Biphasic effects of endothelin in the guinea-pig ileum

The intestinal effects of porcine endothelin (ET-1), a potent endothelium-derived vasoconstrictor, were studied on the guinea-pig isolated ileum. ET-1 (3 x 10(-10)-3 x 10(-7) M) caused biphasic responses on spontaneous smooth muscle tone, an initial relaxation followed by a late contraction. The contractile response was elicited in a concentration-dependent manner. Both the relaxing and contractile phases were not affected by pretreatment with tetrodotoxin, phentolamine, tolazoline, propranolol, guanethidine, 8-phenyl-theophylline, naloxone, methylsergide, [D-Pro4,D-Try7,9]SP-(4-11), diphenylhydralamine and indomethacin. Atropine (3 x 10(-7) M) also had no effect on the ET-1-induced contraction. The ET-1-induced contraction, however, was markedly inhibited by verapamil (greater than 10(-8) M) and H-7 (3 x 10(-5) M). These results suggest that, in intestinal smooth muscle, ET-1-induced contraction can be attributed to the direct effect on muscle and appears to be mediated by increased Ca2+ influx through voltage-dependent Ca2+ channels as well as protein kinase C activation. On the other hand, ET-1-induced relaxation is due neither to the indirectly evoked release of inhibitory neurotransmitters nor to the direct activation of adrenoceptors, and purine and opiate receptors. The exact mechanism responsible for ET-1-induced relaxation needs to be further studied.