Chronically elevated endothelin levels reduce pulmonary vascular reactivity to nitric oxide

Although local tissue activation of the endothelin (ET) system contributes to the development of pulmonary hypertension, the impact of isolated chronic plasma hyperendothelinemia on the pulmonary circulation is unknown. METHODS: Mini-osmotic pumps were implanted in rats to deliver ET-1 during 7 or 28 days. After in vivo hemodynamics, the lungs were isolated to derive pressure-flow relations. Small pulmonary arteries ( approximately 250 microm) were mounted on an isometric myograph to study their reactivity. RESULTS: Plasma ET-1 approximately doubled (p < 0.05) after 7 and 28 days. Lung tissue ET-1 level increased fourfold after 7 days (p < 0.001) but was no longer significantly elevated after 28 days. Right ventricular systolic pressure was unaffected. The pulmonary pressure-flow relation shifted upward with a steeper slope (p < 0.05) at 7 days, but not after 28 days. Maximum dilatations to both acetylcholine (p < 0.01) and sodium nitroprusside (p < 0.001) were greatly reduced by approximately 50% after 28 days and were normalized by the addition of the nitric oxide synthase inhibitor L-NNA and the antioxidant N-acetyl-L-cysteine, respectively. CONCLUSION: Chronic hyperendothelinemia reduces the pulmonary vasodilator reserve in response to nitric oxide. Correction by an antioxidant and L-NNA suggests that this relates to increased production of reactive oxygen species, which may have clinical relevance for conditions associated with chronic increase of ET. Further studies are required to determine if, in the long term, this could contribute to the development of pulmonary hypertension.