title: Urodilatin, a natriuretic peptide stimulating particulate guanylate cyclase, and the phosphodiesterase 5 inhibitor dipyridamole attenuate experimental pulmonary hypertension: synergism upon coapplication.
abstract: 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 microg/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 microg/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 microg/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.
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany. Ralph.schermuly@innere.med.uni-giessen.de
authors.forename: R T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: N
authors.initials: N
authors.lastname: Weissmann
authors.forename: B
authors.initials: B
authors.lastname: Enke
authors.forename: H A
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: W G
authors.initials: WG
authors.lastname: Forssmann
authors.forename: F
authors.initials: F
authors.lastname: Grimminger
authors.forename: W
authors.initials: W
authors.lastname: Seeger
authors.forename: D
authors.initials: D
authors.lastname: Walmrath
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000633:toxicity; D000280:Administration, Inhalation; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000097:blood; D004176:Dipyridamole / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D006162:Guanylate Cyclase / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D007262:Infusions, Intravenous; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D011652:Pulmonary Circulation / Q000187:drug effects; D011817:Rabbits
chemical_list: D010446:Peptide Fragments; D010726:Phosphodiesterase Inhibitors; D004176:Dipyridamole; C056452:Ularitide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D009320:Atrial Natriuretic Factor; D006162:Guanylate Cyclase; D006152:Cyclic GMP