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1.
Eur Rev Med Pharmacol Sci ; 12 Suppl 1: 21-31, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18924441

ABSTRACT

Capsaicin-sensitive extrinsic afferent nerves have been demonstrated to release biologically active substances in the gastrointestinal (GI) tract. This fact may be useful for identifying sensory transmitter substances in isolated organ experiments. In the GI tract of animals neuropeptides like tachykinins and calcitonin gene-related peptide (CGRP) mediate specific excitatory and inhibitory effects of capsaicin; some evidence indicates a participation of purinergic mechanisms as well. The human gut (especially the circular musculature) is powerfully relaxed by capsaicin, and this effect seems to have a completely different transmitter background (nitric oxide (NO) and maybe VIP, neither of them of intrinsic neuronal origin). We propose that NO may be a sensory neurotransmitter. The "local efferent" (mediator-releasing) effect of extrinsic afferent neurons can also be demonstrated in vivo, both in animals and man. Yet, nearly normal motility of the small and large intestines (i.e., the most "autonomous" part of the GI tract) is maintained in animals with functionally inhibited capsaicin-sensitive nerves. The importance of this system in regulating GI movements may be exaggerated under pathopysiological conditions, first of all inflammation. The afferent function of capsaicin-sensitive nerves plays a role in sympathetic reflexes, such as the inhibition of GI motility after laparotomy or by peritoneal irritation.


Subject(s)
Gastrointestinal Motility/physiology , Neurons, Afferent/physiology , Animals , Capsaicin/pharmacology , Gastrointestinal Diseases/drug therapy , Gastrointestinal Diseases/physiopathology , Gastrointestinal Motility/drug effects , Humans , Neurons, Afferent/drug effects
2.
Wien Klin Wochenschr ; 113(17-18): 647-60, 2001 Sep 17.
Article in English | MEDLINE | ID: mdl-11603099

ABSTRACT

We refer to the gut as a neurological organ to emphasize the particular importance of the nervous system in the regulation of digestive functions, given that the gastrointestinal tract is innervated by five different classes of neurons: intrinsic enteric neurons, vagal afferents, spinal afferents, parasympathetic efferents and sympathetic efferents. Virtually each aspect of digestive activity is under the regulatory influence of neurons, among which the enteric nervous system (ENS) plays the most important part. The ENS acts like a brain in the gut that functions independently of the central nervous system, contains programmes for a variety of gastrointestinal behaviours and governs the activity of all gastrointestinal effector systems according to need. Intrinsic sensory neurons supply the ENS with the kind of information that this system requires for its autonomic control of digestion, whereas extrinsic afferents notify the brain about any data that are relevant to energy and fluid homeostasis and the sensation of discomfort and pain. Many diseases of the gut, particularly the functional bowel disorders, seem to be related to dysfunction of the ENS and other components of the gastrointestinal innervation. The ENS and extrinsic afferents are hence prime targets for the therapeutic management of gut diseases and for the relief of the pain and discomfort associated with these disorders.


Subject(s)
Autonomic Nervous System/physiology , Colonic Diseases, Functional/physiopathology , Digestive System/innervation , Neurons/physiology , Abdominal Pain/etiology , Animals , Autonomic Nervous System/physiopathology , Colonic Diseases, Functional/complications , Gastrointestinal Motility , Humans , Neural Pathways , Neurons/pathology
3.
Curr Opin Pharmacol ; 1(6): 583-90, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11757813

ABSTRACT

The tachykinins substance P and neurokinin A participate in the regulation of gastrointestinal motility, secretion, vascular permeability and pain sensitivity. Advances made during the past two years corroborate a causal involvement of tachykinins in inflammation-induced disturbances of gut function, such as dysmotility, secretory diarrhoea, oedema and hyperalgesia. It would therefore appear that tachykinin receptors, which in the digestive system are expressed in a cell-specific manner, represent attractive targets for novel therapeutics in gastroenterology.


Subject(s)
Digestive System Physiological Phenomena , Gastrointestinal Diseases/metabolism , Receptors, Tachykinin/metabolism , Animals , Colonic Diseases, Functional/drug therapy , Digestive System/metabolism , Digestive System/pathology , Gastrointestinal Diseases/drug therapy , Gastrointestinal Diseases/pathology , Gastrointestinal Motility , Humans , Inflammatory Bowel Diseases/drug therapy , Neurokinin A/metabolism , Neurokinin A/physiology , Receptors, Neurokinin-1/metabolism , Receptors, Neurokinin-2/metabolism , Receptors, Neurokinin-3/metabolism , Receptors, Tachykinin/antagonists & inhibitors , Substance P/metabolism , Substance P/physiology
4.
Pain ; 80(1-2): 319-28, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10204745

