(Circulation. 1995;91:771-775.)
© 1995 American Heart Association, Inc.
Articles |
In Vivo Evidence of an Endothelin-Induced Vasopressor Tone After Inhibition of Nitric Oxide Synthesis in Rats
From the Department of Pharmacology, VACOMED, IFRMP, Rouen University Medical School and Rouen University Hospital, France (V.R., M.H., C.T.), and the Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland (M.C., B-M.L.).
Correspondence to Vincent Richard, PhD, Service de Pharmacologie, Hôpital de Bois Guillaume, CHU de Rouen, 76031 Rouen CEDEX, France.
Background Continuous production of nitric oxide (NO) from endothelial cells permanently inhibits the synthesis and the vasoconstrictor effects of endothelin. Thus, inhibition of NO synthesis might unmask a vasopressor response to endothelin. To assess whether endothelin contributes to the pressor response induced by inhibition of NO synthesis, we tested whether bosentan, a nonpeptide antagonist of ETA and ETB endothelin receptors, affected the hypertensive response induced by the NO synthase inhibitor NG-nitro L-arginine methyl ester (L-NAME).
Methods and Results Anesthetized rats received increasing doses of L-NAME (0.1 to 3 mg · kg-1) in the absence or the presence of bosentan (3 mg · kg-1 IV 15 minutes before L-NAME). Bosentan itself did not affect blood pressure. L-NAME induced a dose-dependent increase in mean arterial pressure (percent increase from baseline after 3 mg · kg-1, 25±5%), and this was reduced by bosentan (13±3%; P<.05) or by the selective ETA antagonist BQ-123 (3 mg · kg-1: controls, 25±4%; BQ-123, 14±5%; P<.01). In contrast, bosentan did not affect the pressor response to phenylephrine (1 to 100 µg · kg-1). The response to L-NAME (3 mg · kg-1) was also reduced by bosentan in ganglion-blocked (chlorisondamine 2.5 mg · kg-1: controls, 89±10%; bosentan, 45±7%) or pithed rats (controls, 165±9%; bosentan, 85±12%; P<.01). Bosentan also inhibited the pressor response to another inhibitor of NO synthesis, NG-nitro L-arginine (3 mg · kg-1) in normal (controls, 24±5%; bosentan, 10±3%; P<.01) or ganglion-blocked (controls, 86±13%; bosentan, 25±8%; P<.01) rats. Finally, L-NAME induced a modest increase in plasma levels of endothelin-1 (controls, 26.8±4.1 pg · mL-1; L-NAME, 38.5±3.3 pg · mL-1; P<.05).
Conclusions These experiments demonstrate that inhibition of NO synthesis unmasks a tonic pressor influence of endothelin, suggesting that this peptide could play a major role in pathophysiological situations associated with an impaired formation of NO.
Key Words: endothelin • endothelium-derived factors • blood pressure
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