HETEROGENEITY OF NK-2 TACHYKININ RECEPTORS IN HAMSTER AND RABBIT SMOOTH MUSCLES

The possible existence of NK-2 receptor subtypes in peripheral smooth muscle preparations from rabbit and hamster was investigated by studying the effect of neurokinin A, the selective NK-2 receptor agonist [beta-Ala8] neurokinin A (4-10), the selective NK-2 tachykinin receptor antagonists, MEN 10,376, L 659,877 and R 396, and the pseudopeptide derivative of neurokinin A (4-10), MDL 28,564. All experiments were performed in the presence of peptidase inhibitors (captopril, bestatin and thiorphan, 1-mu-M each). Both neurokinin A and [beta-Ala8] neurokinin A (4-10) produced concentration-dependent contractions of the rabbit isolated bronchus and hamster isolated stomach and colon, as well as enhancement of the nerve-mediated twitches of rabbit isolated vas deferens (pars prostatica). MEN 10,376, L 659,877 and R 396 antagonized the effect of the NK-2 receptor selective agonist in all four tissues under study, although marked differences in antagonist potency were evident for the three antagonists. Thus MEN 10,376 was distinctly more potent (about 100 times) in rabbit than in hamster preparations while L 659,877 and R 396 were more potent in hamster than rabbit preparations. MDL 28,564 showed a distinct agonist character in rabbit preparations while it was virtually inactive in hamster preparations, where it antagonized the effect of the NK-2 receptor selective agonist. These findings provide further evidence for heterogeneity of the NK-2 tachykinin receptor which, on a pharmacological basis, can be classified in at least two subtypes as follows: NK-2A receptors having the rank order of antagonist potency MEN 10,376 > L 659,877 > R 396 and NK-2B receptors having the rank order of antagonist potency L 659,877 > R 396 > MEN 10,376. MDL 28,564 has agonist activity at NK-2A receptors and antagonist activity at NK-2B receptors. It is as yet unclear as to whether NK-2A and NK-2B receptors represent true receptor subtypes or are species-related variations of the NK-2 tachykinin receptor.