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Tyrosine kinase involvement in apamin-sensitive inhibitory responses of rat distal colon

Tadayoshi Takeuchi *¹, Masami Kishi *, Nobue Hirayama *, Michiru Yamaji *, Toshiaki Ishii *¹, Hideaki Nishio *, Fumiaki Hata *¹ and Tadashi Takewaki ²

It has been suggested that pituitary adenylate cyclase activating peptide (PACAP) may be involved in the non-adrenergic, non-cholinergic (NANC) inhibitory response of longitudinal muscle of rat distal colon. In this study, we have investigated the intracellular mechanism of PACAP-induced relaxation in this muscle.

PACAP induced an apamin-sensitive relaxation of the longitudinal muscle. The tyrosine kinase inhibitors genistein at 10 µM and tyrphostin 25 at 30 µM, but not the cyclic AMP-dependent protein kinase inhibitor R_p-8-bromoadenosine-3',5'-cyclic monophosphorothioate at 30 µM significantly inhibited the PACAP-induced relaxation to 60 % and 25 % of control values, respectively. PACAP did not increase the cyclic AMP content of the muscle.

Tyrphostin 25 at 10 µM significantly inhibited the relaxation of longitudinal muscle induced by electrical field stimulation (EFS), to 50 % of control values. Apamin at 1 µM, an antagonist of small conductance Ca²⁺-activated K⁺ channels, also inhibited the relaxation, to 42 % of control values. The inhibitory effects of tyrphostin 25 and apamin were not additive (44 % of control values).

PACAP induced an apamin-sensitive, slow hyperpolarization of the cell membrane of the muscle. Tyrphostin 25 at 3 µM inhibited this PACAP-induced hyperpolarization. Tyrphostin 25 at 10 µM and genistein at 10 µM inhibited the apamin-sensitive inhibitory junction potentials induced by a single pulse of EFS.

The PACAP-induced relaxation of longitudinal muscle occurred with a concomitant decrease in intracellular Ca²⁺ levels ([Ca²⁺]_i). Tyrphostin 25 at 10 µM and apamin at 1 µM abolished these PACAP-induced responses.

From these findings it is suggested that the activation of tyrosine kinase is involved in PACAP-induced relaxation of longitudinal muscle from rat distal colon, 'upstream of' the activation of apamin-sensitive K⁺ channels.

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