Kinins, receptors, antagonists

Abstract

Kinins are potent myotropic agents acting on a variety of smooth muscle preparations: isolated arteries, veins, intestines, tracheae, urinary bladders, uteri, etc. In these tissues, kinins activate at least two different receptor types, B1 and B2. B1 and B2 receptors for kinins have been identified by measuring the order of potency of agonists and the affinities of specific and competitive antagonists. Results of pharmacological studies have been confirmed by several investigators using binding assays with labelled bradykinin (BK) or desArg9BK. Antagonists for kinins active on B1 and B2 receptors have been identified. Anti-B1 antagonists are specific, competitive and fairly potent: anti-B2 antagonists have been identified among compounds primarily developed as anti-tachykinins: these compounds are non-specific, non-competitive and rather weak. They however may provide interesting new pharmacological tools, active against both kinins and tachykinins, two groups of endogenous peptides involved in the inflammatory process. The type (direct, indirect) and the site (endothelial cell, smooth muscle fiber, autonomic nerve endings) of action of kinins in isolated vessels have been investigated. The results of various studies indicate that kinins do not act on the sympathetic nerve terminals of isolated organs in contrast with other peptides. Kinins do not promote the release of histamine or of 5-hydroxy-tryptamine from isolated arteries and veins. Kinins are equally active in the presence and absence of indomethacin (an inhibitor of cyclooxygenase) or of BW 755C (an inhibitor of lipoxygenase) in some organs, while the actions of kinins on other organs are reduced to a variable extent by these inhibitors. In general, B1 receptor systems do not depend on the activation of arachidonic acid, while B2 receptor systems do: activation of the arachidonic acid cascade may be a feature of B2 receptors. Stimulant effects of kinins on arterial or venous vessels are independent on the endothelium, while the relaxant effect on the dog carotid artery occurs only in vessels with intact endothelium. The mechanism of action of kinins and tachykinins appears to be different from that of acetylcholine, since the peptides effects are not influenced by BW 755C and ETYA, two inhibitors of lipooxygenase that reduce significantly the effect of acetylcholine.