PT  - JOURNAL ARTICLE
AU  - Willette, Robert N.
AU  - Ohlstein, Eliot H.
AU  - Mitchell, Marcus P.
AU  - Sauermelch, Charles F.
AU  - Beck, George R.
AU  - Luttmann, Mark A.
AU  - Hay, Douglas W. P.
TI  - Nonpeptide Endothelin Receptor Antagonists. VIII: Attenuation of Acute Hypoxia-Induced Pulmonary Hypertension in the Dog
DP  - 1997 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 695--701
VI  - 280
IP  - 2
4099  - http://jpet.aspetjournals.org/content/280/2/695.short
4100  - http://jpet.aspetjournals.org/content/280/2/695.full
SO  - J Pharmacol Exp Ther1997 Feb 01; 280
AB  - 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 ETAand 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. The American Society for Pharmacology and Experimental Therapeutics