Virchows Archiv A

, Volume 412, Issue 4, pp 291–299 | Cite as

Effects of verapamil and timolol on cellular morphometric changes in cat hearts with regional ischaemia

  • Gottfried Greve
  • Svein Rotevatn
  • Ketil Berstad
  • Harald Jodalen
  • Ketil Grong
  • Lodve Stangeland


In twenty-one anaesthetized open chest cats the left anterior descending coronary artery (LAD) was occluded for three hours. Seven cats were pretreated with a bolus injection of Verapamil, followed by a continuous infusion of Verapamil during the ischaemic period. Seven cats were pretreated with a bolus injection of Timolol to a heart rate reduction of 20 beats/min or more and seven cats were given saline. In the latter two groups the cats received a continuous infusion of saline during the period of coronary occlusion. Biopsies were taken from the mid-myocardium of the normal, border and ischaemic zones, as defined by fluorescein staining, and verified by blood flow measurements with radiolabelled microspheres. Standard point counting techniques were used for calculations of fractional volumes of mitochondria, cytoplasm and myofibrils as well as of mitochondrial surface density and surface to volume ratio. We observed a cytoplasmic oedema in the border and ischaemic zones, that was not altered by medical treatment. In the border zone of the control cats there is greater mitochondrial swelling than in the ischaemic zone. This particular swelling is not seen in the treatment groups. However, in the normal and border zones of the verapamil group the mitochondria are smaller when compared with the respective zones in the two other groups, but increases relatively more in size in the border and ischaemic zones. Furthermore, we measured the water content, sarcomere length and per cent heavily damaged cells. These variables were not altered by Verapamil or Timolol in any zone when compared with the respective zones in the control group.

