Background: Conventional microelectrode techniques were used to compare the concentration-dependent effects of vesnarinone (0.1-100 μM) and amrinone (1 μM-1 mm) on action potential duration (APD) and developed force in both isolated dog ventricular trabeculae and Purkinje strands.
Methods and Results: Both drugs increased contractility of trabecular muscle preparations, while, in Purkinje strands, vesnarinone failed to increase developed force during continuous pacing at 2 Hz. Vesnarinone lengthened APD in both preparations; although this effect was more marked in Purkinje strands. Ventricular muscle APD was not affected by amrinone (1 μM to 1 mM), while, in Purkinje strands, amrinone produced a biphasic effect on APD. Low concentrations (1-100 μM) of amrinone shortened Purkinje fiber APD, while only the highest concentration (1 mM) used lengthened APD. In addition, in Purkinje strand preparations the effects of vesnarinone (10 μM) on APD and developed force were proportional to pacing cycle length at frequencies slower than 2 Hz; however, at frequencies faster than 2 Hz vesnarinone decreased developed force while APD was lengthened. In ventricular trabecular muscle preparations, the effects of vesnarinone were not affected by frequency.
Conclusions: These results indicate clear differences between the effects of vesnarinone and amrinone in isolated cardiac preparations. These differences in experimental effects in isolated cardiac preparations may help provide an explanation for the disappointing clinical response of patients in heart failure to amrinone, while vesnarinone has appeared to be beneficial.
Curfman DG. Inotropic therapy for heart failure: An unfulfilled promise. N Engl J Med325:1509, 1991
2.
Leier CV. Current status of non-digitalis positive inotropic drugs. Am J Cardiol68:1206, 1992
3.
Armstrong PW, Moe GW. Medical advances in the treatment of congestive heart failure. Circulation88:2941, 1993
4.
Om A, Hess ML. Inotropic therapy of the failing myocardium. Clin Cardiol165, 1993
5.
Packer M. The development of positive inotropic agents for chronic heart failure: How have we gone astray?J Am Coll Cardiol22:119A, 1993
6.
Packer M. The search for the ideal positive inotropic agent [editorial; comment]. N Engl J Med329:201, 1993
7.
Wood MA, Hess ML. Long-term oral therapy of congestive heart failure with phosphodiesterase inhibitors. Am J Med Sci297:105, 1989
8.
Uretsky BF, Jessup M, Konstam MA, Dec W, Leier CV, Benotti J, Murali S, Hermann HC, Sandberg JA. Multicenter trial of oral enoximone in patients with moderate to moderately severe congestive heart failure. Circulation82:774, 1990
9.
Packer M. Effect of phosphodiesterase inhibitors on survival of patients with chronic congestive heart failure. Am J Cardiol63:41A, 1989
10.
Sasayama SM, Inoue H, Asanoi K, Kodama M, Hori M, Sakurai T, Kawai C. Acute hemodynamic effects of a new inotropic agent, OPC-8212, on severe congestive heart failure. Heart Vessels2:23, 1986
11.
Inoue M, Kim BH, Hori M, Tsuneoka Y, Matsubara N, Kamada T, Kodama K, Naka M, Nanto S, Higashino Y. Oral OPC-8212 for the treatment of congestive heart failure: Hemodynamic improvement and increased exercise capacity. Heart Vessels2:166, 1986
12.
Inoue M, Hori M, Yasuda H, Takishima T, Sugimoto T, Sasayama S, Sakurai T, Nonogi H, Kodama K, Kusukawa R, et al. A multicenter study of a new inotropic agent, piperanometozine (OPC-8212) in congestive heart failure: Clinical improvement during short-term treatment. Cardiovasc Drugs Ther1:169, 1987
13.
Kubo SH, Rector TS, Strobaeck JE, Cohn JN. OPC-8212 in the treatment of congestive heart failure: Results of a pilot study. Cardiovasc Drugs Ther2:653, 1988
14.
Feldman AM, Decker LC, Llewellyn MP, Baughman KL. Evaluation of a new inotropic agent. OPC-8212, in patients with dilated cardiomyopathy and heart failure. Am Heart J116:771, 1988
15.
Feldman AM, Bristow MR, Parmley WV, Carson PE, Pepine CJ, Gilbert EM, Strobeck JE, Hendrix GH, Powers ER, Bain RP, White BG. Effects of vesnarinone on morbidity and mortality in patients with heart failure. N Engl J Med329:149, 1993
16.
Feldman AM, Strobeck JE. Quinolinone derivatives in the management of congestive heart failure. Coron Artery Dis5:107, 1991
17.
Lathrop DA, Schwartz A. Electromechanical effects of 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(lH)-quinolinone (OPC-8212), a new positive inotropic agent: Isolated adult canine Purkinje strands and ventricular trabeculae. Arzneimittelforschung34:371, 1984
18.
Lathrop DA. Schwartz A.Evidence for possible increase of sodium channel open time and involvement of Na/Ca exchange by a new positive inotropic drug: OPC-8212. Eur J Pharmacol117:391, 1985
19.
Lathrop DA, Varró A, Schwartz A. Rate-dependent electro-physiological effects of OPC-8212: Comparison to sotalol. Eur J Pharmacol164:487, 1989
20.
Lathrop DA, Nánási PP, Schwartz A, Varró B A. Ionic basis for OPC-8212-induced increase in action potential duration in isolated rabbit, guinea pig and human ventricular myocytes. Eur J Pharmacol240:127, 1993
21.
