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J Thorac Cardiovasc Surg 2001;122:103-112
© 2001 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology (CSP)

₁-Adrenoceptors during simulated ischemia and reoxygenation of the human myocardium: Effect of the dose and time of administration

From the Division of Cardiac Surgery/ Department of Surgery, University of Leicester, Glenfield Hospital, Leicester, United Kingdom.

Received for publication Oct 27, 2000. Revisions requested Jan 4, 2001; revisions received Jan 22, 2001. Accepted for publication Jan 29, 2001. Address for reprints: Professor Manuel Galiñanes, Division of Cardiac Surgery/Department of Surgery, University of Leicester, Glenfield Hospital, Leicester, LE3 9QP, United Kingdom (E-mail: mg50{at}le.ac.uk).

Abstract

Objective: We sought to investigate the effect of ₁-adrenoceptor activity on the ischemic and reoxygenated human myocardium.
Methods: Right atrial appendages (n = 6 per group) obtained during elective cardiac operations were sliced and stabilized in normoxic normothermic buffer solution for 30 minutes and then subjected to 90 minutes of simulated ischemia, followed by 120 minutes of reoxygenation. In study 1 the dose responses to the ₁-adrenoceptor agonist phenylephrine (0.01, 0.1, 1, 10, and 100 µmol/L) and to the ₁-adrenoceptor antagonist prazosin (0.1, 1, 10, and 100 µmol/L) when administered for 10 minutes before ischemia, during ischemia, and during reoxygenation were examined. The influence of the time of administration (ie, before ischemia, during ischemia, or during reoxygenation) of phenylephrine (0.1 µmol/L) and prazosin (10 µmol/L) was then investigated in study 2. In study 3 the effect of the combined administration of phenylephrine given before ischemia and prazosin given during ischemia was investigated. In study 4 the protective effect of phenylephrine given before ischemia (for 10 minutes or for 5 minutes with a 5-minute washout period) was compared with that of ischemic preconditioning (5 minutes of ischemia and 5 minutes of reoxygenation). At the end of each protocol, the leakage of creatine kinase (in units per gram of wet weight) and the reduction of 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide to insoluble formazan dye (in millimoles per gram of wet weight) were measured.
Results: Phenylephrine is maximally beneficial at 0.1 and 1 µmol/L (creatinine kinase, 0.97 ± 0.06 and 0.95 ± 0.03 U/g, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 153.0 ± 7.8 and 156.2 ± 6.7 mmol/g, respectively) compared with ischemic control (creatine kinase, 1.87 ± 0.03 U/g; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 108.5 ± 6.8 mmol/g; P < .05) but prazosin is detrimental at concentrations above 10 µmol/L (creatine kinase, 5.22 ± 0.29 U/g; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 69.8 ± 2.9 mmol/g; P < .05 vs ischemic control). In addition, phenylephrine (0.1 µmol/L) is protective when given before ischemia (creatine kinase, 2.06 ± 0.21 U/g; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 148.5 ± 4.5 mmol/g; P < .05 vs ischemic control) but is detrimental when given during ischemia alone (creatine kinase, 4.49 ± 0.98 U/g; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 70.5 ± 6.1 mmol/g; P < .05 vs ischemic control) and has no significant effect during reoxygenation. In contrast, prazosin (10 µmol/L) is beneficial when given during ischemia alone (creatine kinase, 1.34 ± 0.10 U/g; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 148.5 ± 4.5 mmol/g; P < .05 vs ischemic control), is detrimental when given during reoxygenation alone (creatine kinase, 1.5 ± 0.16 U/g; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 85.0 ± 4.7 mmol/g; P < .05 vs ischemic control), and has no effect when given before ischemia. The use of phenylephrine before ischemia alone is as protective as prazosin given during ischemia alone, but the combination of the two drugs does not cause additional benefit. Interestingly, the protection afforded by phenylephrine when given before ischemia is similar to that obtained with ischemic preconditioning.
Conclusions: In the human myocardium activation of ₁-adrenoceptors before ischemia is protective but is detrimental during ischemia, whereas blockade of ₁-adrenoceptors is beneficial during ischemia but detrimental during reoxygenation. The degree of protection achieved by activation of the ₁-adrenoceptors before ischemia is similar to that obtained with blockade of ₁-adrenoceptors during ischemia and that of ischemic preconditioning.

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