Contractile proteins: possible targets for the cardiotonic action of MCI-154 a novel cardiotonic agent?

Kitada, Yoshimi; Narimatsu, Akihiro; Matsumura, Noriko; Endo, Makoto

doi:10.1016/0014-2999(87)90170-1

Cited by 39 publications

(14 citation statements)

References 2 publications

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“…We have also demonstrated that MCI-154 increased the Ca2+ sensitivity of the con tractile protein system in the skinned cardiac muscle of the guinea pig (14,15). These results together with those in the present study support the view that the main mecha nism for the cardiotonic action of MCI-154 is the enhancement of the Ca2+ sensitivity of the cardiac contractile proteins (14,15).…”

Section: Discussionmentioning

confidence: 76%

“…However, as the effect was relatively weak, it would not be the primary mechanism for the positive inotropic effect of the agent. The effect also provides an explanation for why relaxation time of contraction was not prolonged by MCI-154 in spite of its in creasing effect on the Ca2+ sensitivity of contractile proteins (14,15). Compared with an agent like pimobendan, which is reported to increase the Ca2+ sensitivity and prolong relaxation time (23), no impairment of the relaxation by MCI-154 would be advan tageous because not only contraction but also relaxation of the heart is impaired in patients with heart failure (26,27).…”

Section: Discussionmentioning

confidence: 97%

“…Such examinations are important to compare the pharmacological profile of MCI-154 with those of new cardiotonic agents such as amrinone and milrinone, since species dif ference in the inotropic response and the direct positive chronotropic response to these agents have been reported (11)(12)(13). Concerning the mechanisms responsible for the cardiotonic action of MCI-154, we have reported that 1) MCI-154 increased the Ca2+ sensitivity of the contractile protein system in the skinned cardiac muscle of the guinea pig (14,15), 2) MCI-154 exerted little effect on the crude phosphodiesterase of the canine heart (9), and 3) MCI-154 did not increase significantly cyclic AMP content in the dog heart (9). These results suggest that the Ca2+-sensitivity increasing effect may be the main mechanism for the positive inotropic action of MCI-154.…”

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confidence: 99%

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In vitro characterization of the effects of MCI-154, anovel cardiotonic agent, on cardiac tissues.

Narimatsu¹,

Kitada²,

Satoh³

et al. 1989

Jpn.J.Pharmacol

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Abstract-In vitro cardiac effects of a cardiotonic drug, MCI-154, for which the main action mechanism was proposed to be the enhancement of Ca2+ sensitivity of cardiac contractile proteins, were investigated.MCI-154 (3X10-8-3X10-4 M) increased the developed tension in isolated ventricular muscles from cats, dogs, guinea pigs and rats and increased that of isolated left atrial muscles of guinea pigs and rats. However, species differences were observed in the responses to MCI 154. The positive inotropic potency of MCI-154 was stronger than those of amrinone and milrinone.In the isolated right atria from guinea pigs and rats, properties of the chronotropic effect of MCI-154 were different from those of amrinone and milrinone.The positive inotropic action of MCI-154 was not affected by phentolamine, propranolol, cimetidine and tetrodotoxin.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

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In vitro characterization of the effects of MCI-154, anovel cardiotonic agent, on cardiac tissues.

Narimatsu¹,

Kitada²,

Satoh³

et al. 1989

Jpn.J.Pharmacol

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“…Unlike most new nonglycoside and nonsympathomimetic cardiotonic agents, the drug scarcely increases intracellular cyclic AMP in dog ventricular muscle, ruling out the major role of an increase in intracellular cyclic AMP in its positive inotropy (4). MCI 154 has been found definitely to increase the sensitivity to calcium ions of contractile proteins in chemically skinned papillary muscles of the guinea-pig ventricle (5,6). Thus, it is a drug with a novel mechanism of action.…”

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confidence: 99%

Improvement of pentobarbital-induced heart failure by MCI-154, a novel and potent cardiotonic agent, in the dog heart-lung preparation.

et al. 1988

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“…Furthermore, it affects neither Na+-K+ ATPase activity (2,3) nor the cyclic AMP level (5). Recently, we have proposed a unique mechanism of ac tion of MCI-154, i.e., increasing the Ca2+ sensitivity of the contractile protein system (6,7).…”

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confidence: 99%

Changes in membrane potentials and currents of ventricular cells of the guinea pig heart by a new cardiotonic drug, MCI-154.

et al. 1987

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Abstract-Effectsof MCI-154, a newly synthetized cardiotonic drug with vaso dilator property, on the membrane potential and currents of the isolated papillary muscles and the single ventricular cells of the guinea pig were examined. MCI 154 (10-7-10-4 M) increased the developed tension in a dose-dependent manner without significant changes in the action potential configuration of the guinea pig papillary muscle. The slow response action potential obtained by increasing the extracellular K+ concentration to 24 mM was augmented by MCI-154 (10-6 and 10-4M). This effect of MCI-154 was not blocked by atenolol (10-6 M). In voltage clamp experiments on single ventricular cells, the slow inward current was not affected, but the inward rectifier K+ current was reduced by higher concentration of MCI-154 (10-4 M). Considering the "run down" phenomenon of the slow inward current, the possibility that MCI-154 might have a slight increasing effect on the slow inward current could not be ruled out. From these results, it can be concluded that the positive inotropic action of MCI-154 can be explained partially by the decrease in the inward rectifier K+ current, and probably by the increase in the Ca2+ sensitivity of the contractile protein system.

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Contractile proteins: possible targets for the cardiotonic action of MCI-154 a novel cardiotonic agent?

Cited by 39 publications

References 2 publications

In vitro characterization of the effects of MCI-154, anovel cardiotonic agent, on cardiac tissues.

In vitro characterization of the effects of MCI-154, anovel cardiotonic agent, on cardiac tissues.

Improvement of pentobarbital-induced heart failure by MCI-154, a novel and potent cardiotonic agent, in the dog heart-lung preparation.

Changes in membrane potentials and currents of ventricular cells of the guinea pig heart by a new cardiotonic drug, MCI-154.

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