An enhanced effect of arginine vasopressin in bradykinin B-2 receptor nullmutant mice

Under water restriction, arginine vasopressin (AVP) is released and promote s water reabsorption in the distal nephron, mainly through AVP V-2-receptor s, It has been proposed that renal kinins counteract the hydro-osmotic effe ct of AVP. We hypothesized that kinins acting through B-2 receptors antagon ize the urinary concentrating effect of AVP. To test this, bradykinin B-2 r eceptor knockout mice (B-2-KO) and 129/SvEv mice (controls) were placed in metabolic cages and urine collected for 24 hours (water ad libitum), After that, urine was again collected from the same mice during 24 hours of water restriction. Urinary volume (UV), urinary osmolarity (UOsm), and urinary N a+ (UNaV) and K+ (UKV) excretion were determined. On water restriction, UV in controls decreased by approximate to 25%, whereas in B-2-KO mice there w as almost a 60% drop in urinary output (P=0.001 versus controls). In the co ntrols, water restriction increased UOsm by 347 mOsm/kg H2O, approximate to 14% above baseline (NS), whereas in knockout mice the increase was 3 times that seen in the controls: >1000 mOsm/kg H2O (P=0.001 versus controls). Co mpared with normohydration, UNaV and UKV in the water-restricted state incr eased more in controls than in B-2-KO mice. This difference in electrolyte excretion could be explained by greater dehydration in the controls (dehydr ation natriuresis). In a second protocol, we tried to mimic the effect of e ndogenous AVP by exogenous administration of an AVP V-2-receptor agonist, d esmopressin (DDAVP). To suppress endogenous AVP levels before DDAVP adminis tration, mice were volume-overloaded with dextrose and alcohol. UOsm was 68 5+/-125 and 561+/-58 mOsm/kg H2O in water-loaded controls and B-2-KO mice, respectively. After DDAVP was injected subcutaneously at a dose of 1 mu g/k g, UOsm increased to 1175+/-86 mOsm/kg H2O (Delta+490 mOsm) in the controls and 2347+/-518 mOsm/kg H2O (Delta+1786 mOsm) in B-2-KO mice (P<0.05 versus controls). We concluded that water restriction or exogenous administration of an AVP V-2-receptor agonist has a greater urinary concentrating effect in B-2-KO mice than in controls, suggesting that endogenous kinins acting t hrough B-2 receptors oppose the antidiuretic effect of AVP in vivo.