Smooth muscle-selective deletion of guanylyl cyclase-A prevents the acute but not chronic effects of ANP on blood pressure

Rita Holtwick, Michael Gotthardt, Boris Skryabin, Martin Steinmetz, Regine Potthast, Bernd Zetsche, Robert E Hammer, Joachim Herz, Michaela Kuhn

Research output: Contribution to journalArticle

208 Citations (Scopus)

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 ≈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.

Original languageEnglish (US)
Pages (from-to)7142-7147
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number10
DOIs
StatePublished - May 14 2002

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Atrial Natriuretic Factor
Smooth Muscle
Blood Pressure
Smooth Muscle Myocytes
Blood Vessels
Arterial Pressure
Knockout Mice
atrial natriuretic factor receptor A
Atrial Natriuretic Factor Receptors
Natriuresis
Diuresis
Capillary Permeability
Renin-Angiotensin System
Transgenes
Vascular Smooth Muscle
Vasodilation
Exons
Alleles
Messenger RNA

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Smooth muscle-selective deletion of guanylyl cyclase-A prevents the acute but not chronic effects of ANP on blood pressure. / Holtwick, Rita; Gotthardt, Michael; Skryabin, Boris; Steinmetz, Martin; Potthast, Regine; Zetsche, Bernd; Hammer, Robert E; Herz, Joachim; Kuhn, Michaela.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 10, 14.05.2002, p. 7142-7147.

Research output: Contribution to journalArticle

Holtwick, Rita ; Gotthardt, Michael ; Skryabin, Boris ; Steinmetz, Martin ; Potthast, Regine ; Zetsche, Bernd ; Hammer, Robert E ; Herz, Joachim ; Kuhn, Michaela. / Smooth muscle-selective deletion of guanylyl cyclase-A prevents the acute but not chronic effects of ANP on blood pressure. In: Proceedings of the National Academy of Sciences of the United States of America. 2002 ; Vol. 99, No. 10. pp. 7142-7147.
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