electrical recording
Transmembrane potentials were recorded by impaling myocytes with conventional intracellular glass microelectrodes inserted near to the lower end of the muscle preparation. The micropipettes (20 to 30 MOhm) were pulled from filamented capillary tubes (GC200F-15, 1.5 mm outer diameter, PHYMEP sarl, Paris, France) on a single-barreled microelectrode puller (Ealing Beck Ltd., Watford, England), filled with potassium chloride 3 mol/L, and coupled to silver–silver chloride microelectrode holders (EH4FS-15, 1.5 mm inner diameter, PHYMEP sarl, Paris, France) leading to the input stage of a high impedance capacitance-neutralizing amplifier (Electro 705, WPI, New Haven, Conn.). The reference silver–silver chloride electrode (RC-1, 2.0 mm outer diameter, PHYMEP sarl, Paris, France) was positioned in the immersion fluid, close to the preparation.

Action potentials were monitored on a digital memory oscilloscope (Tektronix 2230, Tektronix Inc., Beaverton, Ore.) and simultaneously recorded on the Gould multichannel direct-writing polygraph described earlier. Action potential data were digitized and stored on a hard disk at a sampling frequency of 8 kHz (Datapac 2.0, developed by Morel and Rouet, University of Normandy, Caen, France), with the use of a model Tm7466 computer (Tandon Corp., Moorpark, Calif.). Resting membrane potential and action potential duration were measured (respectively, millivolts and milliseconds) automatically by Datapac 2.0. Although action potential duration was calculated at 30%, 50%, 70%, and 90% of action potential amplitude, only the 90% figure is reported here.

Statistics
Data in GoTable I, figures, and text are expressed as means ± standard error of the mean. Data in GoTable II are presented as means ± standard deviation. Intergroup comparisons to evaluate the effects of the various treatments tested in this investigation were made with BMDP statistical software Go 38 and an IBM-compatible 486 personal computer by analysis of variance and unpaired t tests (BMDP-7D and 3D). Linear correlation (BMDP-1R) was used to test the null hypothesis of correlation between two parameters. Finally, we used all possible subset analyses (BMDP-9R) to predict multivariately, by using a linear model, the effects of the various treatments on recovery of percent developed tension/time to peak tension at 60 minutes of reoxygenation (as dependent variable). To evaluate the weight of treatment (or pretreatment) groups, while running BMDP-9R, we created dummy variables based on a contingency 5 x 5 table (see legend to GoTable II for details). The reference for dummy variables was vehicle.


View this table:
[in this window]
[in a new window]
  		Table II. Predictive covariates of recovery of isometric contractility at 60 minutes of reoxygenation after 120 minutes of cold hypoxic cardioplegia in guinea pig right ventricular papillary muscle(n = 36: 90% of the overall preparations)
 
Included covariates in the multivariate model (as independent variables) were as follows: basal mechanical data before hypoxia (time to peak tension, developed tension, and time to half relaxation), percent developed tension/time to peak tension both at the end of drug pretreatment and at 30 seconds of superfusion with CPS, time to arrest of contraction, and temperatures both at 30 seconds of CPS superfusion and at time of arrest. Inclusion of these covariates in the multivariate model enables the evaluation of their respective statistical contribution to predict contractility changes (percent developed tension/time to peak tension) at 60 minutes of reoxygenation. Absolute basal values of developed tension/time to peak tension were not included in the multivariate model to prevent errors resulting from colinearity between the latter and the dependent variable. BMDP-9R computes the regression coefficient of each independent variable (univariate approach), eliminates those that contribute little to the prediction of the independent variable (multivariate approach based on best subset method), and provides ± standard error of the regression coefficient of those independent variables that are significantly related to (and therefore predict) the independent variable. Dividing regression coefficient by standard error yields |t|, and the equation applies: t > |1.96| = p < 0.05. By default, BMDP-9R eliminates cases that have missing values (for variables included in the model).

BMDPD-9R was also used to investigate the role of action potential changes (as percent of basal values) and the effects of pretreatment assignment on contractility. To this purpose only 24 preparations were considered (vehicle, group A, and glib). Included covariates were percent developed tension/time to peak tension, percent time to half relaxation, percent resting membrane potential, and percent action potential duration at the end of pretreatment, along with dummy variables to code treatment assignment (groups A and glib) versus vehicle group. The independent variable was again percent developed tension/ time to peak tension at 60 minutes of reoxygenation.

