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This Article Full Text Full Text (PDF) All Versions of this Article: 290/4/L723    most recent 00485.2004v2 00485.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Evgenov, O. V. Articles by Ichinose, F. Search for Related Content PubMed PubMed Citation Articles by Evgenov, O. V. Articles by Ichinose, F.

Inhibition of phosphodiesterase 1 augments the pulmonary vasodilator response to inhaled nitric oxide in awake lambs with acute pulmonary hypertension

Oleg V. Evgenov,¹ Cornelius J. Busch,^1,2 Natalia V. Evgenov,³ Rong Liu,¹ Bodil Petersen,¹ George E. Falkowski,¹ Beata Peth,⁴ Ádám Vas,⁴ Kenneth D. Bloch,^1,2 Warren M. Zapol,¹ and Fumito Ichinose^1,2

¹Department of Anesthesia and Critical Care, ²Cardiovascular Research Center, and ³Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and ⁴Gedeon Richter Ltd., Budapest, Hungary

Submitted 30 December 2004 ; accepted in final form 7 November 2005

Phosphodiesterase 1 (PDE1) modulates vascular tone and the development of tolerance to nitric oxide (NO)-releasing drugs in the systemic circulation. Any role of PDE1 in the pulmonary circulation remains largely uncertain. We measured the expression of genes encoding PDE1 isozymes in the pulmonary vasculature and examined whether or not selective inhibition of PDE1 by vinpocetine attenuates pulmonary hypertension and augments the pulmonary vasodilator response to inhaled NO in lambs. Using RT-PCR, we detected PDE1A, PDE1B, and PDE1C mRNAs in pulmonary arteries and veins isolated from healthy lambs. In 13 lambs, the thromboxane A₂ analog U-46619 was infused intravenously to increase mean pulmonary arterial pressure to 35 mmHg. Four animals received an intravenous infusion of vinpocetine at incremental doses of 0.3, 1, and 3 mg·kg^–1·h^–1. In nine lambs, inhaled NO was administered in a random order at 2, 5, 10, and 20 ppm before and after an intravenous infusion of 1 mg·kg^–1·h^–1 vinpocetine. Administration of vinpocetine did not alter pulmonary and systemic hemodynamics or transpulmonary cGMP or cAMP release. Inhaled NO selectively reduced mean pulmonary arterial pressure, pulmonary capillary pressure, and pulmonary vascular resistance index, while increasing transpulmonary cGMP release. The addition of vinpocetine enhanced pulmonary vasodilation and transpulmonary cGMP release induced by NO breathing without causing systemic vasodilation but did not prolong the duration of pulmonary vasodilation after NO inhalation was discontinued. Our findings demonstrate that selective inhibition of PDE1 augments the therapeutic efficacy of inhaled NO in an ovine model of acute chemically induced pulmonary hypertension.

guanosine 3',5'-cyclic monophosphate; vinpocetine; sheep

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