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P Holzer

Publications and source records attributed to P Holzer.

At least 73 records · Page 4Linked to original sources
PubMed1998

Tachykinins as targets of gastroenterological pharmacotherapy.

The term "tachykinins" is the name for a large family of small peptides. In the digestive tract, tachykinins (substance P, neurokinin A) are neurotransmitters which regulate motor activity, secretion of ions and fluid, and vascular functions. Their effects are mediated by three different receptors (NK(1), NK(2), NK(3)) which are expressed by the gastrointestinal effector systems in a cell-specific manner. Pathophysiological implications of the tachykinins substance P and neurokinin A in the gut include: changes in the expression of tachykinins and tachykinin receptors; implications of tachykinins in gastrointestinal motor disturbances; implications of tachykinins in diarrhea and gastrointestinal inflammation; and implications of tachykinins in visceral sensitivity and pain. Gut disorders of various etiology, particularly those due to infection or inflammation, are related to changes in the gastrointestinal expression of tachykinins and their receptors. It is hypothesized, therefore, that the contribution of tachykininergic neurons to normal gastrointestinal physiology is out of balance in the diseased gut.

Journal Article↗
PubMed1997

Inhibition of acid-induced hyperaemia in the rat stomach by endogenous NK2 receptor ligands.

Since exogenously applied tachykinins (substance P and neurokinin A) prevent the neurogenic hyperaemia which is elicited by acid back-diffusion in the rat stomach, we investigated whether endogenous tachykinins would act in a similar manner. Acid back-diffusion, induced by perfusing the stomach with 15% ethanol in the presence of 0.05 M HCI, increased gastric mucosal blood flow (GMBF) by 60-100% as determined by hydrogen clearance in urethane-anaesthetized rats. This response remained unchanged after pretreatment with the tachykinin NK1 receptor antagonist SR 140,333 (300 nmol/kg) but tended to be enhanced by the NK2 receptor antagonist MEN 10,627 (200 nmol/kg). When given during ongoing acid back-diffusion, MEN 10,627 significantly enhanced the acid-evoked vasodilatation as compared with vehicle or SR 140,333. We conclude that endogenously released tachykinins, acting via NK2 receptors, limit the gastric hyperaemic response to acid.

Animals↗
PubMed1997

Involvement of nitric oxide in the substance P-induced inhibition of intestinal peristalsis.

Although considered as an intestinal motor stimulant, substance P can inhibit intestinal peristalsis via stimulation of tachykinin NK1 receptors. Since NK1 receptors are present on enteric nitrergic neurones, the contribution of nitric oxide (NO) to the peristaltic motor inhibition caused by tachykinins was examined in luminally perfused segments of isolated guinea-pig ileum. Substance P (100 nM) and the NK1 receptor agonist substance P methyl ester (100 nM) increased the intraluminal pressure threshold at which peristaltic contractions were elicited. This inhibitory influence on peristalsis was prevented by the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (300 microM) in an enantiomer-selective manner. It is concluded that the substance P/NK1 receptor-mediated depression of intestinal peristalsis involves inhibitory motor pathways utilizing NO as a transmitter.

Animals↗
PubMed1997

Tachykinins in the gut. Part I. Expression, release and motor function.

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.

Animals↗
PubMed1997

Tachykinins in the gut. Part II. Roles in neural excitation, secretion and inflammation.

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.

Animals↗
PubMed1997

Gastric mucosal blood flow regulation in response to different stimuli.

