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PubMed2002

Anthelmintic paraherquamides are cholinergic antagonists in gastrointestinal nematodes and mammals.

Oxindole alkaloids in the paraherquamide/marcfortine family exhibit broad-spectrum anthelmintic activity that includes drug-resistant strains of nematodes. Paraherquamide (PHQ), 2-deoxoparaherquamide (2DPHQ), and close structural analogs of these compounds rapidly induce flaccid paralysis in parasitic nematodes in vitro, without affecting adenosine triphosphate (ATP) levels. The mechanism of action of this anthelmintic class was investigated using muscle tension and microelectrode recording techniques in isolated body wall segments of Ascaris suum. None of the compounds altered A. suum muscle tension or membrane potential. However, PHQ blocked (when applied before) or reversed (when applied after) depolarizing contractions induced by acetylcholine (ACh) and the nicotinic agonists levamisole and morantel. These effects were mimicked by the nicotinic ganglionic blocker mecamylamine, suggesting that the anthelmintic activity of PHQ and marcfortines is due to blockade of cholinergic neuromuscular transmission. The effects of these compounds were also examined on subtypes of human nicotinic ACh receptors expressed in mammalian cells with a Ca2+ flux assay. 2DPHQ blocked nicotinic stimulation of cells expressing alpha3 ganglionic (IC50 approximately 9 microm) and muscle-type (IC50 approximately 3 microm) nicotinic cholinergic receptors, but was inactive at 100 microm vs. the alpha7 CNS subtype. PHQ anthelmintics are nicotinic cholinergic antagonists in both nematodes and mammals, and this mechanism appears to underlie both their efficacy and toxicity.

Animals↗
PubMed1992

Role of the sympathetic system in impairment of the cerebrovascular CO2 responsiveness during moderate hypoglycemia.

We examined the mechanism of impairment of the cerebrovascular CO2 responsiveness in moderate hypoglycemia. Twelve fasted cats were used. The brain-PO2, brain-PCO2 and brain-pH were measured continuously with electrodes placed on the brain surface. Hypoglycemia was induced with insulin. Intravenous injection of hexamethonium (a sympathetic ganglion blocker, C6; 0.1 mg/kg) was performed at the following stages: Control, hypoglycemia and recovery. Before and after the C6 administration, 5% CO2 in air was inhaled for 3 min at the respective stages. The CO2 responsiveness (cerebrovascular dilatory response to increased PaCO2) at the control stage was not altered after the ganglionic blockade. At the hypoglycemic stage, the increase in BrPO2 by CO2 inhalation was significantly less than that at the control stage. This reduction of delta BrPO2 was significantly improved after the administration of C6. At the recovery stage, the CO2 responsiveness before and after the administration of C6 was not significantly different. An impaired CO2 responsiveness in the hypoglycemic state was improved by sympathetic ganglion blockade with C6 which did not alter the reactivity during normoglycemia. It is suggested that the sympathetic activity plays an important role in impairment of the cerebrovascular CO2 responsiveness during moderate hypoglycemia.

Animals↗
PubMed1991

Sympathoneural and skeletal muscle contributions to plasma dopa responses in pithed rats.

Dihydroxyphenylalanine (DOPA) in plasma has been thought to originate from sympathetic nerve endings and to reflect catecholamine biosynthesis, because changes in DOPA levels follow pharmacologically- or environmentally-induced manipulations that alter turnover of the sympathetic neurotransmitter, norepinephrine (NE). Skeletal muscle may be an additional, non-neural source of circulating DOPA. In the present study we examined sympathoneural and skeletal muscle contributions to DOPA in arterial plasma in pithed rats. Electrical stimulation of the spinal cord causes discharges of sympathetic post-ganglionic neurons, with attendant release of NE into the bloodstream, and discharges of spinal motoneurons, which causes diffuse contraction of skeletal muscle. Stimulation of the spinal cord rapidly elevated arterial plasma concentrations of NE, dihydroxyphenylglycol (DHPG), and DOPA. Pre-treatment with curare, a skeletal muscle relaxant, did not affect the NE and DHPG responses but attenuated the DOPA responses by about 50%. Administration of chlorisondamine, a ganglionic blocker, abolished NE and DHPG responses to cord stimulation, and DOPA responses were decreased by about 90%. Adrenal-demedullation did not affect the stimulation-induced DOPA responses. The results demonstrate that in pithed rats undergoing spinal cord stimulation, DOPA is released into the bloodstream. Since this response is markedly inhibited after ganglionic blockade and also attenuated after skeletal muscle paralysis, the results provide indirect evidence that DOPA formed in sympathetic neurons can be stored in a non-neuronal pool and released during skeletal muscle contraction.

