Sinus node inhibitors for reducing exercise-induced myocardial ischemia: Evidence from experimental animal studies

  • Brian D. Guth
Conference paper


The physician is faced with the dilemma of how best to protect the myocardium subjected to effort-induced ischemia. The ultimate therapeutic solution is the elimination of the stenotic lesion. However, prior to vessel dilation or surgery (or in patients in which such procedures may not be advisable), treatment to minimize ischemic damage to the post-stenotic myocardium is indicated. The reduction of heart rate (or prevention of tachycardia) is an attractive therapeutic approach in the treatment of effort angina pectoris since it has a dual beneficial effect on the potentially ischemic post-stenotic myocardium. On the one hand, reduction of the number of contractions per minute of the heart reduces its work and, consequently, oxygen demand. At the same time, heart rate reduction acts to enhance myocardial blood flow and to improve its distribution within the ischemic myocardium by prolonging the diastolic interval and reducing coronary “steal”. Thus, the inequality between an enhanced metabolic demand and a reduced nutritive supply is lessened from both sides of the supply-demand equation.


Myocardial Blood Flow Coronary Stenosis Heart Rate Reduction Regional Myocardial Blood Flow Exercise Heart Rate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Ball RM, Bache RJ (1976) Distribution of myocardial blood flow in the exercising dog with restricted coronary artery inflow. Circ Res 38: 60–66PubMedGoogle Scholar
  2. 2.
    Ball RM, Bache RJ, Cobb FR, Greenfield Jr JC (1975) Regional myocardial blood flow during graded treadmill exercise in the dog. J Clin Invest 55: 43–49PubMedCrossRefGoogle Scholar
  3. 3.
    Bache RJ, Cobb FR (1977) Effect of maximal coronary vasodilation on transmural myocardial perfusion during tachycardia in the awake dog. Circ Res 41: 648–653PubMedGoogle Scholar
  4. 4.
    Bassenge E, Kucharczyk M, Holtz J, Stoian D (1972) Treadmill exercise in dogs under beta-adrenergic blockade: adaptation of coronary and systemic hemodynamics. Pfluegers Arch 332: 40–55CrossRefGoogle Scholar
  5. 5.
    Becker L (1976) Effect of tachycardia on left ventricular blood flow distribution during coronary occlusion. Am J Physiol 230: 1072–1077PubMedGoogle Scholar
  6. 6.
    Berdeaux A, Garnier M, Boissier JR, Giudicelli JF (1979) The role of beta-adrenoceptors in coronary blood flow distribution in normal and ischemic canine myocardium. Eur J Pharmacol 53: 261–271PubMedCrossRefGoogle Scholar
  7. 7.
    Buck JD, Hardman HF, Warltier DC, Gross GJ (1981) Changes in ischemic blood flow distribution and dynamic severity of a coronary stenosis induced by beta blockade in the canine heart. Circulation 64: 708–715PubMedCrossRefGoogle Scholar
  8. 8.
    Canty JM (1988) Coronary pressure-function and steady-state pressure-flow relations during autoregulation in the unanesthetized dog. Circ Res 63: 821–836PubMedGoogle Scholar
  9. 9.
    Domenech RJ, de la Prida JM (1975) Mechanical effects of heart contraction on coronary flow. Cardiovasc Res 9: 509–514PubMedCrossRefGoogle Scholar
  10. 10.
    Epstein SE, Braunwald E (1966) Beta-adrenergic receptors blocking drugs. Mechanisms of action and clinical applications. N Engl J Med 275: 1106–1112PubMedCrossRefGoogle Scholar
  11. 11.
    Gallagher KP, Folts JD, Shebuski RJ, Rankin JHG, Rowe GG (1980) Subepicardial vasodilator reserve in the presence of critical coronary stenosis in dogs. Am J Cardiol 46: 67–73PubMedCrossRefGoogle Scholar
  12. 12.
    Gallagher KP, Matsuzaki M, Koziol JA, Kemper WS, Ross Jr J (1984) Regional myocardial perfusion and wall thickening during ischemia in conscious dogs. Am J Physiol 247: H727–H738PubMedGoogle Scholar
  13. 13.
    Gallagher KP, Matsuzaki M, Osakada G, Kemper WS, Ross Jr J (1983) Effect of exercise on the relationship betwen myocardial blood flow and systolic wall thickening in dogs with acute coronary stenosis. Circ Res 52: 716–729PubMedGoogle Scholar
  14. 14.
    Gallagher KP, Osakada G, Matsuzaki M, Kemper WS, Ross Jr J (1982) Myocardial blood flow and function with critical coronary stenosis in exercising dogs. Am J Physiol 243: H698–H707PubMedGoogle Scholar
  15. 15.
    Garcia-Dorado D, Theroux P, Elizaya J, Galinanes M, Solares J, Riesgo M, Gomez MJ, Garcia-Dorado A, Aviles Ff (1987) Myocardial reperfusion in the pig heart model: infarct size and duration of coronary occlusion. Cardiovas Res 21: 537–544CrossRefGoogle Scholar
  16. 16.
    Gregg DE (1974) The natural history of coronary collateral development. Circ Res 35: 335–344PubMedGoogle Scholar
  17. 17.
    Gross GJ, Dämmgen JW (1987) Effect of the new specific bradycardic agent AQ-A 39 (falipamil) on coronary collateral blood flow in dogs. J Cardiovasc Pharmacol 10: 123–127PubMedCrossRefGoogle Scholar
  18. 18.
    Gross GJ, Lamping KG, Warltier DC, Hardman HF (1984) Effects of three bradycardiac drugs on regional myocardial blood flow and function in areas distal to a total or partial coronary occlusion in dogs. Circulation 69: 391–399PubMedCrossRefGoogle Scholar
  19. 19.
    Guth BD, Tajimi T, Seitelberger R, Lee JD, Matsuzaki M, Ross Jr J (1986) Experimental exercise-induced ischemia: drug therapy can eliminate regional dysfunction and oxygen supply-demand imbalance. J Am Coll Cardiol 7: 1036–1046PubMedCrossRefGoogle Scholar
  20. 20.
    Guth BD, Heusch G, Seitelberger R, Ross Jr J (1987) Elimination of exercise-induced regional myocardial dysfunction by a bradycardic agent in dogs with chronic coronary stenosis. Circulation 75: 661–669PubMedCrossRefGoogle Scholar
  21. 21.
    Guth BD, Heusch G, Seitelberger R, Ross Jr J (1987) Mechanism of beneficial effect of beta-adrenergic blockade on exercise-induced myocardial ischemia in conscious dogs. Circ Res 60: 738–746PubMedGoogle Scholar
  22. 22.
    Guth BD, Schulz R, Thaulow E (1991) Intervertricular redistribution of myocardial blood flow during metabolic vasodilation. Pflügers Arch 417: 485–492PubMedCrossRefGoogle Scholar
  23. 23.
    Heusch G, Schulte W, Rüddel H, Neus H (1981) Laerm und vegetatives Nervensystem. Therapiewoche 31: 33–36Google Scholar
  24. 24.
    Hjalmarson A (1984) The Göteborg metoprolol trial in acute myocardial infarction. Am J Cardiol 53 Suppl.: 1DGoogle Scholar
  25. 25.
    Indolfi C, Guth BD, Miura T, Miyazaki S, Schulz R, Ross Jr J (1989) Mechanisms of improved ischemic regional dysfunction by bradycardia. Studies on ULFS 49 CL in swine. Circulation 80: 983–993PubMedCrossRefGoogle Scholar
  26. 26.
    Matsuzaki M, Gallagher KP, Patritti J, Tajimi T, Kemper WS, White FC, Ross Jr J (1984) Effects of a calcium-entry blocker (diltiazem) on regional myocardial flow and function during exercise in conscious dogs. Circulation 69: 801–814PubMedCrossRefGoogle Scholar
  27. 27.
    Matsuzaki M, Guth BD, Tajimi T, Kemper WS, Ross Jr J (1985) Effects of the combination of diltiazem and atenolol on exercise-induced regional myocardial ischemia in conscious dogs. Circulation 72: 233–243PubMedCrossRefGoogle Scholar
  28. 28.
    Matsuzaki M, Patritti J, Tajimi T, Miller M, Kemper WS, Ross Jr J (1984) Effects of ß-blockade on regional myocardial flow and function during exercise. Am J Physiol 247: H52–H60PubMedGoogle Scholar
  29. 29.
    Murakami H, Kim S-J, Downey HF (1989) Persistent right coronary flow reserve at low perfusion pressure. Am J Physiol 256: H1176–H1184PubMedGoogle Scholar
  30. 30.
    Neill WA, Oxendine JM, Phelps NC, Anderson RP (1975) Subendocardial ischemia provoked by tachycardia in conscious dogs with coronary stenosis. Am J Cardiol 35: 30–36PubMedCrossRefGoogle Scholar
  31. 31.
    Neill WA, Phelps NC, Oxendine JM, Mahler DJ, Sim DN (1973) Effect of heart rate on coronary blood flow distribution in dogs. Am J Cardiol 32: 306–312PubMedCrossRefGoogle Scholar
  32. 32.
    Pantely GA, Bristow JD, Swenson LJ, Ladley HD, Johnson WE, Anselone CG (1985) Incomplete coronary vasodilation during myocardial ischemia in swine. Am J Physiol 249: H638–H647PubMedGoogle Scholar
  33. 33.
    Pasyk S, Flameng W, Wüsten B, Schaper W (1976) Influence of tachycardia on regional myocardial flow in chronic experimental coronary occlusion. Basic Res Cardiol 71: 243–251PubMedCrossRefGoogle Scholar
  34. 34.
    Pitt B, Gregg DE (1968) Coronary hemodynamic effects of increasing ventricular rate in the unanesthetized dog. Circ Res 22: 753–761PubMedGoogle Scholar
  35. 35.
    Raberger G, Krumpl G, Schneider W (1987) Effects of bradycardic agent ULFS 49 CL on exercise-induced regional contractile dysfunction in dogs. Int J Cardiol 14: 343–354PubMedCrossRefGoogle Scholar
  36. 36.
    Raff WK, Kosche F, Lochner W (1971) Herzfrequenz und extravasale Komponente des Coronarwiderstandes. Pfluegers Arch 323: 241–249CrossRefGoogle Scholar
  37. 37.
    Ross J Jr (1989) Mechanism of regional ischemia and antianginal drug action during exercise. Prog Cardiovasc Dis 31: 455–466PubMedCrossRefGoogle Scholar
  38. 38.
    Santamore WP, Bove AA, Carey RA (1982) Tachycardia induced reduction in coronary blood flow distal to a stenosis. Int J Cardiol 2: 23–37PubMedCrossRefGoogle Scholar
  39. 39.
    Sasayama S, Franklin D, Ross Jr J, Kemper WS, McKown D (1976) Dynamic changes in left ventricular wall thickness and their use in analyzing cardiac function in the conscious dogs. Am J Cardiol 38: 870–879PubMedCrossRefGoogle Scholar
  40. 40.
    Schulz R, Miyazaki S, Miller M, Thaulow E, Heusch G, Ross J Jr, Guth BD (1989) Consequences of regional inotropic stimulation of ischemic myocardium on regional myocardial blood flow and function in anesthetized swine. Circ Res 64: 1116–1126PubMedGoogle Scholar
  41. 41.
    Stein PD, Marzilli M, Sabbah HN, Lee T (1980) Systolic and diastolic pressure gradients within the left ventricular wall. Am J Physiol 238: H625–H630PubMedGoogle Scholar
  42. 42.
    Thuillez C, Berdeaux A, Bonhenry C, Duhaye P, Guidicelli JF (1983) Effects of propranol on regional myocardial blood flow and function during severe coronary stenosis in dogs. Eur J Pharmacol 92: 171–179PubMedCrossRefGoogle Scholar
  43. 43.
    Vatner SF (1980) Correlation between acute reductions in myocardial blood flow and function in conscious dogs. Circ Res 47: 201–207PubMedGoogle Scholar
  44. 44.
    Waagstein F, Hjalmarson AC (1976) Double-blind study of the effect of cardioselective beta-blockade on chest pain in acute myocardial infarction. Acta Med Scand 587 Suppl.: 201–208Google Scholar

Copyright information

© Dr. Dietrich Steinkopff Verlag GmbH & Co. KG, Darmstadt 1991

Authors and Affiliations

  • Brian D. Guth
    • 1
    • 2
  1. 1.Abteilung für PathophysiologieUniversitätsklinikum EssenGermany
  2. 2.Pharmakologie E, J81Dr. Karl Thomae, GmbHBiberach an der RißGermany

Personalised recommendations