Urodilatin, a natriuretic peptide stimulating particulate guanylate cyclase, and the phosphodiesterase 5 inhibitor dipyridamole attenuate experimental pulmonary hypertension synergism upon coapplication

In a model of acute pulmonary hypertension in intact rabbits, we investigat ed the vasodilatory potency of intravascularly administered urodilatin, a r enal natriuretic peptide type A known to stimulate particulate guanylate cy clase. Urodilatin infusion was performed in the absence and presence of the phosphodiesterase (PDE) type 5 inhibitor dipyridamole. Stable pulmonary hy pertension was evoked by continuous infusion of the thromboxane mimetic U46 619, resulting in approximate doubling of the pulmonary artery pressure (PA P). When infused as sole agents, both urodilatin and dipyridamole dose-depe ndently attenuated the pulmonary hypertension, with doses for a 20% decreas e in PAP being 30 ng/kg min for urodilatin and 10 mug/kg min for dipyridamo le. 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 mug/kg min), which per se did not affect pulmonary and systemic hemodynamics, and a standard dose of urodila tin (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 ti me, manifold enhanced plasmatic cyclic guanosine monophosphate (cGMP) level s were detected. Aerosolized dipyridamole also dose-dependently attenuated pulmonary hypertension, with only 1 mug/kg min being sufficient for a 20% d ecrease in PAP, with no SAP decline. Preceding administration of subthresho ld aerosolized dipyridamole (50 ng/kg min) did, however, cause only a minor amplification of the pulmonary vasodilatory response to a subsequently inf used standard dose of urodilatin. In conclusion, this is the first study to show that urodilatin does possess vasodliatory potency in the pulmonary ci rculation, and enhanced plasma levels of cGMP and synergy with the PDE5 inh ibitor dipyridamole both strongly suggest that this effect proceeds via gua nylate cyclase activation. The effect of infused urodilatin is, however, no t selective for the pulmonary vasculature, as the systemic vascular resista nce declines in a corresponding fashion.