Animals↗
PubMed1991

Microinjections of norepinephrine into the intermediolateral cell column of the spinal cord exert excitatory as well as inhibitory effects on the cardiac function.

Cardiac responses to microinjections of norepinephrine (NE) into the intermediolateral column of the spinal cord (IML) at T2 level were studied in pentobarbital-anesthetized, immobilized and artificially ventilated, male Wistar rats. For describing the effects of NE conveniently, the doses of NE were divided into two ranges. The small dose-range consisted of 20 nl volumes of 50, 75 and 100 micromolar (microM) solutions (i.e. 1, 1.5 and 2 pmole in 20 nl, respectively). The larger dose-range consisted of 20 nl volumes of 2.5, 25, 40 and 50 millimolar (mM) solutions (i.e. 0.05, 0.5, 0.8 and 1 nmole in 20 nl, respectively). Injections of small doses of NE (1-2 pmole) into the IML increased heart rate (HR); intravenous injections of these doses did not alter either blood pressure (BP) or HR. Larger doses of NE (0.05-1 nmole) elicited a decrease in HR; intravenous injections of these doses increased HR and BP. Maximum increase in HR was produced by injections of 1.5 pmole of NE into the IML; this effect was blocked by prior injections of prazosin (an alpha 1 adrenergic receptor antagonist; 50 pmole) but not idazoxan (an alpha 2 adrenergic receptor blocker; 10 pmole) into the IML. Maximum decrease in HR was elicited by injections of 0.8 nmole of NE into the IML; this effect was blocked by idazoxan (10 pmole) but not prazosin (50 pmole). Microinjections of idazoxan (10 pmole) alone increased HR while prazosin (50 pmole) alone was ineffective. Intravenous injections of chlorisondamine (a ganglion blocker) blocked the increase in HR elicited by injections of 1.5 pmole of NE into the IML.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1990

Differential venous effects of isoprenaline in conscious rats.

The role beta-adrenoceptors in the control of venous tone is not clear. This study examines the dose-response effects of isoprenaline, a non-selective beta-adrenoceptor agonist, on mean circulatory filling pressure (MCFP), an index of body venous tone, in conscious and unrestrained rats. Dose-response curves of isoprenaline were constructed in three groups of rats, namely, I, intact; III, pretreated with the ganglionic blocker hexamethonium; and V, pretreated with noradrenaline. Three additional groups, Groups II, IV and VI, served as time controls and were treated similar to I, III and V, respectively, except that they were given normal saline in place of isoprenaline. The infusion of isoprenaline in intact rats dose dependently decreased mean arterial pressure (MAP) and increased heart rate (HR) and MCFP while in the ganglionic-blocked rat, it caused similar effects on MAP and HR but had no significant effects on MCFP. In rats given noradrenaline, isoprenaline again decreased MAP and increased HR and, in contrast to the other two groups, it decreased MCFP. The results show that isoprenaline has variable venous effects depending on existing venous tone. It causes reflex-mediated venoconstriction under normal conditions due to its hypotensive effects and direct venodilatation when venous tone is elevated by the infusion of noradrenaline.

Animals↗
PubMed2000

Portal GLP-1 administration in rats augments the insulin response to glucose via neuronal mechanisms.

The incretin glucagon-like peptide-1 (GLP-1)-(7---36) amide is an important factor in prandial glucose homeostasis. Findings that GLP-1 is rapidly inactivated led to the hypothesis that the target of GLP-1 is close to the site of release. To investigate whether the target tissue is located in the hepatoportal system, we administered GLP-1 with glucose into the portal vein of rats and compared this with peripheral GLP-1 administration (jugular vein) and studied the effects of blockers of the nervous system. Portal GLP-1 augmented the insulin response to a portal glucose bolus by 81% (P < 0.01) and markedly improved the glucose disposal rate (P < 0.05). Peripheral administration of GLP-1 produced a similar augmentation of the insulin response (88%) and of the glucose disposal rate. However, only the effect of portal GLP-1 on insulin secretion was blocked by the ganglionic blocker chlorisondamine. The data suggest that prandial beta-cell stimulation by GLP-1 is evoked via a neural reflex triggered in the hepatoportal system. Because absorbed nutrients and GLP-1 first appear in the portal system, this mechanism may constitute a major pathway of GLP-1 action during meals.

