Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1988 Aug;94(4):1207–1217. doi: 10.1111/j.1476-5381.1988.tb11640.x

Protection of rat atrial myocardium against electrical, mechanical and structural aspects of injury caused by exposure in vitro to conditions of simulated ischaemia.

A M Northover 1, B J Northover 1
PMCID: PMC1854103  PMID: 3207981

Abstract

1. Rat isolated and superfused atria were exposed for varying periods to a solution simulating the composition of extracellular fluid during myocardial ischaemia (SI). 2. Atria subjected to SI showed a loss of systolic contractile tension, a rise in diastolic tension, a shortening of electrical refractory periods, a slowing of action potential conduction velocity and disruption of the mitochondrial ultrastructure. All these features were reversible when the muscle was returned to normal superfusate. 3. Atria pretreated with a superfusate containing a calcium channel antagonist, a calmodulin inhibitor or an intracellular calcium antagonist showed fewer features of the response to SI than did controls. 4. Atria pretreated with a superfusate containing various non-steroidal anti-inflammatory agents did not show identical responses to SI. Sulphinpyrazone protected against all features of the response to SI but ibuprofen, flurbiprofen and GP25671 (a metabolite of sulphinpyrazone) had little effect. Flufenamate, phenylbutazone and salicylate enhanced the responses to SI.

