Guanylyl cyclase inhibition reduces contractility and decreases cGMP and cAMP in isolated rat hearts

OBJECTIVE: Several studies have shown that increasing cGMP in the heart reduces contractility, however, decreasing basal cGMP levels have also been shown in some studies to reduce contractility. This study was designed to evaluate the hypothesis that decreasing basal levels of cGMP decreases ventricular contractility, and that this depressed function is associated with a decrease in cAMP. METHODS: Using paced, constant flow, buffer-perfused rat hearts, we determined the effects of intracoronary infusions of the guanylyl cyclase inhibitor, LY83583 (10(-5) M), on ventricular function, oxygen consumption, and ventricular content of cGMP and cAMP. These experiments were conducted in the absence and presence of isoproterenol (ISO) to increase baseline left ventricular developed pressure (LVDP) and cAMP. RESULTS: LY83583, infused for 25 min, decreased LVDP by 44 +/- 3 (SE), 77 +/- 20 and 120 +/- 38 mmHg, in control, 10(-9) M, and 10(-8) M ISO-stimulated hearts, respectively. Regardless of the level of ISO stimulation, LY83583 reduced LVDP to the same sub-basal level. Oxygen consumption also decreased, but proportionately less than LVDP. ISO increased cAMP without changing cGMP. LY83583 decreased cGMP by about 25% at all levels of ISO, and decreased cAMP by 22% in the 10(-8) M ISO-stimulated group. CONCLUSION: Guanylyl cyclase inhibition by LY83583 decreased cGMP, cAMP and ventricular contractility. However, LY83583 depression of contractility was not always associated with a reduction in cAMP, suggesting that LY83583 can depress contractility by both cAMP-dependent and independent mechanisms.