ROLE OF ENDOTHELIN AND NITRIC-OXIDE IMBALANCE IN THE PATHOGENESIS OF HYPOXIA-INDUCED ARTERIAL-HYPERTENSION

Background. We have recently demonstrated that prolonged hypobaric hyp oxia can lead to a hematocrit-independent sustained arterial hypertens ion (HTN) in genetically normotensive Sprague-Dawley rats. The rise in blood pressure in the hypoxic animals was accompanied by a marked but transient increase in plasma endothelin level. In addition, hypoxia h as been shown to decrease nitric oxide (NO) production by cultured end othelial cells. This study was designed to lest the hypothesis that hy poxia-induced HTN may be mediated by increased endothelin and/or decre ased NO production. Methods. Blood pressure, plasma endothelin and uri nary NO metabolites (NOx) were monitored in rats during a 24-day expos ure to hypobaric hypoxia (air pressure = 390 mm Hg). The results were compared with those obtained in animals maintained under normoxic cond ition (control group). To test the possible role of excess endothelin and depressed NO production, the studies were repeated using subgroups of animals treated with either an endothelin receptor ET-A/B blocker (L-754,142) or L-arginine. Results. The untreated hypoxic fall in urin ary NOx, prior to the onset plasma endothelin and a threefold of HTN. Endothelin receptor blockade led to a further fall in urinary NOx excr etion and failed to mitigate HTN. In contrast, L-arginine supplementat ion improved the urinary NOx excretion and prevented HTN. Neither ther apy affected the hypoxia-induced erythrocytosis. Conclusions. We concl ude that hypoxia-induced HTN is associated with depressed NO productio n and can be mitigated by L-arginine supplementation.