Dilated and Failing Cardiomyopathy in Bradykinin B
            <sub>2</sub>
            Receptor Knockout Mice

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

doi:10.1161/01.cir.100.23.2359

Cited by 160 publications

(126 citation statements)

References 42 publications

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“…12 Moreover, it has been demonstrated that BK B2 receptor knockout mice develop spontaneous congestive HF. 13 These data strongly suggest that BK is involved in the pathogenesis of HF and in the beneficial effects of ACE inhibitor in HF. However, it remains unknown whether BK per se exerts protective effects during HF.…”

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confidence: 87%

Chronic Infusion of Bradykinin Delays the Progression of Heart Failure and Preserves Vascular Endothelium-Mediated Vasodilation in Conscious Dogs

et al. 2004

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Background-This study examined the effects of chronic bradykinin infusion on hemodynamics and myocardial and endothelial functions during the development of heart failure. Methods and Results-Sixteen instrumented dogs were randomized to receive through the left atria either vehicle or bradykinin (1 g/min) during ventricular pacing (250 bpm, 5 weeks). Hemodynamic and left ventricular (LV) parameters and the vasodilator responses to intravenous acetylcholine (0.3 to 3 g/kg) and nitroglycerin (1 to 10 g/kg) were examined in the control and after 3 and 5 weeks of pacing. The expression of endothelial NOS in femoral, carotid, and renal arteries was determined by Western blot analysis. After 3 weeks of pacing, changes in LV diastolic and systolic parameters were significantly lower in bradykinin-treated than vehicle-treated dogs (LV end-diastolic pressure, ϩ10Ϯ3 versus ϩ19Ϯ2 mm Hg; time constant of LV isovolumic relaxation, ϩ11Ϯ2 versus ϩ17Ϯ1 ms; LV wall thickening, Ϫ33Ϯ18% versus Ϫ75Ϯ9%; and cardiac output, Ϫ16Ϯ6% versus Ϫ32Ϯ6%; all PϽ0.05). Compared with vehicle-treated dogs, bradykinin-treated dogs had a reduced rightward shift of the diastolic LV pressure-diameter relation and a reduced diastolic LV wall stress. Similar trends were observed after 5 weeks. The vasodilator response to nitroglycerin was preserved in both groups. The response to acetylcholine was blunted in vehicle-treated but preserved in bradykinin-treated dogs. Vascular endothelial NOS expression decreased in vehicle-treated but was preserved in bradykinin-treated dogs. Conclusions-In

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confidence: 87%

Chronic Infusion of Bradykinin Delays the Progression of Heart Failure and Preserves Vascular Endothelium-Mediated Vasodilation in Conscious Dogs

et al. 2004

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“…Of interest are the reports of tachycardiac phenotypes being associated with cardiomyopathy and heart failure in several strains of mice (Emanueli et al, 1999;Engelhardt et al, 1999;Du et al, 2000;Liggett et al, 2000;Hardt et al, 2002). The demonstration of the HR-lowering action of oral ivabradine in the mouse indicates the possibility of studying the role of an increased HR in the development of cardiomyopathy phenotypes by administrating HR-reducing agents.…”

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confidence: 99%

I_f channel inhibitor ivabradine lowers heart rate in mice with enhanced sympathoadrenergic activities

Gao

et al. 2004

British J Pharmacology

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1 Ivabradine selectively reduces heart rate (HR) by inhibiting the cardiac pacemaker I f current, thus prolonging the duration of spontaneous depolarization in the sinus node. The activity of ivabradine under conditions of enhanced sympathoadrenergic activity has been addressed by investigating the effects of repeated oral administration in mice with sympathoadrenergic activation due to either stress, cardiac-restricted overexpression of b 2 -adrenergic receptors (b 2 AR), or b-agonist administration. HR and left ventricular fractional shortening (FS) were determined by echocardiography.2 Initial experiments showed that the conscious restrained state was associated with stress-mediated sympathetic activation, while sympathetic withdrawal occurred under anaesthetized conditions. In wild-type mice, ivabradine reduced HR under both conscious and anaesthetized states, with a similar degree in absolute reduction under both states. FS was unchanged by the treatment. 3 Ivabradine was similarly effective in reducing HR in the b 2 AR transgenic mice. Further, ivabradine at 10 mg kg À1 day À1 reduced the maximal HR increase in response to the b-agonist isoproterenol, without modifying the response of contractile parameters. 4 These data indicate that oral administration of ivabradine in mice reduces HR while ventricular performance is maintained. This specific HR-reducing action of ivabradine is well preserved under conditions that are associated with significant activation of the sympathoadrenergic system.

