Cardioprotective properties of bradykinin: role of the B2 receptor

Abstract

Following the introduction of angiotensin-converting enzyme (ACE) inhibitors in the treatment of hypertension and ischemic heart disease, there has been increasing interest in the bradykinin-mediated aspects of ACE inhibition. Several preclinical and clinical studies have been conducted using genetically engineered animals or pharmacological agonists and antagonists of the two receptors of bradykinin, B 1 R and B 2 R. The results have mostly indicated that the B 1 R, whose expression is induced by tissue damage, seem to have mostly noxious effects, whereas the constitutively expressed B 2 R, when activated, exert mostly beneficial actions. Accumulating evidence in the recent literature suggests that the B 2 R have an important role in the process of ischemic post-conditioning that limits the ischemia/reperfusion injury of the myocardium. In this article, we describe a series of experiments conducted on mice submitted to acute myocardial infarct and treated either with ACE inhibition (which produces potentiation of bradykinin resulting in non-selective B 1 R and B 2 R activation) or with a potent and highly selective B 2 R agonist. These data suggest that this latter pharmacological approach offers functional and structural benefits and is therefore a promising cardioprotective therapeutic modality against acute ischemic events. INTRODUCTIONThe possible role of bradykinin (BK) in cardiovascular regulation has intrigued scientists for many years. A member of the kinin system discovered in the late 1920s, BK is a nonapeptide whose existence was first recognized by Roha e Silva et al. 1 from its effects on intestinal smooth muscle. Since then, several other actions of BK were described, including vascular contraction and relaxation, participation in the process of inflammatory reactions, interaction with central and peripheral neural structures, stimulation of synthesis and release of various vasoactive substances, enhanced insulin-dependent glucose transport and utilization, etc.Circulatory homeostasis is the result of a constant equilibrium between vasoconstrictors (e.g., pressor neurohormonal factors like angiotensin II, catecholamines, vasopressin, endothelin) and vasodilators (like kinins, prostaglandins, NO, etc.). Bradykinin, a tissue hormone that regulates the regional blood flows of vital organs, is an important member of the latter group. 2 The role of BK in cardiovascular regulation under physiological and pathological conditions attracted the interest of clinicians with the advent of angiotensinconverting enzyme (ACE) inhibitors, which in the last two decades have become standard therapy for hypertension, ischemic heart disease and heart failure. 3 In recent years the work of many investigators has produced a lot of new information regarding the role of kinins in the pathophysiology of hypertension and the prevention of its end-organ complications.

Control of ENaC-Mediated Sodium Reabsorption in the Distal Nephron by Bradykinin

“…The kallikrein-kinin system (KKS) has been proposed to regulate a plethora of physiological processes, including inflammation, coagulation, pain, cell proliferation, vasodilation, and blood pressure (BP) (Kakoki & Smithies, 2009;Kayashima, Smithies, & Kakoki, 2012;Manolis, Marketou, Gavras, & Gavras, 2010;Regoli, Plante, & Gobeil, 2012). Furthermore, beneficial roles of KKS activation were documented in diabetic nephropathy (Kakoki & Smithies, 2009;Kakoki, Takahashi, Jennette, & Smithies, 2004), glomerulosclerosis (Hirawa et al, 1999), ischemiareperfusion injury (Kakoki, McGarrah, Kim, & Smithies, 2007), chronic renal failure (Wolf, Yoshida, Agata, Chao, & Chao, 2000), and possibly in polycystic kidney disease (Braun et al, 2002).…”

Bradykinin-related peptides (BRPs) from skin secretions of three genera of phyllomedusine leaf frogs and their comparative pharmacological effects on mammalian smooth muscles

“…ACE may not be expressed on the smooth muscles of the uterus and hence this preparation responds best to the BK nonapeptide ligand. Thus the target receptor and its ligand structure/activity requirements may actually be the same in both preparations consistent with that of a classical BK B 2 -receptor [15,16]. T 6 -BK was the most potent ligand for contraction of urinary bladder smooth muscle but was 15-to 50-fold less potent than in arterial and uterus smooth muscle.…”

Bradykinin prevents the apoptosis of NIT-1 cells induced by TNF-α via the PI3K/Akt and MAPK signaling pathways

“…Bradykinin B1, whose expression is induced by tissue damage, seem to have mostly noxious effects, whereas the constitutively expressed B2, when activated, exerts mostly beneficial actions. Accumulating evidence in the literature suggests that the B2 receptor has an important role in the homeostasis of endocrinology (21). Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor (22), and similarly pharmacological blockade of the B2-kinin receptor reduces renal protective effect of the angiotensin-converting enzyme inhibition (ramipril) in the db/db mouse model (23).…”