IN-VIVO EVIDENCE OF AN ENDOTHELIN-INDUCED VASOPRESSOR TONE AFTER INHIBITION OF NITRIC-OXIDE SYNTHESIS IN RATS

Background Continuous production of nitric oxide (NO) from endothelial cells permanently inhibits the synthesis and the vasoconstrictor effe cts of endothelin. Thus, inhibition of NO synthesis might unmask a vas opressor response to endothelin. To assess whether endothelin contribu tes to the presser response induced by inhibition of NO synthesis, we tested whether bosentan, a nonpeptide antagonist of ET(A) and ET(B) en dothelin receptors, affected the hypertensive response in duced by the NO synthase inhibitor N-G-nitro L-arginine methyl ester (L-NAME). Met hods and Results Anesthetized rats received increasing doses of L-NAME (9.1 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 b lood pressure. L-NAME induced a dose-dependent increase in mean arteri al 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 selecti ve ET(A) antagonist BQ-123 (3 mg.kg(-1): controls, 25+/-4%; BQ-123, 14 +/-5%; P<.01). In contrast, bosentan did not affect the presser respon se to phenylephrine (1 to 100 mu g kg(-1)). The response to L-NAME (3 mg.kg(-1)) was also reduced by bosentan in ganglion-blocked (chlorison damine 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 presser response to another inhibitor of NO synthesis, N -G-nitro L-arginine (3 mg.kg(-1)) in normal (controls, 24+/-5%; bosent an, 10+/-3%; P<.01) or ganglion-blocked (controls, 86+/-13%; bosentan, 25+/-8%; P<.01) rats. Finally, L-NAME induced a modest increase in pl asma levels of endothelin-1 (controls, 26.8+/-4.1 pg mL(-1); L-NAME, 3 8.5+/-3.3 pg mL(-1); P<.05). Conclusions These experiments demonstrate that inhibition of NO synthesis unmasks a tonic presser influence of endothelin, suggesting that this peptide could play a major role in pa thophysiological situations associated with an impaired formation of N O.