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First published on March 1, 2006; DOI: 10.1124/mol.105.020909

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Received for publication November 16, 2005.
Revised February 28, 2006.
Accepted for publication February 28, 2006.

Desensitization of NO/cGMP signaling in smooth muscle: Blood vessels versus airways

Florian Mullershausen 1, Alexander Lange 1, Evanthia Mergia 1, Andreas Friebe 1, Doris Koesling 1*

1 Ruhr-Universitat Bochum

* Address correspondence to: E-mail: doris.koesling{at}ruhr-uni-bochum.de

Abstract

The NO/cGMP signaling pathway plays a major role in the cardiovascular system where it is involved in the regulation of smooth muscle tone and inhibition of platelet aggregation. Under pathophysiological conditions such as endothelial dysfunction, coronary artery disease and airway hyperreactivity, smooth muscle containing arteries and bronchi are of great pharmacological interest. In these tissues, NO mediates its effects by stimulating guanylyl cyclase (GC) to form cGMP; the subsequent increase in cGMP is counteracted by the cGMP-specific phosphodiesterase (PDE5) which hydrolyses cGMP. In platelets, allosteric activation of PDE5 by cGMP paralleled by phosphorylation has been shown to govern the sensitivity of NO/cGMP signaling. Here, we demonstrate that the functional responsiveness to NO correlates with the relative abundance of GC and PDE5 in aortic and bronchial tissue, respectively. We show a sustained desensitization of the NO-induced relaxation of aortic and bronchial rings caused by a short-term exposure to NO. The NO treatment caused heterologous desensitization of ANP-induced relaxation whereas relaxation by the cGMP analog 8-pCPT-cGMP was unperturbed. Impaired relaxation was shown to be paralleled by PDE5 phosphorylation; this indicates enhanced cGMP degradation as mechanism of desensitization. In sum, our results demonstrate the physiological impact of PDE5 activation on the control of smooth muscle tone and provide an explanation for the apparent impairment of NO-induced vasorelaxation.


Key words: Nitric oxide, cGMP, Phosphodiesterases


This article has been cited by other articles:


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[Abstract] [Full Text] [PDF]


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