Animals↗
PubMed1998

Insulin secretion by gastrin-releasing peptide in mice: ganglionic versus direct islet effect.

Gastrin-releasing peptide (GRP) stimulates insulin secretion by a direct islet effect. In this study, we initially demonstrated, by immunocytochemistry of the mouse pancreas, GRP immunoreactive nerve fibers within exocrine tissue, islets, and intrapancreatic ganglia. A more pronounced GRP innervation was found in ganglia compared with in islets. We therefore studied whether indirect cholinergic mechanisms contribute to the insulinotropic action of GRP. In mice, the insulinotropic response to GRP (4.25 nmol/kg i.v.) was inhibited by the m3-selective, muscarinic receptor antagonist 4-diphenylacetoxy-N-methyl piperidine methobromide (4-DAMP, 0.21 mol/kg; by 68%, P < 0.05) and by the ganglionic blocker hexamethonium (28 mol/kg; by 98%, P < 0.05). In contrast, in isolated islets, 4-DAMP or hexamethonium (10 or 100 microM) did not inhibit GRP (100 nM)-induced insulin secretion. Furthermore, afferent denervation by neonatal capsaicin did not affect the insulin response to GRP. We conclude that the insulinotropic effect of GRP in the mouse is mediated by both direct islet effects and through activation, at the ganglionic level, of postganglionic cholinergic nerves. In vivo, the indirect cholinergic mechanism predominates.

Animals↗
PubMed1990

Effects of calcium channel blockers and hydralazine on plasma glucose levels in streptozotocin-induced diabetic rats in vivo.

Effects of calcium channel blockers from structurally different classes and hydralazine on plasma glucose levels were examined in streptozotocin-induced diabetic rats in vivo. Non-dihydropyridine calcium channel blockers (verapamil, diltiazem, 1.0-10 mg/kg, i.p.) did not significantly affect the basal plasma glucose level, and dihydropyridine calcium channel blockers (nifedipine, 0.1-0.3 mg/kg, i.p,; nicardipine, 0.35-0.70 mg/kg, i.p.) caused mild hyperglycemia, which was blocked by the administration of the beta-adrenoceptor antagonist propranolol. In contrast, hydralazine markedly produced hyperglycemia, which was also inhibited by the combined administration of propranolol. The selective alpha 1-adrenoceptor antagonist prazosin greatly potentiated the hydralazine-induced hyperglycemia. Isoproterenol alone showed hyperglycemia similar to that of hydralazine. Hexamethonium (40 mg/kg, i.p.), a ganglionic blocker, blocked the hydralazine-induced hyperglycemia. There was a negative correlation between the hyperglycemic effect and the blood pressure lowering effect by different doses of hydralazine in streptozotocin-diabetic rats, but not in normal rats. These results suggest that endogenous catecholamines are involved in the hydralazine-induced hyperglycemia through the interaction with beta-adrenoceptors in streptozotocin-diabetic rats in vivo.

Animals↗
PubMed1989

Nicotine-induced inhibition of cerebellar Purkinje neurons: specific actions of nicotine and selective blockade by mecamylamine.

The specificity and pharmacological characteristics of the effects of local administration of nicotine on cerebellar Purkinje cells in the rat were examined electrophysiologically. Local application of nicotine, whether by pressure-ejection or by iontophoresis, depressed the spontaneous discharge of Purkinje neurons in a reversible and dose-dependent manner. This action could not be mimicked by local application of vehicle alone. The inhibitory effects of (-)-nicotine were several-fold more potent than that of the (+)-enantiomer. Systemic administration of the ganglion blocker mecamylamine reliably and reproducibly antagonized the nicotine-induced inhibitions of Purkinje cells whereas nicotine-induced excitation of interneurons was not altered. Local pressure-ejection of mecamylamine also antagonized the inhibitory actions of nicotine, administered by iontophoresis. Since the central effects of nicotine on behavior are stereospecific and sensitive to mecamylamine, the data in this study further support the hypothesis that the actions of nicotine on Purkinje neurons are mediated by ganglionic-like receptors. These findings also suggest that the Purkinje cell may serve as a good cellular model for studies on central pharmacology of nicotine.

Animals↗
PubMed1987

Effects of cholinergic drugs on muscle contraction in Moniliformis moniliformis (Acanthocephala).

