Endothelin modulation of neuroeffector transmission in smooth muscle

In a series of muscle preparations, the peptides endothelin-1 (ET-1) and endothelin-3 (ET-3) were investigated for effects on basal muscle tone, responses to transmural nerve stimulation, and release of [3H]norepinephrine or [3H]acetylcholine. ET-1 and ET-3 contracted rat vas deferens and guinea pig ileum, ET-1 being the most potent. In the guinea pig taenia coli, ET-1 induced a relaxation whereas ET-3 was almost without relaxing effect. In the rat vas deferens, ET-1 and ET-3 enhanced contractile responses to nerve stimulation, whereas the nerve-induced release of [3H]norepinephrine was inhibited by ET-1 but not by ET-3. Contractions to exogenous ATP were increased by ET-1 whereas contractions to norepinephrine were not. In the guinea pig ileum, nerve-induced contractions were inhibited by ET-1 and ET-3 as was acetylcholine release, whereas contractions to exogenous acetylcholine were enhanced by ET-1. The inhibition of nerve-induced contractions by the endothelins was not affected by treatment with 8-(p-sulfophenyl)theophylline, BW755C, or indomethacin. The relaxation by ET-1 in the guinea pig taenia coli was not affected by treatment with NG-monomethyl-L-arginine, BW755C, or indomethacin. In conclusion, ET-1 exerted a stimulatory postjunctional effect and concomitantly an inhibitory prejunctional effect on adrenergic and cholinergic neurotransmission. Also, ET-3 exerted a stimulatory postjunctional effect, whereas a prejunctional inhibitory effect of ET-3 only was evident on cholinergic neurotransmission. Blockade of the production of nitric oxide or arachidonic acid metabolites or application of an adenosine antagonist did not alter the effects of ET-1 or ET-3.