Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1986 Aug;88(4):779–789. doi: 10.1111/j.1476-5381.1986.tb16250.x

Molsidomine prevents post-ischaemic ventricular fibrillation in dogs.

J P Cano, J C Guillen, R Jouve, F Langlet, P E Puddu, P H Rolland, A Serradimigni
PMCID: PMC1917061  PMID: 3755634

Abstract

Forty anaesthetized dogs were subjected to left circumflex coronary artery ligation followed by reperfusion. Molsidomine was randomly administered to 20 dogs (50 micrograms kg-1 as an i.v. bolus - 15 min prior to coronary occlusion - followed by an infusion of 0.05 micrograms kg-1 min-1. Standard electrocardiographic leads 2 and 3 were continuously recorded to measure ST segment and delta R% changes and to document both the number of ventricular premature beats and the onset of ventricular fibrillation; aortic pressure and cardiac output were measured; thromboxane B2 plasma levels, platelet aggregation produced by ADP, and molsidomine plasma levels were determined before and at 10, 30 and 75 min after the start of the drug protocol. Molsidomine protected the treated animals from early (10 min) post-ischaemic ventricular fibrillation (0 of 20 vs 6 of 20, P = 0.0202), reduced the incidence of overall post-occlusion ventricular fibrillation (3 of 20 vs 10 of 20, P = 0.0407) and improved the total survival rate (P = 0.0067). In molsidomine treated dogs: mean aortic pressure and the rate-pressure product were lowered 10 min after the start of the drug; immediate post-occlusion (3 min) ST segment changes (0.82 +/- 0.52 vs 1.52 +/- 0.78 mV, P less than 0.025) and delta R% changes (37 +/- 50 vs 90 +/- 84%, P less than 0.025) were less marked; the number of ventricular premature beats was lowered and finally, a progressive decline of platelet aggregation produced by ADP was achieved after 75 min of drug infusion. These results were obtained in the presence of mean plasma levels of molsidomine ranging from 20 to 28 ng ml-1. The time-action curve of the antifibrillatory effect of molsidomine parallels those at the level of post-ischaemic electrocardiographic changes.

