Acute renal response to the non-peptide vasopressin V2-receptor antagonist SR 121463B in anesthetized rats.
Vasopressin V2-receptor antagonists are promising agents for the use in water-retaining diseases. Potential renal mechanisms of action include effects on water permeability in the collecting duct as well as on electrolyte transport in the thick ascending limb of Henle's loop (TALH). To elucidate sites of action upstream of the distal tubule, e.g., in TALH, micropuncture experiments were performed in anesthetized rats during application of the V2-receptor antagonist SR 121463B. As compared to vehicle-treated rats, SR 121463B (0.3 mg/kg i.v.) did not affect mean arterial blood pressure (means +/- SEM, n=10 rats per group: 108+/-4 mmHg vs. 107+/-4 mmHg), whole kidney GFR (1.1+/-0.1 ml/min vs. 1.1+/-0.1 ml/min), or whole kidney fractional reabsorption (FR) of potassium (66+/-5% vs. 68+/-4%). The drug, however, reduced whole kidney FR of fluid (92+/-1% vs. 99+/-1%), increased urinary flow rate (84+/-7 microl/min vs. 8+/-1 microl/min) and electrolyte-free-water clearance (72+/-8 microl/min vs. 2+/-1 microl/min), and reduced urinary osmolality (148+/-11 mosmol/kg vs. 1,200+/-185 mosmol/kg). This pronounced diuretic response was associated with a minor reduction in whole kidney FR of sodium (99.6+/-0.1% vs. 99.9+/-0.1%) and chloride (98.3+/-0.2% vs. 98.9+/-0.1%). As compared to vehicle application, SR 121463B did not significantly alter single nephron GFR (39+/-2 nl/min vs. 39+/-1 nl/min, n=22 and 23 nephrons, respectively) or the FR up to the early distal tubule of fluid (76+/-2% vs. 76+/-1%), sodium (92+/-1% vs. 93+/-1%), potassium (91+/-1% vs. 90+/-1%) or chloride (90+/-1% vs. 91+/-1%). Together these data indicate a predominant aquaretic effect of SR 121463B which is located downstream of the early distal tubule. This response is compatible with blockade of vasopressin V2-receptors in the collecting duct and, as directly demonstrated by immunohistochemistry, subsequent retrieval of aquaporin-2 from apical plasma membrane, which inhibits water permeability and transport.
Huang
D Y
DY
Department of Pharmacology, University of Tübingen, Germany.
Pfaff
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Serradeil-Le Gal
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Vallon
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D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins / Q000187:drug effects* / Q000378:metabolism; D004231:Diuresis / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D011677:Punctures; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology*
D065092:Antidiuretic Hormone Receptor Antagonists; C496025:Aqp2 protein, rat; D051399:Aquaporin 2; D051403:Aquaporin 6; D020346:Aquaporins; D009025:Morpholines; D013141:Spiro Compounds; D012964:Sodium; C103281:satavaptan