Neurotensin: contractile activity, specific binding, and lack of effect on cyclic nucleotides in intestinal smooth muscle.

Nuerotensin contracted the isolated longitudinal smooth muscle strip of the guinea-pig intestine. It induced a biphasic response (relaxation followed by contraction) when the muscle was contracted by histamine. Tetrodotoxin blocked the contraction and the contraction phase of the biphasic response. Dose responses of the relaxing effect of neurotensin and its analogs D-Arg8-neurotensin and D-Arg 9-neurotensin on tetrodotoxin-treated muscle gave EC50 values of 5 nM, 5.5 nM and 110 nM for the three peptides, respectively. [3H]Neurotensin bound specifically to membranes prepared from isolated longitudinal muscle strips of the guinea-pig intestine. In binding studies using [3H]neurotensin and unlabelled peptides, the KDs of neurotensin, D-Arg 8-neurotensin and D-Arg9 neurotensin were 4 nM, 2 nM and 300 nM, respectively, values which are in close agreement with the EC50 of the three peptides. Neurotensin had no effect on the cAMP and cGMP contents in longitudinal intestinal muscle strips of the guinea pig, an observation which suggests that cyclic nucleotides are not involved in the mechanism of action of neurotensin in this muscle preparation.     

Neurotensin contracts the guinea-pig longitudinal ileal smooth muscle by inducing acetylcholine release.

Neurotensin contracted the isolated longitudinal smooth muscle strip of the guinea-pig ileum, but was only 22% as effective as histamine. Neostigmine (0.1 micrometer) increased the effectiveness of neurotensin 4-fold. Atropine (0.1 micrometer) completely inhibited the contracting effect of neurotensin measured in the presence of neostigmine, whereas hexamethonium (0.1 micrometer) was without effect. It is concluded that in the longitudinal smooth muscle of the guinea-pig ileum, the contracting effect of neurotensin is mediated by the release of acetylcholine from nerve endings in response to a postganglionic stimulation of cholinergic nerve fibers.     

Electrophysiological study of the action of neurotensin on the smooth muscle of the guinea-pig taenia coli.

The effects of neurotensin on the membrane potential and conductance, and on the tension of the guinea-pig taenia coli were investigated using the sucrose gap method. In preparations spontaneously active at 37 degrees C, neurotensin (0.5--10 nM) increased the frequency of spikes and induced a smooth muscle membrane depolarization which led to a block of spike discharges. These electrical events were accompanied by phasic and tonic contractions of the smooth muscle. At 20 degrees C the guinea-pig taenia coli exhibited little or no spontaneous activity. Neurotensin (50 nM) rapidly depolarized the smooth muscle membrane and increased its conductance. Concentration--response curves of neurotensin-induced depolarization and contraction gave an EC50 of 1.7 nM and 4.5 nM respectively, with a maximally effective concentration of peptide around 50 nM for both effects. Studies in modified or substituted salt solutions indicated that the neurotensin-induced increase in smooth muscle membrane conductance was primarily due to an increase in Na+ and Ca2+ conductances.     

Neurotensin is a potent inhibitor of guinea-pig colon contractile activity

The investigation concerned the effects of neurotensin (NT) on the mechanical activity of segments of guinea-pig proximal colon. The peptide, in concentrations ranging from 0.1 nM to 100 nM, induced a quick relaxation of the preparations which was followed upon washout by a rebound contraction. Tetrodotoxin had no effect on either the NT-induced relaxation or the rebound contraction. Blocking agents of α- and β-adrenoceptors were also without effect. The bee venom toxin apamin inhibited and even converted to contractions the NT-induced relaxations in the guinea-pig colon. Concentration-response curves for the inhibitory effect of NT, adrenaline and ATP indicated that NT (IC_{50 0.32 nM}) was 100 times more potent that adrenaline (IC₅₀ 32 nM) and 50 000 times more potent than ATP (IC₅₀ 16 μM). The data show that NT exerts a potent myogenic relaxing effect on the longitudinal smooth muscle of the guinea-pig proximal colon. The properties of this effect suggest the presence of high affinity NT receptors on colonic smooth muscle cells and this points to a possible role for NT as a modulator of guinea-pig proximal colon motility.     

