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Limitation of myocardial necrosis with verapamil during sustained coronary occlusion in the closed-chest dog

Summary

Studies were undertaken to determine whether cardioprotection afforded by verapamil could be sustained in the dog heart during permanent coronary artery occlusion. In 48 dogs a coronary artery was occluded for 24 or 48 hours using a closed-chest embolization procedure. Dogs were assigned to either untreated control or to verapamil-treated (200 μg/kh, intravenous bolus within 5 minutes after coronary occlusion and then 5 μg/kg/min as a continuous intravenous infusion for 24 or 48 hours) groups. After 24 or 48 hours of permanent coronary occlusion, tissue necrosis was evaluated using tetrazolium staining and was related to the major baseline predictors of infarct size including anatomic risk zone (radiolabeled microsphere autoradiography) and coronary collateral flow. The correlation between infarct size and subepicardial coronary collateral flow was calculated in untreated control dogs (r=−0.91 and -0.80 for 24 and 48 hour controls, respectively); analysis of covariance indicated that verapamil treatment shifted this relation downward in both the 24- and 48-hour drug treatment groups. The equation of this regression was used to calculate the size of the infarct that would have occurred in treated dogs if drug treatment had not been initiated. The ratio of observed and calculated infarct size provides a “salvage index.” In conclusion, verapamil was able to limit the extent of tissue necrosis and this cardioprotection appears to be sustained during 48 hours of permanent coronary occlusion.

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References

  1. Yellon DM, Hearse DJ, Maxwell MP, et al. Sustained limitation of myocardial necrosis 24 hours after coronary artery occlusion: Studies with verapamil infusion in dogs with small infarcts. Am J Cardiol 1983; 51:1409–1413.

    Google Scholar 

  2. Yoshida S, Downey JM, Chambers DE, et al. Nifedipine limits infarct size 24 hours following coronary embolization in the closed-chest dog. Basic Res Cardiol 1985; 80:76–87.

    Google Scholar 

  3. Denniss AR, Kingma JGJr, Hearse DJ, et al. Anipamil limits myocardial necrosis in the closed-chest dog during 24 hours of coronary artery occlusion (abstr). J Mol Cell Cardiol 1986; 18 (Suppl 1):359.

    Google Scholar 

  4. Henry PD, Shuchleib R, Borda LJ, et al. Effects of nifedipine on myocardial perfusion and ischemic injury in dogs. Circ Res 1978; 372–380.

  5. DeBoer LWV, Strauss HW, Kloner RA, et al. Autoradiographic method for measuring the ischemic myocardium at risk: Effects of verapamil on infarct size after experimental coronary artery occlusion. Proc Natl Acad Sci USA 1980; 77:6119–6123.

    Google Scholar 

  6. Zamanis A, Verdetti J, de Leiris J. Reduction of ischemia-induced myocardial necrosis in the rat with permanent coronary artery occlusion under the effect of diltiazem. J Mol Cell Cardiol 1982; 14:53–62.

    Google Scholar 

  7. Melin JA, Becker LC, Hutchins GM. Protective effect of early and late treatment with nifedipine during myocardial infarction in the conscious dog. Circulation 1984; 69:131–141.

    Google Scholar 

  8. Campbell CA, Kloner RA, Alker KJ, Braunwald E. Effect of verapamil on infarct size in dogs subjected to coronary occlusion with transient reperfusion. J Am Coll Cardiol 1986; 8:1169–1174.

    Google Scholar 

  9. Yoshida S, Downey JM, Yellon DM, et al. Diltiazem reduced infarct size but not ventricular arrhythmias in 48 hour coronary embolized dogs. Can J Cardiol 1985; 1:346–353.

    Google Scholar 

  10. Chagrasulis RW, Downey JM. Selective coronary embolization in closed chest dogs. Am J Physiol 1977; 233:335–337.

    Google Scholar 

  11. Miura T, Yellon DM, Hearse DJ, Downey JM. Determinants of infarct size during permanent occlusion of a coronary artery in the closed chest dog. J Am Coll Cardiol 1987; 9:647–654.

    Google Scholar 

  12. Fishbein MC, Meerbaum S, Rit J, et al. Early phase acute myocardial infarct size quantification: Validation of the triphenyltetrazolium chrorid tissue enzyme staining technique. Am Heart J 1981; 101:593–600.

    Google Scholar 

  13. Schaper W, Frenzel H, Hort W. Experimental coronary artery occlusion. I. Measurement of infarct size. Basic Res Cardiol 1979; 74:46–53.

    Google Scholar 

  14. Kloner RA, Darsee JR, DeBoer LWV, Carlson N. Early pathologic detection of acute myocardial infarction. Arch Pathol Lab Med 1981; 105:403–406.

