Effects of AR-L 115 on contraction and relaxation of isolated mammalian cardiac muscle.

Abstract

We studied the mode of action of a new cardiotonic agent (AR-L115) contractile performance of isolated cardiac muscle. We analyzed its effects on the contraction and relaxation of partially skinned, single cardiac cells of rat ventricle, and of intact papillary muscles of the right ventricle of the cat. AR-L115 (30-100 micrograms/ml) reversibly increased the frequency, but not the amplitude, of spontaneous isotonic and isometric contractions of the single cells with functioning sarcoplasmic reticulum (SR), thereby resembling the action of caffeine. It did not affect contractions of mechanically skinned and detergent-pretreated cells without functioning SR, which were activated through iontophoretic calcium pulses. In papillary muscles, AR-L115 (1-40 micrograms/ml) significantly increased directly measured maximum unloaded velocity of shortening at zero load, peak velocity of isotonic shortening and lengthening, peak total isometric tension development, and peak rate of tension development, indicating augmented contractility. These effects were less pronounced than those of increasing the calcium concentration in the bathing solution from 2.5 to 7.5 mM. After beta-adrenergic blockade (propranolol or toliprolol 10(-5) M), the maximal effects of AR-L115 were markedly diminished. Load dependence of isotonic relaxation and the time of half-isometric relaxation were not affected by the drug. Accordingly, AR-L115 is a mild positive inotropic agent, which mainly increases contractility during the contraction phase without markedly affecting load dependence of relaxation. These effects are probably mediated both through a catecholaminelike action on beta-receptors and through a separate caffeinelike action on the calcium-sequestering membrane systems. In contrast to digitalis glycosides, AR-L115 does not exhibit tachyphylaxis in chronically AR-L115-loaded animals.