DUAL EFFECTS OF ENDOTHELINS-1, ENDOTHELINS-2 AND ENDOTHELINS-3 ON GUINEA-PIG FIELD-STIMULATED ILEUM - POSSIBLE MEDIATION BY 2 RECEPTORS COUPLED TO PERTUSSIS TOXIN-INSENSITIVE MECHANISMS

This study compared the effects of endothelin-1 (ET-1), ET-2 and ET-3 on the guinea pig field-stimulated ileum. All ETs (0.330 nM) caused graded inhibitions of nerve-mediated responses followed by sustained contractions. The rank order of potencies for the twitch depressor effect (IC50s) was ET-3 = ET-1 > ET-2, with ET-3 causing greater maximal inhibition than ET-1 or ET-2. The rank order of potencies for contraction (EC50s) was ET-1 = ET-2 > ET-3, with ET-1 causing greater maximal contraction than ET-2 or ET-3. Twitch inhibition by ET-1 (3 nM) was unaffected by indomethacin (5.6-mu-M), cromakalim (10-mu-M), glibenclamide (3-mu-M) or nicardipine (0.1-mu-M). ET-1 -induced contraction was unaltered by tetrodotoxin (0.3-mu-M), atropine (0.3-mu-M) or glibenclamide, but was reduced by indomethacin. Cromakalim and nicardipine virtually abolished ET-1-induced contraction. ET-1 (p to 30 nM) did not potentiate submaximal contractions induced by acetylcholine, histamine, bradykinin or substance P. ET-3 relaxed ileal segments precontracted with either acetylcholine (0.3-mu-M) or histamine (1-mu-M). Pretreatment of guinea pigs with pertussis toxin (50-mu-g/kg i.p., 6 days beforehand) did not influence either effects of ET-1 on the field-stimulated ileum. Our data suggest that the dual effects of ETs on the guinea pig isolated ileum are mediated by distinct receptors and possibly involve different mechanisms of action. The transient inhibition of responses to field stimulation seems unrelated to activation of ATP-sensitive potassium channels and is rather insensitive to L-type Ca++ channel blockade. In contrast, the contractile effect of the ETs is modulated by generation of cyclooxygenase products of arachidonic acid and depends largely on influx of extracellular Ca++ through nicardipine-sensitive L-type channels, possibly subsequent to depolarization of smooth muscle. As ETs are present in the intestine, the current findings suggest they may have physiological roles in controlling intestinal functions. The guinea pig ileum, with its intrinsic nerves and multiple ET receptors, may constitute a valuable preparation in which to analyze various aspects of ET pharmacology.