Full text

PDF
779

Images in this article

782Figure 2
on p.782

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ALLEN J. B., LEADT J. R. The effect of the level of the ligature on mortality following ligation of the circumflex coronary artery in the dog. Am Heart J. 1950 Feb;39(2):273–278. doi: 10.1016/0002-8703(50)90221-3. [DOI] [PubMed] [Google Scholar]
  2. BORN G. V. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature. 1962 Jun 9;194:927–929. doi: 10.1038/194927b0. [DOI] [PubMed] [Google Scholar]
  3. Balakumaran K., Hugenholtz P. G., Tijssen J. G., Chadha D. R. Molsidomine, an effective long-acting anti-anginal drug. Eur Heart J. 1983 Sep;4(9):655–661. doi: 10.1093/oxfordjournals.eurheartj.a061538. [DOI] [PubMed] [Google Scholar]
  4. Balestrini A. E., Menzio A. C., Cabral R., Feldman R., Mercogliano C., Flichtentrei D., Albera H. P., Vazquez A. Penbutolol and molsidomine synergism in angina pectoris. A double blind ergometric trial. Eur J Clin Pharmacol. 1984;27(1):1–5. [PubMed] [Google Scholar]
  5. Balke C. W., Kaplinsky E., Michelson E. L., Naito M., Dreifus L. S. Reperfusion ventricular tachyarrhythmias: correlation with antecedent coronary artery occlusion tachyarrhythmias and duration of myocardial ischemia. Am Heart J. 1981 Apr;101(4):449–456. doi: 10.1016/0002-8703(81)90135-6. [DOI] [PubMed] [Google Scholar]
  6. Baudry C. The antianginal effect of molsidomine in prolonged oral therapy. A double blind, crossover, randomized study. Acta Cardiol. 1982;37(1):23–30. [PubMed] [Google Scholar]
  7. Block H. U., Förster W., Heinroth I. SIN-1, the main metabolite of molsidomine, inhibits prostaglandin endoperoxide analogue- and arachidonic acid-induced platelet aggregation as well as platelet thromboxane A2 formation. Arzneimittelforschung. 1982;32(3):189–194. [PubMed] [Google Scholar]
  8. Burke S. E., Antonaccio M. J., Lefer A. M. Lack of thromboxane A2 involvement in the arrhythmias occurring during acute myocardial ischemia in dogs. Basic Res Cardiol. 1982 Jul-Aug;77(4):411–422. doi: 10.1007/BF02005341. [DOI] [PubMed] [Google Scholar]
  9. Coker S. J., Parratt J. R., Ledingham I. M., Zeitlin I. J. Evidence that thromboxane contributes to ventricular fibrillation induced by reperfusion of the ischaemic myocardium. J Mol Cell Cardiol. 1982 Aug;14(8):483–485. doi: 10.1016/0022-2828(82)90156-0. [DOI] [PubMed] [Google Scholar]
  10. Coker S. J., Parratt J. R., Ledingham I. M., Zeitlin I. J. Thromboxane and prostacyclin release from ischaemic myocardium in relation to arrhythmias. Nature. 1981 May 28;291(5813):323–324. doi: 10.1038/291323a0. [DOI] [PubMed] [Google Scholar]
  11. Darius H., Ahland B., Rücker W., Klaus W., Peskar B. A., Schrör K. The effects of molsidomine and its metabolite SIN-1 on coronary vessel tone, platelet aggregation, and eicosanoid formation in vitro--inhibition of 12-HPETE biosynthesis. J Cardiovasc Pharmacol. 1984 Jan-Feb;6(1):115–121. [PubMed] [Google Scholar]
  12. David D., Michelson E. L., Naito M., Schaffenburg M., Dreifus L. S. Increased R-wave amplitude induced by acute myocardial ischemia in the dog: a predictor of malignant ventricular arrhythmias. Am J Cardiol. 1982 Oct;50(4):844–848. doi: 10.1016/0002-9149(82)91243-7. [DOI] [PubMed] [Google Scholar]
  13. Dell D., Chamberlain J. Determination of molsidomine in plasma by high-performance liquid column chromatography. J Chromatogr. 1978 Nov 1;146(3):465–473. doi: 10.1016/s0378-4347(00)81205-0. [DOI] [PubMed] [Google Scholar]
  14. Detry J. M., Melin J., Brasseur L. A., Cosyns J., Rousseau M. F. Hemodynamic effects of molsidomine at rest and during submaximal and maximal exercise in patients with coronary artery disease limited by exertional angina pectoris. Am J Cardiol. 1981 Jan;47(1):109–115. doi: 10.1016/0002-9149(81)90298-8. [DOI] [PubMed] [Google Scholar]