In whole Moniliformis moniliformis spontaneous muscle contractions were rhythmic; longitudinal contractions were measured with a force transducer. The cholinergic agonists levamisole and nicotine significantly increased muscle tension in whole worms; these contractions were tonic and were antagonised by the ganglionic blocker pentolinium and by piperazine. In addition, levamisole-induced contractions were inhibited by gallamine, hexamethonium, and norepinephrine. In worm segments, where drugs in solution were injected through the worms, acetylcholine (ACh) and nicotinic agonists were effective in causing contractions, whereas muscarinic agonists in concentrations up to 1 mM had no effect. Although muscle contraction in M. moniliformis was induced by nicotinic agonists, these contractions were effectively antagonised by a range of chemicals that block ganglionic, skeletal, and muscarinic sites in vertebrates. The presence of ACh in M. moniliformis and the effects of nicotinic agonists on muscle contraction suggest that ACh is a putative excitatory neurotransmitter.

Acanthocephala↗
PubMed1994

Epibatidine, an alkaloid from the poison frog Epipedobates tricolor, is a powerful ganglionic depolarizing agent.

Epibatidine, a newly discovered alkaloid from the skin of Dendrobatidae frogs, has structural similarities to nicotine. We examined the effects of epibatidine on cardiorespiratory function and ganglionic synaptic transmission. Superior cervical or splanchnic sympathetic nerve discharge (sSND) and phrenic nerve discharge (PND) were recorded along with arterial pressure (AP) in urethane-anesthetized, paralyzed and artificially ventilated rats. Epibatidine administered i.v. at low doses (0.5-2 micrograms/kg) produced a transient increase in AP and sSND, followed by a decrease and return to baseline; this low dose of epibatidine also produced a dose-dependent increase in PND. At high doses (cumulative dose of 8-16 micrograms/kg), epibatidine produced bradycardia, a profound depression in sSND and a transient elimination of PND. After i.v. administration of the ganglionic blocker chlorisondamine (5 mg/kg), AP was still increased by 1 microgram/kg epibatidine (+39 +/- 11 mm Hg). This pressor effect was not altered by pretreatment with the alpha-1 adrenergic antagonist phentolamine (+40 +/- 10 mm Hg); however, it was blocked by additional pretreatment with the vasopressin antagonist [beta-mercapto-beta,beta-cyclopentamethylenepropiony1, O-ET-Tyr2,Val4,Arg8]vasopressin (50 micrograms/kg i.v.; +2 +/- 0.4 mm Hg). Low doses of epibatidine (0.5-2 micrograms/kg) produced firing of postganglionic neurons in a decentralized ganglion preparation and potentiated synaptic transmission; at high doses (cumulative dose of 8-16 micrograms/kg), the alkaloid blocked ganglionic synaptic transmission. These results suggest that epibatidine is a potent agonist of ganglionic nicotinic receptors and that the alkaloid elicits cardiorespiratory effects similar to those of nicotine.

Alkaloids↗
PubMed1984

Effect of paraventricular lesions on corticotropin-releasing factor (CRF)-like immunoreactivity in the stalk-median eminence: studies on the adrenocorticotropin response to ether stress and exogenous CRF.

Corticotropin-releasing factor-like immunoreactivity (CRF) and plasma ACTH were measured in rats bearing bilateral lesions of the paraventricular nucleus (PVN). Four to 6 days after stereotaxic surgery, CRF-like immunoreactivity content of the stalk-median eminence was reduced by 87-90% and the ACTH response to a 3-min ether stress was greatly attenuated (70-85% reduction). In order to differentiate between possible effects of CRF, catecholamines, and arginine vasopressin (AVP), the following treatments were used: group I, sham/vehicle; group II, sham/AVP-antagonist; group III, sham/ganglionic blocker chorisondamine; group IV, PVN-lesions/vehicle; group V, PVN-lesion/AVP antagonist; group VI, PVN-lesion/chlorisondamine. Blood was sampled at 0, 5, and 15 min after a 3-min exposure to ether vapor. PVN lesions alone greatly attenuated the ACTH response to ether stress by 70-85% (group IV), whereas basal ACTH levels were not affected. Chlorisondamine alone (group III) was as effective as PVN lesions in reducing the secretion of ACTH due to stress. When PVN-lesioned animals were treated with the ganglionic blocker, the residual ACTH response was completely abolished (group VI). The AVP-antagonist alone reduced the response at +15 min by 45%, whereas the antagonist given to PVN-lesioned animals completely abolished the response at 15 min. Injection of 0.15 nmol ovine CRF into PVN-lesioned rats resulted in a dramatically increased ACTH response (328% at 15 min) in comparison to the response of sham-operated rats. We conclude that: 1) CRF originating from neurons within the PVN is the predominant regulator of stress-induced ACTH secretion; 2) catecholamines and AVP are involved in mediating stress-induced ACTH secretion, most probably as CRF-potentiating agents; and 3) pituitary hyperresponsiveness to exogenous CRF results from removal of endogenous CRF.