ABSTRACT

Traction of the mesentery is known to induce strong autonomic reactions in patients undergoing abdominal surgery. An experimental model using this stimulus in anaesthetized rats has been developed, which allows the comparison of noxious mechanical and chemical stimulation of the mesentery. Graded traction on a bundle of jejunal vessels with 2-30 g led to reflex changes in blood pressure and intragastric pressure, the size of which correlated with the strength of the stimulus. Comparable responses were elicited by clamping the same vessels either at their distal or proximal end or by applying 100 microl 0.6% acetic acid or 0. microM bradykinin. These reflexes are fairly insensitive towards impairment of the autonomic system. Only the combination of phentolamine and propranolol reduced the cardiovascular responses to all stimuli but at the same time, significantly lowered basal blood pressure. The adrenoceptor antagonists affected the gastric response to acid only. Atropine on its own was ineffective. Administered together with the combination of adrenoceptor blockers it had no further influence on the cardiovascular reflexes but significantly reduced the gastric responses to stretch, proximal clamping and acid. Acute desensitization of small diameter afferents with capsaicin almost abolished the reflex responses to acid. The cardiovascular, but not the gastric, response to traction was reduced by capsaicin. Morphine led to dose-dependent reductions of the reflex responses in a naloxone-reversible manner, whereas indomethacin was inactive. The bradykinin B2-antagonist icatibant abolished the reflex in response to the application of bradykinin but not to acid or traction. It is concluded that the measurement of the cardiovascular and gastric responses of anaesthetized rats to traction on the mesentery is a suitable method to investigate acute visceral nociception. Chemical stimuli to the mesentery are transmitted by capsaicin-sensitive afferents, but there is a dichotomy regarding capsaicin's influence on visceral mechanonociception. Opioid mechanisms are always involved, whereas prostaglandins or bradykinin have no role in the reflexes evoked by acid or traction. Intact alpha- or beta-adrenergic (as tested with unselective receptor antagonists) or muscarinic mechanisms are required for the reaction of the end organs in the reflex but they have no role in the afferent or central processing.


Subject(s)
Mesentery/physiopathology , Nociceptors/physiology , Pain/physiopathology , Viscera/physiopathology , Anesthesia , Animals , Autonomic Nervous System/physiopathology , Blood Pressure , Disease Models, Animal , Female , Neurons, Afferent/drug effects , Neurons, Afferent/physiology , Rats , Rats, Sprague-Dawley , Stomach/physiopathology , Stress, Mechanical
5.
Pharmacol Ther ; 73(3): 173-217, 1997.
Article in English | MEDLINE | ID: mdl-9175155

ABSTRACT

The preprotachykinin-A gene-derived peptides substance P and neurokinin (NK) A are expressed in distinct neural pathways of the mammalian gut. When released from intrinsic enteric or extrinsic primary afferent neurons, tachykinins have the potential to influence both nerve and muscle by way of interaction with three different types of tachykinin receptor, termed NK1, NK2 and NK3 receptors. Most prominent among the effects of tachykinins is their excitatory action on gastrointestinal motor activity, which is seen in virtually all regions and layers of the mammalian gut. This action depends not only on a direct activation of the muscle through NK1 and/or NK2 receptors, but also on stimulation of excitatory enteric motor pathways through NK3 and/or NK1 receptors. In addition, tachykinins can inhibit motor activity by stimulating either inhibitory neuronal pathways or interrupting excitatory relays. A synopsis of the available data indicates that endogenous substance P and NKA interact with other enteric transmitters in the physiological control of gastrointestinal motor activity. Derangement of the regulatory roles of tachykinins may be a factor in the gastrointestinal dysmotility associated with infection, inflammation, stress and pain. In a therapeutic perspective, it would seem conceivable, therefore, that tachykinin agonists and antagonists are adjuncts to the treatment of motor disorders that involve pathological disturbances of the gastrointestinal tachykinin system.