In this investigation a p value less than 0.05 was considered statistically significant.

RESULTS

The absolute basal parameters of isometric contractility are shown in GoTable I along with values of other variables later included in the multivariate linear model, subdivided according to grouping. Although for most variables the data refer to eight preparations per group, percent developed tension/time to peak tension at 30 seconds of cardioplegia was lacking in three control and one group A preparations, respectively. No significant difference was detected among groups in prehypoxia basal time to peak tension, developed tension, and developed tension/time to peak tension. However, prehypoxia basal time to half relaxation was slightly but significantly (p < .01) lower in the glib group than in the control group and the among-group difference was significant (p < 0.01). Temperature had a similar descending trend in all groups, so that at 30 seconds of cardioplegia no among-group difference was seen. However, because significant differences in time to arrest of mechanical activity were present, temperature at the time of arrest was significantly different among groups (GoTable I).

Isometric contraction indexes at the end of drug pretreatment (or at corresponsing points in time in control and vehicle groups) are shown in Fig. 2 (top panel) as percent changes of prehypoxic basal values. Both group A and group B showed decreased percent developed tension, percent time to peak tension, and percent time to half relaxation, significantly decreased as compared with both the vehicle and glib groups. These indexes were not differently decreased among group A and B preparations. However, GoTable I shows that the lowest average percent developed tension/time to peak tension at the end of drug pretreatment was seen in group A.




View larger version (120K):
[in this window]
[in a new window]
  		Fig. 2. Isometric contraction indexes of papillary muscle preparations (expressed as percent of prehypoxia basal values) either at the end of drug pretreatment (top panel) or after cold cardioplegic hypoxia followed by reperfusion with Tyrode's solution (bottom panel). Group A, Nicorandil pretreatment alone; group B, nicorandil pretreatment plus treatment; glib, glibenclamide pretreatment plus treatment. Mean values ± standard error are presented.

 
Time to arrest of isometric contraction after CPS superfusion is shown in GoTable I. Both group A and group B showed shorter times to arrest than the vehicle and glib groups. The lowest time to arrest of mechanical activity was observed in group A. Because these times significantly (p < 0.001, GoTable I) and largely (coefficient of variation 0.5931, GoTable II) varied among groups, with the smallest value at 30 seconds and the largest at 307 seconds after CPS superfusion, and because significantly lower contractility at the end of pretreatment, in comparison with vehicle, was observed only in nicorandil groups (both A and B), percent developed tension/time to peak tension at 30 seconds of cardioplegia was measured. Indeed, 30 seconds was a point at which all preparations were still contracting. It is evident from GoTable I that group A and B preparations significantly differ; depressed contractility, in comparison to the vehicle group, was observed only in group B.

Isometric contraction indexes at 60 minutes of reoxygenation are shown in Fig. 2 (bottom panel) for all groups. Vehicle and control groups had similarly modified (and expected Go Go 24-26) isometric contraction indexes at 60 minutes of reoxygenation: percent developed tension was severely depressed, percent time to peak tension was slightly decreased, and percent time to half relaxation was moderately increased. Therefore influence of DMSO, if any, on contraction indexes in this experimental model was minimal. The unexpected result was full recovery of isometric contraction indexes in both group A and group B. On the other hand, glib preparations had a completely opposite pattern: percent developed tension was the smallest and percent time to half relaxation the largest among groups, whereas percent time to peak tension was depressed. Because in group glib recovery of percent developed tension was 40% ± 4%, significantly less than in group A and group B (p < 0.001, p < 0.01, respectively) but not significantly different from the vehicle group, we made comparison with the four papillary muscle preparations included in the parallel study and subjected to hypothermic noncardioplegic hypoxia. In the latter study, papillary muscles continued to contract under hypothermic noncardioplegic hypoxia, and the recovery of percent developed tension at 60 minutes of reoxygenation was 20% ± 3% of prehypoxic basal values. The average recovery of percent developed tension in hypothermic noncardioplegic preparations was significantly (p < 0.01) less than in the control, vehicle, and glib groups. This is further evidence that average 180 mm Hg oxygen tensions measured at 30 and 110 minutes of either hypothermic non-CPS or CPS were enough to affect the development of tension in our preparations, an abnormality that was prevented in part by the CPS itself.

