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

Although it is clear that vascular endothelial cells synthesize and re lease endothelin (ET), the contribution of this vasoconstrictor peptid e to the regulation of vascular tone appears limited in normal conditi ons. One possibility to explain this moderate effect is that continuou s production of nitric oxide (NO) may permanently inhibit the release and the vasoconstrictor effects of ET. In these conditions, inhibition of NO synthesis might unmask a vasopressor response to ET. Thus, we t ested whether bosentan (3 mg/kg i.v.), a non-peptide antagonist of ET( A) and ET(B) receptors, or BQ-123 (3 mg/kg), an antagonist of ET(A) re ceptors, affected the hypertensive response induced by the NO synthase inhibitors N-G-nitro-L-arginine methyl ester (L-NAME 3 mg/kg) or N-G- nitro L-arginine (3 mg/kg) in anesthetized, normotensive rats. Bosenta n or BQ-123 did not affect blood pressure. L-NAME significantly increa sed mean arterial pressure (% increase from baseline : 25 +/- 5 %), an d this was reduced by bosentan (13 +/- 3 %; p < 0.05) or by BQ-123 (14 +/- 5 %; p < 0.01). In contrast, bosentan did not affect the presser response to phenylephrine. The response to L-NAME (3 mg/kg) was also r educed by bosentan in ganglion-blocked (chlorisondamine : 2.5 mg/kg; c ontrols 89 +/- 10; bosentan:45 +/- 7 %) or pithed rats (controls : 165 +/- 9; bosentan 85 +/- 12 %; p < 0.01). Bosentan also inhibited the p resser response to N-G-nitro L-arginine (3 mg/kg(-1)) in normal (contr ols 24 +/- 5, bosentan 10 +/- 3 %; p < 0.01) or ganglion-blocked rats (controls 86 +/- 13; bosentan 25 +/- 8; p < 0.01). Finally, L-NAME ind uced a modest increase in plasma levels of ET-1 (controls : 26.8 +/- 4 .1; L-NAME : 38.5 +/-: 3.3 pg/ml; p < 0.05). Thus, acute inhibition of NO synthesis unmasks a tonic vasopressor influence of ET.