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(Hypertension. 1998;32:503-509.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Renovascular Hypertension in Bradykinin B₂-Receptor Knockout Mice

Paolo Madeddu; Anna Franca Milia; Maria Bonaria Salis; Leonardo Gaspa; Wolkmar Gross; Andrea Lippoldt; ; Costanza Emanueli

From the Clinica Medica and Terapia Medica, Medical School (P.M.), and the Department of Animal Biology, Section of Pharmacology (A.F.M., B.S.), University of Sassari, Sassari, Italy; the National Laboratory of the National Institute of Biostructures and Biosystems (P.M., L.G., C.E.), Osilo, Italy; the Department of Nephrology, Max Delbruck Center (W.G., A.L.), Berlin Buch, Germany; and the Department of Vascular Pathology, Istituto Dermopatico dell'Immacolata (C.E.), Rome, Italy.

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—We evaluated whether kinins exert a protective action against the development of two-kidney, one clip (2K1C) hypertension, a model characterized by an activated renin-angiotensin system in the ischemic kidney and increased expression of the bradykinin (BK) B₂ receptor in the contralateral kidney. BK B₂-receptor knockout (B₂^-/-), wild-type (B₂^+/+), and heterozygous (B₂^+/-) mice underwent clipping of the left renal artery, with the other kidney remaining untouched. Basal systolic blood pressure (SBP, via tail-cuff plethysmography) was higher in B₂^-/- mice than in B₂^+/- or B₂^+/+ mice (121±2 versus 113±2 and 109±1 mm Hg; P<0.05 for both comparisons). SBP did not change from basal values after sham operation, but it increased in mice that underwent clipping. The increase in SBP was greater in 2K1C B₂^-/- mice than in B₂^+/- or B₂^+/+ mice (28±2 versus 14±2 and 14±2 mm Hg, respectively, at 2 weeks; P<0.05 for both comparisons). Blockade of the BK B₂ receptor by Icatibant enhanced the pressure response to clipping in B₂^+/+ mice (29±2 mm Hg at 2 weeks). Intra-arterial mean blood pressure (MBP) was higher in 2K1C than in respective sham-operated mice, with the MBP difference being higher in B₂^-/- mice (32 and 38 mm Hg, at 2 and 4 weeks, respectively), and higher in B₂^+/+ mice given Icatibant (30 and 32 mm Hg) than in B₂^+/+ mice without Icatibant (17 and 18 mm Hg). At 4 weeks, acute injection of an angiotensin type 1 receptor antagonist normalized the MBP of 2K1C hypertensive mice. A tachycardic response was observed 1 week after clipping in B₂^-/- and B₂^+/- mice, but this effect was delayed in B₂^+/+ mice. However, the HR response to clipping in B₂^+/+ mice was enhanced by Icatibant. Within each strain, heart weight to body weight ratio was greater in 2K1C hypertensive mice than in sham-operated control animals (B₂^-/-: 5.7±0.1 versus 5.2±0.1; B₂^+/+: 5.1±0.1 versus 4.5±0.1; P<0.01 for both comparisons). The clipped kidney weight to nonclipped kidney weight ratio was consistently reduced in mice with 2K1C hypertension. Our results indicate that kinins acting on the BK B₂ receptor exert a protective action against excessive blood pressure elevation during early phases of 2K1C hypertension.

Key Words: angiotensin • hypertension, renovascular • mice, kinin B₂-receptor, knockout • hypertrophy, myocardial • kallikrein-kinin system

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