Potent cardiorenal actions in experimental heart failure with dual activation of soluble and particulate guanylate cyclases by bay 58-2667 and B-type natriuretic peptide: a novel therapeutic strategy

Abstract

Background: Soluble guanylate cyclase (sGC) is an important enzyme, which via cyclic guanosine monophosphate (cGMP) production mediates potent vasodilating actions in multiple vascular beds. Particulate guanylate cyclase (pGC) via cGMP results in potent renal natriuretic and diuretic actions with vasodilating properties. Importantly, sGC and pGC may in part be differentially localized which may limit maximal cGMP activating pathways with sole activation of either pGC or sGC. BAY 58-2667 belongs to the new pharmacological class of direct sGC activators that, unlike conventional nitrates, activate sGC without the development of tolerance and without cGMP-independent actions. B-type natriuretic peptide (BNP), which is a pGC activator, is natriuretic and vasodilating, but in experimental congestive heart failure (CHF) does not increase cardiac output or reduce systemic vascular resistance. We hypothesized that co-administration of BAY 58-2667 and BNP in experimental CHF would complement the beneficial cardiac unloading actions of BAY 58-2667 with the beneficial renal actions of BNP. Methods: CHF was induced in two groups of male dogs (both N=7) by tachypacing. After 10 days, cardiorenal parameters were measured in clearances at baseline and with two intravenous doses of BAY 58-2667 (0.1 and 0.3 μg/kg/min, respectively) alone or in combination with BNP (10 and 50 ng/kg/min, respectively). Clearances were compared within groups by repeated measures ANOVA, while groups were compared qualitatively. Results: BAY 58-2667 alone potently (p<0.05) decreased mean arterial pressure, cardiac filling pressures, and systemic and renal vascular resistance, while cardiac output and renal blood flood increased. These actions occurred to a similar degree when BNP was added to BAY 58-2667. However, in addition there were significant (p<0.05) increases in urinary flow, urinary sodium excretion, glomerular filtration rate, and filtration fraction. Both regimens did not further activate the renin-angiotensin-aldosterone system. Conclusion: Direct sGC activation by BAY 58-2667 has potent beneficial cardiac unloading actions in experimental CHF. While additional pGC activation with BNP does not augment hemodynamic actions with BAY 58-2667, it enhances renal function. These findings suggest that coactivation of sGC and pGC may be a beneficial and a novel strategy in the treatment of CHF.