TACHYKININ NK1 AND NK2 RECEPTORS MEDIATE NONADRENERGIC NONCHOLINERGICEXCITATORY NEUROMUSCULAR-TRANSMISSION IN THE GUINEA-PIG STOMACH

By using selective tachykinin NK1 and NK2 receptor antagonists and ago nists, we studied the excitatory non-adrenergic non-cholinergic transm ission to the circular muscle of the corpus of guinea-pig stomach by t he sucrose-gap method. After elimination of inhibitory junction potent ials by apamin (0.1 mu M), L-nitroarginine (30 mu M) and tetraethylamm onium (10 mM): electrical field stimulation (10 Hz) in the presence of atropine (1 mu M) and nifedipine (1 mu M) evoked a pure excitatory ju nction potential and contraction. The selective tachykinin NK2 recepto r antagonist, MEN 11420, concentration-dependently inhibited the non-a drenergic non-cholinergic excitatory junction potential (EC50=0.09 mu M) and contraction (EC50=0.01 mu M) evoked by electrical field stimula tion. On the other hand, the selective NK1 receptor antagonist GR 8233 4 (3 mu M) only slightly (by about 30%) inhibited the excitatory junct ion potential while leaving the contraction unaffected. The combined a dministration of GR 82334 (1 mu M) and MEN 11420 (0.3 mu M) produced a n additive inhibition of the excitatory junction potential, significan tly larger than that produced by each antagonist alone. In the presenc e of both GR 82334(1 mu M) and MEN 11420 (0.3 mu M), the P-2 purinorec eptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (30 mu M) remarkably inhibited the fast component of the excitatory j unction potential. In the presence of atropine (1 mu M), indomethacin (3 mu M) and guanethidine (3 mu M) either the selective NK2 receptor a gonist, [beta Ala(8)]neurokinin A (4-10) (0.01 mu M), or the selective NK, receptor agonist, [Sar(9)]substance P sulfone (0.3 mu M), produce d tetrodotoxin-(1 mu M) and nifedipine-(1 mu M) resistant depolarizati on and contraction. The [Sar(9)]substance P sulfone (0.3 mu M)-induced contraction, but not that induced by [beta Ala(8)]neurokinin A (4-10) (0.01 mu M), was potentiated by apamin (0.1 mu M) plus L-nitroarginin e (30 mu M). In the presence of atropine (1 mu M), indomethacin (3 mu M), guanethidine (3 mu M), apamin (0.1 mu M) and L-nitroarginine (30 m u M), the selective tachykinin NK, and NK, receptor agonists, [beta Al a(8)]neurokinin A (4-10) and [Sar(9)]substance P sulfone, both produce d a concentration-dependent depolarization and contraction of the circ ular muscle. MEN 11420 inhibited the responses to [beta Ala(8)]neuroki nin A (4-10) without affecting the responses to [Sar(9)]substance P su lfone, while GR 82334 inhibited the responses to [Sar(9)]substance P s ulfone but not that to [beta Ala(8)]neurokinin A (4-10). These data pr ovide evidence that tachykinin NK, receptors predominantly mediate the non-adrenergic non-cholinergic excitatory transmission to the circula r muscle of the corpus of guinea-pig stomach. In addition. after block ing the non-adrenergic non-cholinergic inhibitory junction potential b y apamin, L-nitroarginine and tetraethylammonium, the Fast component o f the non-adrenergic non-cholinergic excitatory junction potential cou ld be mediated by adenosine triphosphate. (C) 1997 IBRO. Published by Elsevier Science Ltd.