Full text

PDF
1212

Images in this article

1209Figure 1
on p.1209
1210Figure 1
on p.1210

Selected References

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

  1. Anno T., Kodama I., Shibata S., Toyama J., Yamada K. Effects of calcium, calcium entry blockers and calmodulin inhibitors on atrioventricular conduction disturbances induced by hypoxia. Br J Pharmacol. 1986 May;88(1):277–284. doi: 10.1111/j.1476-5381.1986.tb09496.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barron E., Marshall R. J., Martorana M., Winslow E. Comparative antiarrhythmic and electrophysiological effects of drugs known to inhibit calmodulin (TFP, W7 and bepridil). Br J Pharmacol. 1986 Nov;89(3):603–612. doi: 10.1111/j.1476-5381.1986.tb11162.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cavero I., Boudot J. P., Feuvray D. Diltiazem protects the isolated rabbit heart from the mechanical and ultrastructural damage produced by transient hypoxia, low-flow ischemia and exposure to Ca++-free medium. J Pharmacol Exp Ther. 1983 Jul;226(1):258–268. [PubMed] [Google Scholar]
  4. Chiou C. Y., Malagodi M. H. Studies on the mechanism of action of a new Ca-2+ antagonist, 8-(N,N-diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride in smooth and skeletal muscles. Br J Pharmacol. 1975 Feb;53(2):279–285. doi: 10.1111/j.1476-5381.1975.tb07359.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Del Maschio A., Livio M., Cerletti C., De Gaetano G. Inhibition of human platelet cyclo-oxygenase activity by sulfinpyrazone and three of its metabolites. Eur J Pharmacol. 1984 Jun 1;101(3-4):209–214. doi: 10.1016/0014-2999(84)90158-4. [DOI] [PubMed] [Google Scholar]
  6. Elharrar V., Gaum W. E., Zipes D. P. Effect of drugs on conduction delay and incidence of ventricular arrhythmias induced by acute coronary occlusion in dogs. Am J Cardiol. 1977 Apr;39(4):544–549. doi: 10.1016/s0002-9149(77)80164-1. [DOI] [PubMed] [Google Scholar]
  7. Eller B. T., Lynch J. J., Patterson E., Lucchesi B. R. Electrophysiologic and antiarrhythmic actions of sulphinpyrazone and its sulfide metabolite G25671. Pharmacology. 1987;34(2-3):121–130. doi: 10.1159/000138261. [DOI] [PubMed] [Google Scholar]
  8. Ferrari R., Albertini A., Curello S., Ceconi C., Di Lisa F., Raddino R., Visioli O. Myocardial recovery during post-ischaemic reperfusion: effects of nifedipine, calcium and magnesium. J Mol Cell Cardiol. 1986 May;18(5):487–498. doi: 10.1016/s0022-2828(86)80914-2. [DOI] [PubMed] [Google Scholar]
  9. Ferrier G. R., Moffat M. P., Lukas A. Possible mechanisms of ventricular arrhythmias elicited by ischemia followed by reperfusion. Studies on isolated canine ventricular tissues. Circ Res. 1985 Feb;56(2):184–194. doi: 10.1161/01.res.56.2.184. [DOI] [PubMed] [Google Scholar]
  10. Fitzpatrick D. B., Karmazyn M. Comparative effects of calcium channel blocking agents and varying extracellular calcium concentration on hypoxia/reoxygenation and ischemia/reperfusion-induced cardiac injury. J Pharmacol Exp Ther. 1984 Mar;228(3):761–768. [PubMed] [Google Scholar]
  11. Fleet W. F., Johnson T. A., Graebner C. A., Engle C. L., Gettes L. S. Effects of verapamil on ischemia-induced changes in extracellular K+, pH, and local activation in the pig. Circulation. 1986 Apr;73(4):837–846. doi: 10.1161/01.cir.73.4.837. [DOI] [PubMed] [Google Scholar]
  12. Fujimoto T., Peter T., Hamamoto H., Mandel W. J. Effects of diltiazem on conduction of premature impulses during acute myocardial ischemia and reperfusion. Am J Cardiol. 1981 Nov;48(5):851–857. doi: 10.1016/0002-9149(81)90349-0. [DOI] [PubMed] [Google Scholar]
  13. Hassid A., Oudinet J. P. Relationship between cellular calcium and prostaglandin synthesis in cultured vascular smooth muscle cells. Prostaglandins. 1986 Sep;32(3):457–478. doi: 10.1016/0090-6980(86)90012-2. [DOI] [PubMed] [Google Scholar]
  14. Hatmi M., del Maschio A., Lefort J., de gaetano G., Vargaftig B. B., Cerletti C. Effects of sulfinpyrazone and its metabolite G25671 on platelet activation and desensitization and on bronchoconstriction induced by the prostaglandin endoperoxide analog U46619. J Pharmacol Exp Ther. 1987 May;241(2):623–627. [PubMed] [Google Scholar]
