Specialization of tachykinin NK1 and NK2 receptors in producing fast and slow atropine-resistant neurotransmission to the circular muscle of the guinea-pig colon.
We studied the relative contribution of tachykinin NK1 and NK2 receptors in producing nonadrenergic noncholinergic excitation of the circular muscle of the guinea-pig proximal colon in response to electrical field stimulation. All experiments were performed in the presence of atropine, guanethidine, indomethacin, apamin and L-nitroarginine. In organ bath experiments, electrical stimulation produced a tetrodotoxin-sensitive frequency-dependent contraction. The NK1 receptor antagonists, FK 888 (1-10 microM) and GR 82,334 (0.3-3 microM) markedly reduced but did not abolish the nonadrenergic noncholinergic response. The NK2 receptor antagonist, GR 94,800 (0.3-3 microM) was partly effective at 3 microM. The combined administration of FK 888 (10 microM) and GR 94,800 (3 microM) or GR 82,334 and GR 94,800 abolished the nonadrenergic noncholinergic contraction. The response to a prolonged period of stimulation (3 Hz for 5 min) was evenly depressed by FK 888 or GR 82,334, while GR 94,800 was more effective in inhibiting the late (87% inhibition) than the peak response (25% inhibition). In the presence of nifedipine (1 microM) a marked inhibition of the nonadrenergic noncholinergic contraction was observed and a time lag was evident between stimulus application and onset of contraction, which showed slow onset and offset kinetics. The nifedipine-resistant nonadrenergic noncholinergic contraction was unaffected by FK 888 or GR 82,334 but was suppressed by GR 94,800. Submaximally effective (1-3 nM) concentrations of substance P and neurokinin A produced distinct patterns of contraction: the response to substance P was fast and declined rapidly toward baseline; the response to neurokinin A was slow and sustained. In the presence of nifedipine, the response to substance P was greatly depressed and became slower in onset; nifedipine did not affect the contraction to neurokinin A but slowed its time-course. In sucrose gap experiments, either a short (10 Hz for 1 s) or a prolonged period of electrical stimulation (3 Hz for 3 min) evoked membrane depolarization, action potentials and contraction: in response to the "prolonged" stimulation, distinct phasic and tonic component of contraction were observed. Nifedipine abolished action potentials and the phasic contraction produced by a short period of stimulation, reduced by about 50% the maximal contraction developed during the prolonged stimulation without affecting the amplitude of the tonic response. In the presence of nifedipine, GR 82,334 (3 microM) blocked the membrane depolarization but did not affect contraction; GR 94,800 (0.1 microM) did not affect depolarization but abolished contraction.(ABSTRACT TRUNCATED AT 400 WORDS)
Maggi
C A
CA
Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
Zagorodnyuk
V
V
Giuliani
S
S
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001285:Atropine / Q000494:pharmacology*; D001341:Autonomic Nervous System / Q000187:drug effects; D003106:Colon / Q000187:drug effects / Q000294:innervation / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation / Q000378:metabolism*; D015288:Neurokinin A / Q000494:pharmacology; D009469:Neuromuscular Junction / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010803:Physalaemin / Q000031:analogs & derivatives / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D018041:Receptors, Neurokinin-2 / Q000378:metabolism*; D013373:Substance P / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*
D004151:Dipeptides; D007211:Indoles; D009842:Oligopeptides; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; C079014:GR 82334; C078949:FK 888; C088270:GR 94800; D010803:Physalaemin; D013373:Substance P; D001285:Atropine; D015288:Neurokinin A; D009543:Nifedipine