Adrenocorticotropic Hormone↗
PubMed1984

Nicotinic receptors in mammalian brain.

Nicotine has marked effects on CNS function increasing brain excitability and spontaneous activity and also has antinociceptive actions. Agonist radioligands for the nicotinic cholinergic receptor bind with high affinity in a saturable manner. Binding is however, insensitive to the ganglionic blockers, hexamethonium and mecamylamine. This suggests that agonists and antagonists bind to different sites on the receptor or that the nicotinic receptor in brain is different from that found in peripheral tissues. The nicotinic antagonist, dihydro-beta-erythroidine binds with high affinity (Kd = 4 nM) to rat brain membranes in a stereospecific, saturable, manner with a regional distribution similar to that seen with radiolabeled acetylcholine. Binding is insensitive to hexamethonium and mecamylamine. It is concluded that the nicotinic recognition sites to which dihydro-beta-erythroidine binds are neuromuscular rather than ganglionic in nature.

Animals↗
PubMed1990

Neurophysiological evidence for and characterization of the post-ganglionic innervation of the adrenal gland in the rat.

The aim of this study was to examine and characterize the post-ganglionic innervation of the adrenal gland, using a neurophysiological nerve recording technique. Adrenal multifibre nerve activity was recorded in chloralose-anaesthetized Wistar rats. To test for post-ganglionic nerve activity, trimethaphan, a ganglionic blocker, was given intravenously. About 60% of the adrenal nerve preparations tested responded with a marked decrease in nerve activity (to 52 +/- 11% of pre-trimethaphan activity, P less than 0.01), while other nerves responded with an increase in activity (to 152 +/- 29% of pre-trimethaphan activity, P less than 0.01). Based on these responses, the nerves were considered to contain predominantly post- or preganglionic fibres respectively, and the difference in response to an intravenous injection of trimethaphan between the two groups was significant (P less than 0.01). It was also demonstrated that the post-ganglionic adrenal nerve activity had a greater variability in firing pattern than preganglionic adrenal nerve activity. We also examined whether there was any cardiac rhythmicity in the investigated nerves. There was a weak cardiac rhythmicity in six out of 12 post-ganglionic adrenal nerves, but there was no cardiac rhythmicity in the remaining six post-ganglionic nerves, and we observed no cardiac rhythmicity in preganglionic nerves. In contrast, renal sympathetic nerves showed a profound cardiac rhythmicity. Our results might explain recent histological findings of a direct post-ganglionic innervation of the adrenal cortex. We speculate that this nerve population is involved in steroid synthesis indirectly via regulation of the cortical blood flow or directly via a direct innervation of parenchymal cells in the adrenal cortex.

Adrenal Glands↗
PubMed1987

Neurogenic vasodilatation produced by fenoldopam in the rat hindquarters vascular bed.

1 The effects of local administration of the selective DA1-receptor agonist fenoldopam into the isolated autoperfused rat hindquarters were studied in order to investigate the site of action of fenoldopam in this vascular bed. 2 Bolus injections of fenoldopam produced reductions in perfusion pressure in the preconstricted, constant flow perfused rat hindquarters vascular bed. 3 The vasodilator effect of fenoldopam was abolished by sectioning of the lumbar sympathetic nerves and by pretreatment with the ganglion-blocker hexamethonium or the alpha-adrenoreceptor antagonists phentolamine and prazosin. At the same concentration, local infusion of fenoldopam had no effect on vasoconstrictor responses to locally administered noradrenaline and phenylephrine. 4 The vasodilator effect of fenoldopam was antagonized by the non-selective dopamine receptor antagonist RS-sulpiride and by the selective DA1-receptor antagonist SCH 23390, but not by the selective DA2-receptor antagonist domperidone. 5 These results provide no evidence for the presence of postsynaptic DA1-receptors in the rat hindquarters vascular bed; they show that fenoldopam induces neurogenic vasodilatation in this vascular bed, probably via stimulation of ganglionic DA1-receptors.

Animals↗
PubMed1983

Possible mechanism of action of metoclopramide-induced aldosterone secretion: in vivo and in vitro studies in the sheep.