We compared changes in gastric mucosal blood flow (GMBF) and left gastric artery blood flow (LGABF) in response to pharmacological, physiological, and pathological stimuli. GMBF and LGABF were measured by the hydrogen gas clearance and perivascular ultrasonic transit time techniques, respectively, under baseline conditions and following intravenous infusion of vasopressin or pentagastrin, isovolemic hemodilution, or gastric perfusion with HCl-taurocholate. Blood flow changes following vasopressin or hemodilution were significantly larger in the left gastric artery than in the gastric mucosa. In contrast, the increment in blood flow associated with pentagastrin-stimulated acid secretion was significantly greater in the gastric mucosa than in the extramural artery. Barrier disruption with acid-taurocholate induced similar changes in both measurement sites. The gastric hyperemia induced by either mechanism was significantly attenuated by blockade of NO synthesis. These data demonstrate that although functional changes in GMBF are primarily supported by changes in blood flow at the extramural gastric arteries, the gastric mucosal microvasculature is also under the influence of independent local control mechanisms.

Anemia↗
PubMed1997

Nitric oxide-dependent and -independent vascular hyporeactivity in mesenteric arteries of portal hypertensive rats.

1. Increased production of nitric oxide (NO) has been suggested to underlie both the vascular hyporeactivity to vasoconstrictors and the splanchnic vasodilatation seen in portal hypertension. This study assessed the role of NO in the vasoconstrictor hyporeactivity of portal vein-ligated (PVL) rats in isolated and in situ perfused mesenteric arterial beds. 2. Isolated perfused mesenteric arteries of PVL rats were significantly less reactive to noradrenaline (NA), methoxamine (METH), arginine vasopressin (AVP) and endothelin-1 (ET-1) than those from sham-operated (Sham) rats. 3. Blockade of NO synthesis with NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) in isolated perfused mesenteric arteries from PVL rats restored the reactivity to bolus injections of AVP and ET-1, but had little effect on the hyporeactivity to NA or METH. Cyclo-oxygenase inhibition with indomethacin (5 microM) likewise did not restore reactivity to METH of isolated perfused mesenteric arteries of PVL rats. 4. The hyporeactivity to METH seen in isolated perfused mesenteric arteries from PVL rats was reduced by low concentrations of AVP (20 nM) or ET-1 (1 nM) which per se caused only a slight increase in perfusion pressure. When L-NAME (100 microM) was combined with AVP (20 nM) or ET-1 (1 nM), respectively, reactivity to METH of isolated perfused mesenteric arteries of PVL rats was restored to the level seen in Sham rats. These effects of AVP and ET-1 were not mimicked by precontracting the vessels with 5-hydroxytryptamine (5 microM). 5. The differential effects of L-NAME and AVP on the hyporesponsiveness to methoxamine and AVP were corroborated by experiments performed with the in situ perfused mesenteric vascular bed preparation. 6. These data indicate that both NO-dependent and NO-dependent mechanisms are involved in the vasoconstrictor hyporesponsiveness of mesenteric arteries from portal hypertensive rats. The hyporeactivity to AVP and ET-1 is mediated by NO whereas the reduced responsiveness to adrenoceptor agonists appears to be predominantly NO-independent AVP and ET-1, in addition, seem to inhibit the NO-independent mechanism of vascular hyporeactivity, since the hyporesponsiveness to METH was reduced in the presence of AVP or ET-1 and abolished by the combination of these peptides with L-NAME.

Animals↗
PubMed1997

Dilatation by angiotensin II of the rat femoral arterial bed in vivo via pressure/flow-induced release of nitric oxide and prostaglandins.

