NONADRENERGIC, NONCHOLINERGIC CONTRACTILE RESPONSES OF THE GUINEA-PIG HILAR BRONCHUS INVOLVE THE PREFERENTIAL ACTIVATION OF TACHYKININ NEUROKININ2 RECEPTORS

Experiments were designed to characterize receptor(s) that mediate nonadrenergic, noncholinergic contractions of the guinea pig hilar bronchus using selective neurokinin (NK)1 (CP 96,345) and NK2 (R396 and MEN 10,376) tachykinin receptor antagonists. Left and right hilar bronchi were studied as pairs in the presence of atropine, propranolol, phentolamine, indomethacin and thiorphan. (2S, 3S)-cis-2-(diphenylmethyl)-N-(2-methoxyphe nyl)-1-azabicyclo[2,2,2]octan-3-amine (CP 96,345) selectively antagonized contractions of the bronchus to the NK1 agonist Ac-[Arg6,Sar9,Met(O2)11]-SP(6-11) with a -log molar K(B) value of about 8.0. Similarly, Ac-Leu-Asp-Gln-Trp-Phe-Gly-NH2 (R396) and [Tyr5,D-Trp6,8,9, Lys10]-NKA(4-10) (MEN 10,376) selectively antagonized contractions to the NK2 agonist [beta-Ala8]-NKA(4-10) with -log molar K(B) values of about 5.5 and 6.7, respectively. CP 96.345 (3 X 10(-7) M) had no effect on contractions evoked by transmural electrical stimulation (TES). However, both R396 (1 X 10(-5) to 1 X 10(-4) M) and MEN 10,376 (1 x 10(-6) to 1 x 10(-6) M) caused blockade of responses to TES. CP 96,345 (3 x 10(-7) M) antagonized TES-induced contractions only when studied after substantial blockade by R396 or MEN 10,376. Contractions to TES were not abolished by R396, MEN 10,376 or a combination of these antagonists with CP 96,345. R396 (1 x 10(-6) M) increased the maximum contraction to TES and potentiated the frequency-response curve in bronchi treated with MEN 10,376 (1 x 10(-6) M). R396 (1 x 10(-6) M) also diminished the magnitude of blockade by MEN 10,376 (1 x 10(-6) M) of TES-induced contractions. These results provide evidence for the existence of NK1 and NK2 receptors on the smooth muscle of the guinea pig hilar bronchus. The results suggest, however, that the NK2 receptor is preferentially activated in nonadrenergic, noncholinergic contractile responses. A R396-sensitive receptor also appears to be capable of modulating the nonadrenergic, noncholinergic excitatory responses. In addition, nonadrenergic, noncholinergic contractions of the hilar bronchus may involve activation of receptors other than NK1 or NK2.