Fatal gastrointestinal obstruction and hypertension in mice lacking nitric oxide-sensitive guanylyl cyclase

doi:10.1073/pnas.0609778104

Fatal gastrointestinal obstruction and hypertension in mice lacking nitric oxide-sensitive guanylyl cyclase

Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Ruhr-Universität Bochum, 44780 Bochum, Germany

Edited by Joseph A. Beavo, University of Washington School of Medicine, Seattle, WA, and approved March 26, 2007 (received for review November 3, 2006)

Abstract

The signaling molecule nitric oxide (NO), first described as endothelium-derived relaxing factor (EDRF), acts as physiological activator of NO-sensitive guanylyl cyclase (NO-GC) in the cardiovascular, gastrointestinal, and nervous systems. Besides NO-GC, other NO targets have been proposed; however, their particular contribution still remains unclear. Here, we generated mice deficient for the β₁ subunit of NO-GC, which resulted in complete loss of the enzyme. GC-KO mice have a life span of 3–4 weeks but then die because of intestinal dysmotility; however, they can be rescued by feeding them a fiber-free diet. Apparently, NO-GC is absolutely vital for the maintenance of normal peristalsis of the gut. GC-KO mice show a pronounced increase in blood pressure, underlining the importance of NO in the regulation of smooth muscle tone in vivo. The lack of an NO effect on aortic relaxation and platelet aggregation confirms NO-GC as the only NO target regulating these two functions, excluding cGMP-independent mechanisms. Our knockout model completely disrupts the NO/cGMP signaling cascade and provides evidence for the unique role of NO-GC as NO receptor.

Footnotes

*To whom correspondence should be addressed at:
Institut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, Medizinische Fakultät MA N1, Universitätsstrasse 150, 44780 Bochum, Germany.
E-mail: andreas.friebe{at}rub.de
Author contributions: A.F. and D.K. designed research; A.F., E.M., O.D., and A.L. performed research; A.F., O.D., A.L., and D.K. analyzed data; and A.F. and D.K. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0609778104/DC1.
Abbreviations:

GSNO,

S-nitrosoglutathione;

NO-GC,

NO-sensitive guanylyl cyclase;

NOS,

NO synthase;

PKG,

cGMP-dependent protein kinase;

GTN,

glycerol trinitrate;

PDE5,

phosphodiesterase type 5;

KO,

knockout.