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Herein, the effect of pharmacological blockade of MRPs on cGMP signalling in the heart and vasculature was investigated <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Proliferation of human coronary artery smooth muscle cells (hCASMCs), vasorelaxation of murine aorta and reductions in mean arterial BP (MABP) in response to NO donors or natriuretic peptides were 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\u2010induced heart failure was also explored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>MK571 attenuated hCASMC growth and enhanced the anti\u2010proliferative effects of NO and atrial natriuretic peptide (ANP). MRP blockade caused concentration\u2010dependent relaxations of murine aorta and augmented responses to ANP (and to a lesser extent NO). MK571 did not decrease MABP <jats:italic>per se<\/jats:italic> but enhanced the hypotensive actions of ANP and improved structural and functional indices of disease severity in experimental heart failure. These beneficial actions of MRP inhibition were associated with a greater intracellular:extracellular cGMP ratio <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>MRP blockade promotes the cardiovascular functions of natriuretic peptides <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>, 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>LINKED ARTICLES<\/jats:title><jats:p>This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v179.11\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v179.11\/issuetoc<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15593","type":"journal-article","created":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T03:25:20Z","timestamp":1623813920000},"page":"2443-2459","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Multidrug resistance proteins preferentially regulate natriuretic peptide\u2010driven cGMP signalling in the heart and vasculature"],"prefix":"10.1111","volume":"179","author":[{"given":"Robert M. 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