Multidrug resistance proteins preferentially regulate natriuretic peptide-driven cGMP signalling in the heart & vasculature.

BACKGROUND & PURPOSE: Cyclic-3',5'-guanosine monophosphate (cGMP) underpins the bioactivity of nitric oxide (NO) and natriuretic peptides and is key to cardiovascular homeostasis. Cyclic GMP-driven responses are terminated primarily by phosphodiesterases but cellular efflux via multidrug resistance proteins (MRPs) might contribute. Herein, the effect of pharmacological blockade of MRPs on cGMP signalling in the heart and vasculature was investigated in vitro and in vivo. EXPERIMENTAL APPROACHES: Proliferation of human coronary artery smooth muscle cells (hCASMC), vasorelaxation of murine aorta and reductions in mean arterial blood pressure (MABP) in response to NO-donors or natriuretic peptides was determined in the absence and presence of the MRP inhibitor MK571. The ability of MRP inhibition to reverse morphological and contractile deficits in a murine model of pressure overload-induced HF was also explored. KEY RESULTS: MK571 attenuated hCASMC growth and enhanced the anti-proliferative effects of NO and ANP. MRP blockade caused concentration-dependent relaxations of murine aorta and augmented responses to ANP (and to a lesser extent NO). MK571 did not decrease MABP, but enhanced the hypotensive actions of ANP and improved structural and functional indices of disease severity in experimental HF. These beneficial actions of MRP inhibition were associated with a greater intra:extra -cellular cGMP ratio in vitro and in vivo. CONCLUSIONS & IMPLICATIONS: MRP blockade promotes the cardiovascular functions of natriuretic peptides in vitro and in vivo, with more modest effects on NO. MRP inhibition may have therapeutic utility in cardiovascular diseases triggered by dysfunctional cGMP signalling, particularly those associated with altered natriuretic peptide bioactivity

Multiplicity of Nitric Oxide and Natriuretic Peptide Signalling in Heart Failure.

"This is a non-final version of an article published in final form in Journal of Cardiovascular Pharmacology: July 24, 2019 - Volume Publish Ahead of Print - Issue - p doi: 10.1097/FJC.0000000000000724"Heart failure (HF) is a common consequence of several cardiovascular diseases, and is understood as a vicious cycle of cardiac and haemodynamic decline. The current inventory of treatments either alleviate the pathophysiological features (e.g., cardiac dysfunction, neurohumoral activation, ventricular remodelling) and/or target any underlying pathologies (e.g., hypertension, myocardial infarction). Yet, since these do not provide a cure, the morbidity and mortality associated with HF remains high. Therefore, the disease constitutes an unmet medical need, and novel therapies are desperately needed. Cyclic guanosine 3',5'-monophosphate (cGMP), synthesised by nitric oxide (NO)- and natriuretic peptide (NP)- responsive guanylyl cyclase (GC) enzymes, exerts numerous protective effects on cardiac contractility, hypertrophy, fibrosis, and apoptosis. Impaired cGMP signalling, which can occur following GC deactivation and the upregulation of cyclic nucleotide-hydrolysing phosphodiesterases (PDEs), promotes cardiac dysfunction. Herein we review the role that NO/cGMP and NP/cGMP signalling plays in HF. After considering disease aetiology, the physiological effects of cGMP in the heart are discussed. We then assess the evidence from pre-clinical models and patients that compromised cGMP signalling contributes to the HF phenotype. Finally, the potential of pharmacologically harnessing cardioprotective cGMP to rectify the present paucity of effective HF treatments is examined