Subject(s)
Esophagus/metabolism , Gastric Mucosa/metabolism , Intestinal Mucosa/metabolism , Neurokinin A/metabolism , Substance P/metabolism , Animals , Gastrointestinal Diseases/etiology , Gastrointestinal Diseases/metabolism , Gastrointestinal Motility/physiology , Humans , Nerve Fibers/metabolism , Neurokinin A/genetics , Neurokinin A/physiology , Neurokinin-1 Receptor Antagonists , Neurons, Afferent/cytology , Neurons, Afferent/metabolism , Receptors, Neurokinin-1/agonists , Receptors, Neurokinin-1/metabolism , Receptors, Neurokinin-2/agonists , Receptors, Neurokinin-2/antagonists & inhibitors , Receptors, Neurokinin-2/metabolism , Receptors, Neurokinin-3/agonists , Receptors, Neurokinin-3/antagonists & inhibitors , Receptors, Neurokinin-3/metabolism , Signal Transduction/physiology , Substance P/genetics , Substance P/physiology
6.
Pharmacol Ther ; 73(3): 219-63, 1997.
Article in English | MEDLINE | ID: mdl-9175156

ABSTRACT

The preprotachykinin-A gene-derived peptides substance (substance P; SP) and neurokinin (NK) A are expressed in intrinsic enteric neurons, which supply all layers of the gut, and extrinsic primary afferent nerve fibers, which innervate primarily the arterial vascular system. The actions of tachykinins on the digestive effector systems are mediated by three different types of tachykinin receptor, termed NK1, NK2 and NK3 receptors. Within the enteric nervous system, SP and NKA are likely to mediate, or comediate, slow synaptic transmission and to modulate neuronal excitability via stimulation of NK3 and NK1 receptors. In the intestinal mucosa, tachykinins cause net secretion of fluid and electrolytes, and it appears as if SP and NKA play a messenger role in intramural secretory reflex pathways. Secretory processes in the salivary glands and pancreas are likewise influenced by tachykinins. The gastrointestinal arterial system may be dilated or constricted by tachykinins, whereas constriction and an increase in the vascular permeability are the only effects seen in the venous system. Various gastrointestinal disorders are associated with distinct changes in the tachykinin system, and there is increasing evidence that tachykinins participate in the hypersecretory, vascular and immunological disturbances associated with infection and inflammatory bowel disease. In a therapeutic perspective, it would seem conceivable that tachykinin antagonists could be exploited as antidiarrheal, antiinflammatory and antinociceptive drugs.


Subject(s)
Digestive System Physiological Phenomena , Neurokinin A/physiology , Neurons, Afferent/physiology , Substance P/physiology , Animals , Digestive System/blood supply , Digestive System/innervation , Gastric Mucosa/blood supply , Gastric Mucosa/innervation , Gastric Mucosa/metabolism , Gastrointestinal Diseases/drug therapy , Gastrointestinal Diseases/etiology , Gastrointestinal Diseases/physiopathology , Humans , Intestinal Mucosa/blood supply , Intestinal Mucosa/innervation , Intestinal Mucosa/metabolism , Neurokinin A/therapeutic use , Neurons, Afferent/cytology , Pancreas/metabolism , Receptors, Tachykinin/metabolism , Regional Blood Flow/physiology , Saliva/metabolism , Signal Transduction/physiology , Substance P/therapeutic use , Synaptic Transmission/physiology
7.
Article in English | MEDLINE | ID: mdl-8878066

ABSTRACT

Nitric oxide is an important mediator of the relaxation in the rat gastric fundus. The present study investigates the role of NO in the rat gastric corpus in vitro, since the corpus differs from the fundus with regard to its physiological function and its spontaneous motor behaviour. In the presence of guanethidine electrically induced relaxations of circular, mucosa-free corpus strips precontracted with bethanechol were concentration-dependently reduced by the NO-synthase inhibitors L-NG-nitro-arginine (L-NNA) or L-NG-nitro-arginine-methyl-ester (L-NAME). The D-enantiomers were markedly less active. The inhibitory effect of L-NAME could be prevented by L-arginine. L-NNA and L-NAME, however, did not influence spontaneous motility or the bethanechol-induced contraction. Vasoactive intestinal polypeptide or sodium nitroprusside also relaxed the muscle strips, but these relaxations were not affected by L-NAME. When the corpus strips were stimulated electrically from baseline, they reacted with a contraction followed by relaxation. L-NNA or L-NAME blocked the relaxatory and enhanced the contractile component. In strips that also reacted with a rebound contraction, it was blunted by L-NAME. These effects of the NO-synthase inhibitors were abolished in the presence of atropine. Apamin increased the electrically induced contraction of the muscle strips. Inhibition of the relaxation together with a further shift to contraction could only be seen when apamin was combined with L-NNA. The inhibitory action of apamin and apamin + L-NNA was not influenced by atropine. The results demonstrate a role of NO in the relaxation of the circular muscle of the rat gastric corpus both at a postsynaptic site and via inhibition of acetylcholine release. The relaxation induced by vasoactive intestinal polypeptide does not involve NO.