Fig. 3 shows resting membrane potential throughout the experimental phases of the protocol in a smaller series (20 of 40). This was so because we were unable to maintain stable microelectrode impalements in all preparations, especially during the initial period of cold cardioplegia. Resting membrane potential did not differ among groups. Overall, resting membrane potential decreased from -86 to -58 mV (-33%, p < 0.001) as a result of cold cardioplegia. It is easy to calculate that these changes were much like those expected for potassium equilibrium potential with extracellular potassium concentration of 16 mmol/L at 20° C. At the end of the reoxygenation period, average resting membrane potential was -80 mV (-8%, NS* as compared with prehypoxic basal values).



View larger version (30K):
[in this window]
[in a new window]
  		Fig. 3. Resting membrane potential (RMP) changes throughout the experimental phases of the protocol. Legend as in Fig. 2. No significant among-group difference was observed at any time. Mean values ± standard error are presented.

 
Linear correlation between time to arrest and percent developed tension at 60 minutes of reoxygenation among all groups is presented in Fig. 4. A negative correlation between these two variables (Y = 91.031 - 0.216X, r = - 0.454; p < 0.01) was observed: the shorter the time to arrest, the higher the percent developed tension at 60 minutes of reoxygenation. However, in no way does statistical correlation demonstrate a cause and effect relationship. Moreover, because GoTable I shows that several further statistical differences among groups were present, multivariate statistics were applied as a method to control for random variability and therefore to obtain, if any, a more reliable result, especially addressing the question concerning the role of treatment assignment.



View larger version (25K):
[in this window]
[in a new window]
  		Fig. 4. Correlation between time to arrest of contraction in cold St. Thomas' Hospital solution and recovery of developed tension (as percent of prehypoxia basal values) after 60 minutes of reoxygenation with Tyrode's solution.

 
Multivariate statistical analysis was performed in 36 (90%) preparations of the study because percent developed tension/time to peak tension at 30 seconds of cardioplegia, was lacking in four cases. The results are shown in GoTable II, which provides means to assess the distribution (coefficient of variation, smallest and largest values, skewness, and kurtosis) of the independent covariates included in the linear multivariate model. Univariate correlations between each independent variable and the dependent variable are also presented. A highly significant multiple correlation (n = 36, r = 0.80, p < 0.00001) in predicting percent developed tension/time to peak tension at 60 minutes of reoxygenation by covariates included in the final solution (those with statistically significant |t| values) out of all possible subsets regression is illustrated. Squared multiple correlation (r 2), that is, the proportion of variability in percent developed tension/ time to peak tension at 60 minutes of reoxygenation which might be explained by the covariates included in the predictive model, was 0.65. Predictive covariates were the presence of nicorandil pretreatment alone (group A, t = 4.70, p = 0.0001) and the presence of nicorandil pretreatment plus treatment (group B, t = 7.23, p = 0.0001). The contribution that significant covariates provided to the r 2, that is, the amount by which r 2 would be reduced if that variable was removed from the regression equation, was, respectively, 0.24 for the presence of nicorandil pretreatment alone (group A) and 0.56 for the presence of nicorandil pretreatment plus treatment (group B).

The role of action potential changes induced by pretreatment was assessed in 10 (42%) preparations (4 vehicle, 4 group A, and 2 glib) and showed univariate correlations, at the end of pretreatment, between percent developed tension/time to peak tension and, respectively, percent action potential duration 90% (r = 0.956, p < 0.001) and percent resting membrane potential (r = - 0.337, NS). Moreover, whereas percent resting membrane potential at the end of pretreatment was not (r = 0.099, NS), percent action potential duration 90% was significantly and negatively correlated (r = - 0.641, p < 0.05) with percent developed tension/time to peak tension at 60 minutes of reoxygenation. Multivariate analysis predicted percent developed tension/time to peak tension at 60 minutes of reoxygenation very accurately (r 2 = 0.95) and significantly (p = 0.0071), based on contractility (t = - 2.33) and action potential duration (t = 1.61) changes and on the presence of glibenclamide (t = - 4.11). Nicorandil (not included in the final solution) was an effective negative inotropic agent (average developed tension/time to peak tension 24% of basal), shortened percent action potential duration (to average 15% of basal), and only slightly hyperpolarized resting membrane potential (average 1.60%); by contrast, glibenclamide prolonged percent action potential duration 90% (by 23%), was moderately hyperpolarizing (average 4.49%), prolonged time to half relaxation (average 14%), and only slightly reduced contractility (to 87% of basal). Therefore the presence of glibenclamide was a significant risk factor to oppose late recovery of contractility on reoxygenation, whereas negative inotropism had a significant protective role. These opposite actions were related at least in part to changes in percent action potential duration 90%: prolongation (caused by glibenclamide) and shortening (caused by nicorandil). Caution is needed, however, to transfer these results to the overall study, because only a fraction of it was included. The significance of this post hoc (retrospective) analysis is therefore to complement the overall study results, and no definite mechanistic conclusion might be reached before a new ad hoc (prospective) investigation is undertaken.

