RT Journal Article
SR Electronic
T1 Effect of Hydroxyeicosatetraenoic Acids on Furosemide-Sensitive Chloride Secretion in Rat Distal Colon
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 133
OP 138
VO 295
IS 1
A1 Markus Wegmann
A1 Antje Kämpen
A1 Susanne Weber
A1 Hannsjörg W. Seyberth
A1 Arnold Köckerling
YR 2000
UL http://jpet.aspetjournals.org/content/295/1/133.abstract
AB Arachidonic acid metabolites such as prostaglandins, thromboxanes, and leukotrienes are well known modulators of intestinal vascular perfusion, motility, and electrogenic ion transport. We investigated the effect of different hydroxyeicosatetraenoic acids (HETEs) from cytochrome P450- and lipoxygenase-dependent arachidonate metabolism on electrogenic chloride secretion in rat distal colon. Using conventional Ussing techniques, basolateral 12-HETE significantly decreased basal short-circuit current (Isc) and inhibited furosemide-sensitive Cl− secretion stimulated by either dibutyryl cAMP, prostaglandin E2, or theophylline in a concentration-dependent manner (IC50 = 1.5 nM). These data were underlined by significant inhibition of JnetCl in unidirectional 36Cl flux measurements. Direct regulation of the basolateral Na+-K+-2Cl− cotransporter or the Na-K-ATPase could be excluded because 12-HETE had no effect on furosemide-sensitive K+ secretion induced by epinephrine, or ouabain-sensitive Na+ reabsorption stimulated by aldosterone. Inhibitors of Ca2+-activated and voltage-gated K+ channels such as apamin, charybdotoxin, and dendrotoxin did not affect secretagogue-dependent Isc and its regulation by 12-HETE. In contrast, glibenclamide significantly attenuated the effect of 12-HETE on secretagogue-induced Isc, whereas chromanol 293B, an inhibitor of cAMP-dependent K+ conductance, had an additive effect. We speculate that 12-HETE, like glibenclamide, affects intestinal Cl−secretion by inhibiting basolateral K+ATPchannels. In contrast to these findings, neither 5-HETE nor 20-HETE had any effect on basal Isc or cAMP-dependent Cl−secretion. The American Society for Pharmacology and Experimental Therapeutics