Potentiation of pulmonary arteriolar vasoconstriction to endothelin-1 by inhibition of nitric oxide synthesis in the intact lung

Objective: To observe pulmonary arteriolar effects of endothelin-1 (ET-1) i n the intact lung and determine if constriction to ET-1 is potentiated by i nbibition of nitric oxide (NO) synthesis. Methods: In anesthetized male Spragrue-Dawley rats with open chest, the lun gs were ventilated with air through the lon-er trachea and in vivo response s of pulmonary arterioles were examined by video microscopy. Observations w ere made when the lungs were statically inflated with oxygen to a pressure of approximately 10 cm H2O for brief periods. A lens with a dipping cone wa s held at the pleural surface. ET-1 (10(-7)-10(-5)M; approximately 0.1 ml) was applied topically to the fluid layer under the dipping cone. Results: ET-1 (10(-6)M) constricted parent arterioles 60 +/- 5 mu m in diam eter by 52 +/- 12% (range: 20-100%) and branches 45 +/- 3 mu m in diameter by 36 +/- 4% (19-48%). Constriction persisted and there was a dramatic long -lasting decrease in flow. Alveolar walls quickly became pale, indicating r educed capillary perfusion. A lower concentration of ET-1 (10(-7)M) constri cted (p > 0.05) parent arterioles 61 +/- 4 mu m in diameter by 7 +/- 3% ini tially, and by 13 +/- 8% after 14 +/- 2 minutes, while smaller branches did not respond. In separate experiments, infusion of the NO synthase inhibito r L-NAME (1 mg/kg per mim-lte), modestly (10 +/- 3%) decreased (p < 0.05) b aseline parent arteriolar diameter from 72 +/- 7 mu m to 64 +/- 5 mu m. Bra nch diameter changed insignificantly from 42 +/- 7 mu m to 38 +/- 7 mu m. A fter L-NAME, ET-1 (10(-7) M) constricted (p < 0.05) parent arterioles by 17 +/- 4% initially and 40 +/- 14% after 14 +/- 2 minutes. Concurrently, bran ches constricted (p < 0.05) by 14 +/- 4% and 26 +/- 15%. Conclusions: Arterioles less than 80 mu m in diameter were very responsive to ET-1. which could be a factor in altering pulmonary microvascular resist ance. Inhibition of NO synthesis appears to potentiate constriction to ET-1 .