Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1991 Aug;103(4):1973–1979. doi: 10.1111/j.1476-5381.1991.tb12362.x

Effects of zaprinast and rolipram on platelet aggregation and arrhythmias following myocardial ischaemia and reperfusion in anaesthetized rabbits.

M Holbrook 1, S J Coker 1
PMCID: PMC1908205  PMID: 1655149

Abstract

1. This study was designed to compare the effects of two selective inhibitors of certain phosphodiesterase (PDE) isoenzymes on arrhythmias induced by coronary artery occlusion and reperfusion. The drugs used were zaprinast which inhibits guanosine 3':5'-cyclic monophosphate (cyclic GMP)-specific PDE (PDE V) and rolipram which inhibits cyclic GMP-insensitive, adenosine 3':5'-cyclic monophosphate (cyclic AMP)-specific PDE (PDE IV). 2. Pretreatment of anaesthetized rabbits with zaprinast (300 micrograms kg-1 plus 30 micrograms kg-1 min-1) had no significant effect on ischaemia- or reperfusion-induced ST-segment changes, or arrhythmias. In contrast, rolipram (30 micrograms kg-1 plus 3 micrograms kg-1 min-1) and (100 micrograms kg-1 plus 10 micrograms kg-1 min-1) increased the severity of arrhythmias. With the higher dose of rolipram, ST-segment changes were increased in magnitude and mortality due to ventricular fibrillation during ischaemia or reperfusion was increased to 80% compared with 30% in controls (n = 10 per group). 3. Zaprinast caused small but significant increases in heart rate and arterial blood pressure whereas rolipram decreased diastolic arterial pressure, increased left ventricular (LV) dP/dtmax and substantially increased heart rate. 4. At the end of each experiment platelet aggregation was measured ex vivo. Pretreatment of rabbits with either dose of rolipram had no significant effect on platelet aggregation induced by adenosine diphosphate (ADP), collagen, arachidonic acid or thrombin or on isoprenaline- or prostacyclin-induced inhibition of aggregation. Aggregatory responses to ADP and collagen were increased in platelets obtained from rabbits which had received zaprinast.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
1973