1. The haemodynamic effects of angiotensin II (AII) and, for comparison, arginine vasopressin (AVP) in the femoral and superior mesenteric artery of urethane-anaesthetized rats were analysed with the ultrasonic transit time shift technique. 2. I.v. bolus injection of AII (0.1-3 nmol kg-1) and AVP (0.03-1 nmol kg-1) increased blood pressure which was accompanied by a decrease in blood flow through the superior mesenteric artery and an increase in femoral blood flow. The femoral hyperaemia was in part due to vasodilatation as indicated by a rise of femoral vascular conductance up to 200% relative to baseline. The femoral vasodilatation caused by AVP, but not AII, was followed by vasoconstriction. 3. Blockade of angiotensin AT1 receptors by telmisartan (0.2-20 mumol kg-1) prevented all haemodynamic responses to AII. 4. The femoral dilator responses to AII and AVP depended on the increase in vascular perfusion pressure since vasodilatation was reversed to vasoconstriction when blood pressure was maintained constant by means of a gravity reservoir. However, the AII-evoked femoral vasodilatation was not due to an autonomic or neuroendocrine reflex because it was not depressed by hexamethonium (75 mumol kg-1), prazosin (0.25 mumol kg-1) or propranolol (3 mumol kg-1). 5. The AII-induced femoral vasodilatation was suppressed by blockade of nitric oxide (NO) synthesis with NG-nitro-L-arginine methyl ester (L-NAME, 40 mumol kg-1) and reversed to vasoconstriction when L-NAME was combined with indomethacin (30 mumol kg-1), but was left unaltered by antagonism of endothelin ETA/B receptors with bosentan (37 mumol kg-1). 6. These results demonstrate that the effect of AII to increase systemic blood pressure and the resulting rise of perfusion pressure in the femoral artery stimulates the formation of NO and prostaglandins and thereby dilates the femoral arterial bed. This local vasodilator mechanism is sufficient to mask the direct vasoconstrictor response to AII.

Angiotensin II↗
PubMed1997

Dual excitatory and inhibitory effect of nitric oxide on peristalsis in the guinea pig intestine.

The implications of the enteric neurotransmitter nitric oxide (NO) in intestinal peristalsis were investigated. Propulsive motility in isolated segments of the guinea pig ileum was triggered by intraluminal fluid infusion to distend the intestinal wall, and the pressure threshold for eliciting peristaltic waves was used to quantify facilitation (decrease in threshold) or inhibition (increase in threshold) of peristalsis. The NO donor sodium nitroprusside (0.1-100 microM serosally) caused a prompt facilitation of peristalsis, which in the presence of a threshold concentration of atropine (10 nM) was followed by a concentration-related blockade of peristalsis. Further analysis showed that sodium nitroprusside (10 and 100 microM) first relaxed, then contracted, and finally relaxed the longitudinal muscle of the guinea pig isolated ileum, the contraction being blocked by atropine (1 microM). Inhibition of NO synthase by NG-nitro-L-arginine methylester (100-300 microM) facilitated peristalsis, an effect that was reduced by L-arginine (1 mM) but left unaltered by atropine (10 nM). Blockade of inhibitory neuromuscular transmission by successive exposure of the ileum to apemin (0.5 microM) and NG-nitro-L-arginine methylester (300 microM), in this or reverse order, disrupted the coordinated pattern of peristalsis and caused irregular nonpropulsive contractions of the circular muscle. It is concluded that NO has a dual excitatory and inhibitory effect on intestinal motility. The excitatory effect involves cholinergic motor neurons, whereas the inhibitory effect reflects relaxation of intestinal muscle. Abolition of peristalsis by combined exposure to NG-nitro-L-arginine methylester and apamin attests to an essential role of enteric inhibitory motor neurons in the coordination of propulsive motility in the intestine.

Animals↗
PubMed1997

Neurokinin A-induced vasoconstriction and muscular contraction in the rat isolated stomach: mediation by distinct and unusual neurokinin2 receptors.

