The Kallikrein-Kinin System: Current and Future Pharmacological Targets

Abstract

Abstract. The kallikrein-kinin system is an endogenous metabolic cascade, triggering of which results in the release of vasoactive kinins (bradykinin-related peptides). This complex system includes the precursors of kinins known as kininogens and mainly tissue and plasma kallikreins. The pharmacologically active kinins, which are often considered as either proinflammatory or cardioprotective, are implicated in many physiological and pathological processes. The interest of the various components of this multi-protein system is explained in part by the multiplicity of its pharmacological activities, mediated not only by kinins and their receptors, but also by their precursors and their activators and the metallopeptidases and the antiproteases that limit their activities. The regulation of this system by serpins and the wide distribution of the different constituents add to the complexity of this system, as well as its multiple relationships with other important metabolic pathways such as the renin-angiotensin, coagulation, or complement pathways. The purpose of this review is to summarize the main properties of this kallikrein-kinin system and to address the multiple pharmacological interventions that modulate the functions of this system, restraining its proinflammatory effects or potentiating its cardiovascular properties.

Some new insights into the molecular mechanisms of pain perception

“…Both events are initiated through activation of B 2 receptors and the hydrolysis of PIP 2 , but they are induced by different second messengers: acute pain is induced by IP 3 and the subsequent release of Ca 2+ , with consequent inhibition of M-channels and activation of TMEM16A channels; and pain sensitization is induced by diacylglycerol (DAG), activation of the Ca 2+ -independent protein kinase PKCε, and consequent phosphorylation and enhanced thermal sensitivity of TRPV1 channels. This recalls the dual effects of bradykinin via IP 3 and DAG previously reported in neuroblastoma cells (16), though the functional end points differ. In principle, TRPV1 sensitization also could contribute to the acute effect of bradykinin if the thermal threshold of TRPV1 channels was reduced to ambient body temperature; and indeed there have been some reports suggesting this (2).…”

“…Kallikrein is formed from an inactive precursor, prekallikrein. In damaged tissue, this conversion of prekallikrein to kallikrein is accelerated by clotting factor XII (also known as Hageman factor); this occurs, along with the formation of bradykinin, when the three generator proteins (Hageman factor, prekallikrein, and kininogen) come into contact with negatively charged cell surfaces such as those of endothelial cells (3). Once formed, bradykinin is quite rapidly inactivated in the plasma and lungs by peptidases called kininases, so its effects are largely confined to the tissues where it is formedi.e., it acts as a local inflammatory mediator and induces nocifensive responses.…”

Current and prospective pharmacological targets in relation to antimigraine action

“…The nonapeptide bradykinin belongs to the kinin family and is synthesized by cleavage of high and low molecular weight kininogens through serine proteases (kininogenases; Moreau et al 2005). Plasma and tissue kallikrein are the two main kininogenases.…”

“…Since B 1 receptors are expressed following noxious stimuli and mediate vasodilatation and neurogenic plasma extravasation, B 1 -receptor antagonists may be useful as antimigraine drugs. Moreover, several B 2 -receptor antagonists have analgesic properties (Moreau et al 2005), which could be explained by the capability of bradykinin to stimulate primary afferent nerves during inflammation. Thus, both B 1 -and B 2 -receptor antagonists might potentially be useful in the treatment of migraine.…”

Kinin B1 receptor gene ablation affects hypothalamic CART productionb

“…These receptors in turn trigger distinct intracellular signal transduction cascades, which are classically correlated to effects on blood pressure, nociception and inflammation systems (for a comprehensive review see Moreau et al , 2005 ). Contrary to the B2 kinin receptor, whose expression is constitutive, the B1 receptor is mostly expressed in inflammatory conditions in response to tissue injury (Prado et al , 2002 ).…”