Effects of new inotropic agents on cyclic nucleotide metabolism and calcium transients in canine ventricular muscle

Abstract

In isolated canine ventricular trabeculae and papillary muscles driven electrically at 0.5 Hz at 37 degrees C, the positive inotropic effects of milrinone, amrinone, MDL 17,043, MDL 19,205, OPC-8212, and forskolin were all associated with simultaneous elevations in tissue cyclic AMP levels. After the administration of sulmazole (AR-L 115 BS), the increase in force preceded that of cyclic AMP levels. Bay k 8644 increased the force of isometric contractions without producing any change in cyclic AMP levels. None of these agents affected the cyclic GMP level. Intracellular calcium transients were determined in similar preparations in which multiple superficial cells had been microinjected with the Ca++-sensitive bioluminescent protein aequorin. The aequorin signals increased in parallel with increases in force in response to cumulative administration of milrinone, amrinone, MDL 17,043, OPC-8212, forskolin, and low concentrations of sulmazole (less than or equal to 3 X 10(-4) M). Forskolin and sulmazole produced larger increases in the amplitude of the calcium transients than the other agents, and their inotropic effects were less variable in magnitude. High concentrations (greater than 3 X 10(-4)M) of sulmazole decreased the amplitude of the calcium transients while increasing further the force. The increases in cyclic AMP levels, calcium transients, and force produced by all of the inotropic agents except Bay k 8644 and high concentrations of sulmazole were effectively antagonized by carbachol. These results indicate that the accumulation of cyclic AMP resulting from the inhibition of cyclic AMP phosphodiesterase plays an important role in the action of new positive inotropic agents, milrinone, amrinone, MDL 17,043, MDL 19,205, OPC-8212, and sulmazole (less than or equal to 3 X 10(-4)M), on dog ventricular muscle.