Inhibition of phosphodiesterase 1 augments the pulmonary vasodilator response to inhaled nitric oxide in awake lambs with acute pulmonary hypertension.
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 A(2) 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.
Evgenov
Oleg V
OV
Dept. of Anesthesia and Critical Care, Mass. General Hospital, Boston, MA 02114, USA. evgenov@etherdome.mgh.harvard.edu
Busch
Cornelius J
CJ
Evgenov
Natalia V
NV
Liu
Rong
R
Petersen
Bodil
B
Falkowski
George E
GE
Petho
Beata
B
Vas
Adám
A
Bloch
Kenneth D
KD
Zapol
Warren M
WM
Ichinose
Fumito
F
D000208:Acute Disease; D000280:Administration, Inhalation; D000818:Animals; D000831:Animals, Newborn; D001808:Blood Vessels / Q000503:physiopathology; D006152:Cyclic GMP / Q000378:metabolism; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D008168:Lung / Q000378:metabolism; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects; D011652:Pulmonary Circulation / Q000187:drug effects*; D012756:Sheep; D014664:Vasodilation / Q000187:drug effects*; D014748:Vinca Alkaloids / Q000008:administration & dosage / Q000494:pharmacology
D010726:Phosphodiesterase Inhibitors; D014748:Vinca Alkaloids; D009569:Nitric Oxide; C013983:vinpocetine; D010727:Phosphoric Diester Hydrolases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D006152:Cyclic GMP