Selected References

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

  1. Beavo J. A., Reifsnyder D. H. Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors. Trends Pharmacol Sci. 1990 Apr;11(4):150–155. doi: 10.1016/0165-6147(90)90066-H. [DOI] [PubMed] [Google Scholar]
  2. Billman G. E. Effect of carbachol and cyclic GMP on susceptibility to ventricular fibrillation. FASEB J. 1990 Apr 1;4(6):1668–1673. doi: 10.1096/fasebj.4.6.2156744. [DOI] [PubMed] [Google Scholar]
  3. Bolli R., Fisher D. J., Entman M. L. Factors that determine the occurrence of arrhythmias during acute myocardial ischemia. Am Heart J. 1986 Feb;111(2):261–270. doi: 10.1016/0002-8703(86)90138-9. [DOI] [PubMed] [Google Scholar]
  4. Coker S. J. Anesthetized rabbit as a model for ischemia- and reperfusion-induced arrhythmias: effects of quinidine and bretylium. J Pharmacol Methods. 1989 Jul;21(4):263–279. doi: 10.1016/0160-5402(89)90064-8. [DOI] [PubMed] [Google Scholar]
  5. Coker S. J., Parratt J. R. Relationships between the severity of myocardial ischaemia, reperfusion-induced ventricular fibrillation, and the late administration of dazmegrel or nifedipine. J Cardiovasc Pharmacol. 1985 Mar-Apr;7(2):327–334. doi: 10.1097/00005344-198503000-00019. [DOI] [PubMed] [Google Scholar]
  6. Collins M. N., Billman G. E. Autonomic response to coronary occlusion in animals susceptible to ventricular fibrillation. Am J Physiol. 1989 Dec;257(6 Pt 2):H1886–H1894. doi: 10.1152/ajpheart.1989.257.6.H1886. [DOI] [PubMed] [Google Scholar]
  7. Colucci W. S., Wright R. F., Braunwald E. New positive inotropic agents in the treatment of congestive heart failure. Mechanisms of action and recent clinical developments. 2. N Engl J Med. 1986 Feb 6;314(6):349–358. doi: 10.1056/NEJM198602063140605. [DOI] [PubMed] [Google Scholar]
  8. Dundore R. L., Pratt P. F., Hallenbeck W. D., Wassey M. L., Silver P. J., Buchholz R. A. Sodium nitroprusside potentiates the depressor response to the phosphodiesterase inhibitor zaprinast in rats. Eur J Pharmacol. 1990 Aug 21;185(1):91–97. doi: 10.1016/0014-2999(90)90214-q. [DOI] [PubMed] [Google Scholar]
  9. Hogan J. C., Lewis M. J., Henderson A. H. In vivo EDRF activity influences platelet function. Br J Pharmacol. 1988 Aug;94(4):1020–1022. doi: 10.1111/j.1476-5381.1988.tb11616.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Holbrook M., Coker S. J. Comparison of the effects of isobutylmethylxanthine and milrinone on ischaemia-induced arrhythmias and platelet aggregation in anaesthetized rabbits. Br J Pharmacol. 1989 Sep;98(1):318–324. doi: 10.1111/j.1476-5381.1989.tb16897.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kithas P. A., Artman M., Thompson W. J., Strada S. J. Subcellular distribution of high-affinity type IV cyclic AMP phosphodiesterase activity in rabbit ventricular myocardium: relations to the effects of cardiotonic drugs. Circ Res. 1988 Apr;62(4):782–789. doi: 10.1161/01.res.62.4.782. [DOI] [PubMed] [Google Scholar]
  12. Lidbury P. S., Antunes E., de Nucci G., Vane J. R. Interactions of iloprost and sodium nitroprusside on vascular smooth muscle and platelet aggregation. Br J Pharmacol. 1989 Dec;98(4):1275–1280. doi: 10.1111/j.1476-5381.1989.tb12674.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lincoln T. M. Cyclic GMP and mechanisms of vasodilation. Pharmacol Ther. 1989;41(3):479–502. doi: 10.1016/0163-7258(89)90127-7. [DOI] [PubMed] [Google Scholar]
  14. Lukas A., Ferrier G. R. Electrophysiological effects of amrinone and milrinone in an isolated canine cardiac tissue model of ischemia and reperfusion. J Pharmacol Exp Ther. 1988 Jan;244(1):348–354. [PubMed] [Google Scholar]
  15. Lynch J. J., Kitzen J. M., Hoff P. T., Lucchesi B. R. Effects of pimobendan (UD-CG 115 BS), a new positive inotropic agent, on ventricular tachycardia and ischemic ventricular fibrillation in a conscious canine model of recent myocardial infarction. J Cardiovasc Pharmacol. 1988;12(5):547–554. doi: 10.1097/00005344-198811000-00008. [DOI] [PubMed] [Google Scholar]
  16. McMahon E. G., Palomo M. A., Mehta P., Olins G. M. Depressor and natriuretic effects of M&B 22,948, a guanosine cyclic 3',5'-monophosphate-selective phosphodiesterase inhibitor. J Pharmacol Exp Ther. 1989 Dec;251(3):1000–1005. [PubMed] [Google Scholar]
  17. Muller B., Lugnier C., Stoclet J. C. Involvement of rolipram-sensitive cyclic AMP phosphodiesterase in the regulation of cardiac contraction. J Cardiovasc Pharmacol. 1990 Nov;16(5):796–803. doi: 10.1097/00005344-199011000-00016. [DOI] [PubMed] [Google Scholar]
  18. Neal M. J., Shah M. A. Development of tolerance to the effects of vigabatrin (gamma-vinyl-GABA) on GABA release from rat cerebral cortex, spinal cord and retina. Br J Pharmacol. 1990 Jun;100(2):324–328. doi: 10.1111/j.1476-5381.1990.tb15803.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Shahid M., Nicholson C. D. Comparison of cyclic nucleotide phosphodiesterase isoenzymes in rat and rabbit ventricular myocardium: positive inotropic and phosphodiesterase inhibitory effects of Org 30029, milrinone and rolipram. Naunyn Schmiedebergs Arch Pharmacol. 1990 Dec;342(6):698–705. doi: 10.1007/BF00175715. [DOI] [PubMed] [Google Scholar]
  20. Simpson A. W., Reeves M. L., Rink T. J. Effects of SK&F 94120, an inhibitor of cyclic nucleotide phosphodiesterase type III, on human platelets. Biochem Pharmacol. 1988 Jun 15;37(12):2315–2320. doi: 10.1016/0006-2952(88)90357-7. [DOI] [PubMed] [Google Scholar]
  21. Wachtel H. Potential antidepressant activity of rolipram and other selective cyclic adenosine 3',5'-monophosphate phosphodiesterase inhibitors. Neuropharmacology. 1983 Mar;22(3):267–272. doi: 10.1016/0028-3908(83)90239-3. [DOI] [PubMed] [Google Scholar]
  22. Waldman S. A., Murad F. Cyclic GMP synthesis and function. Pharmacol Rev. 1987 Sep;39(3):163–196. [PubMed] [Google Scholar]
  23. Weishaar R. E., Kobylarz-Singer D. C., Steffen R. P., Kaplan H. R. Subclasses of cyclic AMP-specific phosphodiesterase in left ventricular muscle and their involvement in regulating myocardial contractility. Circ Res. 1987 Oct;61(4):539–547. doi: 10.1161/01.res.61.4.539. [DOI] [PubMed] [Google Scholar]
  24. Weishaar R. E. Multiple molecular forms of phosphodiesterase: an overview. J Cyclic Nucleotide Protein Phosphor Res. 1986;11(7):463–472. [PubMed] [Google Scholar]
  25. Willis A. L., Smith D. L., Loveday M., Fulks J., Lee C. H., Hedley L., VanAntwerp D. Selective anti-platelet aggregation synergism between a prostacyclin-mimetic, RS93427 and the nitrodilators sodium nitroprusside and glyceryl trinitrate. Br J Pharmacol. 1989 Dec;98(4):1296–1302. doi: 10.1111/j.1476-5381.1989.tb12677.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES