Pomolic acid reduces contractility and modulates excitation-contraction coupling in rat cardiomyocytes

Abstract

Pomolic acid (PA) isolated from Licania pittieri has hypotensive effects in rats, inhibits human platelet aggregation and elicits endothelium-dependent relaxation in rat aortic rings. The present study was designed to investigate the effects of PA on cardiomyocytes. Trabeculae and enzymatically isolated cardiomyocytes from rats were used to evaluate the concentration-dependent effects of PA on cardiac muscle tension and excitation-contraction coupling (ECC) by recording Ca²⁺ transients reported with Fluo-3 and Fura-2, as well as L-type Ca²⁺ currents (LTCC). PA reduced the contractile force in rat cardiac trabeculae with an EC₅₀ = 14.3 ± 2.4 μM. PA also reduced the amplitude of Ca²⁺ transients in a concentration-dependent manner, with an EC₅₀ = 10.5 ± 1.3 μM, without reducing sarcoplasmic reticulum (SR) Ca²⁺ loading. PA decreased the half width of the Ca²⁺ transient by 31.7 ± 3.3% and increased the decay time and decay time constant (τ) by 7.6 ± 2.7% and 75.6 ± 3.7%, respectively, which was associated with increased phospholamban (PLN) phosphorylation. PA also reversibly reduced the macroscopic LTCC in the cardiomyocyte membrane, but did not demonstrate any effects on skeletal muscle ECC. In conclusion, PA reduces LTCC, Ca²⁺ transients and cardiomyocyte force, which along with its vasorelaxant effects explain its hypotensive properties. Increased PLN phosphorylation protected the SR from Ca²⁺ depletion. Considering the effects of PA on platelet aggregation and the cardiovascular system, we propose it as a new potential, multitarget cardiovascular agent with a demonstrated safety profile.

Keywords: Cardiac excitation-contraction coupling; Cardiomyocyte; Hypertension; Licania pittieri; Pomolic acid.