Nitric oxide induces acetylcholine-mediated contractions in the guinea-pig small intestine

In longitudinal muscle/myenteric plexus preparations of the guinea-pig ileum, exogenous nitric oxide (NO) induced concentration-dependent relaxations. In tissues at basal tone, NO (3 × 10^–6 M) induced a moderate relaxation followed by a pronounced contraction, consisting of a quick and sustained component. Tetrodotoxin (5 × 10^–7 M) abolished both phases of the contraction. Atropine (5 × 10^–7 M) abolished the quick component and reduced the sustained component of the contraction; the latter was further suppressed by the selective NK₁ receptor antagonist CP 96,345. Hexamethonium (5 × 10^–5 M) failed to affect the contractile response to NO. It is concluded that administration of exogenous NO in the guinea-pig ileum can lead to activation cholinergic and to a lesser degree tachykininergic neurones. Correspondence to: L. Barthó at the above address     

Neurotensin and prostaglandin interactions in smooth muscle of the guinea pig stomach

Neurotensin, xenopsin and neuromedin N had a biphasic effect (initial small relaxation followed by a sustained contraction) on the motility of longitudinal muscle strips from the guinea pig gastric corpus. Kinetensin was without effect. Tetrodotoxin, adrenaline, histamine, 5-hydroxytryptamine, opioid peptides, angiotensin II and antagonists of acetylcholine, and desensitization of the strips to bradykinin did not modify the action of neurotensin. The contraction phase was inhibited in a concentration-dependent manner by indomethacin and acetylsalicylate, demonstrating that this activity of neurotensin was dependent on prostaglandin synthesis. The preparation responded to exogenous prostaglandins E1, E2, F1 alpha and F2 alpha with concentration-dependent contractions. The relaxation phase was abolished by verapamil and apamin, indicating the presence of inhibitory neurotensin receptors on smooth muscle cells that are linked to ionic channels.     

Comparison of some biological properties of neurotensin and its natural analogue LANT-6

The biological properties of neurotensin (NT) and the chicken peptide [Lys8,Asn9]neurotensin-(8-13) (LANT-6) were compared in 3 in vitro assays: (1) competitive inhibition of [3H]NT binding to rat brain synaptic membranes, (2) relaxation of the rat ileum, and (3) contraction of the guinea-pig ileum. The data show that LANT-6 interacted with NT receptors like a weak agonist having full intrinsic activity and low affinity. LANT-6 is unlikely to represent a physiological activator of NT receptors.     

Effects of endothelin-1 on the isolated guinea-pig ileum: role of Na+ ions

Summary Endothelin-1 induced an unusual transient biphasic effect (relaxation followed by contraction) in the isolated guinea-pig ileum. The contractile component of the response was concentration-dependent in the dose range studied, but the relaxant component was not. Neuronal mechanisms and cyclic GMP do not seem to be involved in the relaxing effect since this component was not affected by either tetrodotoxin, atropine or methylene blue. Endothelin-1 induced desensitization which was well characterized for the contractile component of the response, and was only partially reversed after a 3-h resting period. The effects of endothelin-1 were particularly sensitive to decreases in the Na⁺ gradient induced either by lowering the Na⁺ concentration in the medium or by treating the tissue with ouabain or by a previous treatment with acetylcholine. Amiloride partially inhibited the response induced by endothelin-1 indicating that Na⁺ channels and/or Na⁺/H⁺ exchange are probably involved in its action. Our results suggest that the contractile response induced by endothelin-1 in the isolated guinea-pig ileum depends greatly on Na⁺ ions, in contrast to the responses observed in vascular smooth muscle. Send offprint requests to N. Miasiro at the above address     

The biphasic response of the isolated guinea-pig ileum by bradykinin

The isolated guinea-pig ileum, challenged by agonist, was used to study the effect of bradykinin. In the presence of acetylcholine producing approximately 60% of maximum contraction, bradykinin caused relaxation followed by contraction. The biphasic response to bradykinin was also found in the presence of histamine, eledoisin, angiotensin, prostaglandin F_2α and transmural electrical stimulation. The conditions for bradykinin-induced relaxation were not found after treatment by bradykinin, and potassium or barium chloride. Under conditions where bradykinin produced a biphasic response, acetylcholine, histamine, eledoisin, angiotensin, prostaglandin F_2α and lysine-vasopressin only contracted the ileum, while adrenaline, noradrenaline, oxytocin, calcium and magnesium chloride only relaxed. On increasing the percentage of maximum contraction with acetylcholine, an inverse relationship with relaxation by bradykinin was found. Tachyphylaxis was not present with the bradykinin-induced relaxation. The relaxing effect of bradykinin is more likely to be due to a direct action on the muscle cell membrane than to a release of a mediator or to blockade of a receptor mediating contraction.     

