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Molecular Pharmacology Fast Forward
First published on March 1, 2006; DOI: 10.1124/mol.105.020909

0026-895X/06/6906-1969-1974$20.00
Mol Pharmacol 69:1969-1974, 2006

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Desensitization of NO/cGMP Signaling in Smooth Muscle: Blood Vessels Versus Airways

Florian Mullershausen1, Alexander Lange, Evanthia Mergia, Andreas Friebe, and Doris Koesling

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

The NO/cGMP signaling pathway plays a major role in the cardiovascular system, in which 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 hydrolyzes 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 atrial natriuretic peptide-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 a mechanism of desensitization. In summary, 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.

Received November 16, 2005; accepted February 28, 2006

Address correspondence to: Dr. Doris Koesling, Institut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, Medizinische Fakultät MA N1, Universitätsstrasse 150, 44780 Bochum, Germany. E-mail: doris.koesling{at}ruhr-uni-bochum.de




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Am J Physiol Lung Cell Mol Physiol, July 1, 2007; 293(1): L84 - L95.
[Abstract] [Full Text] [PDF]


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