Dy. Huang et al., Acute renal response to the non-peptide vasopressin V-2-receptor antagonist SR 121463B in anesthetized rats, N-S ARCH PH, 362(3), 2000, pp. 201-207
Vasopressin V-2-receptor antagonists are promising agents for the use in wa
ter-retaining diseases. Potential renal mechanisms of action include effect
s on water permeability in the collecting duct as well as on electrolyte tr
ansport in the thick ascending limb of Henle's loop (TALH). To elucidate si
tes of action upstream of the distal tubule, e.g., in TALH, micropuncture e
xperiments were performed in anesthetized rats during application of the V-
2-receptor antagonist SR 121463B. As compared to vehicle-treated rats, SR 1
21463B (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 rea
bsorption (FR) of potassium (66+/-5% vs. 68+/-4%). The drug, however, reduc
ed whole kidney FR of fluid (92+/-1% vs. 99+/-1%), increased urinary now ra
te (84+/-7 mu l/min vs. 8+/-1 mu l/min) and electrolyte free-water clearanc
e (72+/-8 mu l/min vs. 2+/-1 mu l/min), and reduced urinary osmolality (148
+/-11 mosmol/kg vs. 1200+/-185 mosmol/kg). This pronounced diuretic respons
e 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 comp
ared 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, respect
ively) 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 chlori
de (90+/-1% vs. 91+/-1%). Together these data indicate a predominant aquare
tic effect of SR 121463B which is located downstream of the early distal tu
bule. This response is compatible with blockade of vasopressin V-2-receptor
s in the collecting duct and, as directly demonstrated by immunohistochemis
try, subsequent retrieval of aquaporin-2 from apical plasma membrane, which
inhibits water permeability and transport.