This study examined the pharmacological identity of the tachykinin receptors which in the rat stomach mediate vasoconstriction and muscular contraction. The vasculature of the rat isolated stomach was perfused with oxygenated Krebs buffer containing 3% dextran. Vasoconstrictor responses were recorded as increases in the vascular perfusion pressure and gastric contractions were measured as increases in the intraluminal pressure. By examining the effects of selective agonists and antagonists for tachykinin neurokinin (NK)1, NK2 and NK3 receptors it was found that the vasculature contained only NK2 receptors that were activated by the NK2 receptor agonist [betaAla8]-NKA-(4-10) and inhibited by the NK2 receptor antagonists MEN-10,627 and GR-94,800. However, the vasoconstrictor action of NKA was blocked only when the preparations were exposed to a combination of NK1, NK2 and NK3 receptor antagonists (SR-140,333, MEN-10,627, PD-161,182). In contrast, the NKA-evoked contraction of the gastric musculature was suppressed by NK2 receptor antagonists but little affected by NK1 or NK3 receptor antagonists. This observation was consistent with the predominance of NK2 receptors on the muscle as revealed by the effects of receptor-selective NK1, NK2 and NK3 agonists and antagonists. These results demonstrate that the major tachykinin receptor type present on the gastric vasculature and musculature is a NK2 receptor that is sensitive to receptor-selective agonists and antagonists. The NKA-evoked gastric contraction is also primarily due to NK2 receptor activation, whereas the NKA-induced vasoconstriction is mediated by a distinct and unusual type of NK2-like receptor that is blocked by a combination of NK1, NK2 and NK3 receptor antagonists only.

Animals↗
PubMed1996

Differential expression of c-fos messenger RNA in the rat spinal cord after mucosal and serosal irritation of the stomach.

Expression of the immediate early gene c-fos is considered to be a marker for neuronal activation in the spinal cord in response to afferent input. Since the stomach is continually exposed to injurious chemicals, the present study examined whether application of acid (0.15 M HCl) and formalin (5%) to the gastric mucosa or serosal surface of the stomach stimulates c-fos transcription in the caudal thoracic spinal cord of anaesthetized rats. The spinal cord was removed 15, 45 or 120 min after exposure of the stomach to the noxious chemicals and processed for quantitative in situ hybridization autoradiography of c-fos messenger RNA. Exposure of the gastric mucosa to acid or formalin failed to increase the expression of c-fos messenger RNA in the thoracic spinal cord. Application of acid to the serosal surface of the stomach was also unable to stimulate c-fos transcription, whereas serosal application of formalin led to substantial expression of c-fos messenger RNA in the superficial but also deeper laminae of the spinal dorsal horn when examined 45 min, but not 15 or 120 min, post-stimulation. The highest expression of c-fos messenger RNA was seen when formalin was injected subcutaneously into one hindpaw and c-fos transcription was examined in the lumbar spinal cord. These data indicate that acute exposure of the gastric mucosa to chemical injury does not provide the afferent input which is necessary to cause appreciable c-fos transcription in second order neurons within the spinal cord. Stimulation of the gastric mucosa by acid and formalin was followed, however, by gastric hyperaemia in which spinal afferents releasing vasodilator peptides have been implicated. It is concluded, therefore, that acute stimulation of nociceptive afferents in the stomach causes local homoeostatic reactions but does not necessarily provide afferent input sufficient to recruit spinal nociceptive circuits.

Animals↗
PubMed1996

Tachykinin inhibition of acid-induced gastric hyperaemia in the rat.

