Enhanced Blood Pressure Sensitivity to Deoxycorticosterone in Mice With Disruption of Bradykinin B ₂ Receptor Gene

Abstract

Abstract-The renal kallikrein-kinin system is activated under conditions of mineralocorticoid excess. To evaluate whether endogenous kinins exert a protective role against the development of mineralocorticoid-induced hypertension, we studied the cardiovascular effects induced by long-term administration of deoxycorticosterone (DOC; 0.3 mol/g body wt SC once per week for 6 weeks) or vehicle in transgenic mice (Bk2r Ϫ/Ϫ ) lacking the bradykinin B 2 receptor gene and in wild-type controls (Bk2r ϩ/ϩ ). Under basal conditions, Bk2r Ϫ/Ϫ mice showed higher systolic blood pressure (tail-cuff plethysmography) than wild-type Bk2r ϩ/ϩ and heterozygous Bk2r ϩ/Ϫ mice (121Ϯ2 versus 114Ϯ2 and 115Ϯ2 mm Hg, respectively; PϽ0.05 for both comparisons). Heart rate was higher in Bk2r Ϫ/Ϫ and Bk2r ϩ/Ϫ than in Bk2r ϩ/ϩ (459Ϯ12 and 418Ϯ7 versus 390Ϯ7 bpm; PϽ0.05 for both comparisons). Systolic blood pressure was increased by DOC in transgenic as well as in wild-type mice, whereas no change was induced by the vehicle. The pressor response to DOC was more rapid and pronounced in Bk2r Ϫ/Ϫ than in Bk2r ϩ/ϩ and Bk2r ϩ/Ϫ (30Ϯ5 versus 15Ϯ4 and 6Ϯ3 mm Hg, respectively, at 3 weeks; PϽ0.01 for both comparisons). The difference in systolic blood pressure was consistent with that detected by direct intra-arterial measurements of mean blood pressure. Neither DOC nor its vehicle altered heart rate or gain in body weight over time. Under basal conditions, urinary sodium excretion did not differ between strains. During DOC administration, cumulative urinary sodium excretion was lower in Bk2r Ϫ/Ϫ than in Bk2r ϩ/ϩ (2.59Ϯ0.15 versus 3.31Ϯ0.22 mmol, respectively, during the first week; PϽ0.05). Urinary kinin excretion was increased by DOC in both Bk2r Ϫ/Ϫ (from 0.65Ϯ0.17 to 4.27Ϯ0.80 pmol/24 h; PϽ0.01) and Bk2r ϩ/ϩ (from 0.55Ϯ0.09 to 6.27Ϯ1.48 pmol/24 h; PϽ0.05). The increase in urinary kinin excretion was similar between strains. These results show that integrity of the bradykinin B 2 receptor is essential for regulation of blood pressure and heart rate under basal conditions. In addition, they indicate that activation of the kallikrein-kinin system represents a compensatory response against the development of hypertension induced by mineralocorticoid excess. (Hypertension. 1998;31:1278-1283.) Key Words: mineralocorticoids Ⅲ blood pressure Ⅲ kallikrein-kinin system K inins, the enzymatic products of kininogen cleavage by kallikrein, induce vasodilatation, diuresis, and natriuresis by promoting the release of endothelium-derived relaxing factors and prostaglandins.1-4 They act as local hormones by activating specific receptors named B 1 and B 2 , with most of the cardiovascular and renal effects being mediated by the B 2 receptor.5 It has been hypothesized that a dysfunction of the KKS, leading to unbalanced predominance of vasoconstrictor and antinatriuretic systems, may contribute to the pathogenesis of arterial hypertension. Interestingly, at variance with other models of genetic or experimental hypertension characterized by a defective renal synthesis...

Early Onset Salt-Sensitive Hypertension in Bradykinin B 2 Receptor Null Mice

“…On the basis of these and other results, [2][3][4] we conclude that the kallikrein-kinin system protects both developing and mature animals from salt-sensitive hypertension. The B 2 R-deficient mouse is a monogenetic model that can be used to study the developmental aspects of salt-sensitive hypertension.…”

“…3 Additional studies by the same group of investigators found that B 2 R null mice are highly susceptible to mineralocorticoid-induced hypertension. 4 Together, these studies indicate that kinins play an important role in the prevention of salt-sensitive hypertension and that this may be achieved by maintaining renal blood flow under conditions of HS intake.…”

“…Alfie et al 2 demonstrated that although B 2 R null mutant mice maintained on a normal salt (NS) diet are normotensive, chronic high salt (HS) intake provokes hypertension and decreases renal blood flow compared with wild-type controls. Studies by Madeddu et al 3 and Emanueli et al 4 have shown that B 2 R null mice have a slightly higher resting blood pressure (BP) than wild-type controls and that salt loading or deoxycorticosterone treatment causes hypertension in these mice. Thus, B 2 R gene inactivation results in salt-sensitive hypertension in the adult animal.…”

Normal Blood Pressure and Renal Function in Mice Lacking the Bradykinin B 2 Receptor

“…Either an increased or no change in sensitivity to deoxycorticosterone acetate-salt has been reported for B 2 receptor-deficient mice. 19,20 We found no increases in heart rate or altered baroreceptor control of heart rate in our animals, with or without a high salt diet, as have been described by others. 21,22 We did observe an increase in baroreceptor heart rate reflex activity and sensitivity with the higher salt intake.…”

DOCA-salt treatment enhances responses to endothelin-1 in murine corpus cavernosumThis article is one of a selection of papers published in the special issue (part 1 of 2) on Forefronts in Endothelin.

“…By using 4 mouse strains (129/Sv, C57BL/6, and F1 and F2 intercrosses of 129/Sv × C57BL/6), Hartner and colleagues (2003) showed that 129/Sv mice are more susceptible to the development of DOCA-induced high blood pressure and renal damage than C57BL/6 mice (Hartner et al 2003). In addition, in 129Sv/Ev mice, the renal kallikrein-kinin system, which is activated under conditions of mineralocorticoid excess, exerts a protective role against the development of mineralocorticoid-induced hypertension (Emanueli et al 1998). Whether the protective role of endogenous kinins is greater in C57BL/ 6 mice than in 129Sv/Ev or rats has not been investigated.…”