Comparison of the effects of MCI-154, a new cardiotonic agent, and some Ca2+-sensitizing agents on the response of the contractile system to Ca2+ in skinned cardiac muscle.

Abstract

Abstract-Several cardiotonic agents (MCI-154, sulmazole, pimobendan and adibendan) were examined for their ability to influence Ca2+-activated tension development and MgATP-activated tension development in the absence of free Ca2+ (rigor tension), using the chemically skinned fiber from guinea pig papillary muscles. MCI-154, sulmazole, pimobendan and adibendan all increased the tension development induced by pCa (-log[Ca2+]M) 5.8 in a concentration dependent manner (10-6 to 10-4 M). The order of the potency was as follows: MCI-1 54>pimobendan>adibendan>sulmazole.MCI-154 enhanced the maximum tension developed at pCa 4.4 but sulmazole, pimobendan and adibendan did not enhance it. MCI-154, but not sulmazole, pimobendan and adibendan, enhanced the tension development induced by pMgATP (-log[MgATP]M) 6.0 in the absence of free Ca2+. MCI-154, sulmazole, pimobendan and adibendan concentration dependently (10-7 to 10-4 M) increased the force of contraction in isolated guinea pig papillary muscles. The order of the potency was as follows: MCI-154> adibendan>pimobendan>sulmazole.These results demonstrated that the Ca2+ sensitizing action on the contractile system may be involved in the positive inotropic action of MCI-154, sulmazole, pimobendan and adibendan, and that MCI-154 is the most potent among these drugs. Furthermore, sulmazole, pimobendan and adibendan did not enhance the interaction of actin and myosin, suggesting that the mechanism of actions of these drugs are qualitatively different from that of MCI-154.

Pharmacological activities of pyridazines and pyridazinone Derivatives: A Review on biologically active scaffold

“…However, most of the Ca 2+ sensitizers may impair cardiac diastolic function as a result of raised Ca 2+ sensitivity of the myofilaments. MCI-154, 6-[4-(4'pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride trihydrate, is a calcium sensitizer that has more potent positive inotropic effect than that of pimobendan, adibendan and sulmazole [38,39]. Over the past few years, a number of pyridazine derivatives have been applied to antiarrhythmics and antianginals [40].…”

“…The 3-Amido-7-(2,6-dichlorobenzyl)-6methyl-triazolo [4,3-b]pyridazine was also defensive against PTZ-induced and strychnine-induced seizures [78]. Some 6-substituted pyridazinone ring derivatives (37,38) were exhibited anticonvulsant activity against MES [72].…”

“…The 5-benzylidene-6-methyl-4,5-dihydropyridazine-3(2H)-one (38) their ester, hydrazide and acetic acid derivatives were exhibited anticonvulsant activities by PTZ induced seizure. Some compound showed an anticonvulsant effect similar to ethosuximide [22].…”

Pimobendan

“…Pimobendan and its active O-demethyl metabolite, UD-CG 212, enhance the contractility of isolated papillary muscle and ventricular trabeculae from various animal species within a concentration range of 0.03 to 1000 Jlmol/L (Berger et al 1985;Brunckhorst et al 1989;Endoh et al 1991;Fujino et al 1988;Honerjager et al 1984;Imagawa et al 1987;Kitada et al 1989;Meulemans & Brutsaert 1991;Solaro et al 1989). On isolated guinea-pig papillary muscle, pimobendan was approximately 30 times less potent than UD-CG 212, producing a peak (3-fold) increase in contractile force at a concentration of 300 Jlmol/L (Berger et al 1985).…”

“…The calcium-sensitising action of pimobendan on the contractile proteins is reflected in an increase in the tension developed, at a given submaximal cytosolic calcium concentration, by chemically skinned animal (Fujino et al 1988;Kitada et al 1989;Lee et al 1989;Ruegg 1986;Ruegg & Morano 1989;Solaro et al 1989;Van Mee11987) and human (Bohm et al 1991;Fritsche et al 1986;ScheId et al 1989) myocardial fibres exposed to pimobendan at concentrations of 1 to 300 IlmollL. Skinned myocardial fibres are devoid of a cell membrane, and the inotropic action of .pimobendan cannot therefore be related to membrane-bound phosphodiesterase inhibition.…”