MRS2339, a cardiac P2X4 receptor nucleotide activator, improves systolic function in heart failure

Growing evidence is highlighting purinergic receptors as therapeutic targets in cardiac diseases. MRS2339, a charged (N)-methanocarba derivative of 2-Cl-adenosine monophosphate, is efficacious in multiple animal models of systolic heart failure with reduced ejection fraction following infarction, pressure overload, calsequestrin overexpression, rapid pacing, and other injuries. In this study, we explored the beneficial mechanisms of this nucleotide analog in dogs with rapid pacing-induced systolic heart failure and in mice with postinfarct ischemic heart failure. In dogs, sustained infusion of the nucleotide analog increased stroke volume, cardiac output, arterial blood pressure, and arterial oxygen level without any vascular effects, suggesting direct cardiac effects of the drug. In the murine model, MRS2339 caused an increase in myocardial cyclic GMP level, a known cardioprotective second messenger in wild type mice, but no effects in P2X4 receptor knockout mice. Previous data showed that MRS2339 was able to elicit a current in adult mouse cardiomyocytes. The present data showed that MRS2339 could not stimulate a current through rat homomeric P2X4 receptors expressed in HEK293 cells. While the composition of endogenous cardiomyocyte P2X receptors is not known, P2X4 receptors in the heart appear necessary for MRS2339-induced cyclic GMP increase. Our findings support a novel cardiac P2X 4 receptor-mediated cyclic GMP enhancement by MRS2339 as a cellular mechanism of action in heart failure. Stimulating cardiac P2X receptors with increased cyclic GMP level to yield hemodynamic improvement is a potential new therapeutic target in heart failure.