  15. Duchene-Marullaz P., Fabry-Delaigue R., Gueorguiev G., Kantelip J. P. Influence of chloralose and pentobarbitone sodium on atrioventricular conduction in dogs. Br J Pharmacol. 1982 Oct;77(2):309–317. doi: 10.1111/j.1476-5381.1982.tb09300.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fiedler V. B., Buchheim S., Göbel H., Nitz R. E. Effects of molsidomine and dopamine infusion on the size of canine experimental myocardial infarct. Naunyn Schmiedebergs Arch Pharmacol. 1982 Dec;321(4):314–320. doi: 10.1007/BF00498520. [DOI] [PubMed] [Google Scholar]
  17. Fiedler V. B. Reduction of occlusive coronary artery thrombosis and myocardial ischemia by molsidomine in anesthetized dogs. Can J Physiol Pharmacol. 1982 Aug;60(8):1104–1111. doi: 10.1139/y82-159. [DOI] [PubMed] [Google Scholar]
  18. Franz M. R., Flaherty J. T., Platia E. V., Bulkley B. H., Weisfeldt M. L. Localization of regional myocardial ischemia by recording of monophasic action potentials. Circulation. 1984 Mar;69(3):593–604. doi: 10.1161/01.cir.69.3.593. [DOI] [PubMed] [Google Scholar]
  19. Geary G. G., Smith G. T., McNamara J. J. Defining the anatomic perfusion bed of an occluded coronary artery and the region at risk to infarction. A comparative study in the baboon, pig and dog. Am J Cardiol. 1981 Jun;47(6):1240–1247. doi: 10.1016/0002-9149(81)90253-8. [DOI] [PubMed] [Google Scholar]
  20. Gobel F. L., Norstrom L. A., Nelson R. R., Jorgensen C. R., Wang Y. The rate-pressure product as an index of myocardial oxygen consumption during exercise in patients with angina pectoris. Circulation. 1978 Mar;57(3):549–556. doi: 10.1161/01.cir.57.3.549. [DOI] [PubMed] [Google Scholar]
  21. Guerchicoff S., Vazquez A., Kunik H., Drajer S., Díaz F. Acute double blind trial of a new anti-anginal drug: molsidomine. Eur J Clin Pharmacol. 1978 Jun 19;13(4):247–250. doi: 10.1007/BF00716358. [DOI] [PubMed] [Google Scholar]
  22. HARRIS A. S. Delayed development of ventricular ectopic rhythms following experimental coronary occlusion. Circulation. 1950 Jun;1(6):1318–1328. doi: 10.1161/01.cir.1.6.1318. [DOI] [PubMed] [Google Scholar]
  23. Hale S. L., Lange R., Alker K. J., Kloner R. A. Correlates of reperfusion ventricular fibrillation in dogs. Am J Cardiol. 1984 May 1;53(9):1397–1400. doi: 10.1016/0002-9149(84)90100-0. [DOI] [PubMed] [Google Scholar]
  24. Hiatt N., Rabinowitz B., Yamakawa T., Miller A., Sheinkopf J. A., Warner N. E. Prevention of ventricular fibrillation after ligation of circumflex artery. J Thorac Cardiovasc Surg. 1973 Aug;66(2):283–286. [PubMed] [Google Scholar]
  25. Hill J. D. The significance of foreleg positions in the interpretation of electrocardiograms and vectorcardiograms from research animals. Am Heart J. 1968 Apr;75(4):518–527. doi: 10.1016/0002-8703(68)90009-4. [DOI] [PubMed] [Google Scholar]
  26. Hirata M., Kikuchi K. Coronary collateral vasodilator action of N-ethoxycarbonyl-3-morpholinosydnonimine (SIN-10) in heart with chronic coronary insufficiency in dogs. Jpn J Pharmacol. 1970 Jun;20(2):187–193. doi: 10.1254/jjp.20.187. [DOI] [PubMed] [Google Scholar]
  27. Jouve R., Langlet F., Puddu P. E., Rolland P. H., Guillen J. C., Cano J. P., Serradimigni A. Cicletanide improves outcome after left circumflex coronary artery occlusion-reperfusion in the dog. J Cardiovasc Pharmacol. 1986 Jan-Feb;8(1):208–215. doi: 10.1097/00005344-198601000-00030. [DOI] [PubMed] [Google Scholar]
  28. Jouve R., Puddu P. E., Langlet F., Guillen J. C., Gautier T., Cano J. P., Serradimigni A. Epoprostenol (PGI2) prevents postischemic ventricular fibrillation and improves outcome in a canine model of sudden death. J Pharmacol. 1985 Apr-Jun;16(2):139–157. [PubMed] [Google Scholar]
  29. Jouve R., Rolland P. H., Delboy C., Mercier C. Thromboxane B2, 6-keto-PGF1 alpha, PGE2, PGF2 alpha, and PGA1 plasma levels in arteriosclerosis obliterans: relationship to clinical manifestations, risk factors, and arterial pathoanatomy. Am Heart J. 1984 Jan;107(1):45–52. doi: 10.1016/0002-8703(84)90132-7. [DOI] [PubMed] [Google Scholar]