Effect of capsaicin on gastric corpus smooth muscle of the rat in vitro

Circular strips of the rat gastric corpus muscle were mounted in Krebs solution for isometric tension recording. Addition of capsaicin usually led to either relaxation or contraction, but in some strips a biphasic response was observed. Although no clear-cut concentration-response relationship could be established, capsaicin predominantly induced contraction at 500 nM, whereas at 5 microM it mainly induced relaxation. In Krebs solution containing atropine plus guanethidine, the contraction induced by 500 nM capsaicin was significantly reduced. The contraction induced by capsaicin was abolished by spantide, a tachykinin antagonist, or by tachyphylaxis to substance P. Calcitonin gene-related peptide relaxed gastric smooth muscle, however, a dose-response relationship could not be established. This peptide contracted the muscle strips only at 1 microM. Tachyphylaxis to calcitonin gene-related peptide did not significantly influence the action of capsaicin. Vasoactive intestinal polypeptide dose dependently relaxed gastric corpus strips; however, these responses were qualitatively different from those to capsaicin. It is concluded that capsaicin contracts rat gastric smooth muscle via the release of tachykinins; cholinergic interneurones are involved. The mediator of the capsaicin-induced relaxation has yet to be determined.     

Neurotensin receptors on the ileum of the guinea-pig: evidence for the coexistence of inhibitory and excitatory receptors

Neurotensin caused a complex muscular response of the longitudinal muscle-myenteric plexus preparation of guinea-pig ileum: picomoles of neurotensin produced inhibition while larger concentrations caused an inhibitory effect followed by a delayed dose-dependent contraction. The inhibitory phase of the neurotensin-induced muscular activity was not modified by tetrodotoxin but was potently antagonized in a non-competitive manner by apamin, a bee venom toxin. The contractile component was blocked by tetrodotoxin but not by apamin. These toxins were used to dissect the neurotensin muscular response into an inhibitory phase and an excitatory component. It was possible to further characterize the two neurotensin muscular components by their kinetics of desensitization. The inhibitory neurotensin response showed a fast rate of desensitization and presented a relatively low spare receptor capacity. In contrast, desensitization to the excitatory action of neurotensin was much slower, the excitatory receptors apparently having a larger spare receptor capacity. Desensitization to the action of neurotensin was selective for the neuropeptide not altering the contractile activity of substance P, angiotensin II, bradykinin, histamine or acetylcholine. These results strongly suggest the presence of two subsets of neurotensin receptors in the ileum: the inhibitory set probably localized at the postsynaptic effector level and excitatory neurotensin receptors probably of neuronal origin whose function is probably to modulate the release of neurotransmitters. The physiological implications of these two subtypes of neurotensin receptors in the control of gastrointestinal motility are discussed.     

Effects of adrenergic blockers on the relaxation of the guinea-pig ileum by bradykinin and adrenaline

α- and β-adrenergic blockers have been examined on the bradykinin- and adrenaline-induced relaxation of the acetylcholamine contracted guinea-pig ileum. The α-adrenergic blocker piperoxan potentiated, while phentolamine reduced the bradykinin relaxation. Both reduced the acetylcholamine contraction, but had no effect on the adrenaline relaxation. The bradykinin relaxation of the guinea-pig ileum was about 10 times more sensitive to phentolamine than the rat duodenum.The β-adrenergic blocker propranolol potentiated the bradykinin relaxation and reduced the acetylcholine contraction. Sotalol was in these respects less potent than propranolol. The adrenaline relaxation was partially blocked by propranolol, but almost completely by satalol. A combination of phentolamine and propranolol slightly potentiated the bradykinin relaxation, and partially blocked the adrenaline relaxation. The bradykinin relaxation is not due to a direct action on either the α- and β-adrenergic receptors of the guinea-pig ileum. The potentiation of the 0radykinin relaxation is probably indirect via the reduction of the acetylcholine contraction. The action of phentolamine cannot be explained by this mechanism. Seemingly only β-adrenergic receptor activity mediates relaxation with adrenaline.     