  15. Hearse D. J., Garlick P. B., Humphrey S. M. Ischemic contracture of the myocardium: mechanisms and prevention. Am J Cardiol. 1977 Jun;39(7):986–993. doi: 10.1016/s0002-9149(77)80212-9. [DOI] [PubMed] [Google Scholar]
  16. Henry P. D., Schuchleib R., Davis J., Weiss E. S., Sobel B. E. Myocardial contracture and accumulation of mitochondrial calcium in ischemic rabbit heart. Am J Physiol. 1977 Dec;233(6):H677–H684. doi: 10.1152/ajpheart.1977.233.6.H677. [DOI] [PubMed] [Google Scholar]
  17. Holland D. R., Armstrong W. M., Steinberg M. I. Calcium fluxes and contractility in isolated guinea pig atrium: effect of A23187. Am J Physiol. 1978 Jul;235(1):C13–C19. doi: 10.1152/ajpcell.1978.235.1.C13. [DOI] [PubMed] [Google Scholar]
  18. Holland D. R., Steinberg M. I., Armstrong W. M. A23187: a calcium ionophore that directly increases cardiac contractility (38704). Proc Soc Exp Biol Med. 1975 Apr;148(4):1141–1145. [PubMed] [Google Scholar]
  19. Jennings R. B., Schaper J., Hill M. L., Steenbergen C., Jr, Reimer K. A. Effect of reperfusion late in the phase of reversible ischemic injury. Changes in cell volume, electrolytes, metabolites, and ultrastructure. Circ Res. 1985 Feb;56(2):262–278. doi: 10.1161/01.res.56.2.262. [DOI] [PubMed] [Google Scholar]
  20. Karmazyn M. Contribution of prostaglandins to reperfusion-induced ventricular failure in isolated rat hearts. Am J Physiol. 1986 Jul;251(1 Pt 2):H133–H140. doi: 10.1152/ajpheart.1986.251.1.H133. [DOI] [PubMed] [Google Scholar]
  21. Karmazyn M., Pierce G. N., Williams S. Effect of nonsteroidal anti-inflammatory drugs on the hypoxic rat heart. J Pharmacol Exp Ther. 1981 Aug;218(2):488–496. [PubMed] [Google Scholar]
  22. Kimura S., Nakaya H., Kanno M. Effects of verapamil and lidocaine on changes in action potential characteristics and conduction time induced by combined hypoxia, hyperkalemia, and acidosis in canine ventricular myocardium. J Cardiovasc Pharmacol. 1982 Jul-Aug;4(4):658–667. doi: 10.1097/00005344-198207000-00019. [DOI] [PubMed] [Google Scholar]
  23. Kimura S., Nakaya H., Kanno M. Electrophysiological effects of diltiazem, nifedipine and Ni2+ on the subepicardial muscle cells of canine heart under the condition of combined hypoxia, hyperkalemia and acidosis. Naunyn Schmiedebergs Arch Pharmacol. 1983 Nov;324(3):228–232. doi: 10.1007/BF00503900. [DOI] [PubMed] [Google Scholar]
  24. Kloner R. A., DeBoer L. W., Carlson N., Braunwald E. The effect of verapamil on myocardial ultrastructure during and following release of coronary artery occlusion. Exp Mol Pathol. 1982 Jun;36(3):277–286. doi: 10.1016/0014-4800(82)90057-0. [DOI] [PubMed] [Google Scholar]
  25. Kloner R. A., Fishbein M. C., Braunwald E., Maroko P. R. Effect of propranolol on mitochondrial morphology during acute myocardial ischemia. Am J Cardiol. 1978 May 1;41(5):880–886. doi: 10.1016/0002-9149(78)90728-2. [DOI] [PubMed] [Google Scholar]
  26. Koomen J. M., Schevers J. A., Noordhoek J. Myocardial recovery from global ischemia and reperfusion: effects of pre- and/or post-ischemic perfusion with low-Ca2+. J Mol Cell Cardiol. 1983 Jun;15(6):383–392. doi: 10.1016/0022-2828(83)90322-x. [DOI] [PubMed] [Google Scholar]
  27. Lewis M. J., Grey A. C., Henderson A. H. Determinants of hypoxic contracture in isolated heart muscle preparations. Cardiovasc Res. 1979 Feb;13(2):86–94. doi: 10.1093/cvr/13.2.86. [DOI] [PubMed] [Google Scholar]
  28. Lipasti J. A., Alanen K. A., Eskola J. U., Nevalainen T. J. Ischaemic contracture in isolated rat heart: reversible or irreversible myocardial injury? Exp Pathol. 1985;28(2):89–95. doi: 10.1016/s0232-1513(85)80019-0. [DOI] [PubMed] [Google Scholar]
  29. Mix L. L., Dinerstein R. J., Villereal M. L. Mitogens and melittin stimulate an increase in intracellular free calcium concentration in human fibroblasts. Biochem Biophys Res Commun. 1984 Feb 29;119(1):69–75. doi: 10.1016/0006-291x(84)91619-x. [DOI] [PubMed] [Google Scholar]
