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J Thorac Cardiovasc Surg 1994;107:964-967
© 1994 Mosby, Inc.

LETTERS TO THE EDITOR

Extension of tissue survival time in multiorgan block preparation with a delta opioid DADLE ([D-Ala2,D-Leu5]-enkephalin)

Sufan Chien, MD, Peter R. Oeltgen, PhD, John N. Diana, PhD, Robert K. Salley, MD

Departments of Surgery, Pathology,
and Physiology and Biophysics
University of Kentucky Medical Center
Lexington, KY 40536

Tsung-Ping Su, PhD

Alcohol, Drug Abuse, and Mental Health Administration
National Institute on Drug Abuse Addiction Research Center
Baltimore, MD 21224

To the Editor:

In 1988, weGo 1 reported our results with a newly developed, autoperfused, multiorgan block preparation for long-term organ preservation for transplantation When plasma from hibernating woodchucks, containing hibernation-induction trigger (HIT), was used in the preparation, the preservation time was substantially extended.Go 2 We have also previously shown that onlyDADLE([D-AlaGo 2, D-LeuGo 5]-enkephalin), a delta class of opioid, could induce hibernation in summer-active ground squirrels (the traditional seasonally restrictive bioassay)in a fashion similar to injection with plasma fractions derived, from deeply hibernating woodchucks,containing the HIT molecule.Go 3 Representative mu opioids morphine and morphiceptin, as well as kappa opioids dynorphin A and U-69593, were without effect.Go 4 We have also previously shown that the HIT fraction infused intracerebroventricularly into primates produced a profound yet reversible behavioral and physiologic depression (bradycardia, hypothermia, and long-term hypophagia), a hibernation-like state that could be totally reversed or blocked by the infusion of the opiate antagonists naloxone and naltrexone.Go 5 Such evidence indicates the opioid nature of the HIT molecule. Only the delta class of opioids, represented by DADLE, may be intimately involved in natural hibernation. To test the hypothesis that the delta opioid DADLE could also extend tissue survival time in a multiorgan preservation experiment, we performed another group of preservation studies in which the results were comparable to those obtained from the HIT study.

Six mongrel dogs weighing 15 to 25 kg were used: 25 mg DADLE (Peninsula Laboratories,Belmont, Calif.) was given intravenously 2 hours before the operation. The surgical procedure,monitoring, and interventions during the preservation period were performed in the same manner as in the HIT study, except that DADLE (1 mg/kg every 2 hours) was substituted for HIT-containing plasma. The survival time ranged from 41 to 60 hours, with a mean of 46.6 hours (Fig. 1). Aortic systolic pressure ranged from 62 ± 6 mm Hg to 79 ± 3 mm Hg, and aortic diastolic pressure ranged from 33 ± 4 mm Hg to 49 ± 7 mm Hg. Pressures were easily adjusted by blood or plasma transfusions and no inotropic drugs were needed. Heart rate ranged from 86 ± 8 beats/min to 100 ± 12 beats/min. Left ventricular maximum rate of pressure rise ranged from 1250 ± 323 mm Hg/sec to 1920 ± 164 mm Hg/sec.Left ventricular maximum ratio of pressure development to pressure ranged from 17.2 ± 2.2sec-1 to25.6 ± 5.3 sec-1. The serum potassium level was kept relatively low and no preparation was influenced by hyperkalemia. In all preparations, the pericardium remained intact and there was no pericardial effusion at the end of the preservation period.



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  		Fig. 1. Distribution of organ survival time.