Subject(s)
Apamin/pharmacology , Muscle, Smooth/drug effects , Nitric Oxide/physiology , Stomach/drug effects , Animals , Electric Stimulation , Enzyme Inhibitors/pharmacology , Female , In Vitro Techniques , Male , Muscle Contraction/drug effects , Muscle Relaxation/drug effects , NG-Nitroarginine Methyl Ester/pharmacology , Rats , Rats, Sprague-Dawley
8.
Br J Pharmacol ; 116(4): 2274-8, 1995 Oct.
Article in English | MEDLINE | ID: mdl-8564259

ABSTRACT

1. Cholecystokinin octapeptide (CCK-8) and gastrin-17 augment gastric mucosal blood flow in the rat. The present study examined whether the gastric vasodilator effect of these peptides is mediated by CCKA or CCKB receptors. 2. Intravenous injection of CAM-1481 (1 mg kg-1), a dipeptoid antagonist of CCKA receptors, or CAM-1028, a dipeptoid CCKB receptor antagonist (1 mg kg-1), had no effect on basal gastric mucosal blood flow as determined by the clearance of hydrogen in urethane-anaesthetized rats. 3. Intravenous infusion of CCK-8 or gastrin-17 (8-200 pmol min-1) increased gastric mucosal blood flow in a dose-dependent fashion. The CCKB receptor antagonist, CAM-1028, significantly attenuated the hyperaemic response to CCK-8 and gastrin-17 whereas the CCKA receptor antagonist, CAM-1481, did not antagonize CCK-8 but caused a slight attenuation of the vasodilator response to gastrin-17. 4. The selectivity of the two antagonists was proved by the findings that CAM-1028, but not CAM-1481, inhibited gastric acid secretion evoked by CCK-8 or gastrin-17 (CCKB receptor assay) while CAM-1481, but not CAM-1028, inhibited the CCK-8-induced contraction of guinea-pig isolated gall bladder strips (CCKA receptor assay). 5. These data show that the actions of CCK-8 and gastrin-17 to increase mucosal blood flow in the rat stomach are primarily mediated by CCKB receptors.


Subject(s)
Cholecystokinin/physiology , Gastric Mucosa/physiopathology , Hyperemia/physiopathology , Receptors, Cholecystokinin/physiology , Animals , Cholecystokinin/pharmacology , Dipeptides/pharmacology , Female , Gallbladder/drug effects , Gastric Acidity Determination , Gastric Mucosa/blood supply , Gastric Mucosa/drug effects , Gastrins/pharmacology , Guinea Pigs , In Vitro Techniques , Indoles/pharmacology , Meglumine/analogs & derivatives , Meglumine/pharmacology , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Rats , Rats, Sprague-Dawley , Receptors, Cholecystokinin/antagonists & inhibitors , Receptors, Cholecystokinin/drug effects , Regional Blood Flow/drug effects , Vasodilation/drug effects
9.
Br J Pharmacol ; 115(3): 486-90, 1995 Jun.
Article in English | MEDLINE | ID: mdl-7582461

ABSTRACT

1. Many studies indicate an involvement of substance P in the transmission of nociceptive stimuli, without, however, presenting any conclusive evidence as to its exact site and mode of action. The present experiments tested the involvement of substance P in the mediation of chemical nociception using the non-peptidic specific tachykinin NK1-receptor antagonist, RP 67580 (2-[1-imino-2-(2-methoxyphenyl-ethyl]-7,7diphenyl-4-perhydroiso indolone (3aR, 7aR)). 2. Mean arterial pressure (MAP) and intragastric pressure (IGP) were measured in anaesthetized rats. The reflex changes of these parameters in response to i.p. or s.c. injections of hydrochloric acid or capsaicin were taken to indicate nociception. 3. Intravenous administration of RP 67580 up to 5 mg kg-1 had little influence on the reflex changes in MAP or IGP in response to hydrochloric acid or capsaicin. In contrast, the sensitization of rats to i.p. capsaicin by preinjection of prostaglandin E2 was significantly reduced by 1 mg kg-1 RP 67580. 4. Intrathecal injection of 5 micrograms RP 67580 inhibited the reflex changes of MAP and IGP in response to i.p. or s.c. capsaicin whereas the inactive enantiomer RP 68651 was ineffective. 5. The results indicate that spinal NK1-receptors are involved in the acute transmission of chemically induced pain, while such receptors in the periphery take part in the sensitization by prostaglandin E2. The rather minor ability of i.v. RP 67580 to inhibit the acute nociceptive reflex is attributed to an insufficient penetration of the blood-brain-barrier.


