title: Smooth muscle-selective deletion of guanylyl cyclase-A prevents the acute but not chronic effects of ANP on blood pressure.
abstract: Atrial natriuretic peptide (ANP) is an important regulator of arterial blood pressure. The mechanisms mediating its hypotensive effects are complex and involve the inhibition of the sympathetic and renin-angiotensin-aldosterone (RAA) systems, increased diuresis/natriuresis, vasodilation, and enhanced vascular permeability. In particular, the contribution of the direct vasodilating effect of ANP to the hypotensive actions remains controversial, because variable levels of the ANP receptor, guanylyl cyclase A (GC-A), are expressed in different vascular beds. The objective of our study was to determine whether a selective deletion of GC-A in vascular smooth muscle would affect the hypotensive actions of ANP. We first created a mutant allele of mouse GC-A by flanking a required exon with loxP sequences. Crossing floxed GC-A with SM22-Cre transgene mice expressing Cre recombinase in smooth muscle cells (SMC) resulted in mice in which vascular GC-A mRNA expression was reduced by approximately 80%. Accordingly, the relaxing effects of ANP on isolated vessels from these mice were abolished; despite this fact, chronic arterial blood pressure of awake SMC GC-A KO mice was normal. Infusion of ANP caused immediate decreases in blood pressure in floxed GC-A but not in SMC GC-A knockout mice. Furthermore, acute vascular volume expansion, which causes release of cardiac ANP, did not affect resting blood pressure of floxed GC-A mice, but rapidly and significantly increased blood pressure of SMC GC-A knockout mice. We conclude that vascular GC-A is dispensable in the chronic and critical in the acute moderation of arterial blood pressure by ANP.
authors: Institut für Pharmakologie und Toxikologie, Westfälische Wilhelms-Universität Münster, D-48149 Münster, Germany.
authors: Rita
authors: R
authors: Holtwick
authors: Michael
authors: M
authors: Gotthardt
authors: Boris
authors: B
authors: Skryabin
authors: Martin
authors: M
authors: Steinmetz
authors: Regine
authors: R
authors: Potthast
authors: Bernd
authors: B
authors: Zetsche
authors: Robert E
authors: RE
authors: Hammer
authors: Joachim
authors: J
authors: Herz
authors: Michaela
authors: M
authors: Kuhn
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D001794:Blood Pressure; D015870:Gene Expression; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D009124:Muscle Proteins / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism*; D012146:Rest; D019076:Transgenes; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D008840:Microfilament Proteins; D009124:Muscle Proteins; C058992:Tagln protein, mouse; D014665:Vasodilator Agents; C051615:transgelin; D009320:Atrial Natriuretic Factor; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A