Novel cilostamide analogs, phosphodiesterase ۳ inhibitors, produce positive inotropic but differential lusitropic and chronotropic effects on isolated rat atria

Objective(s): Recently, we showed that some new synthetic compounds structurally related to cilostamide (۴-(۱,۲-dihydro-۲-oxoquinolin-۶-hydroxy)- N-cyclohexyl-N-methylbutanamide), a selective phosphodiesterase ۳ (PDE۳) inhibitor, produce inotropic effect comparable to that of IBMX (۳-isobutyl-۱-methylxanthine), a non-selective PDE inhibitor, but with differential chronotropic effect. In this investigation, we compared the pharmacological effects of these compounds as potential cardiotonic agents using the spontaneously beating atria model. Materials and Methods: In each experiment, rats were treated with reserpine.  The atrium was isolated and mounted in an organ bath. We assessed chronotropic and inotropic effects using cumulativelogconcentration-response curves of isoprenaline alone or in combination of each test-compound. Results: Majority of test compounds augment atria contraction force (ACF) significantly but with different potencies on atrium contraction rate. Cilostamide, MCPIP ([۴-(۴-methyl piperazin-۱-yl)-۴-oxobutoxy)-۴-methylquinolin-۲(۱H)-one]), methyl carbostyril compounds- (mc۱), mc۲ and mc۵ increased the isoprenaline effect on ACF synergistically. But, mc۶ failed to potentiate the effect of isoprenalin; mc۳ and mc۴ did not increase ACF, which may be because of their higher hydrophilic nature. It was interesting that mc۲, alone or in combination with isoprenaline, produced the highest inotropic effect while it did not affect the basal contraction rate and almost blocked the isoprenaline chronotropic effect. Conclusion: Combination of mc۲ with isoprenaline had synergistic effect on inotropic effect, but this combination reduced isoprenaline chronotropic effect; therefore, these effects cannot be related to reducing B-adrenergic receptors activity. These compounds showed different effects; probably all of them were not mediated via PDE۳ inhibition and other mechanisms are involving.

Keywords:

Cilostamide , Inotropic activity , Isoprenaline , PDE inhibitor , Rat atria