Regulation of ion transport by endothelins in rat colonic mucosa: effects of an ETA antagonist (FR139317) and an ETB agonist (IRL1620).
Rat colonic mucosa contains ETA and ETB receptors with Kd values for endothelin (ET)-1 of 32 and 11 pM and maximal binding capacities of 277 and 181 fmol/mg protein, respectively. In muscle-stripped rat colon without tonic nerve activity in Ussing chambers, the serosal addition of ET-1, ET-3 and IRL1620 inhibited amiloride-sensitive noncoupled Na+ entry and enhanced diphenylamine-2-carboxylate-sensitive Cl- secretion, producing a sustained decrease and a transient increase in the short-circuit current (Isc) and the transepithelial conductance, respectively. EC50 values of ET-1, ET-3 and IRL1620 and the maximal changes in Isc were 2.0, 10.2 and 10.9 nM and -12.7, -7.0 and -7.1 muA/cm2, respectively for the Na+ entry; these values were 50, 220 and 225 nM and +57.3, +47.3 and +21.3 muA/cm2, respectively, for the Cl- secretion. FR139317 (100 nM) inhibited ET-1-induced Na+ and Cl- movements, shifting the concentration-response curves to the right (EC50 = 25 nM and 1 microM, respectively), and inhibited ET-3 (> 100 nM)-induced Cl- movement, decreasing the maximal response to 35%, but it did not inhibit either ET-3-induced Na+ movement nor IRL1620-induced Na+ and Cl- movements. The removal of serosal Ca++ reduced 100 nM ET-1- and IRL1620-evoked changes in Isc by 50% and 70% for the Na+ entry and by 80% and 100% for the Cl- secretion, respectively. Indomethacin (1 microM) also reduced changes in Isc by 30% and 70% for the Cl- secretion but did not affect the Na+ entry. Our results show that ETA and ETB receptors regulate Na+ and Cl- transport by different mechanisms.
Hosokawa
M
M
Department of Internal Medicine (1st Division), Faculty of Medicine, Kyoto University, Japan.
Tsukada
H
H
Ueda
S
S
Sakai
M
M
Okuma
M
M
Oda
K
K
Takimoto
M
M
Okada
T
T
Urade
Y
Y
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology* / Q000502:physiology*; D007211:Indoles / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism
D001381:Azepines; D002712:Chlorides; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007211:Indoles; D010446:Peptide Fragments; C074308:sovateltide; C079574:FR 139317; D012964:Sodium; D002118:Calcium; D007213:Indomethacin