Spontaneous repetitive response ("arrhythmias") were never observed.

DISCUSSION

The hypothesis that drug-induced opening of the myocardial KATP channels Go Go 8-14 might enhance the degree of myocardial protection achieved by cold CPS is substantiated by the evidence that after long-lasting hypoxia and reoxygenation isometric contractility fully recovered in the two nicorandil groups as compared with the vehicle group, with opposite effects in the glib group (Fig. 2 and GoTable I). The poorest recovery was seen without cardioplegia. The main finding, however, was that percent developed tension/time to peak tension, a load-independent index of contractility, Go Go Go Go 25,30,39,40 was predicted multivariately at 60 minutes of reoxygenation by the presence of nicorandil (GoTable II), coded as either group A or B.

A protocol to mimic the clinical situation at induction of cardioplegia was elaborated. During cardiac operations surgeons deal with low-flow or no-flow ischemia rather than with high-flow hypoxia. Go 41 However, when CPS is administered in the operating room, the heart is perfused with the solution and the flow rate is high. Go 41 The overwhelming importance of rapid induction of diastolic chemical arrest during cardiac operations has been repeatedly stressed. Go 41 It is therefore of interest to note that time to arrest of contraction was shorter in the nicorandil groups than in either the vehicle or glib groups (GoTable I).

Use of the old but simple Bing method Go Go 24-26 in isolated papillary muscles made hypoxic Go 33 and a long period of immersion in cold circulating CPS is a practical and inexpensive model enabling to study activation of KATP channels, a phenomenon implying intracellular breakdown of ATP, Go Go Go Go 1-3,6-8 in turn related principally to hypoxia. Go Go Go 6,8,30 Coronary vascular effects of tested interventions, a confounding factor recognized in previous studies on CPS with KATP activation, Go 17 might reasonably be discounted in our model.

In laboratory cardioplegia studies there is no agreement as to the species or index that might more closely simulate human myocardial electrophysiology and/or mechanics. Go Go Go 17,27,42 Models in the guinea pig might be better than those in rats. Go Go Go Go 24-26,30,43 Excitation-contraction coupling in the rat depends on sarcoplasmic reticular calcium release, contrary to that of guinea pig, which relies on transsarcolemmal calcium influx: these differences might influence inotropic response to hypothermia. Go 44 Finally, physiologic beating is higher inrats than in guinea pigs, Go Go 24-26 an important difference considering that the rate of potassium accumulation during the first minutes of ischemia depends on stimulation (which is needed in in vitro studies to detect electrophysiologic variables), whereas it is entirely absent in quiescent hearts. Go 4

Nicorandil has been reported to have direct cardioprotective action independent of either collateral blood flow or systemic hemodynamic changes. Go Go Go 12,45,46 Improved recovery of mechanical function in our nicorandil-pretreated papillary muscles (groups A and B) is in agreement with the study by Grover, Sleph, and Parham Go 47 in isolated rat hearts in which high-dose (300 µmol/L) nicorandil resulted in improved recovery of left ventricular developed pressure after 25 minutes of global ischemia.

A marked negative inotropic effect was seen in both group A and group B at the end of drug pretreatment, whereas glibenclamide was not negatively inotropic (Fig. 2 and GoTable I). These findings agree with data obtained with the KATP channel opener pinacidil (10 to 100 µmol/ L) and the KATP blocker glibenclamide (1 to 20 µmol/L) in hypoxic, Go 48 metabolically inhibited, Go 48 or ischemic Go Go 10,48 models in vitro, and they compare with those obtained by Yang and associates Go 30 with nicorandil (1 mmol/L) in a preparation similar to our own. Mitani and colleagues Go 13 reported that glibenclamide 10 µmol/L led to decreased developed tension ({cong}30%) in the isolated perfused rat heart but also observed that decreased coronary flow resulting from glibenclamide might have contributed. Similar observations were done by Galiñanes, Shattock, and Hearse. In our study coronary flow changes were not contributory.