Subject(s)
Analgesics/pharmacology , Indoles/pharmacology , Neurokinin-1 Receptor Antagonists , Substance P/physiology , Analgesics/administration & dosage , Animals , Blood Pressure/drug effects , Blood-Brain Barrier/drug effects , Capsaicin/administration & dosage , Capsaicin/toxicity , Female , Hydrochloric Acid/administration & dosage , Hydrochloric Acid/toxicity , Indoles/administration & dosage , Injections, Intraperitoneal , Injections, Intravenous , Injections, Spinal , Injections, Subcutaneous , Isoindoles , Male , Pain/drug therapy , Rats , Rats, Sprague-Dawley , Receptors, Neurokinin-1/physiology , Stereoisomerism , Substance P/antagonists & inhibitors
10.
Regul Pept ; 57(1): 19-42, 1995 May 04.
Article in English | MEDLINE | ID: mdl-7644701

ABSTRACT

For a long time research on the action of TKs on gastrointestinal tissue has been demonstrating the importance of the TKs as non-cholinergic stimulators of motility in most parts of the mammalian gastrointestinal tract. The past years witnessed the development of TK agonists and antagonists selective for the various receptor types, which prompted a wealth of new insight into the pharmacology and molecular biology of the TK receptors. This knowledge now allows a more specific elucidation of the role of TKs and their receptors in the various aspects of gastrointestinal motility, not only in normal tissue but also under pathological conditions.


Subject(s)
Gastrointestinal Motility/physiology , Receptors, Tachykinin/physiology , Amino Acid Sequence , Animals , Humans , Molecular Sequence Data , Species Specificity , Tachykinins/physiology
11.
Eur J Clin Invest ; 24(10): 664-8, 1994 Oct.
Article in English | MEDLINE | ID: mdl-7851466

ABSTRACT

In rats, the combined administration of the 5-HT2 antagonist ketanserin and the 5-HT3 antagonist tropisetron inhibits cholera toxin-induced intestinal secretion. We investigated whether these agents and the 5-HT3 antagonist ondansetron can inhibit cholera toxin-induced secretion in the human jejunum using a segmental perfusion technique. In a first control period the subjects' jejunums were perfused continuously with a plasma-like electrolyte solution. In a second control period they either received a combination of tropisetron plus ketanserin, or tropisetron or ondansetron alone. Cholera toxin 6.25 micrograms was then administered intrajejunally and the experiments were continued for 4 h. Net water movements during the 4th hour after CT administration minus net water movement during the first control period was used for further calculation and was referred to as net luminal gain. In perfusion studies with tropisetron plus ketanserin resp. ondansetron the net luminal gain of water (+ 161 +/- 26 resp. 189 +/- 28 ml 30 cm-1 h-1, mean +/- SEM) was significantly higher compared to perfusion studies with cholera toxin alone (+ 94 +/- 30). Treatment with tropisetron did not change the CT-induced net luminal gain of water (+ 108 +/- 41). Movements of sodium, chloride, bicarbonate and potassium paralleled the movement of water. In agreement with these observations we found a deterioration of clinical parameters after the end of the perfusion studies in four of five subjects treated with CT 25 micrograms plus ketanserin and tropisetron.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Cholera Toxin/pharmacology , Indoles/pharmacology , Jejunum/metabolism , Ketanserin/pharmacology , Serotonin Antagonists/pharmacology , Adult , Biological Transport/drug effects , Cholera Toxin/antagonists & inhibitors , Electrolytes/metabolism , Humans , Jejunum/drug effects , Tropisetron , Water/metabolism
12.
Neuropeptides ; 25(1): 47-50, 1993 Jul.
Article in English | MEDLINE | ID: mdl-7692342

ABSTRACT

The neuropeptide galanin has been shown to occur in nerve fibres in the circular muscle layer of the rat stomach. The present experiments aimed at demonstrating a functional correlate for this observation by testing the motor effects of galanin on circular strips of the rat gastric corpus in vitro. Exogenous galanin elicited only small contractions of the smooth muscle which were dose-related but did not show a clear sigmoid dose-response relationship. These responses were resistant to atropine plus guanethidine or TTX. When the muscle strips were electrically stimulated, they showed pronounced rebound contractions after the end of the stimulus. These rebound contractions were significantly reduced by either desensitizing the strips to galanin or by addition of spantide. It is concluded that galanin is released from the myenteric plexus in the stomach and acts to modulate gastric contractions either postsynaptically or by modifying the release of tachykinins.