To define further the mechanism by which metoclopramide, a dopamine antagonist, stimulates aldosterone secretion, seven lambs were injected iv with metoclopramide during a constant infusion of 5% dextrose in water and again during a constant infusion of trimethapan, a ganglionic blocker. In addition, suspensions of adrenal zona glomerulosa cells from the lambs were incubated in vitro in the presence of various concentrations of metoclopramide and known secretagogues. Plasma aldosterone concentrations increased in response to both metoclopramide and trimethaphan. However, during the trimethaphan infusion, no further increase in plasma aldosterone concentrations occurred after metaclopramide injection. In vitro, aldosterone concentrations in the zona glomerulosa cell suspensions increased in the presence of ACTH, potassium, and angiotensin II, but no increase in aldosterone concentration occurred in the presence of metoclopramide. These results suggest that in the sheep, metoclopramide stimulates aldosterone secretion by an indirect mechanism. This mechanism may involve the autonomic nervous system, since ganglionic blockade appeared to abolish the aldosterone response to metoclopramide.

Adrenal Glands↗
PubMed1988

Activation of the adrenal cortex or the peripheral sympatho-adrenomedullary system does not necessarily influence milk ejection in the rat.

Following a 5-h isolation period, primiparous rats have the same milk supply on days 8/9 and 13/14 post partum, yet in response to suckling they release a greater amount of milk at the latter time. Inasmuch as stress is known to inhibit lactation and handling of the pups is stressful to the dams, the question arose as to whether separation from pups before nursing constitutes a greater stress for the dam at the earlier stage of lactation. This possibility was explored in the present study: As an index of stress, changes in plasma corticosterone were measured from chronically cannulated dams. In addition, the role of adrenal hormones and the peripheral sympathetic nervous system in the regulation of milk ejection under these experimental conditions was assessed following bilateral adrenalectomy and treatment with pentolinium, a ganglionic blocker which does not cross the blood-brain barrier. Corticosterone pellets were implanted subcutaneously following adrenalectomy in order to maintain proper lactation. From the results obtained, lactators demonstrated a greater increase in plasma adrenocorticosteroid levels in response to nursing on day 8/9 than on day 13/14 post partum, but milk yield was significantly less at the earlier than at the later stage of lactation. Adrenalectomy in conjunction with corticosterone replacement pellets did not alter milk supply or milk release. The subsequent treatment with pentolinium did not affect milk ejection. Pups still ingested less milk on day 9 than on day 13/14. It is suggested here that the isolation/suckling condition imposed on lactators may be more stressful earlier in lactation. Inasmuch as removal of the adrenal hormones along with ganglionic blockade did not modify the amount of milk ingested by the pups, it is concluded that the smaller milk release observed on day 9 post partum does not result from a direct suppression by the adrenal hormones or by the peripheral sympathetic nervous system on milk ejection.

Adrenal Cortex↗
PubMed1989

Substance P: mechanism of action and receptor distribution at the feline ileocecal sphincter region.

The purpose of this study was to determine the mechanism of action of substance P at the distal ileum, ileocecal sphincter (ICS), and proximal colon in the cat and to determine the localization of substance P receptors at these sites by autoradiography. Intraluminal pressures and myoelectric activity were recorded at the feline distal ileum, ICS, and colon. Substance P caused a tonic and phasic spike-dependent contractile response at all three sites. The antagonists propranolol, phentolamine, and naloxone did not affect the contractile response to substance P at the ileum, ICS, or colon. The ganglionic blocker trimethaphan camsylate potentiated the response to substance P at all three sites, P less than 0.05. Both atropine and tetrodotoxin reduced the response of substance P at the ileal site. At the ICS, atropine or tetrodotoxin reduced, but did not obliterate, the effect of substance P. Neither atropine nor tetrodotoxin reduced substance P-induced colonic contractions. By use of autoradiography, specific binding for substance P was determined to be present at all three sites with the greatest concentration of substance P receptors in the circular muscle layer. In conclusion, these studies suggest multiple sites of action of substance P. At the ileum, substance P causes contraction via a cholinergic pathway. At the ICS, substance P has an excitatory action through a cholinergic pathway and also at smooth muscle receptors. In the proximal colon, the excitatory action of substance P is via smooth muscle receptors. An inhibitory ganglionic pathway also exists at all three sites. Substance P receptors exist predominantly in the circular muscle region of the ileum, ICS, and the proximal colon.

Animals↗