Negative inotropic effect of KATP openers and improved myocardial protection might be related. Go 10 However, previous investigations made no use of multivariate analysis of data. In our study (GoTable II) neither percent developed tension/time to peak tension at the end of drug pretreatment nor glibenclamide was a predictor of improved contractile function on reoxygenation. The same holds true for percent developed tension/time to peak tension at 30 seconds of cardioplegia, although the lowest values were observed in group B (GoTable I), possibly reflecting further negative inotropic action (an exposure time-related effect Go 30) of nicorandil added to CPS.

Postreoxygenation recovery of both percent developed tension and percent developed tension/time to peak tension did not differ statistically between groups A and B (GoTables I and GoII). This suggests that nicorandil pretreatment improved contractile function irrespective of its presence as an additive to CPS. Furthermore, it is likely Go 29 that nicorandil did not prevent reoxygenation injury but rather hypoxic injury, similar to the reported effectiveness of other KATP openers to improve stunning Go Go 8,11 and simulate preconditioning Go Go Go 19,22,23 in dog experiments with regional ischemia. The mechanism might be related to shortened time to arrest of contraction at induction of cardioplegia (GoTable I), a variable significantly correlated to the degree of recovery of percent developed tension late on reoxygenation (Fig. 4). Nicorandil might also act by shortening of percent action potential duration. Go Go Go Go 8,10,14,48 However, a role for changes in percent action potential duration 90% was seen in a subgroup analysis, whereas time to arrest of contraction did not contribute multivariate statistical prediction (GoTable II) of postreoxygenation recovery of contractility in the overall study.

Abd-Elfattah, Ding, and Wechsler Go 39 have recently stressed that surgically oriented models to investigate myocardial stunning and preconditioning are a cogent necessity if myocardial management in the course of cardiac surgery is to be improved. They stressed that drug-induced cardioprotection should occur before ischemia and myocardial protection should be validated by recovery of contractility by load-independent indexes. Although further dose-related studies Go Go 39,49 are needed to assess the most effective concentration of nicorandil as either pretreatment or adjunct to cardioplegia, our data might have a potential clinical applicability. Short-lived pretreatment with high-dose nicorandil at the time of cardioplegia induction, aimed at shortening the time to contractile arrest and at improving cardioprotection, might be looked for. Among other KATP openers it might be advantageous to test nicorandil because it was approved for clinical use Go Go 15,16 in patients with coronary heart disease.

Acknowledgments

We thank Dr. Hiroshi Nakakimura, Chugai Co., Tokyo, Japan, and Dr. Akinori Akamatsu, Chugai Co., London, United Kingdom, for their generous support and for the gift of nicorandil.