Agonist effects of [D-Pro2,D-Phe7,D-Trp9]substance P--evidence for different receptors

[D-Pro2,D-Phe7,D-Trp9]substance P contracted guinea-pig ileum (GPI) indirectly, probably via substance P (SP) receptors on postganglionic parasympathetic neurones. It also depolarised rat superior cervical ganglion cells and contracted the rabbit external jugular vein, suggesting an agonist action on SP receptors in these tissues. In contrast, it had weak antagonist activity on smooth muscle SP receptors in GPI. This suggests that the receptor in GPI smooth muscle may differ from those in the other tissues.     

Intestinal relaxation by endothelin isopeptides: involvement of Ca(2+)-activated K+ channels.

Our previous studies have shown that endothelin-1 (ET-1) induces an initial relaxation followed by a contraction in the guinea-pig ileum. To test whether other ET isopeptides (ET-2, ET-3, vasoactive intestinal contractor (VIC) and sarafotoxin S6b) and big ET-1, the ET-1 precursor, also induce similar biphasic responses, we compared their effects in isolated guinea-pig ileum. In addition, the mechanism of initial relaxation was studied. At 1-100 nM, ET-1, ET-2 and VIC were equipotent in producing the biphasic responses. S6b also produced similar biphasic responses, except that only a relaxation was elicited at 1 nM. ET-3 was approximately 30- to 100-fold less active than ET-1 in producing the contraction, whereas it was as potent as ET-1 in producing relaxation. Big ET-1 induced a relaxation of slower onset and longer duration, followed by a weak contraction at concentrations higher than 30 nM. The initial relaxation produced by ET-1 was not affected by pretreatment with L-NAME (NW-nitro-L-arginine methyl ester), hemoglobin, 9-AC (anthracene-9-carboxylic acid), SITS (4-acetamido-4'-isothiocyanatostilbene-2-2'-disulfonic acid), glibenclamide, ouabain, phorbol 12,13-dibutyrate, sodium nitroprusside, human atrial natriuretic peptide (hANP) or forskolin, whereas it was abolished by pretreatment with apamin. Although phorbol 12,13-dibutyrate pretreatment had no significant effect on the biphasic response of ET-1, it rapidly reversed the sustained contraction produced by ET-1. These results indicate that the initial relaxation is caused by the activation of Ca(2+)-activated K+ channels.     

Two types of neuronal muscarine receptors modulating acetylcholine release from guinea-pig myenteric plexus

Summary Longitudinal muscle strips of the guinea-pig ileum were incubated with [³H]choline and the effects of muscarinic agonists on smooth muscle contraction and on spontaneous and electrically-evoked outflow of tritium were studied. Muscarine and pilocarpine concentration-dependently increased both muscle contraction and spontaneous outflow of [³H]ACh, and inhibited the electrically-evoked outflow of [³H]ACh. The increase in spontaneous outflow was prevented by tetrodotoxin and scopolamine, but not by hexamethonium. Oxotremorine (1–100 M) did not increase the spontaneous outflow of tritium.Pirenzepine in concentrations of 10 and 100 nM hardly affected the muscle contractions induced by pilocarpine, but significantly antagonized the pilocarpine-evoked increases in [³H]ACh outflow. Likewise, pirenzepine (100 nM) antagonized more effectively the enhancement by muscarine of spontaneous outflow than the inhibitory effect of muscarine on the electrically-evoked release of [³H]ACh. Scopolamine (1 and 10 nM) antagonized to a similar extent the effects of pilocarpine on spontaneous outflow of [³H]ACh and on muscle contraction.The results suggest that the cholinergic nerves of the myenteric plexus are endowed with excitatory (ganglionic) and inhibitory (prejunctional) muscarine receptors which modulate the release of ACh and which differ in their affinities to pirenzepine.     

Neurotensin: dual effect on the motor activity of rat duodenum.

