Published Online
on April 5, 2004

A more recent version of this article appeared on April 13, 2004

This Article Full Text (PDF) All Versions of this Article: 109/14/1711    most recent 01.CIR.0000126286.47618.BDv1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mullershausen, F. Articles by Koesling, D. Search for Related Content PubMed PubMed Citation Articles by Mullershausen, F. Articles by Koesling, D. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB NITRIC OXIDE Related Collections Cell signalling/signal transduction Other Research

Submitted on January 14, 2004
Revised on February 23, 2004
Accepted on February 24, 2004

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, and Doris Koesling MD^*

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

^* To whom correspondence should be addressed. E-mail: doris.koesling{at}ruhr-uni-bochum.de.

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

This article has been cited by other articles:

				B. Roy, E. J. Halvey, and J. Garthwaite An Enzyme-linked Receptor Mechanism for Nitric Oxide-activated Guanylyl Cyclase J. Biol. Chem., July 4, 2008; 283(27): 18841 - 18851. [Abstract] [Full Text] [PDF]

				S. Nimmegeers, P. Sips, E. Buys, P. Brouckaert, and J. Van de Voorde Functional role of the soluble guanylyl cyclase {alpha}1 subunit in vascular smooth muscle relaxation Cardiovasc Res, October 1, 2007; 76(1): 149 - 159. [Abstract] [Full Text] [PDF]

				S. Bruder, A. Schultz, and J. E. Schultz Characterization of the Tandem GAF Domain of Human Phosphodiesterase 5 Using a Cyanobacterial Adenylyl Cyclase as a Reporter Enzyme J. Biol. Chem., July 21, 2006; 281(29): 19969 - 19976. [Abstract] [Full Text] [PDF]

				C. E. Teixeira, F. B. M. Priviero, and R. C. Webb Molecular Mechanisms Underlying Rat Mesenteric Artery Vasorelaxation Induced by the Nitric Oxide-Independent Soluble Guanylyl Cyclase Stimulators BAY 41-2272 [5-Cyclopropyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-4-ylamine] and YC-1 [3-(5'-Hydroxymethyl-2'-furyl)-1-benzyl Indazole] J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 258 - 266. [Abstract] [Full Text] [PDF]

				P. Deruelle, T. R. Grover, and S. H. Abman Pulmonary vascular effects of nitric oxide-cGMP augmentation in a model of chronic pulmonary hypertension in fetal and neonatal sheep Am J Physiol Lung Cell Mol Physiol, November 1, 2005; 289(5): L798 - L806. [Abstract] [Full Text] [PDF]

				D. U. Bawankule, K. Sathishkumar, K. K. Sardar, D. Chanda, A. V. Krishna, V. R. Prakash, and S. K. Mishra BAY 41-2272 [5-Cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-4-ylamine]-Induced Dilation in Ovine Pulmonary Artery: Role of Sodium Pump J. Pharmacol. Exp. Ther., July 1, 2005; 314(1): 207 - 213. [Abstract] [Full Text] [PDF]

				P. Deruelle, T. R. Grover, L. Storme, and S. H. Abman Effects of BAY 41-2272, a soluble guanylate cyclase activator, on pulmonary vascular reactivity in the ovine fetus Am J Physiol Lung Cell Mol Physiol, April 1, 2005; 288(4): L727 - L733. [Abstract] [Full Text] [PDF]

				O. V. Evgenov, F. Ichinose, N. V. Evgenov, M. J. Gnoth, G. E. Falkowski, Y. Chang, K. D. Bloch, and W. M. Zapol Soluble Guanylate Cyclase Activator Reverses Acute Pulmonary Hypertension and Augments the Pulmonary Vasodilator Response to Inhaled Nitric Oxide in Awake Lambs Circulation, October 12, 2004; 110(15): 2253 - 2259. [Abstract] [Full Text] [PDF]

				E. Bischoff, J.-P. Stasch, F. Mullershausen, M. Russwurm, A. Friebe, and D. Koesling Effects of the sGC Stimulator BAY 41-2272 Are Not Mediated by Phosphodiesterase 5 Inhibition * Response Circulation, September 21, 2004; 110(12): e320 - e321. [Full Text] [PDF]