Pre- and postjunctional modulation by endothelin-1 of the adrenergic neurogenic response in canine mesenteric...

Transmural electrical stimulation (5-30 Hz) produced a frequency-dependent increase in the perfusion pressure of isolated, perfused dog mesenteric artery segments, which was suppressed by prazosin and abolished by tetrodotoxin. Treatment with endothelin-1 in low concentrations (10(-10) and 3 x 10(-10) M) inhibited the response to electrical nerve stimulation. The effect was not affected by NG-nitro-L-arginine, indomethacin and removal of the endothelium. The endothelin-1-induced inhibition was antagonized by 10(-7) M BQ123[cyclo(D-Trp-D-Asp-L-Pro-D-Val-L-Leu-)sodium], an endothelin ETA receptor antagonist, but not by 10(-5) M BQ788 [N-cis-2,6-dimethyl-piperidinocarbonyl-L- gamma-methylleucyl-D-1-methoxycarbonyltryptophanyl-D-norleuc ine], an antagonist of endothelin ETB1 and ETB2 receptors. IRL1620 [Suc-[Glu9, Ala11,15]endothelin-1-(8-21)], a selective endothelin ETB1 receptor agonist, did not alter the response to electrical stimulation. However, raising the concentration of endothelin-1 to 10(-9) M or higher potentiated the response. Similar results were also obtained in mesenteric artery strips in response to electrical stimulation. Endothelin-1 at low concentrations did not alter the contraction caused by exogenous norepinephrine in the artery strips, whereas the peptide at high concentrations potentiated the response. 3H-overflow evoked by transmural electrical stimulation from tissues prelabeled with [3H]norepinephrine was decreased by endothelin-1 (3 x 10(-10) M) in the superfused dog mesenteric arteries. It is concluded that endothelin-1 at low concentrations activates prejunctional endothelin ETA receptors and inhibits adrenergic nerve-mediated contractions by an inhibition of amine release, whereas the peptide at high concentrations potentiates the neurally induced contractions by a postjunctional enhancement, via endothelin ETA receptors, of the action of norepinephrine. Low concentrations of endothelin-1 appear to act as a vasodilator in adrenergically innervated mesenteric artery