Summary
Ro 40-5967 is a structurally novel Ca2+ channel blocker that binds to the verapamil-type receptor of cardiac membranes but that has been shown in isolated guinea-pig hearts to be about ten times less potent a negative inotropic agent than verapamil. The goals of the present study were to confirm these findings in vitro in isolated perfused rat hearts as well as in vivo in conscious rats and to compare Ro 40-5967 to verapamil. The effects of Ro 40-5967 and verapamil were tested not only in normal rats, but also in rats with heart failure induced by chronic myocardial infarction. In isolated Langendorff hearts (without heart failure), no decrease of contractility was observed with Ro 40-5967 up to complete AV block. In contrast, verapamil decreased contractility with an IC50 of 100 nM. In isolated, electrically stimulated rat papillary muscles, the IC50 values for the decrease of contractile force were 15,000 and 440 nM for Ro 40-5967 and verapamil, respectively. In vivo, Ro 40-5967 did not decrease left ventricular contractility (as assessed by changes of dP/dt max+) in rats without and with heart failure. In contrast, verapamil was markedly negative inotropic in both conditions.
Similar content being viewed by others
References
Osterrieder W, Holck M. In vitro pharmacological profile of Ro 40-5967, a novel Ca2+ channel blocker with potent vasodilator but weak inotropic action.J Cardiovasc Pharmacol 1989;13:754–759.
The Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction.New Engl J Med 1988;319:385–392.
Selye H, Bajusz E, Grassos S, et al. Simple techniques for the surgical occlusion of coronary vessels in the rat.Angiology 1960;11:398–407.
Sarnoff SJ, Mitchell JH.Control of the function of the heart, Handbook of physiology, section 2, vol. I, 1962.
Ross J. Jr, Covell JW, Sonnenblick EH, et al.. Contractile state of heart characterized by force-velocity relations in variably afterloaded and isovolumic beats.Circ Res 1966; 18:149–163.
Clancy RL, Graham TP, Ross J, et al. Influence of aortic pressure-induced homeometric autoregulation on myocardial performance.Am J Physiol 1968;214:1186–1192.
Wallace AG, Skinner NS Jr, Mitchell JH. Hemodynamic determinants of the maximal rate of left ventricular pressure.Am J Physiol 1963;205:30–36.
Furnival CM, Linden RJ, Snow HM. Inotropic changes in the left ventricle. The effect of changes in heart rate aortic pressure and end-diastolic pressure.J Physiol 1970;211:359–387.
Quinones MA, Gaasch WH, Alexander JK. Influence of acute changes in preload, afterload, contractile state and heart rate on ejection and isovolumic indices of myocardial contractility in man.Circulation 1976;53:293–302.
Little WC. The left ventricular dP/dt max+and diastolic volume relation in closed-chest dogs.Circ Res 1985;56:808–815.
Cohen L, Vereault D, Wasserstrom JA, et al. Evidence that uncharged verapamil inhibits myocardial contractility.J Pharmacol Exp Ther 1987;242:721–725.
Ferry DR, Glossmann H, Kaumann AJ. Relationship between the stereoselective negative inotropic effects of verapamil enantiomers and their binding to putative calcium channels in human heart.Br J Pharmacol 1985;84:811–824.
Packer M, Kessler PD, Lee WH. Calcium-channel blockade in the management of severe chronic congestive heart failure: A bridge too far.Circulation 1987;75(Suppl V):V56-V64.
Briscoe MG, Smith HJ. Sensitivity of cat papillary muscles to verapamil and nifedipine: Enhanced effect in acidosis.Cardiovasc Res 1982;16:173–177.
Konishi T, Nakamura Y, Konishi T, et al. Accentuated negative inotropism of verapamil after ischaemic intervention in isolated working rat heart.Cardiovasc Res 1984;18:639–644.
Smith HJ, Goldstein RA, Griffith JM, et al. Regional contractility: Selective depression of ischemic myocardium by verapamil.Circulation 1976;54:629–635.
Chew CYC, Hecht HS, Collett JT, et al. Influence of severity of ventricular dysfunction on hemodynamic responses to intravenously administered verapamil in ischemic heart disease.Am J Cardiol 1981;47:917–922.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Clozel, JP., Véniant, M. & Osterrieder, W. The structurally novel Ca2+ channel blocker Ro 40-5967, which binds to the [3H] desmethoxyverapamil receptor, is devoid of the negative inotropic effects of verapamil in normal and failing rat hearts. Cardiovasc Drug Ther 4, 731–736 (1990). https://doi.org/10.1007/BF01856562
Issue Date:
DOI: https://doi.org/10.1007/BF01856562