PHARMACOLOGY OF KININ RECEPTORS - RECENT DEVELOPMENTS

Fifteen years after the classification of kinin receptors into B-1 and B-2, both receptors have been shown to differ between species. New receptor types have been proposed and named B-3, B-4, and B-5. However, it is not established whether different pharmacologic profiles describing B, receptors in various species are indicative of different receptor types or of different subtypes (species dependent) subserving the same biological functions. To answer these questions, a systematic search of new pharmacologic tools was undertaken to find monoreceptor systems (isolated organs whose responses are contributed by a single receptor) as well as new selective agonists and competitive or noncompetitive antagonists. Classical pharmacologic experiments were performed in isolated organs for quantifying agonist activities in terms of pD(2) and antagonist affinities in terms of pA(2). Competitivity of antagonists was established from Schild plots. Results obtained in tissues from rabbits or guinea pigs indicate the existence of two different pharmacological entities, well characterized by selective agonists and competitive antagonists. In vivo experiments performed on anesthetized rabbits and guinea pigs have confirmed the B-2 receptor heterogeneity between the two species. Correlations have been established between data obtained in rabbit and guinea pig tissues (biological assays) and in human receptors raised by genic transfection in Chinese hamster ovary (CHO) cells. A good correlation has been found between the IC50 values of kinins and derivatives to displace [H-3]bradykinin from the membranes of CHO cells containing the human receptor and the pD(2) or pA(2) values of the same compounds in the rabbit jugular vein.