Subject(s)
Myenteric Plexus/metabolism , Peptides/metabolism , Stomach/drug effects , Animals , Female , Galanin , Male , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Peptides/antagonists & inhibitors , Peptides/pharmacology , Rats , Rats, Sprague-Dawley , Substance P/analogs & derivatives , Substance P/pharmacology
13.
Gut ; 33(9): 1174-8, 1992 Sep.
Article in English | MEDLINE | ID: mdl-1427368

ABSTRACT

In order to develop a model for secretory diarrhoea and to confirm the in vitro effects of cholera toxin in man in vivo the effect of intrajejunally administered cholera toxin was investigated in healthy volunteers. An intestinal perfusion technique with an occluding balloon proximal to the infusion site was used. The jejunum was perfused under steady state conditions with a plasma like electrolyte solution containing polyethylene glycol as a non-absorbable volume marker. After two control periods of one hour each, during which water was absorbed at a rate of 104 (14) (mean (SEM), n = 15) and 94 (15) ml/30 cm/h, respectively, three different doses of cholera toxin (6.25 micrograms, 12.5 micrograms, 25 micrograms) were administered by bolus into the lumen of the jejunum. Cholera toxin reduced absorption of water and electrolytes progressively over four hours and induced secretion in a dose dependent fashion. In the fourth hour net secretion amounted to 22 (23), 36 (24), and 88 (40) ml/30 cm/h (each n = five) with doses of 6.25, 12.5, and 25 micrograms cholera toxin, respectively. The movement of sodium, chloride, and bicarbonate paralleled water movement. Our results suggest that cholera toxin may serve as a secretory model in the human jejunum which might allow testing of new antisecretory agents.


Subject(s)
Cholera Toxin/pharmacology , Jejunum/drug effects , Adult , Bicarbonates/metabolism , Chlorides/metabolism , Dose-Response Relationship, Drug , Female , Humans , Intestinal Absorption/drug effects , Jejunum/metabolism , Male , Potassium/metabolism , Sodium/metabolism , Water/metabolism
14.
Naunyn Schmiedebergs Arch Pharmacol ; 346(2): 219-25, 1992 Aug.
Article in English | MEDLINE | ID: mdl-1448184

ABSTRACT

Both visceral and somatic nociceptive stimuli elicit reflex changes in blood pressure and gastric motor activity, but the exact type of response varies with the type of nociceptive stimulus and its site of application. Therefore, the present study compared the effects of visceral (i.p. or i.a.) and somatic (s.c.) administration of bradykinin and HCl on both mean arterial blood pressure (MAP) and intragastric pressure in anaesthetized rats. The nervous pathways mediating these responses were investigated by surgical or pharmacological inhibition of the possible reflex arcs. Bradykinin (i.a.--into the aortic arch, i.p., and s.c.), and HCl (i.p. and s.c.), elicited a fall in MAP followed by a transient increase. Intragastric pressure decreased in response to administration of these chemicals. Acute coeliac ganglionectomy reduced the gastric relaxations in response to both bradykinin and HCl, whereas vagotomy reduced only the gastric relaxations induced by HCl. Neither lesion influenced the changes in MAP after either chemical. Ablation of small diameter afferents by capsaicin or chemical sympathectomy by guanethidine reduced the changes in MAP after both chemicals, except that which occurred after i.a. injection of bradykinin. The secondary increase in MAP after i.a. and i.p. administration of algesics was increased after guanethidine. Both pretreatments reduced gastric relaxations in response to either chemical. Pretreatment of the rats with the bradykinin antagonist Hoe-140 reduced the responses to bradykinin but not to HCl. The results show that both visceral and somatic administration of painful chemicals elicit reflex falls in MAP and intragastric pressure.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Blood Pressure/drug effects , Bradykinin/pharmacology , Hydrochloric Acid/pharmacology , Motor Activity/drug effects , Nociceptors/drug effects , Stomach/drug effects , Animals , Bradykinin/administration & dosage , Dose-Response Relationship, Drug , Female , Heart Rate/drug effects , Hydrochloric Acid/administration & dosage , Injections, Intra-Arterial , Injections, Intraperitoneal , Injections, Subcutaneous , Male , Muscle Relaxation/drug effects , Rats , Rats, Sprague-Dawley , Stomach/physiology
15.
Gastroenterology ; 101(2): 325-30, 1991 Aug.
Article in English | MEDLINE | ID: mdl-2065906

ABSTRACT

Neuropeptide Y is a neurotransmitter in enteric and postganglionic sympathetic neurons. In animal models of intestinal water and ion transport, neuropeptide Y decreases stimulated secretion but has no consistent effect on basal transport. In the present study, the effect of neuropeptide Y on jejunal water and electrolyte transport in healthy volunteers was investigated under basal conditions and during intestinal secretion induced by intraluminal administration of prostaglandin E2. The triple-lumen tube technique was used for perfusion of the small intestine with a plasmalike electrolyte solution containing polyethylene glycol as a nonabsorbable volume marker. After an initial control period (saline IV) neuropeptide Y was administered IV at a dose of 400 pmol.kg-1.h-1. Neuropeptide Y significantly increased net absorption of water, sodium, potassium, and chloride under basal conditions. The peptide significantly reduced the secretion of these electrolytes induced by an intraluminal prostaglandin E2 concentration of 5 mumol/L and reduced net water secretion by 36%. The results of the current study suggest that neuropeptide Y can change intestinal water and ion transport from secretion toward absorption.


