Endothelin-1 stimulates contraction and ion transport in the rat colon: different mechanisms of action.
Endothelin-like immunoreactivity has been detected in all regions of the rat gastrointestinal tract. In the present study, we studied the effect of endothelin-1 (ET-1) on muscle contraction and ion transport in the rat colon. Isometric tension was recorded in colonic muscle strips oriented along their longitudinal axis. The effect of ET-1 on ion transport was investigated by assessing changes in short-circuit current in segments of muscle-stripped rat colon in Ussing chambers. ET-1 induced concentration-dependent contraction of the colon (EC50, 3 nM). The concentration-response curve to ET-1 was not modified by the neuronal blocker tetrodotoxin (0.1 microM) or by atropine (1 microM). Pretreatment of colon muscle strips with the calcium channel blockers diltiazem (0.1 microM) or nicardipine (1 microM) had no effect on the contractile response to ET-1. Furthermore, the response was not affected by removal of extracellular calcium. In the ion transport studies, serosal addition of ET-1 produced a transient, bumetanide (chloride secretion inhibitor) -sensitive, increase in transepithelial short-circuit current. The maximal increase was 107 +/- 13 microA/sq. cm, with an EC50 of 2.5 nM. The increase in short-circuit current evoked by ET-1 was not significantly affected by 1 microM atropine, but was reduced by 50% (P less than .05) by 1 microM tetrodotoxin, or removal of extracellular calcium. We conclude that ET-1 stimulates smooth muscle directly, whereas its effect on epithelial chloride secretion is mediated in part via the enteric nerves. Moreover, the effect of ET-1 in these two systems can be differentiated on the basis of sensitivity to extracellular calcium.
Moummi
C
C
Division of Gastrointestinal Diseases Research, Searle Research and Development, Skokie, Illinois.
Xie
Y
Y
Kachur
J F
JF
Gaginella
T S
TS
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D004347:Drug Interactions; D016232:Endothelins / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D013779:Tetrodotoxin / Q000494:pharmacology
D002121:Calcium Channel Blockers; D016232:Endothelins; D013779:Tetrodotoxin; D002118:Calcium