Moxonidine inhibits Na+/H+ exchange in proximal tubule cells and cortical collecting duct.
The imidazoline receptor agonist moxonidine has been recently introduced as an antihypertensive therapy. Imidazoline specific binding sites have also been found in the kidney. Moxonidine induced natriuresis and diuresis in clearance studies in rats. Related substances such as various guanidinium derivatives have been shown to inhibit Na+/H+ exchange in several preparations. We therefore examined whether the renal effects of moxonidine could be mediated by an inhibition of the Na+/H+ exchanger. Intracellular pH (pHi) was measured microfluorimetrically with BCECF in proximal LLC-PK1 cells and in the principal cells of rat cortical collecting ducts (CCD). In LLC-PK1 cells moxonidine (10 mumol/liter) had no effect on the basal pH1; however, it reduced the Na+/H+ activity reversibly by 43 +/- 4% (N = 26) when the exchanger was activated by cellular acidification. In rat CCD cells moxonidine slightly decreased basal pHi by 0.08 +/- 0.03 pH units (N = 12). After acidification the recovery rate of pHi was reduced with moxonidine by 45 +/- 6% (N = 18). The effects of moxonidine could be mimicked in both cell types by inhibitors of the Na+/H+ exchanger (HOE 694, amiloride). In the presence of the imidazoline receptor antagonist idazoxan (10 mumol/liter) the effects of moxonidine were almost completely inhibited. The alpha 2-antagonist yohimbine (10 mumol/liter) did not significantly alter the effects of moxonidine in both cell types. These data suggest that in LLC-PK1 and in rat CCD cells, Na+/H+ is inhibited by moxonidine via an activation of the imidazoline receptor.
Schlatter
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Westfälische Wilhelms-Universität Münster, Medizinische Poliklinik, Germany. schlate@uni-muenster.de
Ankorina-Stark
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Haxelmans
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Hohage
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H
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D005260:Female; D005452:Fluoresceins; D005456:Fluorescent Dyes; D006146:Guanidines / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D019329:Idazoxan / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D007685:Kidney Tubules, Collecting / Q000737:chemistry* / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000737:chemistry* / Q000187:drug effects; D018374:LLC-PK1 Cells; D051381:Rats; D017208:Rats, Wistar; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology; D013552:Swine; D015016:Yohimbine / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D005452:Fluoresceins; D005456:Fluorescent Dyes; D006146:Guanidines; D007093:Imidazoles; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C074107:3-methylsulfonyl-4-piperidinobenzoyl guanidine; D015016:Yohimbine; C043829:2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein; C043482:moxonidine; D019329:Idazoxan