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(Circulation. 1999;100:2359.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Dilated and Failing Cardiomyopathy in Bradykinin B₂ Receptor Knockout Mice

Costanza Emanueli, PhD¹; Roberta Maestri, PhD¹; Domenico Corradi, MD; Roberta Marchione, MD; Alessandra Minasi, PhD; Maria Grazia Tozzi, PhD; Maria Bonaria Salis, BS; Stefania Straino, BS; Maurizio C. Capogrossi, MD; Giorgio Olivetti, MD; Paolo Madeddu, MD

From the National Laboratory of the National Institute of Biostructures and Biosystems (C.E., M.B.S., P.M.), Osilo; Laboratorio di Patologia Vascolare (C.E., A.M., S.S., M.C.C.), Istituto Dermopatico dell’Immacolata, Rome; Department of Pathology (R.M., D.C., R.M., G.O.), University of Parma, Parma; and Institutes of Biochemistry (M.G.T.), Internal Medicine and Department of Biomedical Sciences (P.M.), University of Sassari, Sassari, Italy.

Correspondence to Paolo Madeddu, MD, Institute of Internal Medicine, University of Sassari, Viale S. Pietro 8, 07100 Sassari, Italy. E-mail madeddu{at}ssmain.uniss.it

Background—The activation of B₂ receptors by kinins could exert cardioprotective effects in myocardial ischemia and heart failure.

Methods and Results—To test whether the absence of bradykinin B₂ receptors may affect cardiac structure and function, we examined the developmental changes in blood pressure (BP), heart rate, and heart morphology of bradykinin B₂ receptor gene knockout (B₂^-/-), heterozygous (B₂^+/-), and wild-type (B₂^+/+) mice. The BP of B₂^-/- mice, which was still normal at 50 days of age, gradually increased, reaching a plateau at 6 months (136±3 versus 109±1 mm Hg in B₂^+/+, P<0.01). In B₂^+/- mice, BP elevation was delayed. At 40 days, the heart rate was higher (P<0.01) in B₂^-/- and B₂^+/- than in B₂^+/+ mice, whereas the left ventricular (LV) weight and chamber volume were similar among groups. Thereafter, the LV growth rate of B₂^-/- and B₂^+/- mice was accelerated, leading at 360 days to a LV weight–to–body weight ratio that was 9% and 17% higher, respectively, than that of B₂^+/+ mice. In B₂^-/- mice, hypertrophy was associated with a marked chamber dilatation (42% larger than that of B₂^+/+ mice), an elevation in LV end-diastolic pressure (25±3 versus 5±1 mm Hg in B₂^+/+ mice, P<0.01), and reparative fibrosis.

Conclusions—The disruption of the bradykinin B₂ receptor leads to hypertension, LV remodeling, and functional impairment, implying that kinins are essential for the functional and structural preservation of the heart.

Key Words: bradykinin • angiotensin • myocardium • hypertrophy • heart failure • blood pressure • genes

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