Peptide receptors: From classical pharmacology to molecular biology: The case of kinin receptors

It was a lucky choice to work with the rabbit: this species has provided the best in vitro and in vivo preparations for the study of kinin receptors: the rabbit jugular vein for the B-2, the rabbit aorta and mesenteric vein for the B-1, the anesthetized rabbit not treated or previously (5 hours before anesthesia) treated with LPS for blood pressure assays respectively of the B-2 or the B-1 receptor. It was a lucky choice to work on isolated vessels, since we could study the pharmacology of the receptors and the biochemistry (conversion, activation, inactivation) of the peptides in the same preparations: in the aorta, the B-1 receptor and carboxypeptidase M (kininase I), in the jugular vein, the B-2 receptor and kininase II which inactivates the kinins and activates Ang I. It was a lucky coincidence to work at the same time on angiotensin and on kinin pharmacology. By extrapolating from one system to the other, we found the first B-1 receptor antagonist and could propose the existence of two different receptors, B-1 and B-2. The initial proposal of the existence of two kinin receptors has been confirmed and validated by data obtained with molecular biology techniques. This has contributed to extend our knowledge of kinin receptors and provides accurate and useful in vitro (on transfected cells) and in vivo (on knocked out animals) assays for modem pharmacology of kinin receptors. B-2 receptor is constitutive, B-1 is inducible in vitro and in vivo through activation of cytokines (in vivo by LPS). B-2 may be important in physiology, to protect endothelia, B-1 may prolong such protective action but may also play a role (sometimes with B-2) in pain, inflammation, diabetes, hypertension and even nervous diseases. Thus, agonists and antagonists may be needed for therapeutic purposes. At present, for the B-1, we have only peptides; for the B-2, we have peptides as well as some non-peptide agents active per os (FR 190997 FR 173657). Such new pharmacological tools are essential for defining the role of this system in physiopathology and to design new therapeutically useful agents.