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“…Some of these lines, e.g., deletions of ␦-sarcoglycan and the actin-associated muscle LIM protein MLP or a R403N point mutation in the cardiac myosin heavy chain, resemble the phenotype of human hereditary DCM (8)(9)(10). On the other hand, multiple genetically altered mouse lines developing hereditary DCM are currently lacking human counterparts, e.g., overexpression of tumor necrosis factor ␣ or retinoic receptor ␣, inactivation of the cAMP response elementbinding protein, and deletion of the bradikinin B2 receptor and the mitochondrial transcription factor A (Tfam; [11][12][13][14][15][16][17].…”

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confidence: 99%

Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L

Stypmann

Gläser

Roth

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

167

124

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Dilated cardiomyopathy is a frequent cause of heart failure and is associated with high mortality. Progressive remodeling of the myocardium leads to increased dimensions of heart chambers. The role of intracellular proteolysis in the progressive remodeling that underlies dilated cardiomyopathy has not received much attention yet. Here, we report that the lysosomal cysteine peptidase cathepsin L (CTSL) is critical for cardiac morphology and function. Oneyear-old CTSL-deficient mice show significant ventricular and atrial enlargement that is associated with a comparatively small increase in relative heart weight. Interstitial fibrosis and pleomorphic nuclei were found in the myocardium of the knockout mice. By electron microscopy, CTSL-deficient cardiomyocytes contained multiple large and apparently fused lysosomes characterized by storage of electron-dense heterogeneous material. Accordingly, the assessment of left ventricular function by echocardiography revealed severely impaired myocardial contraction in the CTSL-deficient mice. In addition, echocardiographic and electrocardiographic findings to some degree point to left ventricular hypertrophy that most likely represents an adaptive response to cardiac impairment. The histomorphological and functional alterations of CTSL-deficient hearts result in valve insufficiencies. Furthermore, abnormal heart rhythms, like supraventricular tachycardia, ventricular extrasystoles, and first-degree atrioventricular block, were detected in the CTSL-deficient mice.

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Dilated and Failing Cardiomyopathy in Bradykinin B ₂ Receptor Knockout Mice

Abstract: The disruption of the bradykinin B(2) receptor leads to hypertension, LV remodeling, and functional impairment, implying that kinins are essential for the functional and structural preservation of the heart.

Cited by 160 publications

References 42 publications

Chronic Infusion of Bradykinin Delays the Progression of Heart Failure and Preserves Vascular Endothelium-Mediated Vasodilation in Conscious Dogs

Chronic Infusion of Bradykinin Delays the Progression of Heart Failure and Preserves Vascular Endothelium-Mediated Vasodilation in Conscious Dogs

I_f channel inhibitor ivabradine lowers heart rate in mice with enhanced sympathoadrenergic activities

Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L

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Dilated and Failing Cardiomyopathy in Bradykinin B 2 Receptor Knockout Mice

Abstract: The disruption of the bradykinin B(2) receptor leads to hypertension, LV remodeling, and functional impairment, implying that kinins are essential for the functional and structural preservation of the heart.

Cited by 160 publications

References 42 publications

Chronic Infusion of Bradykinin Delays the Progression of Heart Failure and Preserves Vascular Endothelium-Mediated Vasodilation in Conscious Dogs

Chronic Infusion of Bradykinin Delays the Progression of Heart Failure and Preserves Vascular Endothelium-Mediated Vasodilation in Conscious Dogs

If channel inhibitor ivabradine lowers heart rate in mice with enhanced sympathoadrenergic activities

Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L

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Dilated and Failing Cardiomyopathy in Bradykinin B ₂ Receptor Knockout Mice

I_f channel inhibitor ivabradine lowers heart rate in mice with enhanced sympathoadrenergic activities