Vasoactive Potential of the B ₁ Bradykinin Receptor in Normotension and Hypertension

Abstract

The B(1) type receptor of bradykinin (Bk B(1)R) is believed to be physiologically inert but highly inducible by inflammatory mediators and tissue damage. To explore the potential participation of the Bk B(1)R in blood pressure (BP) regulation, we studied mice with deleted Bk B(2)R gene with induced experimental hypertension, either salt-dependent (subtotal nephrectomy with 0.5% NaCl as drinking water) or renin/angiotensin-dependent (renovascular 2-kidney-1-clip). Compared with the wild-type controls, the B(2)R gene knockout mice had a higher baseline BP (109.7+/-1.1 versus 101.1+/-1.3 mm Hg, P:=0.002), developed salt-induced hypertension faster (in 19.3+/-2.3 versus 27.7+/-2.4 days, P:=0.024), and had a more severe end point BP (148+/-3.7 versus 133+/-3.1 mm Hg, P:<0.05). On the contrary, renovascular hypertension developed to the same extent (149.7+/-4.3 versus 148+/-3.6 mm Hg) and in the same time frame (14+/-2.2 versus 14+/-2.1 days). A bolus infusion of a selective B(1)R antagonist at baseline produced a significant hypertensive response (by 11.4+/-2 mm Hg) in the knockout mice only. Injection of graded doses of a selective B(1)R agonist produced a dose-dependent hypotensive response in the knockout mice only. Assessment of tissue expression of B(1)R and B(2)R genes by reverse transcription-polymerase chain reaction techniques revealed significantly higher B(1)R mRNA levels in the B(2)R knockout mice at all times (normotensive baseline and hypertensive end points). At the hypertensive end points, there was always an increase in B(1)R gene expression over the baseline values. This increase was significant in cardiac and renal tissues in all hypertensive wild-type mice but only in the clipped kidney of the renovascular knockout mice. The B(2)R gene expression in the wild-type mice remained unaffected by experimental manipulations. These results confirm the known vasodilatory and natriuretic function of the Bk B(2)R; they also indicate that in its absence, the B(1)R can become upregulated and assume some of the hemodynamic properties of the B(2)R. Furthermore, they indicate that experimental manipulations to produce hypertension also induce upregulation of the B(1)R, but not the B(2)R, in cardiac and renal tissues.

Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice

“…Both B1R and B2R are overexpressed in ischemia and diabetes mellitus (19,35). B1R is also markedly induced in the absence of B2R (19,36), suggesting some functional redundancy between the two receptors.…”

Additive renoprotective effects of B2-kinin receptor blocker and PPAR-γ agonist in uninephrectomized db/db mice

“…This compensatory phenomenon is also observed by other researchers in mouse models. 18,22,23 The exact role of the B1R in the diabetic kidney warrants further investigation. Apart from biochemical improvement, there was also histological improvement, and reduced macrophage infiltration and interstitial fibrosis.…”

Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury

“…The B1R is expressed at low levels in normal tissues but is induced after tissue injury or after animals are treated with endotoxins or cytokines (13). It has also been shown that expression of the B1R is markedly induced when B2Rs are absent (14,15). Both the B1R and B2R are coupled with the Gq protein (the heterotrimeric G protein with ␣q␤␥ subunit composition) (13), and their stimulation activates endothelial NO synthase in the vascular endothelium (16)(17)(18)(19).…”

“…In addition, several studies have suggested that agonism of the B1R may have opposite effects from agonism of the B2R on the severity of I/R injury (23). Although expression of the B1R is much less than that of B2R in the kidney and heart of WT mice, it is markedly induced in B2R-null mice (14,15), and expression of both receptors increases in I/R injury (24). However, whether they act synergistically or antagonistically and whether or not the kallikrein-kinin system has net protective effects in I/R injuries remain unanswered questions.…”