Key words

Lateral border zone Mitochondrial swelling Cellular oedema Calcium channel blockers Beta adrenoceptor blockers Regional blood flow 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Conolly ME, Kersting F, Dollery CT (1976) The clinical pharmacology of beta-adrenoceptor-blocking drugs. Prog Cardiovasc Dis 19(3):203–235Google Scholar
  2. DeBoer LWV, Strauss HW, Kloner RA, Rude RE, Davis RF, Maroko PR, Braunwald E (1980) 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 77(10):6119–6123Google Scholar
  3. Downey JM, Hearse DJ, Yoshida S, Maxwell MP, Yellon DM (1985) Verapamil and nifedipine limit infarct size in the dog. Adv Myocardiol 6:529–543Google Scholar
  4. Fawcett DW, McNutt NS (1969) The ultrastructure of the cat myocardium. I Ventricular papillary muscle. J Cell Biol 42:1–45Google Scholar
  5. Fishbein MC, Hare CA, Gissen SA, Spadaro J, Maclean D, Maroko PR (1980) Identification and quantification of histochemical border zones during the evolution of myocardial infarction in the rat. Cardiovasc Res 14:41–49Google Scholar
  6. Frishman WH (1981)β-adrenoceptor antagonists: New drugs and new indications. N Engl J Med 305(9):500–509Google Scholar
  7. Greve G, Rotevatn S, Grong K, Stangeland L (1988) Cellular morphometric changes in cat hearts subjected to 3 hours of regional ischaemia. Virchows Arch A [Pathol Anat] 412:205–213Google Scholar
  8. Grong K, Stangeland L, Andersen KS, Lekven J (1981) Effect of timolol on blood flow distribution in the myocardium during acute regional ischaemia in cats. Cardiovasc Res 15:430–435Google Scholar
  9. Grong K, Stangeland L, Andersen KS, Lekven J (1982) Effects of timolol on blood flow distribution in the feline myocardium with acute regional ischaemia during controlled haemodynamic conditions. Cardiovasc Res 16:269–275Google Scholar
  10. Jennings RB, Ganote CE (1976) Mitochondrial structure and function in acute myocardial ischemic injury. Circ Res 38 (5 Suppl 1):I80-I91Google Scholar
  11. Jodalen H, Stangeland L, Grong K, Vik-Mo H, Lekven J (1985) Lipid accumulation in the myocardium during acute regional ischaemia in cats. J Mol Cell Cardiol 17:973–980Google Scholar
  12. Kloner RA, Braunwald E (1980) Observations on experimental myocardial ischemia. Cardiovasc Res 14:371–395Google Scholar
  13. Kloner RA, DeBoer LWV, Carlson N, Braunwald E (1982) The effect of verapamil on myocardial ultrastructure during and following release of coronary artery occlusion. Exp Mol Pathol 36:277–286Google Scholar
  14. Kloner RA, Fishbein MC, Braunwald E, Maroko PR (1978) Effect of propranolol on mitochondrial morphology during acute myocardial ischemia. Am J Cardiol 41:880–886Google Scholar
  15. Kloner RA, Fishbein MC, Maclean D, Braunwald E, Maroko PR (1977) Effect of hyaluronidase during the early phase of acute myocardial ischemia: An ultrastructural and morphometric analysis. Am J Cardiol 40:43–49Google Scholar
  16. Lange R, Kloner RA, Braunwald E (1983) First ultra-short-acting beta-adrenergic blocking agent: Its effect on size and segmental wall dynamics of reperfused myocardial infarcts in dogs. Am J Cardiol 51:1759–1767Google Scholar
  17. Lefer AM, Cohn JR, Osman GH Jr (1977) Protective action of timolol in acute myocardial ischemia. Eur J Pharmacol 41:379–385Google Scholar
  18. Matlib MA, Schwartz A (1983) Selective effects of diltiazem, a benzothiazepine calcium channel blocker, and diazepam, and other benzodiazepiner on the Na+/Ca2+ exchange carrier system of heart and brain mitochondria. Life Sci 32(25):2837–2842Google Scholar
  19. Matlib MA, Vághy PL, Epps DE, Schwartz A (1983) Actions of certain calcium channel blockers and calmodulin antagonists on inorganic phosphate-induced swelling and inhibition of oxidative phosphorylation of heart mitochondria. Biochem Pharmacol 32(17):2622–2625Google Scholar
  20. Mouillé P, Schmitt H, Cheymol G, Gautier E (1976) Cardiovascular andβ-adrenergic blocking effects of timolol. Eur J Pharmacol 35:235–243Google Scholar
  21. Nayler WG, Fassold E, Yepez C (1978) Pharmacological protection of mitochondrial function in hypoxic heart muscle: Effect of verapamil, propranolol and methylprednisolone. Cardiovasc Res 12:152–161Google Scholar
  22. Page E, Polimeni PI (1977) Ultrastructural changes in the ischemic zone bordering experimental infarcts in rat left ventricles. Am J Pathol 87:81–104Google Scholar
  23. Quinn PJ, Crutcher EC (1984) The action ofβ-adrenoceptor antagonists on rat heart mitochondrial function in vitro: A comparison of propranolol, timolol and atenolol. Cardiovasc Res 18:212–219Google Scholar
  24. Rasmussen MM, Reimer KA, Kloner RA, Jennings RB (1977) Infarct size reduction by propranolol before and after coronary ligation in dogs. Circulation 56(5):794–798Google Scholar
  25. Reimer KA, Jennings RB (1984) Verapamil in two reperfusion models of myocardial infarction. Temporary protection of severely ischemic myocardium without limitation of ultimate infarct size. Lab Invest 51(6):655–666Google Scholar
  26. Slutsky RA, Peck WW (1985) Effects of beta-adrenergic blockade on the natural progression of myocardial infarct size and compensatory hypertrophy. J Am Coll Cardiol 5(5):1132–1137Google Scholar
  27. Sugiyama S, Miyazaki Y, Kotaka K, Ozawa T (1983) The effects of verapamil on mitochondrial dysfunction associated with coronary reperfusion. Jpn Circ J 47(7):830–836Google Scholar
  28. The Norwegian Multicenter Study Group (1981) Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 304(14):801–807Google Scholar
  29. Tumas J, Deth R, Kloner RA (1985) Effects of Nisoldipine: A new calcium antagonist, on myocardial infarct size and cardiac dynamics following acute myocardial infarction. J Cardiovasc Pharmacol 7:361–367Google Scholar
  30. Vághy PL, Johnson JD, Matlib MA, Wang T, Schwartz A (1982) Selective inhibition of Na+-induced Ca2+ release from heart mitochondria by diltiazem and certain other Ca2+ antagonist drugs. J Biol Chem 257(11):6000–6002Google Scholar
  31. Vik-Mo H, Maroko PR, Ribeira LGT (1984) Comparative effects of propranolol, timolol and metoprolol on myocardial infarct size after experimental coronary artery occlusion. J Am Col Cardiol 4:735–741Google Scholar
  32. Wolkowicz PE, Michael LH, Lewis RM, McMillin-Wood J (1983) Sodium-calcium exchange in dog heart mitochondria: Effects of ischemia and verapamil. Am J Physiol 244 (Heart Circ Physiol 13):H644-H651Google Scholar

Copyright information

© Springer-Verlag 1988

Authors and Affiliations

  • Gottfried Greve
    • 1
  • Svein Rotevatn
    • 1
  • Ketil Berstad
    • 1
  • Harald Jodalen
    • 1
  • Ketil Grong
    • 2
  • Lodve Stangeland
    • 2
  1. 1.Department of AnatomyUniversity of BergenBergenNorway
  2. 2.Surgical Research LaboratoryUniversity of BergenBergenNorway

Personalised recommendations