Abstract
BackgroundThe aim of the present study was to evaluate the cardiovascular effects of the novel bradykinin B1 receptor antagonist BI-113823 following myocardial infarction (MI) and to determine whether B1 receptor blockade alters the cardiovascular effects of an angiotensin II type 1 (AT1) receptor antagonist after MI in rats.Methodology/Principal FindingsSprague Dawley rats were subjected to permanent occlusion of the left descending coronary artery. Cardiovascular function was determined at 7 days post MI. Treatment with either B1 receptor antagonist (BI-113823) or AT1 receptor antagonist (irbesartan) alone or in combination improved post-MI cardiac function as evidenced by attenuation of elevated left ventricular end diastolic pressure (LVEDP); greater first derivative of left ventricular pressure (± dp/dt max), left ventricle ejection fraction, fractional shorting, and better wall motion; as we as reductions in post-MI up-regulation of matrix metalloproteinases 2 (MMP-2) and collagen III. In addition, the cardiac up-regulation of B1 receptor and AT1 receptor mRNA were markedly reduced in animals treated with BI 113823, although bradykinin B2 receptor and angiotensin 1 converting enzyme (ACE1) mRNA expression were not significantly affected by B1 receptor blockade.Conclusions/SignificanceThe present study demonstrates that treatment with the novel B1 receptor antagonist, BI-113823 improves post-MI cardiac function and does not influence the cardiovascular effects of AT1 receptor antagonist following MI.
Highlights
Kinins are biologically active peptides that exert a broad spectrum of physiological effects, including vasodilation, smooth muscle contraction, inflammation, and pain induction [1]
Conclusions/Significance: The present study demonstrates that treatment with the novel B1 receptor antagonist, BI-113823 improves post-myocardial infarction (MI) cardiac function and does not influence the cardiovascular effects of angiotensin II type 1 (AT1) receptor antagonist following MI
BI 113823 does not interfere with the blood pressure lowering effects of lisinopril in spontaneoulsly hypertensive rats following a 2 weeks treatment period. The goal of this present study was to evaluate the effects of BI-113823 following myocardial infarction (MI) in rats and to determinate whether B1 receptor blockade with BI-113823 affects the cardiovascular effects of an angiotensin II type 1 (AT1) receptor antagonist following MI in rats
Summary
Kinins are biologically active peptides that exert a broad spectrum of physiological effects, including vasodilation, smooth muscle contraction, inflammation, and pain induction [1]. The biological effects of kinins are mediated through the stimulation of bradykinin B1 and B2 receptors. The latter type is constitutively expressed and is activated by intact kinins, bradykinin, and kallidin. The B2 receptor is believed to play an important role in mediating the beneficial effects of angiotensin 1 converting enzyme (ACE) inhibitors used to treat cardiovascular diseases, but it is involved in the acute phases of inflammation and of somatic and visceral pain [1,2,3]. The B1 receptor participates in chronic inflammation and pain [2,3]; bradykinin B1 receptor antagonists are a potentially novel approach for treating these conditions. The aim of the present study was to evaluate the cardiovascular effects of the novel bradykinin B1 receptor antagonist BI-113823 following myocardial infarction (MI) and to determine whether B1 receptor blockade alters the cardiovascular effects of an angiotensin II type 1 (AT1) receptor antagonist after MI in rats
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