Intracellular Na+ activity and positive inotropic effect of sulmazole in guinea pig ventricular myocardium. Comparison with a cardioactive steroid

Abstract

Recent studies suggest that inhibition of Na+,K+-ATPase may contribute to the positive inotropic action of the imidazopyridine sulmazole. Therefore, we investigated the effect of sulmazole and its stereoisomers and for comparison the effect of the cardioactive steroid dihydroouabain (DHO) on intracellular Na+ activity by means of Na+-sensitive microelectrodes. In the resting papillary muscle of the guinea pig, (±)-sulmazole increased intracellular Na+ activity (a(Na)(i)) within 15-20 minutes by 0.5 ± 0.1 (n = 3), 1.3 ± 0.1 (n = 7), 2.7 ± 0.2 (n = 6), and 4.9 ± 0.5 (n = 6) mM at 60, 100, 300, and 1,000 μM, respectively. (+)-Sulmazole was more effective than the racemate; a(Na)(i) was increased by 1.2 ± 0.3, 2.1 ± 0.3, and 4.0 ± 0.2 mM at 60, 100, and 300 μM, respectively (n = 2 for each concentration). In the contracting papillary muscle (0.2 Hz), (+)- and (±)-sulmazole (600 and 1,000 μM) produced a maximum positive inotropic effect that exceeded that of DHO by 11% and 8%, respectively. As an inotropic agent, (+)-sulmazole was almost twice as potent as the racemate. The maximum direct inotropic effect of (-)-sulmazole (1,000 μM) amounted to only 14% of the DHO maximum and was, in contrast to the racemate and (+)-sulmazole, antagonized by 3 μM carbachol. (-)-Sulmazole did not affect a(Na)(i). DHO increased a(Na)(i) by 0.9 ± 0.1 (n = 5), 1.5 ± 0.1 (n = 7), 2.4 ± 0.1 (n = 5), 2.8 ± 0.2 (n = 4), and 3.8 ± 0.2 (n = 4) mM at 30, 50, 80, 100, and 120 μM, respectively. The increase in a(Na)(i) versus the positive inotropic effect of various concentrations of (±)-sulmazole, (+)-sulmazole, and DHO could be fitted by linear regression (r = 0.970). The results demonstrate that the rise in a(Na)(i), presumably caused by Na+ pump inhibition, exclusively determined the positive inotropic effect of (±)-sulmazole and its (+)-isomer. A cAMP-dependent mechanism was probably responsible for the small inotropic effect of (-)-sulmazole.