Footnotes

. Back

References

  1. Noma A. ATP-regulated K+ channels in cardiac muscle. Nature 1983;305:147-8.[Medline]
  2. Findlay I, Deroubaix E, Guiraudou P, Coraboeuf E. Properties of adenosine triphosphate–regulated potassium channels in mammalian ventricular myocytes. Am J Physiol 1989;257:H1551-9.[Abstract/Free Full Text]
  3. Deutsch N, Klitzner TS, Lamp ST, Weiss JN. Activation of cardiac ATP-sensitive K+ current during hypoxia: correlation with tissue ATP levels. Am J Physiol 1991;261:H671-6.[Abstract/Free Full Text]
  4. Wilde AAM, Escande D, Schumacher CA, et al. Potassium accumulation in the globally ischemic mammalian heart: a role for the ATP-sensitive potassium channel. Circ Res 1990;67:835-43.[Abstract/Free Full Text]
  5. Fosset M, de Weille JR, Green RD, Schmid-Antomarchi H, Lazdunski M. Antidiabetic sulfonylureas control action potential properties in heart cells via high affinity receptors that are linked to ATP-dependent K+ channels. J Biol Chem 1988;263:7933-6.[Abstract/Free Full Text]
  6. Neubauer S, Newell JB, Ingwall JS. Metabolic consequences and predictability of ventricular fibrillation in hypoxia: a 31P- and 23Na-nuclear magnetic resonance study of the isolated rat heart. Circulation 1992;86:302-10.[Abstract/Free Full Text]
  7. Escande D, Cavero I. K+ channel openers and "natural" cardioprotection. Trends Pharmacol Sci 1992;13:269-72.[Medline]
  8. Escande D, Cavero I. Potassium channel openers in the heart. In: Escande D, Standen N, eds. K + channels in cardiovascular medicine. Paris: Springer-Verlag, 1993:225-44.
  9. Grover GJ, McCullough JR, Henry DE, Conder ML, Sleph PG. Antiischemic effects of potassium channel activators, pinacidil and cromakalim and the reversal of these effects with the potassium channel blocker glyburide. J Pharmacol Exp Ther 1989;251:98-104.[Abstract/Free Full Text]
  10. Cole WC, McPherson CD, Sontag D. ATP-regulated K+ channels protect the myocardium against ischemia/reperfusion damage. Circ Res 1991;69:571-81.[Abstract/Free Full Text]
  11. Auchampach JA, Maruyama M, Cavero I, Gross GJ. Pharmacological evidence for a role of ATP-dependent potassium channels in myocardial stunning. Circulation 1992;86:311-9.[Abstract/Free Full Text]
  12. Gross GJ, Auchampach JA, Maruyama M, Warltier DC, Pieper GM. Cardioprotective effects of nicorandil. J Cardiovasc Pharmacol 1992;20(Suppl 3):S22-8.
  13. Mitani A, Kinoshita K, Fukamachi K, et al. Effects of glybenclamide and nicorandil on cardiac function during ischemia and reperfusion in isolated perfused rat heart. Am J Physiol 1991;261:H1864-71.[Abstract/Free Full Text]
  14. Hiraoka M, Fan Z. Activation of ATP-sensitive outward K+ current by nicorandil (2-nicotinamidoethyl nitrate) in isolated ventricular myocytes. J Pharmacol Exp Ther 1989;250:278-85.[Abstract/Free Full Text]
  15. Taira N. Nicorandil as a hybrid between nitrates and potassium channel activators. Am J Cardiol 1989;63:18J-24J.[Medline]
  16. Kinoshita M, Sakai K. Pharmacology and therapeutic effects of nicorandil. Cardiovasc Drugs Ther 1990;4:1075-88.[Medline]
  17. Galiñanes M, Shattock MJ, Hearse DJ. Effects of potassium channel modulation during global ischemia in isolated rat heart with and without cardioplegia. Cardiovasc Res 1992;26:1063-8.[Medline]
  18. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124-36.[Abstract/Free Full Text]
  19. Murry CE, Jennings RB, Reimer KA. New insights into potential mechanisms of preconditioning (Editorial Comment). Circulation 1991;84:442-5.[Free Full Text]
  20. Liu GS, Thornton J, Van Winkle DM, Stanley AWH, Olsson RA, Downey JM. Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation 1991;84:350-6.[Abstract/Free Full Text]
  21. Kirsch GE, Codina J, Birnbaumer L, Brown AM. Coupling of ATP sensitive K+ channels to A1 receptors by G proteins in rat ventricular myocytes. Am J Physiol 1990;259:H820-6.[Abstract/Free Full Text]
  22. Gross GJ, Auchampach A. Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs. Circ Res 1992;70:223-33.[Abstract/Free Full Text]
  23. Grover GJ, Sleph P, Dzwonczyk S. Role of myocardial ATP-sensitive potassium channels in mediating preconditioning in the dog heart and their possible interaction with adenosine A1-receptors. Circulation 1992;86:1310-6.[Abstract/Free Full Text]
  24. Bing OHL, Brooks WW, Messer JV. Prolongation of tension on reoxygenation following myocardial hypoxia: a possible role for mitochondria in muscle relaxation. J Mol Cell Cardiol 1976;8:205-15.[Medline]
  25. Tyberg JV, Yeatman LA, Parmley WW, Urschel CW, Sonnenblick EH. Effects of hypoxia on mechanics of cardiac contraction. Am J Physiol 1970;218:1780-8.[Free Full Text]
  26. Brooks WW, Sturckow B, Bing OHL. Myocardial hypoxia and reoxygenation: electrophysiologic and mechanical correlates. Am J Physiol 1974;226:523-7.[Free Full Text]
