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Involvement of autonomic and sensory substance P (SP) containing neurons in the nonadrenergic noncholinergic(NANC) excitation of the gut
32 INVOLVEMENT OF AUTONOMIC AND SENSORY SUBSTANCE P(SP) CONTAINING NEURONS IN THE NONAORENERGIC NONCHOLINERGIC(NANC) EXCITATION OF THE GUT V. Bauer I n s t . Exp. P h a r m a c o l . ~ CPS S l o v a k Academy of S c i e n c e s , cesta 9, 84216 Bratislava, Czechoslovakia
Ddbravsk~
Autonomic control of the intestinal motility is more complex than previously believed and consists not only of cholinergic and adrenergic but also of NANC components. The presence of inhibitory and excitatory NANC innervation in different regions of the gut was repeatedly demonstrated(£or review see 1,2). However, the nature of the NANC transmitter/s has not yet been clarified. Since the potent excitatory(smooth mucle contractile and membrane depolarizing) effect of SP in the intestine and its presence in intrinsic and extrinsic neurons of the gut has been established(2:3~ 4) the present study was undertaken to further analyze the NANC excitatory responses and the possible involvement of SP in the NANC excitation in the longitudinal muscle of the small and large intestine of the guinea pig. The amplitude of excitatory NANC responses of the guinea pig intestine significantly depends on basal tension, membrane potential and frequency of stimulation. The NANC e.3.P.S at higher frequencies of stimulation(2-30 Hz) were summated and spikes were superimposed on the depolarizations which corresponded with the NANC primary contractions of the longitudinal muscles. These NANC responses were blocked by TTX(O.I ~M) and enlarged by 3~4-diaminopyridine(20 - 500 ~M). Exposure of the longitudinal muscles to a high(1 ~M) SP concentration rendered the muscles insensitive to both the low SP concentration(l riM) and the stimulation of NANC excitatory nerves. Correspondingly: high frequency(20 - 30 Hz) supramaximal NANC stimulation for 10 min significantly reduced both the NANC primary contraction and the action of SP. The involvement of SP in the NANC excitation was further supported by findings that SP antagonists (O_Rro2 D_Trp7,9-Sp; D-Argl,D-TrpT,9,Leull-sp and O-Pro2,D-Phe7,D Trpg-sP) reversibly depressed the smooth muscle contractionselicited by SP and stimulation of excitatory NANC nerves. During desensitization to capsaicin and in its presence the amplitude of NANC responses was reduced by about 60%, to the same level as seen on the histamine(2 ~M) precontracted tissues. Correspondingly the presence of histamine prevented capsaicin from producing any contractile effect and from significantly influencing the NANC contractions. Inhibition of peptidases by bacitracin and their activation by p r o # nisolone enhanced and reduced the NANC excitation, respectively. The present results favor the possible transmitter role of a SP-like peptide in the excitatory NANC transmission and its release from both autonomic and sensory nerve fibres. 1. Burnstock G (1986) Arch int Pharmacodyn 280 Suppl.: i - 15 2. Bauer V (1986) Arch int Pharmacodyn 280 Suppl.: 137 - 163 3. Costa M: Furness JB, LLewellyn-Smith IJ, Cuello AC (1981) Neurosci 6: 411-424 4. Schultzberg M, Hokfelt T, Nilsson G, Terenius L, Rehfeld J, Brown M, Elde R, Goldstein M (1980) Neurosci 5:689-744
Ddbravsk~
Autonomic control of the intestinal motility is more complex than previously believed and consists not only of cholinergic and adrenergic but also of NANC components. The presence of inhibitory and excitatory NANC innervation in different regions of the gut was repeatedly demonstrated(£or review see 1,2). However, the nature of the NANC transmitter/s has not yet been clarified. Since the potent excitatory(smooth mucle contractile and membrane depolarizing) effect of SP in the intestine and its presence in intrinsic and extrinsic neurons of the gut has been established(2:3~ 4) the present study was undertaken to further analyze the NANC excitatory responses and the possible involvement of SP in the NANC excitation in the longitudinal muscle of the small and large intestine of the guinea pig. The amplitude of excitatory NANC responses of the guinea pig intestine significantly depends on basal tension, membrane potential and frequency of stimulation. The NANC e.3.P.S at higher frequencies of stimulation(2-30 Hz) were summated and spikes were superimposed on the depolarizations which corresponded with the NANC primary contractions of the longitudinal muscles. These NANC responses were blocked by TTX(O.I ~M) and enlarged by 3~4-diaminopyridine(20 - 500 ~M). Exposure of the longitudinal muscles to a high(1 ~M) SP concentration rendered the muscles insensitive to both the low SP concentration(l riM) and the stimulation of NANC excitatory nerves. Correspondingly: high frequency(20 - 30 Hz) supramaximal NANC stimulation for 10 min significantly reduced both the NANC primary contraction and the action of SP. The involvement of SP in the NANC excitation was further supported by findings that SP antagonists (O_Rro2 D_Trp7,9-Sp; D-Argl,D-TrpT,9,Leull-sp and O-Pro2,D-Phe7,D Trpg-sP) reversibly depressed the smooth muscle contractionselicited by SP and stimulation of excitatory NANC nerves. During desensitization to capsaicin and in its presence the amplitude of NANC responses was reduced by about 60%, to the same level as seen on the histamine(2 ~M) precontracted tissues. Correspondingly the presence of histamine prevented capsaicin from producing any contractile effect and from significantly influencing the NANC contractions. Inhibition of peptidases by bacitracin and their activation by p r o # nisolone enhanced and reduced the NANC excitation, respectively. The present results favor the possible transmitter role of a SP-like peptide in the excitatory NANC transmission and its release from both autonomic and sensory nerve fibres. 1. Burnstock G (1986) Arch int Pharmacodyn 280 Suppl.: i - 15 2. Bauer V (1986) Arch int Pharmacodyn 280 Suppl.: 137 - 163 3. Costa M: Furness JB, LLewellyn-Smith IJ, Cuello AC (1981) Neurosci 6: 411-424 4. Schultzberg M, Hokfelt T, Nilsson G, Terenius L, Rehfeld J, Brown M, Elde R, Goldstein M (1980) Neurosci 5:689-744