Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1989 Sep;98(1):318–324. doi: 10.1111/j.1476-5381.1989.tb16897.x

Comparison of the effects of isobutylmethylxanthine and milrinone on ischaemia-induced arrhythmias and platelet aggregation in anaesthetized rabbits.

M Holbrook 1, S J Coker 1
PMCID: PMC1854691  PMID: 2478245

Abstract

1. The aim of this study was to compare the effects of the non-selective phosphodiesterase (PDE) inhibitor, isobutylmethylxanthine (IBMX) and the selective PDE III inhibitor, milrinone, in a rabbit model of acute myocardial ischaemia. 2. Coronary artery occlusion caused changes in the ST-segment of the ECG and ectopic activity in all control rabbits. Ventricular fibrillation occurred in 10 out of 14 (71%) of these animals. Pretreatment with IBMX 100 micrograms kg-1 plus 10 micrograms kg-1 min-1, starting 10 min before coronary artery occlusion, reduced ischaemia-induced ST-segment changes and ventricular fibrillation occurred in only 10% of this group (n = 10). A similar dose of milrinone had no antiarrhythmic activity, whereas with a lower dose of milrinone, 30 micrograms kg-1 plus 3 micrograms kg-1 min-1 (n = 10), only 30% of rabbits fibrillated and ST-segment changes were attenuated. 3. Acute administration of both IBMX and milrinone reduced arterial blood pressure. With the higher dose of milrinone a significant effect was still present after 10 min of drug infusion. A greater hypotensive response to the higher dose of milrinone was observed in the rabbits which subsequently fibrillated during ischaemia. A marked tachycardia was also observed after administration of the higher dose of milrinone. 4. At the end of the experiment platelet aggregation was studied ex vivo. ADP-induced aggregation was reduced by pretreatment of the rabbits with milrinone but not IBMX. Both PDE inhibitors enhanced the ability of isoprenaline to inhibit ADP-induced platelet aggregation but milrinone was more effective, particularly at the higher dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
318

Selected References

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

  1. Alousi A. A., Canter J. M., Montenaro M. J., Fort D. J., Ferrari R. A. Cardiotonic activity of milrinone, a new and potent cardiac bipyridine, on the normal and failing heart of experimental animals. J Cardiovasc Pharmacol. 1983 Sep-Oct;5(5):792–803. doi: 10.1097/00005344-198309000-00014. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. Coker S. J., Parratt J. R. Prostacyclin-induced changes in coronary blood flow and oxygen handling in the normal and acutely ischaemic canine myocardium. Basic Res Cardiol. 1981 Jul-Aug;76(4):457–462. doi: 10.1007/BF01908342. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Elks M. L., Manganiello V. C. Selective effects of phosphodiesterase inhibitors on different phosphodiesterases, adenosine 3',5'-monophosphate metabolism, and lipolysis in 3T3-L1 adipocytes. Endocrinology. 1984 Oct;115(4):1262–1268. doi: 10.1210/endo-115-4-1262. [DOI] [PubMed] [Google Scholar]
  6. Haerem J. W. Platelet aggregates in intramyocardial vessels of patients dying suddenly and unexpectedly of coronary artery disease. Atherosclerosis. 1972 Mar-Apr;15(2):199–213. doi: 10.1016/0021-9150(72)90070-6. [DOI] [PubMed] [Google Scholar]
  7. Hartzell H. C., Fischmeister R. Opposite effects of cyclic GMP and cyclic AMP on Ca2+ current in single heart cells. Nature. 1986 Sep 18;323(6085):273–275. doi: 10.1038/323273a0. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Kane K. A., Morcillo-Sanchez E. J., Parratt J. R., Rodger I. W., Shahid M. The relationship between coronary artery occlusion-induced arrhythmias and myocardial cyclic nucleotide levels in the anaesthetized rat. Br J Pharmacol. 1985 Jan;84(1):139–145. [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. Martin W., Furchgott R. F., Villani G. M., Jothianandan D. Phosphodiesterase inhibitors induce endothelium-dependent relaxation of rat and rabbit aorta by potentiating the effects of spontaneously released endothelium-derived relaxing factor. J Pharmacol Exp Ther. 1986 May;237(2):539–547. [PubMed] [Google Scholar]
  12. Mushlin P., Boerth R. C., Wells J. N. Xanthine derivatives that selectively inhibit cyclic GMP hydrolysis potentiate cardiac contractile effects of isoproterenol but not those of bethanecol. Mol Pharmacol. 1981 Jul;20(1):190–194. [PubMed] [Google Scholar]
  13. Nichols W. W., Mehta J. L., Donnelly W. H., Lawson D., Thompson L., ter Riet M. Reduction in coronary vasodilator reserve following coronary occlusion and reperfusion in anesthetized dog: role of endothelium-derived relaxing factor, myocardial neutrophil infiltration and prostaglandins. J Mol Cell Cardiol. 1988 Oct;20(10):943–954. doi: 10.1016/s0022-2828(88)80148-2. [DOI] [PubMed] [Google Scholar]
  14. Parratt J. R., Marshall R. J., Ledingham I. M. Interventions for improving blood flow, oxygen availability and the balance between oxygen supply and demand in the acutely ischaemic myocardium. J Physiol (Paris) 1980;76(7):791–803. [PubMed] [Google Scholar]
  15. Rude R. E., Kloner R. A., Maroko P. R., Khuri S., Karaffa S., DeBoer L. W., Braunwald E. Effects of amrinone on experimental acute myocardial ischaemic injury. Cardiovasc Res. 1980 Jul;14(7):419–427. doi: 10.1093/cvr/14.7.419. [DOI] [PubMed] [Google Scholar]
  16. Weishaar R. E., Burrows S. D., Kobylarz D. C., Quade M. M., Evans D. B. Multiple molecular forms of cyclic nucleotide phosphodiesterase in cardiac and smooth muscle and in platelets. Isolation, characterization, and effects of various reference phosphodiesterase inhibitors and cardiotonic agents. Biochem Pharmacol. 1986 Mar 1;35(5):787–800. doi: 10.1016/0006-2952(86)90247-9. [DOI] [PubMed] [Google Scholar]
  17. 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]

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

RESOURCES