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Vol. 280, Issue 2, 695-701, 1997
Departments of
Cardiovascular and Pulmonary Pharmacology (M.A.L.,
D.W.P.H.), SmithKline Beecham Pharmaceuticals, King of Prussia,
Pennsylvania
It has been proposed that endothelin-1 (ET-1), a potent endogenous
vasoactive peptide, may play an important role in the regulation of
pulmonary blood flow. The purpose of the present study was to
characterize the effects of ET-1 and a nonpeptide mixed ETA and ETB receptor antagonist, SB 209670, in isolated
segments of the canine pulmonary artery and to examine the effects of
SB 209670 in a canine model of acute hypoxia-induced pulmonary
hypertension. In isolated segments of the pulmonary artery, SB 209670 (3-300 nM) produced a concentration-dependent antagonism of
contraction elicited by ET-1 (pA2 = 8.9; slope = 0.9)
and had no effect on phenylephrine responses. In addition, SB 209670 antagonized the small, endothelium-dependent relaxation induced by
sarafotoxin 6c in phenylephrine (10 µM)-precontracted vessels
(pKB = 8.6). In anesthetized dogs, the driving pressure
across the pulmonary circulation increased approximately 100% during
the hypoxic period (area under the curve [AUC] = 267.1 ± 25.3 mm Hg·min). SB 209670 treatment (3 and 30 µg/kg/min i.v.) reduced
pulmonary vascular resistance and produced a profound dose-related
inhibition of hypoxia-induced pulmonary hypertension (AUC = 158.3 ± 22.7 mm Hg·min and 50.1 ± 4.9 mm Hg·min,
respectively). None of the other hemodynamic or arterial blood gas
parameters differed significantly in the vehicle and treatment groups.
In addition, SB 209670 produced a significant reversal of
hypoxia-induced pulmonary hypertension (AUC = 267.1 ± 25.3 mm Hg·min vs. 167.8 ± 23.4 mm Hg·min) when administered at the plateau of the hypoxic response. It was found that
SB 209670 administration significantly elevated plasma levels of
ET-1-LI (
25-fold). These results suggest that ET-1 is an important mediator of hypoxia-induced pulmonary hypertension in the dog and that
SB 209670, a potent and selective mixed ETA and
ETB receptor antagonist in the pulmonary circulation, may
represent an important therapeutic approach to the treatment of
pulmonary hypertension.
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