Bradykinin in the Heart

Abstract

H ypertension and heart failure are marked by activation of both the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system. These forms of neurohumoral activation, in turn, have deleterious effects on the heart, kidney, and other target organs, worsening the prognosis in these disease states. Pharmacological agents that interrupt the RAAS are useful in both improving hemodynamics and preventing morbidity and mortality in such patients. In particular, treatment with ACE inhibitors has been shown to improve survival in patients with advanced heart failure and after myocardial infarction. It is hypothesized that ACE inhibitors exert beneficial effects by inhibiting both circulating and cardiac tissue ACE, thus attenuating unfavorable remodeling of the left ventricle (LV), reducing afterload, and improving the balance between thrombotic and thrombolytic factors. It remains unclear whether the dominant mechanism of action of ACE inhibitors in the setting of LV dysfunction relates to their global hemodynamic effects (which result in improved loading conditions), to reduced production of angiotensin (Ang) II with subsequent diminished Ang II type 1 (AT 1 ) receptor activation, or to alteration of other neurohormonal systems, such as the kallikrein-kinin system. See p 2359Importantly, in addition to generating Ang II from Ang I, ACE catalyzes the degradation of bradykinin (BK) to inactive metabolites. 1 Studies of recombinant full-length ACE have shown that the apparent K m of ACE for BK is substantially lower than for Ang I, which indicates more favorable kinetics for hydrolysis of BK than for conversion of Ang I to Ang II. 2 Furthermore, site-directed mutagenesis demonstrated that the K m for BK was lower than that for Ang I at both N and C active sites of ACE, which suggests that at physiological concentrations, BK could be a preferential substrate over Ang I at both active sites of ACE. 2 The biological effects of BK and other kinins are mediated by stimulation of specific receptors, classified as BK 1 and BK 2 , both of which have been cloned and extensively characterized. 3 BK 1 receptors are expressed mainly in pathological conditions such as tissue injury and are thought to mediate the inflammatory and pain-producing effects of kinins; BK 2 receptors mediate most of the known cardiovascular effects of kinins. In the vasculature, BK-mediated activation of endothelial BK 2 receptors stimulates endogenous nitric oxide synthase (NOS), thus increasing NO and counteracting the effects of Ang II by inhibiting contraction and growth of smooth muscle cells. 4 Both BK 2 receptors 5 and NOS activity have been detected in cardiac myocytes, 6 and an intact kallikrein/kinin system has been found in the heart. 7 Kinins are detectable in the effluent of isolated perfused hearts and are increased by ACE inhibitors, as well as by ischemia, 8,9 which demonstrates that the cardiac kallikrein/ kinin system can be regulated.Studies in a mouse strain with targeted disruption of the BK 2 receptor gene have give...

Cardioprotective Role of AT2 Receptor in Postinfarction Left Ventricular Remodeling

“…24,25 It is possible that the LV dilation and increased mortality rates in Agtr2-mice are mediated by the loss of kinin/NO activation after MI, although the role of kinin/NO system in post-MI remodeling remains incompletely understood. 26 It is also possible that the exaggerated heart failure in Agtr2-mice could be a secondary phenomenon caused by a compromised systemic hemodynamics. Since AT2Rs in the kidney and systemic vasculature are involved in the mechanisms of natriuresis 27 and a vasorelaxation, 27,28 respectively, a deletion of AT2R may causes volume overload and increased systemic vascular resistance, leading to a deterioration of systemic hemodynamics after MI.…”

Presynaptic inhibition of transmitter release from rat sympathetic neurons by bradykinin

“…This adds two novel actions to the known ganglionic stimulation and presynaptic facilitation by bradykinin. Thus, bradykinin is a multifunctional regulator in the sympathetic nervous system, and the inhibitory effects described here may contribute to its cardioprotective action which was previously believed to be mediated by effects on the cardiovascular system (Dell'Italia and Oparil 1999; Emanueli and Madeddu 2001).…”

“…The formation of bradykinin from kininogens has been suggested to mediate both protective as well as noxious effects within the cardiovascular system (Dell'Italia and Oparil 1999). These opposing effects are mediated by actions on the vasculature (Emanueli and Madeddu 2001) on one hand, and on the sympathetic nervous system (Boehm and Kubista 2002) on the other hand and may involve both types of bradykinin receptors B 1 and B 2 .…”

Differential fading of inhibitory and excitatory B2 bradykinin receptor responses in rat sympathetic neurons: a role for protein kinase C

“…Conversely, activation of PKC prevented the detection of the pre‐synaptic inhibition via B 2 receptors. Thus, the pre‐synaptic inhibition by bradykinin which can be assumed to exert protective effects in sympathetically innervated organs such as the heart (Dell’Italia and Oparil 1999) is only transient because of the rather rapid fading of the response. Therefore, the inhibitory effect of bradykinin can be expected to be more and more outweighed by its excitatory action the longer the peptide is present.…”

“…Bradykinin exerts stimulatory and inhibitory actions in the sympathetic nervous system (Boehm and Kubista 2002) which may contribute to both, kinin‐dependent injuries as well as protection within the cardiovascular system (Dell’Italia and Oparil 1999). Post‐ganglionic sympathetic neurons are excited by the peptide (Lewis and Reit 1965; Trendelenburg 1966) via B 2 receptors which results in action potential propagation and ensuing transmitter release from the respective nerve endings (Boehm and Huck 1997).…”