  27. Hearse DJ, Stewart DA, Braimbridge MV. Cellular protection during myocardial ischemia: the development and characterization of a procedure for the induction of reversal ischemic arrest. Circulation 1976;54:193.[Abstract/Free Full Text]
  28. Hearse DJ, Braimbridge MV, Jynge P. Cardioplegic solution in clinical use. In: Hearse DJ, Braimbridge MV, Jynge P, eds. Protection of the ischemic myocardium: cardioplegia. 1st ed. New York: Raven Press, 1982:341-51.
  29. Fox KAA. Reperfusion injury: laboratory phenomenon or clinical reality? Cardiovasc Res 1992;26:656-9.
  30. Yang T, Tande PM, Lathrop DA, Refsum H. Class III antiarrhythmic action by potassium channel blockade: do fetilide attenuates hypoxia induced electromechanical changes. Cardiovasc Res 1992;26:1109-15.[Abstract/Free Full Text]
  31. Lemoine H, Teng KJ, Slee SJ, Kaumann AJ. On minimum cyclic AMP formation rates associated with positive inotropic effects mediated through beta1-adrenoceptors in kitten myocardium: beta1-specific and non-adrenergic stimulant effects of denopamine. Naunyn Schmiedebergs Arch Pharmacol 1989;339:113-28.[Medline]
  32. Warner AL, Bellah KL, Raya TE, Roeske WR, Goldman S. Effects of beta-adrenergic blockade on papillary muscle function and the beta-adrenergic receptor system in noninfarcted myocardium in compensated ischemic left ventricular dysfunction. Circulation 1992;86:1584-95.[Abstract/Free Full Text]
  33. Adams AP, Hahn CEW. Principles and practice of blood gas analysis. 2nd ed. New York: Churchill Livingstone, 1982.
  34. Orita H, Shimanuki T, Fukasawa M, et al. Accelerated myocardial metabolic and functional recovery with terminal nicorandil-Mg cardioplegia in heart transplantation. Cardiovasc Drug Ther 1991;5:727-32.[Medline]
  35. Frydman A. Pharmacokinetics profile of nicorandil in humans: an overview. J Cardiovasc Pharmacol 1992;20(Suppl 3):S34-44.
  36. Schubert T, Vetter H, Owen P, Reichart B, Opie LH. Adenosine cardioplegia: adenosine versus potassium cardioplegia—effect on cardiac arrest and postischemic recovery in the isolated rat heart. J THORAC CARDIOVASC SURG 1989;98:1057-65.[Abstract]
  37. de Jong JW, van der Meer P, Van Loon H, Owen P, Opie LH. Adenosine as adjunct to potassium cardioplegia: effect on function, energy metabolism, and electrophysiology. J THORAC CARDIOVASC SURG 1990;100:445-54.[Abstract]
  38. Dixon WJ, Brown MB, Engelman L, Hill MA, Jennrich RI: BMDP statistical software manual, to accompany the 1988 software release. Vol 1 and 2. Berkeley: The University of California Press, 1988:1-1234.
  39. Abd-Elfattah AS, Ding M, Wechsler AS. Myocardial stunning and preconditioning: age, species, and model related differences—role of AMP-5'-nucleotidase in myocardial injury and protection. J Card Surg 1993;8(suppl):257-61.[Medline]
  40. Braunwald E, Ross J Jr, Sonnenblick EH. Mechanisms of contraction of the normal and failing heart. 2nd ed. Mechanisms of contraction. Boston: Little, Brown, 1976:39-71.
  41. Kirklin JW, Barratt-Boyes BG: Cardiac surgery. Myocardial management during cardiac surgery with cardiopulmonary bypass. 2nd ed. New York: Churchill Livingstone, 1993:129-65.
  42. Galinañes M, Hearse DJ. Species differences in susceptibility to ischemic injury and responsiveness to myocardial protection. Cardioscience 1990;2:127-43.
  43. Borchard U, Berger F, Hafner D. Classification and action of antiarrythmic drugs. Eur Heart J 1989;10(suppl E):31-40.
  44. Shattock MJ, Bers DM. Inotropic response to hypothermia and the temperature-dependence of ryanodine action in isolated rabbit and rat ventricular muscle: implications for excitation-contraction coupling. Circ Res 1987;61:761-71.[Abstract/Free Full Text]
  45. Lamping KA, Christensen CW, Pelc LR, Warltier DC, Gross GJ. Effect of nicorandil and nifedipine on protection of ischemic myocardium. J Cardiovasc Pharmacol 1984;6:536-42.[Medline]
  46. Endo T, Nejima J, Kiuchi K, et al. Reduction of size of myocardial infarction with nicorandil, a new antianginal drug, after coronary artery occlusion in dogs. J Cardiovasc Pharmacol 1988;12:587-92.[Medline]
  47. Grover GJ, Sleph PG, Parham CS. Nicorandil improves postischemic contractile function independently of direct myocardial effects. J Cardiovasc Pharmacol 1990;15:698-705.[Medline]
  48. Nakaya H, Takeda Y, Toshe N, Kanno M. Effects of ATP-sensitive K+ channel blockers on the action potential shortening in hypoxic and ischaemic myocardium. Br J Pharmacol 1991;103:1019-26.[Medline]
  49. Jamieson WRE. Cardioplegic additives: the importance of optimization of dose. In: Roberts AJ, ed. Myocardial protection in cardiac surgery. New York: Marcel Dekker, 1987:321-62.