  30. Nakaya H., Hattori Y., Kanno M. Effects of calcium antagonists and lidocaine on conduction delay induced by acute myocardial ischemia in dogs. Jpn J Pharmacol. 1980 Oct;30(5):587–597. doi: 10.1254/jjp.30.587. [DOI] [PubMed] [Google Scholar]
  31. Nakaya H., Kanno M. Effects of verapamil on conduction delay and potassium efflux induced by global ischemia in isolated rabbit hearts. Eur J Pharmacol. 1982 Apr 23;79(3-4):185–192. doi: 10.1016/0014-2999(82)90624-0. [DOI] [PubMed] [Google Scholar]
  32. Nayler W. G., Williams A. Relaxation in heart muscle: some morphological and biochemical considerations. Eur J Cardiol. 1978 Jun;7 (Suppl):35–50. [PubMed] [Google Scholar]
  33. Northover B. J. A protective effect of sulphinpyrazone against coronary occlusion-induced shortening of myocardial refractory periods in the rat. Br J Pharmacol. 1986 May;88(1):141–148. doi: 10.1111/j.1476-5381.1986.tb09480.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Northover B. J. Electrical changes produced by injury to the rat myocardium in vitro and the protective effects of certain antiarrhythmic drugs. Br J Pharmacol. 1987 Jan;90(1):131–138. doi: 10.1111/j.1476-5381.1987.tb16832.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Penn R. G. The effect of age, species and adrenaline on the recovery of isolated atria from anoxia. Br J Pharmacol. 1970 Jun;39(2):309–316. doi: 10.1111/j.1476-5381.1970.tb12894.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Peter T., Fujimoto T., Hamamoto H., Mandel W. J. Comparative study of the effect of slow channel inhibiting agents on ischemia-induced conduction delay as relevant to the genesis of ventricular fibrillation. Am Heart J. 1983 Nov;106(5 Pt 1):1023–1028. doi: 10.1016/0002-8703(83)90647-6. [DOI] [PubMed] [Google Scholar]
  37. Peter T., Fujimoto T., Hamamoto H., McCullen A., Mandel W. J. Electrophysiologic effects of diltiazem in canine myocardium, with special reference to conduction delay during ischemia. Am J Cardiol. 1982 Feb 18;49(3):602–605. doi: 10.1016/s0002-9149(82)80018-0. [DOI] [PubMed] [Google Scholar]
  38. Pilati C. F., Paradise N. F. Ouabain-induced mechanical toxicity: aberrations in left ventricular function, calcium concentration, and ultrastructure. Proc Soc Exp Biol Med. 1984 Mar;175(3):342–350. doi: 10.3181/00379727-175-41805. [DOI] [PubMed] [Google Scholar]
  39. Poole-Wilson P. A., Harding D. P., Bourdillon P. D., Tones M. A. Calcium out of control. J Mol Cell Cardiol. 1984 Feb;16(2):175–187. doi: 10.1016/s0022-2828(84)80706-3. [DOI] [PubMed] [Google Scholar]
  40. Raeder E. A., Verrier R. L., Lown B. Effects of sulfinpyrazone on ventricular vulnerability in the normal and the ischemic heart. Am J Cardiol. 1982 Aug;50(2):271–275. doi: 10.1016/0002-9149(82)90176-x. [DOI] [PubMed] [Google Scholar]
  41. Rahamathulla P. M., Ashraf M., Schwartz A., Benedict J. Effects of diltiazem on anoxic injury in the isolated rat heart. J Am Coll Cardiol. 1983 Apr;1(4):1081–1089. doi: 10.1016/s0735-1097(83)80110-7. [DOI] [PubMed] [Google Scholar]
  42. Scott J. A., Khaw B. A., Fallon J. T., Locke E., Rabito C. A., Peto C. A., Homcy C. J. The effect of phenothiazines upon maintenance of membrane integrity in the cultured myocardial cell. J Mol Cell Cardiol. 1986 Dec;18(12):1243–1254. doi: 10.1016/s0022-2828(86)80428-x. [DOI] [PubMed] [Google Scholar]
  43. Singal P. K., Lee S. L., Ganguly P. K., Panagia V., Dhalla N. S. Reversibility of ultrastructural, contractile function and Ca2+ transport changes in guinea pig hearts after global ischemia. Can J Physiol Pharmacol. 1986 Nov;64(11):1368–1375. doi: 10.1139/y86-232. [DOI] [PubMed] [Google Scholar]
  44. Wojtczak J. Contractures and increase in internal longitudianl resistance of cow ventricular muscle induced by hypoxia. Circ Res. 1979 Jan;44(1):88–95. doi: 10.1161/01.res.44.1.88. [DOI] [PubMed] [Google Scholar]

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

RESOURCES