  30. Kaplinsky E., Ogawa S., Balke C. W., Dreifus L. S. Two periods of early ventricular arrhythmia in the canine acute myocardial infarction model. Circulation. 1979 Aug;60(2):397–403. doi: 10.1161/01.cir.60.2.397. [DOI] [PubMed] [Google Scholar]
  31. Kent K. M., Smith E. R., Redwood D. R., Epstein S. E. Electrical stability of acutely ischemic myocardium. Influences of heart rate and vagal stimulation. Circulation. 1973 Feb;47(2):291–298. doi: 10.1161/01.cir.47.2.291. [DOI] [PubMed] [Google Scholar]
  32. Kukovetz W. R., Holzmann S. Mechanism of vasodilation by molsidomine. Am Heart J. 1985 Mar;109(3 Pt 2):637–640. doi: 10.1016/0002-8703(85)90669-6. [DOI] [PubMed] [Google Scholar]
  33. Majid P. A., DeFeyter P. J., Van der Wall E. E., Wardeh R., Roos J. P. Molsidomine in the treatment of patients with angina pectoris. N Engl J Med. 1980 Jan 3;302(1):1–6. doi: 10.1056/NEJM198001033020101. [DOI] [PubMed] [Google Scholar]
  34. Manders W. T., Vatner S. F. Effects of sodium pentobarbital anesthesia on left ventricular function and distribution of cardiac output in dogs, with particular reference to the mechanism for tachycardia. Circ Res. 1976 Oct;39(4):512–517. doi: 10.1161/01.res.39.4.512. [DOI] [PubMed] [Google Scholar]
  35. Meesmann W., Gülker H., Krämer B., Stephan K. Time course of changes in ventricular fibrillation threshold in myocardial infarction: characteristics of acute and slow occlusion with respect to the collateral vessels of the heart. Cardiovasc Res. 1976 Jul;10(4):466–473. doi: 10.1093/cvr/10.4.466. [DOI] [PubMed] [Google Scholar]
  36. Menken U., Wiegand V., Bucher P., Meesmann W. Prophylaxis of ventricular fibrillation after acute experimental coronary occlusion by chronic beta-adrenoceptor blockade with atenolol. Cardiovasc Res. 1979 Oct;13(10):588–594. doi: 10.1093/cvr/13.10.588. [DOI] [PubMed] [Google Scholar]
  37. Miller D. D., Waters D. D., Szlachcic J., Théroux P. Clinical characteristics associated with sudden death in patients with variant angina. Circulation. 1982 Sep;66(3):588–592. doi: 10.1161/01.cir.66.3.588. [DOI] [PubMed] [Google Scholar]
  38. Nitz R. E., Martorana P. A. The activity of molsidomine in experimental models of ischemic cardiac disease. Am Heart J. 1985 Mar;109(3 Pt 2):631–636. doi: 10.1016/0002-8703(85)90668-4. [DOI] [PubMed] [Google Scholar]
  39. Previtali M., Klersy C., Salerno J. A., Chimienti M., Panciroli C., Marangoni E., Specchia G., Comolli M., Bobba P. Ventricular tachyarrhythmias in Prinzmetal's variant angina: clinical significance and relation to the degree and time course of S-T segment elevation. Am J Cardiol. 1983 Jul;52(1):19–25. doi: 10.1016/0002-9149(83)90062-0. [DOI] [PubMed] [Google Scholar]
  40. Russek H. I. Propranolol and isosorbide dinitrate synergism in angina pectoris. Am J Cardiol. 1968 Jan;21(1):44–54. doi: 10.1016/0002-9149(68)90012-x. [DOI] [PubMed] [Google Scholar]
  41. Starnes V. A., Primm R. K., Woosley R. L., Oates J. A., Hammon J. W., Jr Administration of prostacyclin prevents ventricular fibrillation following coronary occlusion in conscious dogs. J Cardiovasc Pharmacol. 1982 Sep-Oct;4(5):765–769. doi: 10.1097/00005344-198209000-00011. [DOI] [PubMed] [Google Scholar]
  42. Torresani J., Puddu P. E., Langlet F., Jouve R. Contourographic QT interval measurement. J Electrocardiol. 1983 Oct;16(4):417–418. doi: 10.1016/s0022-0736(83)80093-4. [DOI] [PubMed] [Google Scholar]
  43. Van Trigt P., Christian C. C., Fagraeus L., Spray T. L., Peyton R. B., Pellom G. L., Wechsler A. S. Myocardial depression by anesthetic agents (halothane, enflurane and nitrous oxide): quantitation based on end-systolic pressure-dimension relations. Am J Cardiol. 1984 Jan 1;53(1):243–247. doi: 10.1016/0002-9149(84)90720-3. [DOI] [PubMed] [Google Scholar]
  44. Walinsky P., Smith J. B., Lefer A. M., Lebenthal M., Urban P., Greenspon A., Goldberg S. Thromboxane A2 in acute myocardial infarction. Am Heart J. 1984 Oct;108(4 Pt 1):868–872. doi: 10.1016/0002-8703(84)90447-2. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES