Summary
In previous experiments PY 108-068 (PY) has been found to have more potent calcium antagonistic effects on vascular smooth muscle than on myocardial tissue. We now investigated the effects of PY and verapamil (V) on the increases in myocardial contractile force (measured with a strain gauge) and regional vasoconstriction (measured with tracer microspheres) effected by an infusion of 40 μg/kg ouabain into anaesthetized cats. Ouabain significantly increased contractile force of the left ventricle and caused vasoconstriction in the heart, stomach, small intestine, pancreas, spleen and skin, but not in the kidneys, brain, adrenals and liver. PY (30 μg/kg i.v.) and V (0.3 mg/kg i.v.) antagonized the vasoconstrictor effects of the glycoside in all organs except the skin, i.e. also in organs, where the calcium antagonists normally do not cause vasodilatation. However, PY did not affect the increase in contractile force, whereas V attenuated both the cardiac and peripheral vascular effects of ouabain. The results demonstrate the preferential action of PY on peripheral blood vessels as opposed to left ventricular myocardial tissue. Heart rate was decreased by both PY and V but the PQ-interval was lengthened only by V suggesting that PY in contrast to V preferentially acts on the sinus node rather than A-V conduction. A combination of PY with a glycoside might be beneficial in the treatment of cardiac failure, since this calcium antagonist apparently does not antagonize the positive inotropic action of ouabain on the heart while reducing afterload and reversing the undesirable vasoconstriction induced by cardiac glycosides.
Similar content being viewed by others
References
Aarhus LL, Shepherd JT, Tyce GM, Verbeuren TJ, Vanhoutte PM (1983) Contractions of canine vascular smooth muscle cells caused by ouabain are due to release of norepinephrine from adrenergic nerve endings. Circulat Res 52:501–507
Adams RJ, Wallick ET, Asano G, Di Salvo J, Fondacaro JD, Jacobson ED (1983) Canine mesenteric artery Na+, K+-ATPase: Vasopressor receptor for digitalis? J Cardiovasc Pharmacol 5:468–482
Belardinelli L, Harder D, Sperelakis N, Rubio R, Berne RM (1979) Cardiac glycoside stimulation of inward Ca++ current in vascular smooth muscle of canine coronary artery. J Pharmacol Exp Ther 209:62–66
Cantelli I, Pavesi PC, Parchi C, Naccarella F, Bracchetti D (1983) Acute hemodynamic effects of combined therapy with digoxin and nifedipine in patients with chronic heart failure. Am Heart J 106:308–315
Factor SM, Sonnenblick EH (1982) Hypothesis: Is congestive cardiomyopathy caused by hyperreactive myocardial microcirculation (microvascular spasm). Am J Cardiol 50:1149–1152
Factor SM, Minase T, Cho S, Dominitz R, Sonnenblick EH (1982) Microvascular spasm in the cardiomyopathic Syrian hamster: A preventable cause of focal myocardial necrosis. Circulation 66:342–354
Flaim SF, Di Pette DJ (1979) Digoxin-norepinephrine response and calcium blocker effects in vascular smooth muscle. Am J Physiol 236:H613-H619
Fleckenstein A (1977) Specific pharmacology of calcium in myocardium, cardiac pacemakers, and vascular smooth muscle. Ann Rev Pharmacol Toxicol 17:149–166
Grün G, Fleckenstein A, Weder U (1974) Changes in coronary smooth muscle tone produced by Ca, cardiac glycosides and Ca-antagonistic compounds (verapamil, D 600, prenylamine etc) Pflügers Arch Physiol 347:R1
Fleckenstein A, Kammermeier H, Doering H, Freund HJ (1967) Zum Wirkungsmechanisms neuartiger Koronardilatatoren mit gleichzeitig Sauerstoff-einsparenden Myokard-Effekten, Prenylamin und Iproveratril. Z Kreislaufforsch 56:716–744
Fleming WW (1980) The electrogenic Na+, K+-pump in smooth muscle: Physiologic and pharmacologic significance. Ann Rev Pharmacol Toxicol 20:129–149
Gillis RA, Helke CJ, Kellar KJ, Quest JA (1978) Autonomic nervous system actions of cardiac glycosides. Biochem Pharmacol 27:849–856
Hess T, Scholtysik G, Salzmann R, Riesen W (1983) Digoxin-specific antibody fragments and a calcium antagonist for reversal of digoxin-induced mesenteric vasoconstriction. J Pharm Pharmacol 35:647–651
Hof RP (1983) Calcium antagonists and the peripheral circulation: Differences and similarities between PY 108-068, nicardipine, verapamil and diltiazem. Br J Pharmacol 78:375–394
Hof RP, Hof A (1981) Acceleration of blood in the aorta: A parameter useful for evaluating cardiotonic and afterload reducing substances. J Pharmacol Methods 6:87–95
Hof RP, Hof A, Neumann P (1982) Effects of PY 108-068, a new calcium antagonist on general hemodynamics and regional blood flow in anesthetized cats: A comparison with nifedipine. J Cardiovasc Pharmacol 4:352–362
Hof RP, Hof A, Salzmann R, Wyler F (1981) Trapping and intramyocardial distribution of microspheres with different diameters in cat and rabbit hearts in vitro. Basic Res Cardiol 76:630–638
Hof RP, Vuorela HJ (1983) Assessing calcium antagonism on vascular smooth muscle: A comparison of three methods. J Pharmacol Methods 9:41–52
Hof RP, Vuorela HJ, Neumann P (1982) PY 108-068, a new, potent, and selective inhibitor of calcium-induced contraction of rabbit aortic rings. J Cardiovasc Pharmacol 4:344–351
Hof RP, Scholtysik G (1983) Effects of the calcium antagonist PY 108-068 on myocardial tissues in vitro and on reflex tachycardia in vivo. J Cardiovasc Pharmacol 5:176–183
Hof RP, Wyler F, Stalder G (1980) Validation studies for the use of the microsphere method in cats and young minipigs. Basic Res Cardiol 75:747–756
Jasmin G, Solymoss B, Proschek L (1979) Therapeutic trials in hamster dystrophy. Ann NY Acad Sci 317:338–348
Klugmann S, Salvi A, Camerini F (1980) Haemodynamic effects of nifedipine in heart failure. Br Heart J 43:440–446
Mitchell LB, Jutzy KR, Lewis SJ, Schroeder JS, Mason JW (1982) Intracardiac electrophysiologic study of intravenous diltiazem and combined diltiazem-digoxin in patients. Am Heart J 103:57–66
Nyberg G (1983) Initial phase 2 studies with PY 108-068, a new calcium antagonist, in patients with angina pectoris. Br J Clin Pharmacol 5:130P-131P
Perez JE, Borda L, Schuchleib R, Henry PD (1982) Inotropic and chronotropic effects of vasodilators. J Pharmacol Exp Ther 221:609–613
Rouleau JL, Chuck LHS, Hollosi G, Kidd P, Sievers RE, Wikman-Coffelt J, Parmley WW (1982) Verapamil preserves myocardial contractility in the hereditary cardiomyopathy of the syrian hamster. Circulat Res 50:405–412
Schaper W, Lewi P, Flameng W, Gijpen L (1973) Myocardial steal produced by coronary vasodilatation in chronic coronary artery occlusion. Basic Res Cardiol 68:3–20
Scholtysik G, Schaad A (1983) Cardiac cellular electrophysiology as a tool to prove Ca++ slow channel inhibition by PY 108-068. Triangle 22:49–55
Schwartz A (1976) Is the cell membrane Na+,K+-ATPase enzyme system the pharmacological receptor for digitalis? Circulat Res 39:2–7
Vatner SF, Higgins CB, Franklin D, Brauwald E (1971) Effects of a digitalis glycoside on coronary and systemic dynamics in conscious dogs. Circulat Res 28:470–479
Wagner J, Schümann HJ, Rohm N, Gross G, Knorr A (1980) Einfluß des Kalziumantagonisten Verapamil auf die Wirksamkeit des Herzglykosids Ouabain an der narkotisierten Katze. Herz/ Kreisl 12:286–291
Walus KM, Fondacaro JD, Jacobson ED (1981) Effects of calcium and its antagonists on the canine mesenteric circulation. Circulat Res 48:692–700
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hof, R.P., Hof, A. PY 108-068, a dihydropyridine derivative, and verapamil interact differently with the ouabain effects on the heart and the peripheral circulation. Basic Res Cardiol 80, 66–75 (1985). https://doi.org/10.1007/BF01906745
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF01906745