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From the Departments of Farmacologia (C.E., M.P.D.), Biochimica (A.F.M.,
M.B.S.), and Clinica Medica (M.C., P.M.), University of Sassari (Italy);
Department of Clinical Biochemistry, University of Munich (Germany) (E.F.);
and National Institute of Biostructures and Biosystems, Osilo, Italy (P.M.).
Correspondence to Paolo Madeddu, MD, Clinica Medica, University of Sassari, Viale S. Pietro 8, 07100 Sassari, Italy. E-mail madeddu{at}ssmain.uniss.it
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 µmol/g body wt SC once per week for 6 weeks) or vehicle in
transgenic mice (Bk2r-/-) lacking the bradykinin
B2 receptor gene and in wild-type controls
(Bk2r+/+). Under basal conditions, Bk2r-/-
mice showed higher systolic blood pressure (tail-cuff
plethysmography) than wild-type Bk2r+/+ and heterozygous
Bk2r+/- mice (121±2 versus 114±2 and 115±2 mm Hg,
respectively; P<0.05 for both comparisons). Heart rate
was higher in Bk2r-/- and Bk2r+/- than in
Bk2r+/+ (459±12 and 418±7 versus 390±7 bpm;
P<0.05 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-/-
than in Bk2r+/+ and Bk2r+/- (30±5 versus
15±4 and 6±3 mm Hg, respectively, at 3 weeks;
P<0.01 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-/-
than in Bk2r+/+ (2.59±0.15 versus 3.31±0.22 mmol,
respectively, during the first week; P<0.05). Urinary
kinin excretion was increased by DOC in both Bk2r-/-
(from 0.65±0.17 to 4.27±0.80 pmol/24 h; P<0.01) and
Bk2r+/+ (from 0.55±0.09 to 6.27±1.48 pmol/24 h;
P<0.05). The increase in urinary kinin excretion was
similar between strains. These results show that integrity of the
bradykinin B2 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.
© 1998 American Heart Association, Inc.
Scientific Contributions
Enhanced Blood Pressure Sensitivity to Deoxycorticosterone in Mice With Disruption of Bradykinin B2 Receptor Gene
Key Words: mineralocorticoids • blood pressure • kallikrein-kinin system
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