The effects of neurotensin on mechanical activity of rat duodenum were investigated using an isometric-isovolumic preparation. Neurotensin (1 pM to 10 nM) induced a concentration-dependent, tetrodotoxin (TTX)-insensitive fall in both endoluminal pressure and isometric tension. At higher concentrations of neurotensin (1 nM to 1 microM) the relaxation was followed by a concentration-dependent TTX-insensitive contraction, detected only by an increase in endoluminal pressure. Different concentrations of neurotensin were required to desensitize the relaxant and the contractile actions of the neuropeptide. The relaxation was antagonized by apamin, while the contractile response was blocked by nifedipine. Neurotensin, when tested separately on longitudinal and circular muscular strips, caused relaxation of the longitudinal strips. Circular strips showed contractions in response to neurotensin, following an inhibitory phase, if the strips were spontaneously or pharmacologically activated. The results suggest the presence of two sets of neurotensin receptors with a differential localization between the two muscular layers in rat duodenum.     

Desensitization of PGE2 and PGI2 induced contractions in different smooth muscles of guinea-pig unmasking relaxing properties of prostanoids

Prostaglandin E2 (PGE2) and 16,16-dimethyl PGE2 (16,16-dm PGE2) caused contraction of guinea-pig taenia caeci, contraction and at higher concentrations relaxation of trachea and relaxation of ureter smooth muscle. The prostacyclin derivative iloprost induced contraction of taenia caecum, while it was inactive in the other preparations. After pretreatment of the smooth muscles with 16,16-dm PGE2, stimulation of the PGE2 receptors in taenia caeci and trachea and of PGI2 receptors in taenia caeci caused relaxation. The results indicate that the prostanoid receptor mediating contraction is selectively vulnerable for desensitization in contrast with the receptor mediating smooth muscle relaxation.     

Alpha- and beta-adrenoceptor-mediated responses of the guinea-pig ileum and the effects of neuronal uptake inhibition

Summary The effects of noradrenaline and isoprenaline were examined on preparations of guinea-pig ileum, in which contractions were induced by three different methods; by transmural electrical stimulation, by exogenous carbachol and by potassium depolarization. Alpha- or beta-adrenoceptor-mediated responses were examined by construction of cumulative concentration-response curves in the presence of propranolol (10^–6 M) and phentolamine (5×10^–6 M) respectively. Stimulation of alpha-adrenoceptors by noradrenaline virtually abolished the twitches from transmural stimulation, but only partially inhibited the carbachol- and potassium-induced contractions. The effects on the last two preparations were attributed to a postsynaptic inhibition at alpha-adrenoceptors on the longitudinal smooth muscle. In the transmurally-stimulated preparation there was an additional pre-synaptic alpha-adrenoceptor-mediated inhibition of cholinergic transmission. The maximum beta-adrenoceptor-mediated inhibition of all three preparations to noradrenaline and isoprenaline was of the same magnitude and attributed only to a post-synaptic action on longitudinal smooth muscle.The predominant post-synaptic beta-adrenoceptor-mediated (carbachol-contracted ileum) and pre-synaptic alpha-adrenoceptor-mediated (transmurally-stimulated ileum) relaxations were significantly (P<0.05) potentiated by the neuronal uptake inhibitor desmethylimipramine. These receptors may therefore be considered to be closely associated with the sympathetic innervation. The effect on the post-synaptic alpha-adrenoceptor-mediated relaxation was equivocal. Additional minor excitatory responses were identified as a direct alpha-adrenoceptor-mediated contractile response to noradrenaline and as a beta-adrenoceptor-mediated potentiation of transmural stimulation by isoprenaline, possibly due to facilitation of cholinergic transmitter release.     

Distribution and types of adrenoceptors in the guinea-pig ileum: the action of α-and β-adrenoceptor agonists

