Basic Pharmacology of Bradykinin Receptor Agonists

Review Article

Austin J Pharmacol Ther. 2015; 3(2).1070.

Basic Pharmacology of Bradykinin Receptor Agonists

Sharma JN* and Narayanan P

Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Health Sciences Centre, Kuwait

*Corresponding author: : Sharma JN, Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Health Sciences Centre, P O Box 24923, Safat 1311, Kuwait

Received: November 06, 2014; Accepted: June 18, 2015; Published: June 23, 2015


Kinins are the most potent biologically active polypeptides, which are located in the vascular smooth muscle as well as in the heart. They produce their pharmacological effects by acting on G-protein-coupled constitutive kinin B2 or inducible kinin B1 receptors linked to signaling pathways involving increased intracellular Ca++ concentrations and release of nitric oxide (NO). Pharmacological studies on hypertension, cardiac failure, ischaemia, and myocardial infarction and left ventricular hypertrophy indicate that the reduced activity of the local kallikrein-kinin system (KKS) may be instrumental in the induction of cardiovascular disorders. The ability of kallikrein gene delivery and the use of kinin B2 receptor agonists to produce a wide spectrum of beneficial effects make it a powerful candidate in treating hypertension, cardiovascular and renal diseases. Strategies that activate kinin receptors might be applicable to the treatment of cardiovascular disease.

Keywords: Kinins; Kinin receptor agonists; Cardiac diseases; Cardiac protection


Kinins are potent vasorelaxant polypeptides located in the vascular smooth muscle as well as in the heart. A number of observations obtained from clinical and experimental models of hypertension, cardiac failure, ischaemia, myocardial infarction and left ventricular hypertrophy, have suggested that KKS may be involved in the induction of cardiovascular-related diseases. Evidence suggests that the KKS may play a role in the central regulation of blood pressure in hypertensive rats [1]. Reduction in peripheral and cardiac KKS components may also be the cause of developing high blood pressure in both man and experimental animals. Kinins administered locally exert beneficial cardiac effects [2]. In vitro and in vivo studies suggested that BK reduce the duration and incidence of ischaemia in isolated rat hearts [3]. Studies undertaken in rats, dogs and humans revealed that kinins are released under conditions of ischaemia and myocardial infarction [4]. BK antagonists worsen ischaemic-induced effects 1BKs can contribute to the cardioprotective effects of preconditioning [1]. On the other hand, the reduction in cardiac infarct size by BK, after preconditioning in rabbits was prevented by a BK antagonist Icatibant (HEO 140) treatment [5]. Kinins have a role in protecting the heart against developing left ventricular hypertrophy by releasing nitric oxide [5]. It has been suggested that kinin B2 receptors agonists offer promising therapeutic approaches for the development of drugs for the treatment of cardiovascular diseases [6]. However, none of the currently known potent and selective peptide and nonpeptide agonists of kinin B2 receptor such as RMP-7, JMV-1116, FR- 190997 and FR-191413 have been selected for a clinical assessment in cardiovascular indications [6]. The objective of this review is to discuss the current concepts of BK antagonists.

The Kallikrein-Kinin System

The kinin family mainly includes BK (Arg-Pro-Pro-Gly-Phe-Ser- Pro-Phe-Arg), Kallidin (Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe- Arg) and methionyl-lysyl-BK (Met-Lys-Arg-Pro-Pro-Gly-phe-Arg) [1,5,7]. These are pharmacologically active polypeptides derived from circulating precursors (kininogens) by the action of serine proteases, called kallikreins [1,5,7]. Once released into the circulation, kinins are rapidly (<15 sec) inactivated by enzymes called kininases [1,5,7].

Kininogens are typical secretory multifunctional proteins derived from a2-globulin [1,5,7]. These are synthesized in the liver and circulate in the plasma and body fluids. Two forms of kininogens are present in mammalian circulation, High Molecular Weight Kininogen (HMWK) and Low Molecular Weight Kininogen (LMWK) [1,5,7]. However, they have completely different biochemical, immunologic and functional characteristics [1,2]. In addition, there is a T-kininogen in the rat myocardium, which is considered to be an acute phase reactant of inflammation [8]. This kininogen releases T-kinin by the enzymatic action of T-kallikrein in rats [8].

Tissue kallikrein is found more widely distributed in the tissues (organs), such as kidney (urine), pancreas, salivary glands, intestine, prostate gland and synovial tissue [1,5,7]. These kallikreins are single chain acidic glycoproteins that differ from one another in molecular weight, biological function, and physicochemical and immunological properties [1,5,7]. In tissues the inactive enzyme, tissue kallikrein, is converted into the active form by the cleavage of an amino terminal peptide. The active tissue kallikrein liberates, Kallidin from LMWK [1,5-7]. Plasma kallikrein circulates in an inactive state also known as the pre-kallikrein or Fletcher factor. Inactive prekallikrein can be activated to form kallikrein by activated Hageman factor or factor XIIa, which then liberate BK from the HMWK [1,5-7]. In addition, plasma kallikrein is able to convert inactive factor XII to XIIa by positive feedback reaction [1]. The plasma prekallikrein and HMWK are present together in a complex form [1,5]. Factor XIIa and factor XI circulate with HMWK in the bound form [1,5-7]. Inactive factor XI is converted to active factor XIa through HMWK to participate in the intrinsic coagulation pathway [1,5-7].

Kininases, kinin-inactivating enzymes, are present in the plasma, urine, tissue, endothelial cells and body fluids [1,5]. Their prime function is to monitor the required BK concentrations in the body to perform the necessary physiological activities [1,5-7]. Carboxypeptidases or kininases I cleave the C-terminal arginine from BK and kallidin to produce their corresponding des-Arg derivatives [6]. Two metalloproteinases, neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) also called kininases II degrade BK and kallidin into inactive fragments [1,5-7,9]. ACE is regarded as the most important kinin-degrading enzyme in the cardiovascular system and kidney [5-7]. It has a higher affinity for BK than for angiotensin I (Ang I), resulting in more favourable kinetics for BK than for angiotensin degradation [6]. Hence, ACE that can be inhibited by ACE inhibitors pharmacologically links the KKS with the renin-angiotensin system (RAS). Both ACE- and NEP- inhibitors increase BK peptide levels [9]. ACE- and NEP- inhibitors have different effects on kinin peptide levels in blood, urine, and tissue that may account for the differential contribution of ACE and NEP to kinin peptide metabolism in the multiple compartments in which kinin peptide generation occurs [9]. Figure 1 shows the mode of kinin formation.

Citation: Sharma JN and Narayanan P. Basic Pharmacology of Bradykinin Receptor Agonists. Austin J Pharmacol Ther. 2015; 3(2).1070. ISSN: 2373-6208.