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(Circulation. 2004;109:1711-1713.)
© 2004 American Heart Association, Inc.

Brief Rapid Communications

Inhibition of Phosphodiesterase Type 5 by the Activator of Nitric Oxide–Sensitive Guanylyl Cyclase BAY 41-2272

Florian Mullershausen, PhD; Michael Russwurm, MD; Andreas Friebe, PhD; Doris Koesling, MD

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

Correspondence to Dr Doris Koesling, Insititut für Pharmakologie und Toxikologie, Ruhr-Universität Bochum, Med. Fak. MA N1/43, Universitätsstrasse 150, 44780 Bochum, Germany. E-mail doris.koesling{at}ruhr-uni-bochum.de

Received January 14, 2004; revision received February 23, 2004; accepted February 24, 2004.

Background— By the formation of cGMP, nitric oxide (NO)–sensitive guanylyl cyclase (GC) acts as the effector for the signaling molecule NO and mediates the relaxation of vascular smooth muscle and the inhibition of platelet aggregation. The compounds YC-1 and BAY 41-2272 are regarded as NO-independent activators and sensitizers of NO-sensitive GC. In vivo effects, for example, lowering blood pressure and prolonging tail-bleeding times, turn the compounds into promising candidates for the therapy of cardiovascular diseases. However, YC-1 has also been shown to inhibit the major cGMP-degrading enzyme phosphodiesterase type 5 (PDE5). The synergistic properties of YC-1 on cGMP formation and degradation lead to an excessive NO-induced cGMP accumulation in cells, explaining the observed physiological effects. We assessed a potential inhibition of PDE5 by the new GC activator BAY 41-2272.

Methods and Results— The effects of BAY 41-2272 on NO-sensitive GC and PDE5 activities were tested in vitro. BAY 41-2272 not only sensitized NO-sensitive GC toward activation by NO but also, with comparable potency, inhibited cGMP degradation by PDE5. In intact platelets, BAY 41-2272 greatly potentiated the NO-induced cGMP response that was caused by a synergistic effect of BAY 41-2272 on cGMP formation and degradation.

Conclusions— The physiological effects of BAY 41-2272, which are commonly ascribed to the NO-independent activation of NO-sensitive GC, are rather due to the synergism of sensitization of NO-sensitive GC and inhibition of PDE5.

Key Words: inhibitors • nitric oxide • pharmacology • platelets

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