    Google Scholar 

  15. Jugdutt BI, Hutchins GM, Bulkley BH, Becker LC. Myocardial infarction in the conscious dog: Three dimensional m apping of infarct, collateral flow and region at risk. Circulation 1979; 60:1141–1150.

    Google Scholar 

  16. Repeated measures ANOVA using the SAS GLM procedure. In:SAS User's Guide:Statistics, 5th ed. Cary, NC:SAS Institute, Inc., 1985; 475–485.

  17. Reimer KA, Jennings RB, Cobb FR, et al. Animal models for protecting ischemic myocardium: Results of the NHLBI Cooperative Study. Comparison of unconscious and conscious dog models. Circ Res 1985; 56:651–665.

    Google Scholar 

  18. Vivaldi MT, Kloner RA, Schoen FJ. Triphenyltetrazolium staining of irreversible ischemic injury following coronary artery occlusion in rats. Am J Pathol 1985; 121:522–530.

    Google Scholar 

  19. Klein HH, Puschmann S, Schaper J, Schaper W. The mechanism of the tetrazolium reaction in identifying experimental myocardial infarction. Virchows Arch (Pathol Anat) 1981; 393:287–297.

    Google Scholar 

  20. Reimer KA, Jennings RB. Can we really quantitate myocardial cell injury? In:Hearse DJ, Yellon DM, eds. Approaches to Myocardial Infarct Size Limitation. New York: Raven Press, 1984; 163–184.

    Google Scholar 

  21. Chambers DE, Yellon DM, Hearse DJ, Downey JM. Infarct size or delay? Flurbiprofen limits apparent infarct size after 6 hours of coronary occlusion in the dog, but not after 24 hours of occlusion. Am J Cardiol 1983; 51:884–894.

    Google Scholar 

  22. Sherman LG, Liang CS, Boden WE, Hood WBJr. The effect of verapamil on mechanical performance of acutely ischemic and reperfused myocardium in the conscious dog. Circ Res 1981; 48:224–232.

    Google Scholar 

  23. Downey JM, Chambers DE, Wilkerson RD. The inability of isoproterenol or propranolol to alter the lateral dimensions of experimentally induced myocardial infarcts. Basic Res Cardiol 1982; 77:486–498.

    Google Scholar 

  24. Lowe JE, Reimer KA, Jennings RB. Experimental infarct size as a function of the amount of myocardium at risk. Am J Pathol 1978; 90:363–371.

    Google Scholar 

  25. Geary GG, Smith GT, McNamara JJ. Defining the anotomic perfusion bed of an occluded artery and the region at risk to infarction:A comparative study in the baboon, pig and dog. Am J Cardiol 1981; 47:1240–1246.

    Google Scholar 

  26. Bonow RO, Lipson LC, Sheehan FH, et al. Lack of effect of aspirin on myocardial infarct size in the dog. Am J Cardiol 1981; 47:258–264.

    Google Scholar 

  27. Endo T, Nejima J, Fujita S, et al. Comparative effects of nicardipine, a new calcium antagonist, on size of myocardial infarction after coronary artery occlusion in dogs. Circulation 1986; 74:420–430.

    Google Scholar 

  28. Brazzamano D, Fedor JM, Rembert JC, Greenfield JC. Collateral conductance changes during a brief coronary occlusion in awake dogs. Circulation 1985; 72:225–232.

    Google Scholar 

  29. Ribeiro LGT, Cheung WM, Maroko PR. Influence of the extent of the zone at risk on the effectiveness of drugs in reducing infarct size. Circulation 1982; 66:181–186.

    Google Scholar 

  30. Becker LC, Schuster EH, Jugdutt BI, et al. Relationship between myocardial infarct size and occluded bed size in the dog: Difference between left anterior descending and circumflex coronary artery occlusions. Circulation 1983; 67:549–556.

    Google Scholar 

  31. Zalewski A, Goldberg S, Faria DB, et al. Relation of myocardial salvage to size of myocardium at risk in dogs. Am J Cardiol 1985; 56:974–977.

    Google Scholar 

  32. Schaper W. Experimental coronary artery occlusion: III. The determinants of collateral blood flow in acute coronary occlusion. Basic Res Cardiol 1978; 73:584–592.

    Google Scholar 

  33. Clark RE, Ferguson TB, West PN, et al. Pharmacological preservation of ischemic heart. Ann Thorac Surg 1977; 24:307–314.

    Google Scholar 

  34. Bush LR, Yuk-Ping L, Shlafer M, et al. Protective effects of diltiazem during myocardial ischemia in isolated hearts. J Pharmacol Exp Ther 1981; 218:653–661.