 
Serum lactic acid level was 3.6 ± 0.4 mmol/L before the operation and increased to 7.8± 0.6 mmol/L at 40 hours, but the variability was large and the increase was not statistically significant. Lactate dehydrogenase isoenzyme 1, an indicator of acute myocardial infarction, was 15.98% ± 1.78% before the operation. It increased to 28.87% ± 4.17% at 44 hours, but the change was also not statistically significant. Myocardial tissue wet/dry weight ratio was 4.58 ± 0.18 after preservation, versus 4.55 ± 0.97 for normal control preparations (no statistical difference). When a gas mixture of 50% oxygen, 3% carbon dioxide, and 47% nitrogen was used, arterial blood pH ranged from 7.29 to 7.54. Arterial oxygen tension was 264± 32 mm Hg before the operation. During the preservation period, arterial oxygen tension was maintained between 292 ± 18 mm Hg and 348 ± 9 mm Hg; it was 324± 67 mm Hg at 44 hours. Arterial carbon dioxide tension was 23.8 ± 6.2 mm Hg before the operation. It ranged from 13.3 ± 3.8 mm Hg to 18.4 ± 1.6 mm Hg during the preservation period (Fig. 2). Serum lactate dehydrogenase isoenzyme 3, used for diagnosis of pulmonary emboli, decreased from 20.9% ± 2.3% before the operation to 9.8% ± 0.3% at 44 hours (p < 0.005). The lungs maintained good function and appearance for approximately 36 hours. Lung tissue wet/dry weight ratio was 5.70 ± 0.23 after preservation, versus 4.85 ± 0.01 for normal control preparations (p < 0.01). Total bile production ranged from 150 to 300 ml, with an average hourly bile output of 4.4ml. Serum alanine aminotransferase activity was 78 ± 42 U/L before the operation. It increased to 198 ± 35 U/L at 4 hours (p < 0.05) then decreased gradually to 97 ± 32 U/L at 16 hours, and increased again slowlyto 179 ± 97 U/L at 44 hours. Serum alkaline phosphatase activity was 69 ± 17 U/L before the operation. It ranged from 53 ± 8U/L to 105 ± 43 U/L during the preservation period. Lactate dehydrogenase isoenzyme 5,used for diagnosis of hepatic congestion or injury, changed from 36% ± 4.5% before the operation to 27.9% ± 6.4% at 44 hours. The effect of DADLE on liver preservation was dramatic. Normally, congestion develops quickly in dog livers during this operative procedure because of hepatic vein spasm. Liver congestion starts early, in association with opening the abdomen, and deteriorates during preservation. In this study, however, liver congestion was minimal or absent during the operation. When liver congestion occurred during the preservation period, an intravenous injection of DADLE eliminated congestion and restored normal function. Liver tissue wet/dry ratio was 3.65 ± 0.10 after preservation, versus 3.64 ± 0.81 for normal control preparations. Serum amylase activity ranged from 1049 ± 404 U/L to 1241 ±695 U/L during the preservation period, indicating no major change in this variable. Urinary output ranged from 1600 ml to 2700 ml, with hourly urine production of 50 ± 5 ml, and there were no cases of premature renal failure. Both blood urea nitrogen and creatinine levels decreased during the preservation period. Blood urea nitrogen was 14 ± 1 mg/dl before the operation. It decreased to 6 ± 2 mg/dl at 12 hours (p < 0.025), and was 6 ± 1 mg/dl at 44 hours. Serum creatinine level was 1.0 ± 0.2mg/dl before the operation. It decreased to 0.4 ± 0.1 mg/dl at 4 hours (p < 0.01), varied between 0.4 ± 0.1 mg/dl and 0.8 ± 0.2 mg/dl during the preservation period and was 0.7 ± 0.3 mg/dl at 44 hours. Serum potassium levels varied between 1.9 ± 0.2 mmol/L and 2.9 ± 0.5 mmol/L and total calcium levels variedbetween 8.0 ± 0.7 mg/dl and 9.9 ± 1.6 mg/dl during the preservation period. Serum sodium and chloride levels remained at normal values during the entire experiment. The hematocrit value was stable and the white blood cell count decreased substantially during the preservation period. Free plasma hemoglobin did not increase significantly.



