Am. J. Respir. Cell Mol. Biol., Volume 25, Number 2, August, 2001 219-225

Urodilatin, a Natriuretic Peptide Stimulating Particulate Guanylate Cyclase, and the Phosphodiesterase 5 Inhibitor Dipyridamole Attenuate Experimental Pulmonary Hypertension
Synergism upon Coapplication

Ralph Theo Schermuly, Norbert Weissmann, Beate Enke, Hossein Ardeschir Ghofrani, Wolf Georg Forssmann, Friedrich Grimminger, Werner Seeger, and Dieter Walmrath

Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen; and Niedersächsisches Institut für Peptidforschung, Hannover, Germany

In a model of acute pulmonary hypertension in intact rabbits, we investigated the vasodilatory potency of intravascularly administered urodilatin, a renal natriuretic peptide type A known to stimulate particulate guanylate cyclase. Urodilatin infusion was performed in the absence and presence of the phosphodiesterase (PDE) type 5 inhibitor dipyridamole. Stable pulmonary hypertension was evoked by continuous infusion of the thromboxane mimetic U46619, resulting in approximate doubling of the pulmonary artery pressure (PAP). When infused as sole agents, both urodilatin and dipyridamole dose-dependently attenuated the pulmonary hypertension, with doses for a 20% decrease in PAP being 30 ng/kg min for urodilatin and 10 µg/kg min for dipyridamole. A corresponding decrease in systemic arterial pressure (SAP) was noted to occur in response to both agents. Sequential intravenous administration of a subthreshold dose of dipyridamole (1 µg/kg min), which per se did not affect pulmonary and systemic hemodynamics, and a standard dose of urodilatin (30 ng/kg min) resulted in a significant amplification of both the PAP and the SAP decrease in response to the natriuretic peptide. At the same time, manifold enhanced plasmatic cyclic guanosine monophosphate (cGMP) levels were detected. Aerosolized dipyridamole also dose-dependently attenuated pulmonary hypertension, with only 1 µg/kg min being sufficient for a 20% decrease in PAP, with no SAP decline. Preceding administration of subthreshold aerosolized dipyridamole (50 ng/kg min) did, however, cause only a minor amplification of the pulmonary vasodilatory response to a subsequently infused standard dose of urodilatin. In conclusion, this is the first study to show that urodilatin does possess vasodilatory potency in the pulmonary circulation, and enhanced plasma levels of cGMP and synergy with the PDE5 inhibitor dipyridamole both strongly suggest that this effect proceeds via guanylate cyclase activation. The effect of infused urodilatin is, however, not selective for the pulmonary vasculature, as the systemic vascular resistance declines in a corresponding fashion.

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