This article has been cited by other articles:


Home page
 Cardiovasc ResHome page
R. A Kloner, M. T Speakman, and K. Przyklenk
Ischemic preconditioning: a plea for rationally targeted clinical trials
Cardiovasc Res, August 15, 2002; 55(3): 526 - 533.
[Full Text] [PDF]

Home page
 J. Thorac. Cardiovasc. Surg.Home page
F. Monti, K. Iwashiro, S. Picard, A. Criniti, S. La Francesca, G. Ruvolo, U. Papalia, P. P. Campa, B. Marino, and P. E. Puddu
ADENOSINE TRIPHOSPHATE-DEPENDENT POTASSIUM CHANNEL MODULATION AND CARDIOPLEGIA-INDUCED PROTECTION OF HUMAN ATRIAL MUSCLE IN AN IN VITRO MODEL OF MYOCARDIAL STUNNING
J. Thorac. Cardiovasc. Surg., April 1, 2000; 119(4): 842 - 848.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
D. J. Chambers and D. J. Hearse
Developments in cardioprotection: "polarized" arrest as an alternative to "depolarized" arrest
Ann. Thorac. Surg., November 1, 1999; 68(5): 1960 - 1966.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
L. P. Perrault and P. Menasche
Preconditioning: can nature s shield be raised against surgical ischemic-reperfusion injury?
Ann. Thorac. Surg., November 1, 1999; 68(5): 1988 - 1994.
[Abstract] [Full Text] [PDF]

Home page
 SEMIN CARDIOTHORAC VASC ANESTHHome page
C. E. Schotborgh and A. A.M. Wilde
ATP-Sensitive Potassium Channel Openers and Blockers in the Cardiovascular System: Physiology, Pharmacology, and Clinical Effects
Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 1998; 2(3): 243 - 255.
[Abstract] [PDF]

Home page
 Ann. Thorac. Surg.Home page
M. Kirsch, C. Baufreton, C. Fernandez, S. Brunet, F. Pasteau, A. Astier, and D. Y. Loisance
Preconditioning with cromakalim improves long-term myocardial preservation for heart transplantation
Ann. Thorac. Surg., August 1, 1998; 66(2): 417 - 424.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
B. H. Dorman, L. Hebbar, R. B. Hinton, R. C. Roy, and F. G. Spinale
Preservation of Myocyte Contractile Function After Hypothermic Cardioplegic Arrest by Activation of ATP-Sensitive Potassium Channels
Circulation, October 7, 1997; 96(7): 2376 - 2384.
[Abstract] [Full Text]

Home page
 Ann. Thorac. Surg.Home page
P. Menasche, C. Mouas, and C. Grousset
Is Potassium Channel Opening an Effective Form of Preconditioning Before Cardioplegia?
Ann. Thorac. Surg., June 1, 1996; 61(6): 1764 - 1768.
[Abstract] [Full Text]

Home page
 J. Thorac. Cardiovasc. Surg.Home page
P. Menasche, E. Kevelaitis, C. Mouas, C. Grousset, A. Piwnica, and G. Bloch
PRECONDITIONING WITH POTASSIUM CHANNEL OPENERS:A NEW CONCEPT FOR ENHANCING CARDIOPLEGIC PROTECTION?
J. Thorac. Cardiovasc. Surg., December 1, 1995; 110(6): 1606 - 1614.
[Abstract] [Full Text]

Home page
 J. Thorac. Cardiovasc. Surg.Home page
Y. Qiu, M. Galinanes, and D. J. Hearse
PROTECTIVE EFFECT OF NICORANDIL AS AN ADDITIVE TO THE SOLUTION FOR CONTINUOUS WARM CARDIOPLEGIA
J. Thorac. Cardiovasc. Surg., October 1, 1995; 110(4): 1063 - 1072.
[Abstract] [Full Text]

This Article
Right arrow Abstract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Benedetto Marino
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sugimoto, S.
Right arrow Articles by Marino, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sugimoto, S.
Right arrow Articles by Marino, B.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS