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 re ceptor types have been proposed and named B-3, B-4, and B-5. However, it is not established whether different pharmacologic profiles describ ing B, receptors in various species are indicative of different recept or types or of different subtypes (species dependent) subserving the s ame biological functions. To answer these questions, a systematic sear ch of new pharmacologic tools was undertaken to find monoreceptor syst ems (isolated organs whose responses are contributed by a single recep tor) as well as new selective agonists and competitive or noncompetiti ve antagonists. Classical pharmacologic experiments were performed in isolated organs for quantifying agonist activities in terms of pD(2) a nd antagonist affinities in terms of pA(2). Competitivity of antagonis ts was established from Schild plots. Results obtained in tissues from rabbits or guinea pigs indicate the existence of two different pharma cological entities, well characterized by selective agonists and compe titive antagonists. In vivo experiments performed on anesthetized rabb its and guinea pigs have confirmed the B-2 receptor heterogeneity betw een the two species. Correlations have been established between data o btained in rabbit and guinea pig tissues (biological assays) and in hu man receptors raised by genic transfection in Chinese hamster ovary (C HO) cells. A good correlation has been found between the IC50 values o f kinins and derivatives to displace [H-3]bradykinin from the membrane s of CHO cells containing the human receptor and the pD(2) or pA(2) va lues of the same compounds in the rabbit jugular vein.