© 2001 American Heart Association, Inc.
Molecular Medicine |
Vasoactive Potential of the B1 Bradykinin Receptor in Normotension and Hypertension
From the Hypertension and Atherosclerosis Section of the Department of Medicine, Boston University School of Medicine, Boston, Mass.
Correspondence to Haralambos Gavras, MD, Chief, Hypertension and Atherosclerosis Section, Boston University School of Medicine, 715 Albany St, Boston, MA 02118. E-mail hgavras{at}bu.edu
Abstract—The B1 type receptor of bradykinin (Bk B1R) is believed to be physiologically inert but highly inducible by inflammatory mediators and tissue damage. To explore the potential participation of the Bk B1R in blood pressure (BP) regulation, we studied mice with deleted Bk B2R 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 B2R 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 B1R 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 B1R agonist produced a dose-dependent hypotensive response in the knockout mice only. Assessment of tissue expression of B1R and B2R genes by reverse transcription–polymerase chain reaction techniques revealed significantly higher B1R mRNA levels in the B2R knockout mice at all times (normotensive baseline and hypertensive end points). At the hypertensive end points, there was always an increase in B1R 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 B2R gene expression in the wild-type mice remained unaffected by experimental manipulations. These results confirm the known vasodilatory and natriuretic function of the Bk B2R; they also indicate that in its absence, the B1R can become upregulated and assume some of the hemodynamic properties of the B2R. Furthermore, they indicate that experimental manipulations to produce hypertension also induce upregulation of the B1R, but not the B2R, in cardiac and renal tissues.
Key Words: bradykinin receptors • gene knockout mice • blood pressure • tissue gene expression
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