1 Segments of guinea-pig ileum and the myenteric plexus-longitudinal smooth muscle preparation were used for a study of the actions of adrenaline, noradrenaline, isoprenaline, ephedrine and phenylephrine on the responses of coaxially stimulated ileum at different distances from the ileocaecal valve.2 The responses of the ileum to electrical stimulation were suppressed by adrenaline, nonadrenaline and ephedrine, while phenylephrine and isoprenaline inhibited them only partially.3 The twitch inhibition elicited by these adrenoceptor agonists was the same at all distances from the ileocaecal valve. There was no significant difference between their cumulative and non-cumulative concentration-response curves.4 Smooth muscle relaxation was induced only by isoprenaline and contraction only by phenylephrine at all distances from the ileocaecal junction. Adrenaline and noradrenaline evoked smooth muscle contraction in the terminal (0 to 20 cm), a concentration-dependent, biphasic response in the intermediate part (21 to 50 cm) and a relaxation in the proximal ileum (> 50 cm from the ilecocaecal valve). Ephedrine did not change significantly the smooth muscle tension in the terminal and the intermediate segments and induced smooth muscle relaxation in the proximal ones.5 Ouabain and a potassium-free solution did not appear to influence the prejunctional action of noradrenaline nor the amplitude of smooth muscle relaxation in the proximal ileum, whereas the concentration-contractor response curves were significantly depressed and shifted to the right by ouabain and in a potassium-free solution.6 The brief initial (phasic) contraction induced by acetylcholine was not influenced during the sustained increase or decrease in tension induced by catecholamines. On the contrary, the stimulatory catecholamine actions disappeared or were changed to smooth muscle relaxation by acetylcholine pretreatment. Potassium chloride pretreatment did not change the character of the adrenoceptor agonist action of the agonists studied.7 Since there is a similar prejunctional action at all distances from the ileocaecal valve and a different postjunctional effect of the adrenoceptor agonists at different distances from the ileocaecal junction, it could be suggested that in the guinea-pig ileum there are at least two alpha-adrenoceptors (inhibitory prejunctional-alpha(2), stimulatory postjunctional-alpha(1)), an inhibitory postjunctional beta-adrenoceptor and an as yet uncharacterized inhibitory postjunctional receptor.8 Based on the specific postjunctional action of phenylephrine and the prejunctional action of ephedrine in the guinea-pig ileum, these drugs could be used with success as ;specific' alpha(1)- and alpha(2)-adrenoceptor stimulants.     

Non-cholinergic,non-adrenergic responses to nerve stimulation of different regions of the guinea-pig small intestine

Summary Non-cholinergic, non-adrenergic responses to nerve stimulation recorded from smooth muscles of the guinea-pig duodenum, jejunum, proximal and terminal ileum were investigated in an attempt to characterize these responses.In the presence of atropine (1–2 mol · l^–1) and guanethidine (10 mol · l^–1) coaxial stimulation induced in all regions of the guinea-pig small intestine an initial relaxation (primary relaxation) upon which contraction (primary contraction) appeared, followed by rebound contraction.Noradrenaline decreased the cholinergic smooth muscle twitches, predominantly at low stimulation frequencies, and had a similar effect on the non-cholinergic, non-adrenergic primary relaxation, primary and rebound contractions.ATP decreased the smooth muscle twitches; however, this agent had only a transient influence on the non-cholinergic, non-adrenergic responses of muscle (tension and membrane potential) to single stimuli. With higher stimulus frequencies ATP increased the primary relaxation and decreased the contraction phases. ATP also inhibited the post-tetanic inhibition induced by non-cholinergic, non-adrenergic nerve stimulation.In most of the muscle cells of the guinea-pig proximal and terminal ileum the non-cholinergic, non-adrenergic nerve stimulation generated i.j.p.s., while about 15–20% of the cells responded with e.j.p.s. During long-lasting stimulation (10s) the i.j.p.s. were sometimes interrupted by action potentials or by a gradual depolarization of the membrane. The i.j.p.s. were followed by a marked rebound depolarization accompanying the action potentials. Those cells which generated i.j.p.s. in response to field stimulation, were depolarized by ATP, while those cells, which generated e.j.p.s, were hyperpolarized by ATP.A reduction in the concentration of extracellular sodium chloride decreased both the primary and rebound contractions; the primary contraction was, however, more sensitive than was the rebound contraction.Theophylline increased the primary and rebound contractions with no marked influence on the primary relaxation, lowered the action potential threshold, increased the rebound depolarization and did not markedly influence the i.j.p.s.Quinidine enhanced the primary relaxation and inhibited the primary contraction in a concentration-dependent manner. Inhibition of the rebound contraction by quinidine was slight (less than 50%).The present results demonstrate that primary relaxation, primary and rebound contractions are associated with i.j.p.s and e.j.p.s., and rebound depolarization with action potentials, respectively; they are typical responses of various regions of the guinea-pig small intestine to activation of inhibitory and excitatory non-cholinergic, non-adrenergic nerves. The P₁ and P₂ receptors, proposed by Burnstock (1975), probably do not mediate the non-cholinergic, non-adrenergic postsynaptic responses of the guinea-pig small intestine. A possible physiological function of ATP as a mediator of non-cholinergic, non-adrenergic nerves of the guinea-pig small intestine is discussed.This study was supported in part by JSPS Japan