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  		Fig. 2. Heart and lung function studies during the preservation period.AOP, Aortic pressure;AOSP, aortic systolic pressure;AODP, aortic diastolic pressure;paO2:arterial oxygen tension;paCO2, arterial carbon dioxide tension;dp/dt/p, left ventricular maximum ratio of pressure development to pressure.

 
These results indicate that DADLE can effectively extend tissue survival time in much the same way as HIT in this preparation. This study also produced one of the longest average survival times for organ preservation. Studies of the binding of opioid drugs and peptides to specific sites in brain and other organs have suggested the existence of perhaps as many as eight types of opioid receptors. DADLE belongs to a family of morphine-like opioid agonist substances. It acts as an agonist primarily atµ,{kappa}, and{delta} receptors.Go 6 Therapeutic doses of morphine-like opioids produce peripheral vasodilation, reduced peripheral vascular resistance, and an inhibition of baroreceptor reflexes. The peripheral arteriolar and venous dilation produced by morphine involves several mechanisms. Morphine and most opioids provoke the release of histamine, which sometimes plays a role in the hypotensive response. A similar effect was seen in our study. When DADLE was given to anesthetized animals, systemic blood pressure decreased to as much as 50%of the original value. The reduction in liver congestion was probably related to the ability of DADLE to antagonize hepatic vein spasm, which resulted in the elimination of hepatic congestion. However,the overall effect of DADLE in our multiorgan preservation system extended beyond vasodilation. The improvement of heart and lung function, the elimination of renal failure, and the extension ofsurvival time all seem to suggest a more extensive effect of DADLE.

To track the metabolism of DADLE, we studied the multiorgan preparation with a radionuclide technique. DADLE labeled with iodine 125 (7.5 mg) was injected into the inferior vena cava and the organ system was imaged with a{gamma} camera (Siemens Medical Corp., Iselin, N.J.). The liver, followed by the heart a short time later, had the highest local concentrations of DADLE. Two hours later, most of the DADLE was secreted primarily in the bile and secondarily in the urine, with only a small trace of radiolabeled DADLE seen in the heart and liver. Surprisingly, the lungs did not accumulate any of the labeled DADLE during the procedure, whereas the extension of the lung tissue preservation time was impressive. The mechanism by which DADLE contributes to tissue survival time may be similar to that of HIT. That is, it may be related to the following factors:(1) the inhibition of tissue metabolism, (2) the effect of reducing or eliminating liver congestion, and(3) a reduction in hemolysis. The beneficial effect of DADLE in organ preservation has never been reported before. Whether DADLE mediates these effects through opioid receptors is presently not known.

References

  1. Chien S, Todd EP, Diana JN, O'Connor WN. A simple technique for multiorgan preservation. J THORAC CARDIOVASC SURG 1988;95:55-61.[Abstract]
  2. Chien S, Oeltgen PR, Diana JN, Shi X, Nilekani SP, Salley R. Two-day preservation of major organs with autoperfusion and hibernation induction trigger. J THORAC CARDIOVASC SURG 1991;102:224-34.[Abstract]
  3. Oeltgen PR, Nilekani SP, Nuchols PA, Spurrier WA, Su TP. Further studies on opioids and hibernation: delta opioid receptor ligand selectively induced hibernation in summer-active ground squirrels. Life Sci 1988;43:1565-74[Medline]
  4. Oeltgen PR, Welborn JR, Nuchols PA, Spurrier WA, Bruce DS, Su TP. Opioids and hibernation. II.Effects of kappa opioid U69593 on induction of hibernation in summer-active ground squirrels by"hibernation induction trigger" (HIT). Life Sci 1987;41:2115-20.[Medline]
  5. Oeltgen PR, Walsh JW, Hamann SR, Randall DC, Spurrier WA, Myers RD. Hibernation "trigger" opioid-like inhibitory action on brain function of the monkey. Pharmacol Biochem Behav 1982;17:1271-4.[Medline]
  6. Höllt V. Opioid peptide processing and receptor selectivity. Ann Rev Pharmacol Toxicol 1986;26:59-78.[Medline]



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