Subject(s)
Intestinal Absorption/drug effects , Jejunum/metabolism , Neuropeptide Y/pharmacology , Water-Electrolyte Balance/drug effects , Adult , Bicarbonates/metabolism , Chlorides/metabolism , Dinoprostone/pharmacology , Female , Humans , Jejunum/drug effects , Male , Neuropeptide Y/blood , Potassium/metabolism , Sodium/metabolism , Water/metabolism
16.
Br J Pharmacol ; 103(4): 1958-62, 1991 Aug.
Article in English | MEDLINE | ID: mdl-1717093

ABSTRACT

1. Extrinsic reflexes elicited by changes in gastric wall tension play an important role in regulating gastric tone. The present study investigated whether such reflexes modulate gastric contractions induced by close arterially administered neurokinin A (NKA), substance P (SP), SP-methylester and bethancehol in anaesthetized rats. 2. Reflex pathways were acutely interrupted by either subdiaphragmatic vagotomy or prevertebral ganglionectomy. C-fibre afferent nerve activity was abolished by pretreating rats with capsaicin 10 to 16 days before the experiments. 3. The order of potency in inducing gastric contractions was NKA greater than SP greater than bethanechol. SP-methylester was markedly less effective than SP and its effects did not fit sigmoid dose-response curves (DRCs). The maximal responses to NKA, SP, and bethanechol were similar, whilst the DRC for SP was significantly flatter than those for NKA or bethanechol. Pretreatment of the rats with the peptidase inhibitors phosphoramidon or captopril did not increase the contractile response to SP. 4. Prevertebral ganglionectomy had no significant effect on the DRCs for SP and NKA, whereas vagotomy shifted the DRCs for all three test substances to the left. 5. Capsaicin pretreatment did not change the DRC for NKA in rats with intact vagus but shifted that for bethanechol to the left. The leftward of the DRC for NKA caused by vagotomy was prevented in capsaicin-pretreated rats whereas the vagotomy-induced shift of the DRC for bethanechol remained unaltered. The shift of the DRC for SP seen in response to vagotomy was only slightly reduced by capsaicin pretreatment. 6. These data may be interpreted as demonstrating two neuronal mechanisms for modulating drug-induced gastric contractions. First, the contractions themselves activate a vago-vagal negative feedback involving capsaicin-sensitive afferents. Second, NKA, and to a lesser degree SP, seem to induce a nonvagal non-splanchnic mechanism which via capsaicin-sensitive afferent neurones reinforces tachykinininduced gastric contractions.


Subject(s)
Bethanechol Compounds/pharmacology , Stomach/innervation , Tachykinins/pharmacology , Animals , Bethanechol , Dose-Response Relationship, Drug , Female , Male , Muscle Contraction/drug effects , Neurokinin A/pharmacology , Rats , Rats, Inbred Strains , Reflex/drug effects , Stomach/drug effects , Substance P/pharmacology
17.
Eur J Clin Invest ; 19(3): 272-7, 1989 Jun.
Article in English | MEDLINE | ID: mdl-2553424

ABSTRACT

Atrial natriuretic peptide (ANP) increases renal sodium and water excretion in several species including man. In rats ANP was also found to influence water and electrolyte transport in the small intestine. In the present study we investigated whether ANP can alter transport in the jejunum and ileum of healthy volunteers using a triple-lumen perfusion technique. The small intestine was perfused under steady-state conditions with a plasma-like electrolyte solution using polyethylene glycol as a nonabsorbable volume marker. After an initial control period with intravenous saline infusion ANP was administered intravenously at a dose of 400 pmol kg-1 h-1. This dose led to a significant (P less than 0.05) increase in the plasma levels of ANP (up to 22-fold) and cGMP (up to 15-fold), and of urine volume. Intestinal water and electrolyte transport were, however, not affected by ANP. Our results suggest that circulating ANP does not play a role in the regulation of mucosal water and ion transport in the human small intestine.


