Reciprocal regulation of human soluble and particulate guanylate cyclases in vivo

Background & purpose: We demonstrated previously that reciprocal regulation of soluble (sGC) and particulate (pGC) guanylate cyclases by NO and natriuretic peptides coordinates cyclic cGMP‐mediated vasodilatation in vitro . Herein, we investigated whether such an interaction contributes to vascular homeostasis in mice and humans in vivo . Experimental approach: Mean arterial blood pressure (MABP) changes in anaesthetized mice were monitored in response to i.v. administration of cGMP‐ and cAMP‐dependent vasodilators in wild‐type (WT), endothelial NO synthase (eNOS) and natriuretic peptide receptor (NPR)‐A knockout mice. Forearm blood flow (FBF) in response to intra‐brachial infusion of ANP (25, 50, 100, 200 pmol min ‐1 ) in the absence and presence of the NOS inhibitor N G ‐methyl‐L‐arginine (L‐NMA; 4 μmol min ‐1 ) and the control constrictor noradrenaline (240 pmol min ‐1 ) was assessed in healthy volunteers. Key results: Sodium nitroprusside (SNP; NO‐donor) and atrial natriuretic peptide (ANP) produced dose‐dependent reductions in MABP in WT animals that were significantly enhanced in eNOS KO mice. In NPR‐A K mice, SNP produced a dose‐dependent reduction in MABP that was significantly greater than that in WT mice. Responsiveness to the cAMP‐dependent vasodilator epoprostenol was similar in WT, eNOS KO and NPR‐A KO animals. ANP caused vasodilatation of the forearm resistance vasculature that was significantly greater in individuals lacking endothelium‐derived NO (i.e. L‐NMA treated). Conclusions & implications: These data demonstrate that crosstalk occurs between the NO‐sGC and ANP‐pGC pathways to regulate cGMP‐dependent vasodilatation in vivo in both mice and humans. These findings have implications for understanding the link between natriuretic peptide activity and cardiovascular risk. British Journal of Pharmacology (2006) 149 , 797–801. doi: 10.1038/sj.bjp.0706920