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Endogenous endothelins and nitric oxide in hypoxic pulmonary vasoconstriction

¹ Laboratory of Physiology, Faculty of Medicine, Free University of Brussels, and ² Dept of Intensive Care, Erasme University Hospital, Brussels, Belgium

CORRESPONDENCE: M. Leeman, Dept of Intensive Care, Erasme University Hospital, 808, Lennik road, B-1070, Brussels, Belgium. Fax: 32 25556713. E-mail: marc.leeman@ulb.ac.be

Keywords: endothelins, hypoxic pulmonary vasoconstriction, nitric oxide, pulmonary hypertension

Received: March 28, 2002
Accepted August 16, 2002

This study was supported by grant n° 3.4567.00 from the Fonds de la Recherche Scientifique Médicale (Belgium).

The effects of endothelin receptor blockade on the pulmonary circulation have been reported variably, possibly in relation to a more or less important associated release of endogenous nitric oxide (NO). The aim of this study was to test whether endothelin antagonism would inhibit hypoxic pulmonary vasoconstriction, and if it would not, then would it do so after NO synthase inhibition.

Hypoxic pulmonary vasoconstriction (HPV) was evaluated in anesthetised dogs by the increase in the mean pulmonary artery pressure (P_pa) minus occluded P_pa (P_pao) gradient in response to hypoxia (inspiratory oxygen fraction of 0.1) at constant pulmonary blood flow.

Bosentan, an endothelin A and B receptor antagonist, did not affect baseline P_pa, P_pao or systemic arterial pressure (P_sa) and did not alter HPV (n=8). The NO synthase inhibitor N^G­nitro-L-arginine (L-NA) did not affect baseline P_pa and P_pao, but increased P_sa and enhanced HPV (n=12). The addition of bosentan in these dogs did not affect baseline P_pa or P_pao, but decreased P_sa and inhibited HPV. Exhaled NO was decreased by L-NA and by bosentan and abolished by L-NA+bosentan (n=9).

The authors conclude that endogenous nitric oxide is released by, and opposes the vasoconstricting effects of, endothelins in vivo, reducing systemic blood pressure and limiting hypoxic pulmonary vasoconstriction.

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