Grupap G, Grupp IL, Kojima M, Sperelakis N, Tsuchiya Y, Hosokawa T, Schwartz A. Hemodynamic and electrophysiologic effects of a novel positive inotropic drug, OPC-8212, in normal and “failing” guinea pig heart preparations. J Cardiovasc Pharmacol8:428, 1986
22.
Rapundalo ST, Lathrop DA, Harrison SA, Beavo JA, Schwartz A. Cyclic AMP-dependent and cyclic AMP-independent actions of a novel cardiotonic agent, OPC-8212. Naunyn Schmiedebergs Arch Pharmacol338:692, 1988
23.
Satoh H, Hashimoto K. Effect of 3,4-dihydro-6-[4-(3,4-dimethoxy-benzoyl)-l-piperazinyl]-2(1 H)-quinolinone (OPC-8212) on the membrane currents of rabbit sino-atrial node cells. Arzneimittelforschung34:376, 1984
24.
Iijima T, Taira N. Membrane current changes responsible for the positive inotropic effect of OPC-8212, a new positive inotropic agent, in single ventricular cells of the guinea pig heart. J Pharmacol Exp Ther240:657, 1987
25.
Zha Z, Lan T, Zhou Z, Yang Z. Effect of a new positive inotropic agent (OPC-8212) on intracellular potential of isolated canine ventricular papillary muscle. (Translated by authors from the original Chinese, English abstract available). Hua Hsi I KO Ta Hsueh Hsueh Pao21:159, 1990
26.
Harrison SA, Chang ML, Beavo JA. Differential inhibition of cardiac cyclic nucleotide phosphodiesterase isozymes by cardiotonic drugs. Circulation73: III109, 1986
27.
Kariya T, Wille LJ, Dage RC. Studies on the mechanism of the cardiotonic activity of MDL 19205: Effects on several biochemical systems. J Cardiovasc Pharmacol6:50, 1984
28.
Endoh M, Yanagisawa T, Taka N, Blinks JR. Effects of new inotropic agents on cyclic nucleotide metabolism and calcium transients in canine ventricular muscle. Circulation73:III117, 1986
29.
Rosenthal JE, Ferrier GR. Inotropic and electrophysiologic effects of amrinone in untreated and digitalized ventricular tissues. J Pharmacol Exp Ther221:188, 1982
Siegl PKS, Morgan G, Sweet CS. Responses to amrinone in isolated cardiac muscles from cat, rabbit. and guinea pig. J Cardiovasc Pharmacol6:281, 1984
32.
Sys SU, Goenen MJ, Chalant CH, Brutsaert DL. Inotropic effects of amrinone and milrinone on contraction and relaxation of isolated cardiac muscle. Circulation73:3III25, 1986
33.
Binah O, Legato MJ, Danilo P, Rosen MR. Developmental changes in the cardiac effects of amrinone in the dog. Circ Res52:747, 1983
34.
Alousi AA, Johnson DC. Pharmacology of bipyridines: Amrinone and milrinone. Circulation73:III10, 1986
35.
Kondo N, Shibata S, Kodama I, Yamada K. Electrical and mechanical effects of amrinone on isolated guinea pig ventricular muscle. J Cardiovasc Pharmacol5:903, 1983
36.
Piwonka RWV, Canniff PC, Farah AE. In vitro electrophysiologic properties of amrinone in mammalian cardiac tissue. J Cardiovasc Pharmacol5:1058, 1983
37.
Mörner SE, Wohlfart B. Inotropic mechanisms of amrinone in papillary muscles from guinea pig hearts. Acts Physiol Scand138:575, 1990
38.
Davidenko J, Antzelevitch C. The effects of milrinone on conduction. reflection, and automaticity in canine Purkinje fibers. Circulation69:1026, 1984
39.
Davidenko J, Antzelevitch C. The effects of milrinone on action potential characteristics, conduction, automaticity, and reflected reentry in isolated myocardial fibers. J Cardiovasc Pharmacol7:341, 1985
40.
Carmeliet E. Electrophysiologic and voltage clamp analysis of the effects of sotalol on isolated cardiac muscle and Purkinje fibers. J Pharmacol Exp Ther232:817, 1985
41.
Varró A, Nánási PP, Lathrop DA. Effect of sotalol on transmembrane ionic currents responsible for repolarization in cardiac ventricular myocytes from rabbit and guinea pig. Life Sci49:PL7, 1991
42.
Yatani A, Imoto Y, Schwartz A, Brown AM. New positive inotropic agent OPC-8212 modulates single Ca2+ channels in ventricular myocytes of guinea pig. J Cardiovasc Pharmacol13:812, 1989
43.
Singh BN, Vaughan Williams EM. A third class of antiarrhythmic action: Effects on atrial and ventricular intracellular potentials, and other pharmacological actions on cardiac muscle of MJ1999 and AH 36776. Br J Pharmacol39:675, 1970
44.
Greenspan K, Cranefield PE. Influence of some factors on oxygen uptake of canine cardiac Purkinje fibers. Am J Physiol204:5, 1963
45.
Miyamoto G, Sasabe H. Pharmacokinetics of a new positive inotropic agent, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyll-2(lH)-quinolinone (OPC-8212), in the rat, rabbit, beagle dog and rhesus monkey. Atzneimittelforschung34:391, 1984