    Google Scholar 

  35. Gregg DE. The natural history of coronary collateral development. Circ Res 1974; 35:335–344.

    Google Scholar 

  36. Rivas F, Cobb FR, Bache RJ, Greenfield JCJr. Relationship between blood flow to ischemic regions and extent of myocardial infarction: Serial measurement of blood flow to ischemic regions in dogs. Circ Res 1976; 38:439–447.

    Google Scholar 

  37. Forman R, Eng C, Kirk ES. Comparative effect of verapamil and nitroglycerin on collateral blood flow. Circulation 1983; 67:1200–1204.

    Google Scholar 

  38. Weintraub WS, Hattori S, Akizuki S, et al. Influence of nifedipine on collateral blood flow during acute ischemia in the dog. J Am Coll Cardiol 1984; 3:334–340.

    Google Scholar 

  39. Davenport N, Goldstein RE, Bolli R, Epstein SE. Blood flow to infarct and surviving myocardium: Implications regarding the actions of verapamil on the acutely ischemic dog heart. J Am Coll Cardiol 1984; 3:956–965.

    Google Scholar 

  40. Reimer KA, Jennings RB. Effects of calcium-channel blockers on myocardial preservation during experimental acute myocardial infarction. Am J Cardiol 1985; 55:107B-115B.

    Google Scholar 

  41. Karlsberg RP, Henry PD, Ahmed SA, et al. Lack of protection of ischemic myocardium by verapamil in conscious dogs. Eur J Pharmacol 1977; 42:339–346.

    Google Scholar 

  42. Pasyk S, Bloor CM, Khouri E, Gregg DE. Systemic and coronary effects of coronary artery occlusion in the unanesthetized dog. Am J Physiol 1971; 22:646–654.

    Google Scholar 

  43. Nakamura M, Kikuchi Y, Senda Y, et al. Myocardial blood flow following experimental coronary occlusion. Effects of diltiazem. Chest 1980; 78:2055–2059.

    Google Scholar 

  44. Becker LC. Effect of nitroglycerin and dipyramidole on regional left ventricular blood flow during coronary artery occlusion. J Clin Invest 1976; 58:1287–1296.

    Google Scholar 

  45. Smith HJ, Singh BN, Norris RM, et al. The effect of verapamil on experimental myocardial ischemia with a particular reference to regional myocardial blood flow and metabolism. Aust NZ J Med 1976; 7:114–121.

    Google Scholar 

  46. Elharras V, Gaum WE, Zipes DP. Effect of drugs on conduction delay and incidence of ventricular arrhythmias induced by acute coronary occlusion in dogs. Am J Cardiol 1979; 39:544–549.

    Google Scholar 

  47. El-Sherif N, Lazzara R. Reentrant ventricular arrhythmias in the late myocardial infarction period. 7. Effect of D-600 and the role of the “slow channel.” Circulation 1979; 60:605–615.

    Google Scholar 

  48. Yellon DM, Hearse DJ, Downey JM. Myocardial salvage by pharmacological interventions. In: Paten W, Mitchell J, Turner P, eds. Proceedings IUPHAR Ninth International Congress of Pharmacology. London: Macmillan Press, Ltd. 1984; 251–256.

    Google Scholar 

  49. Lange RL, Ingwall J, Hale SL, et al. Preservation of high energy phosphates by verapamil in reperfused myocardium. Circulation 1984; 70:734–741.

    Google Scholar 

  50. Kloner RA, Braunwald E. Effects of calcium antagonists on infarcting myocardium. Am J Cardiol 1987; 59:84B-94B.

    Google Scholar 

  51. Alps BJ, Calder C, Wilson A. The beneficial effect of nicardipine compared with nifedipine and verapamil in limiting myocardial infarct size in baboons. Arzneimittelforsch Drug Res 1983; 33:868–876.

    Google Scholar 

  52. Kordenat K, Leasure J. Effect of tiapamil on canine myocardial infarct size. Am Heart J 1986; 111:502–509.

    Google Scholar 

  53. Reimer KA, Lowe JE, Jennings RB. Effect of the calcium antagonist verapamil on necrosis following temporary coronary artery occlusion in dogs. Circulation 1977; 55:581–587.

    Google Scholar 

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Kingma, J.G., Yellon, D.M. Limitation of myocardial necrosis with verapamil during sustained coronary occlusion in the closed-chest dog. Cardiovasc Drug Ther 2, 313–323 (1988). https://doi.org/10.1007/BF00054638

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  • DOI: https://doi.org/10.1007/BF00054638

Key words

  • infarct size limitation
  • coronary collateral flow
  • verapamil
  • myocardial ischemia
  • salvage index