Intestinal relaxation by endothelin isopeptides: involvement of Ca(2+)-activated K+ channels.
Our previous studies have shown that endothelin-1 (ET-1) induces an initial relaxation followed by a contraction in the guinea-pig ileum. To test whether other ET isopeptides (ET-2, ET-3, vasoactive intestinal contractor (VIC) and sarafotoxin S6b) and big ET-1, the ET-1 precursor, also induce similar biphasic responses, we compared their effects in isolated guinea-pig ileum. In addition, the mechanism of initial relaxation was studied. At 1-100 nM, ET-1, ET-2 and VIC were equipotent in producing the biphasic responses. S6b also produced similar biphasic responses, except that only a relaxation was elicited at 1 nM. ET-3 was approximately 30- to 100-fold less active than ET-1 in producing the contraction, whereas it was as potent as ET-1 in producing relaxation. Big ET-1 induced a relaxation of slower onset and longer duration, followed by a weak contraction at concentrations higher than 30 nM. The initial relaxation produced by ET-1 was not affected by pretreatment with L-NAME (NW-nitro-L-arginine methyl ester), hemoglobin, 9-AC (anthracene-9-carboxylic acid), SITS (4-acetamido-4'-isothiocyanatostilbene-2-2'-disulfonic acid), glibenclamide, ouabain, phorbol 12,13-dibutyrate, sodium nitroprusside, human atrial natriuretic peptide (hANP) or forskolin, whereas it was abolished by pretreatment with apamin. Although phorbol 12,13-dibutyrate pretreatment had no significant effect on the biphasic response of ET-1, it rapidly reversed the sustained contraction produced by ET-1. These results indicate that the initial relaxation is caused by the activation of Ca(2+)-activated K+ channels.
Lin
W W
WW
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei.
Lee
C Y
CY
D000818:Animals; D001030:Apamin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D016232:Endothelins / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007422:Intestines / Q000187:drug effects*; D009119:Muscle Contraction / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects*; D014757:Viper Venoms / Q000494:pharmacology*
D016232:Endothelins; D015221:Potassium Channels; D014757:Viper Venoms; C057354:sarafotoxins s6; D001030:Apamin; D002118:Calcium