Subject(s)
Atrial Natriuretic Factor/pharmacology , Ileum/drug effects , Jejunum/drug effects , Water-Electrolyte Balance/drug effects , Adult , Atrial Natriuretic Factor/blood , Bicarbonates/metabolism , Blood Pressure/drug effects , Chlorides/metabolism , Cyclic GMP/blood , Female , Heart Rate/drug effects , Humans , Ileum/metabolism , Jejunum/metabolism , Male , Perfusion , Potassium/metabolism , Sodium/metabolism
18.
Eur J Pharmacol ; 162(1): 29-36, 1989 Mar 14.
Article in English | MEDLINE | ID: mdl-2470602

ABSTRACT

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.


Subject(s)
Capsaicin/pharmacology , Muscle, Smooth/drug effects , Animals , Autonomic Nervous System/drug effects , Calcitonin Gene-Related Peptide , Dimethylphenylpiperazinium Iodide/pharmacology , Female , In Vitro Techniques , Male , Muscle Contraction/drug effects , Muscle Relaxation/drug effects , Neuropeptides/pharmacology , Rats , Rats, Inbred Strains , Stomach/drug effects , Substance P/pharmacology , Tachyphylaxis/drug effects , Tetrodotoxin/pharmacology , Vasoactive Intestinal Peptide/pharmacology
19.
Br J Pharmacol ; 90(1): 273-9, 1987 Jan.
Article in English | MEDLINE | ID: mdl-2434177

ABSTRACT

Substance P and neurokinin A (substance K) were infused into the coeliac artery of anaesthetized rats at doses of 0.06-20 nmol min-1. Both tachykinins caused contractions of the stomach, the threshold dose of neurokinin A being 10 times lower than of substance P. The dose-response curve for substance P was flatter than that for neurokinin A. On circular muscle strips from the rat gastric corpus in vitro, the dose-response curves for both tachykinins were parallel, neurokinin A being 10 times more potent than substance P. The contractions in response to 10 microM neurokinin A and to 30 microM substance P were 58 and 54%, respectively, of the maximal contraction to bethanechol (1 mM). The effect of substance P was reduced by atropine both in vivo and in vitro. In vitro, the contractions to substance P were also reduced by tetrodotoxin but left unaffected by methysergide. The action of neurokinin A was not affected by these drugs. It is concluded that neurokinin A contracts rat stomach by a direct action on the circular smooth muscle, whereas the action of substance P is mediated, at least in part, by cholinergic interneurones.


Subject(s)
Gastrointestinal Motility/drug effects , Neuropeptides/pharmacology , Substance P/pharmacology , Animals , Atropine/pharmacology , Bethanechol , Bethanechol Compounds/pharmacology , Female , Guanethidine/pharmacology , In Vitro Techniques , Male , Neurokinin A , Rats , Rats, Inbred Strains , Tetrodotoxin/pharmacology
20.
Br J Pharmacol ; 89(3): 453-9, 1986 Nov.
Article in English | MEDLINE | ID: mdl-2432980

ABSTRACT

The effect of a substance P antagonist, [D-Pro2, D-Trp7,9]-substance P (SPA), on gastric emptying and gastrointestinal transit in the rat was studied in order to elucidate a possible physiological role of endogenous substance P and other tachykinins in gastrointestinal motility. SPA was given by intraperitoneal injection concurrently with the intragastric administration of a test meal containing charcoal and 51Cr. Examination 15 min after the test meal showed that SPA (0.13-1.3 mumol kg-1) inhibited gastric emptying and gastrointestinal transit in a dose-dependent manner. The inhibitory effect of SPA on gastric emptying and gastrointestinal transit remained unchanged after pretreatment of rats with mepyramine (8.7 mumol kg-1) plus cimetidine (19.8 mumol kg-1) or with guanethidine (67 mumol kg-1). Since a full examination of SPA as a specific tachykinin antagonist was not possible in vivo, SPA was also tested on circular muscle strips from the rat gastric corpus in vitro. Submaximal contractions in response to bombesin or bethanechol were not reduced by SPA (50 microM), whereas those in response to substance P were inhibited. The results suggest that SPA inhibits gastric emptying and gastrointestinal transit by interfering with the action of tachykinins released from enteric nerves and that endogenous tachykinins are involved in the regulation of gastrointestinal motility.


Subject(s)
Gastrointestinal Motility/drug effects , Neuropeptides/antagonists & inhibitors , Substance P/analogs & derivatives , Animals , Bombesin/pharmacology , Cimetidine/pharmacology , Female , Gastric Emptying/drug effects , Guanethidine/pharmacology , In Vitro Techniques , Male , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Pyrilamine/pharmacology , Rats , Rats, Inbred Strains , Substance P/pharmacology , Tachykinins
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