Endothelin-1 Does Not Mediate the Endothelium-Dependent Hypoxic Contractions of Small Pulmonary Arteries in Rats

¹ From the Institute of Pathophysiology, University Hospital; the Institute of Physiology, University of Lausanne; and the Division of Hypertension, University Hospital, Lausanne, Switzerland

Various pulmonary artery preparations in vitro demonstrate sustained endothelium-dependent contractions upon hypoxia. To determine whether endothelin-1 could mediate this phenomenon, we examined the effect of bosentan, a new antagonist of both the ETA and ETB subtypes of the endothelin receptor. Small (300 µm) pulmonary arteries from rats were mounted on a myograph, precontracted with prostaglandin F₂, and exposed to hypoxia (Po₂, 10 to 15 mm Hg, measured on-line) for 45 min. Endothelium-intact control rings exhibited a biphasic response, with a transient initial vasoconstriction (phase 1) followed by a second slowly developing sustained contraction (phase 2). Expressed in percent of the maximal response to 80 mmol/L KCl, the amplitudes of phase 1 (peak tension) and 2 (tension after 45 min of hypoxia) averaged 37±12% and 17±14%, respectively (n= 11). In endothelium-denuded rings, phase 1 persisted while the amplitude of phase 2 was reduced to 2±12% (p<0.05, n=8), showing the endothelium dependence of this contraction. Neither phase was significantly decreased in rings treated with 10⁵ mmol/L bosentan (38±15% and 17±12%, respectively, n=6). The Po₂ threshold for onset of hypoxic contraction was not significantly different among these three groups and averaged 32±24 mm Hg. In a separate experiment, we assessed the inhibitory effect of 10⁵ mol/L bosentan on the response to 10⁸ mol/L endothelin-1. Rings treated for 45 min with 10⁸ mol/L endothelin-1 alone exhibited a maximal contraction of 75±27% (n=6). This was reduced to 4±17% (p<0.01, n=6) in rings treated with both 10⁸ mol/L endothelin-1 and 10⁵ mol/L bosentan. We conclude that complete blockade of all endothelin receptor subtypes has no effect on either endothelium-dependent or -independent hypoxic contractions in this preparation. This suggests that endothelial factors other than endothelin-1 mediate the acute hypoxic contractions of small pulmonary arteries in the rat.

Key Words: bosentan • endothelin receptor antagonists • endothelium-derived contracting factor • hypoxic pulmonary • vasoconstriction • isolated small pulmonary artery

Submitted on September 27, 1995
Accepted on January 11, 1996

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