Losartan antagonism of angiotensin-II-induced potassium secretion across rat colon.
The effect of angiotensin II (ANG II) on potassium transport across the short-circuited rat distal colon was investigated using 86Rb+ as a tracer for unidirectional K+ fluxes. The addition of high concentrations of ANG II (>/=10(-6) M) to the serosal bathing solution had no effect on the mucosal to serosal flux of Rb+, but significantly increased the serosal to mucosal flux and abolished the basal net absorptive Rb+ flux. These ANG-II-induced alterations in Rb+ transport were blocked by the AT1 receptor antagonist losartan and its metabolite EXP3174, which is also known to have AT1 receptor antagonistic activity. In contrast, an AT2 receptor antagonist, PD123319, did not prevent the alterations in colonic Rb+ transport induced by ANG II in vitro. At lower bath concentrations (10(-7) M to 10(-10) M ), ANG II had no measurable effects on Rb+ transport across this tissue but ANG II did have a bimodal effect on short-circuit current (Isc), indicating additional effects on the electrogenic transport of other ions. Dose-dependent reductions in Isc were observed between 10(-7) M (DeltaIsc=1.96+/-0.49 microEq.cm-2.h-1, n=6) and 10(-10) M (DeltaIsc=0.16+/-0.19 microEq.cm-2.h-1, n=7) ANG II, whereas Isc was increased at the higher concentrations (DeltaIsc= 3.36+/-0.52 microEq.cm-2.h-1, n=7, at 10(-4) M). The ANG-II-induced increases and decreases in Isc were both blocked by losartan but not by PD123319. These studies are the first to demonstrate an effect of ANG II on K+ transport across rat colon that is independent of aldosterone and mediated by AT1 receptors.
Department of Medicine, Division of Nephrology, University of California at Irvine, CA 92697, USA. mhatch@uci.edu
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Hatch
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Freel
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Vaziri
D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D005110:Extracellular Space / Q000737:chemistry; D006868:Hydrolysis; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D011188:Potassium / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012414:Rubidium Radioisotopes / Q000032:analysis / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D011725:Pyridines; D012414:Rubidium Radioisotopes; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; C066026:losartan carboxylic acid; D019808:Losartan; D011188:Potassium