1. Primary afferent neurones releasing the vasodilator, calcitonin gene-related peptide, mediate the gastric hyperaemic response to acid back-diffusion. The tachykinins neurokinin A (NKA) and substance P (SP) are located in the same neurones and are co-released with calcitonin gene-related peptide. In this study we investigated the effect and possible role of tachykinins in the acid-evoked gastric vasodilatation in urethane-anaesthetized rats. 2. Gastric acid back-diffusion, induced by perfusing the stomach with 15% ethanol in the presence of 0.05 M HCl, increased gastric mucosal blood flow by 60-90%, as determined by the hydrogen clearance technique. NKA and SP (0.14-3.78 nmol min-1 kg-1, infused intra-aortically) inhibited the gastric mucosal hyperaemic response to acid back-diffusion in a dose-dependent manner, an effect that was accompanied by aggravation of ethanol/acid-induced macroscopic haemorrhagic lesions. 3. The inhibitory effect of NKA (1.26 nmol min-1 kg-1) on the acid-induced gastric mucosal vasodilatation was prevented by the tachykinin NK2 receptor antagonists, MEN 10,627 (200 nmol kg-1) but left unaltered by the NK1 receptor antagonist, SR 140,333 (300 nmol kg-1) and the mast-cell stabilizer, ketotifen (4.6 mumol kg-1). 4. Under basal conditions, with 0.05 M HCl being perfused through the stomach, NKA (1.26 nmol min-1 kg-1) reduced gastric mucosal blood flow by about 25%, an effect that was abolished by SR 140,333 but not MEN 10,627 or ketotifen. 5. SR 140,333, MEN 10,627 or ketotifen had no significant effect on basal gastric mucosal blood flow nor did they modify the gastric mucosal hyperaemic reaction to acid back-diffusion. 6. The effect of NKA (1.26 nmol min-1 kg-1) in causing vasoconstriction and inhibiting the vasodilator response to acid back-diffusion was also seen when blood flow in the left gastric artery was measured with the ultrasonic transit time shift technique. 7. Arginine vasopressin (AVP, 0.1 nmol min-1 kg-1) induced gastric mucosal vasoconstriction under basal conditions but was unable to inhibit the dilator response to acid back-diffusion. 8. These data show that NKA has two fundamentally different effects on the gastric circulation. Firstly, NKA reduces gastric blood flow by activation of NK1 receptors. Secondly, NKA inhibits the gastric hyperaemic response to acid back-diffusion through an NK2 receptor-mediated mechanism. These two tachykinin effects appear to take place independently of each other since they are mediated by different receptors. This concept is further supported by the inability of AVP to mimic tachykinin inhibition of the gastric vasodilator response to acid back-diffusion.

Animals↗
PubMed1996

CCK-evoked hyperemia in rat gastric mucosa involves neural mechanisms and nitric oxide.

This study was performed to identify the possible neural mechanisms and mediators that underlie the gastric mucosal hyperemia evoked by cholecystokinin octapeptide (CCK-8). Gastric mucosal blood flow in anesthetized rats was assessed by the clearance of hydrogen and gastric acid secretion determined in the luminally perfused stomach. The gastric mucosal hyperemic effect of a low dose of CCK-8 (0.04 nmol/min iv infusion for 7 min) was abolished by inhibition of nitric oxide synthesis with NG-nitro-L-arginine methyl ester (15 mg/kg iv) and significantly blunted by defunctionalization of afferent neurons with a neurotoxic dose of capsaicin (125 mg/kg sc). The hyperemic reaction to a high dose of CCK-8 (0.2 nmol/min) was not significantly affected by these pharmacological maneuvers. The vasodilator response to low-dose CCK-8 (0.04 nmol/min) was further analyzed and found to be inhibited by acute bilateral subdiaphragmatic vagotomy, atropine (1 mumol/kg ip), and the antagonistic calcitonin gene-related peptide (CGRP) fragment CGRP-(8-37) (6 nmol/ min ia). Cyclooxygenase inhibition with indomethacin (10 mg/kg ip) was ineffective. The CCK-8-induced increment of gastric acid secretion was not significantly altered by any of these procedures. These results indicate that the gastric vasodilator effect of submaximal doses of CCK-8 is brought about by a vagovagal reflex that involves acetylcholine, CGRP or a related peptide, and nitric oxide as vasodilator messengers.

Animals↗
PubMed1996

Morphologic basis of the functional gastric acid barrier.

The gastric mucosa possesses a functional barrier that prevents intrusion of luminal acid. The aim of the present study was to elucidate the morphologic basis of this barrier by exploring the effect of acid challenge on the gastric mucosal epithelium, basal lamina, and microvasculature. The stomachs of urethane-anesthetized rats were perfused, for at least 45 minutes, with 0.05 M HCl or 0.15 M HCl in the absence or presence of the mucosal barrier breaker ethanol (15%) and examined by light, scanning, and transmission electron microscopy. Gastric perfusion with 0.05 M HCl alone caused superficial cell injury, the damaged surface cells loosing the surface membrane, whereas the junctional complex and basolateral membrane were preserved. Perfusion of 0.15 M HCl alone led to focal ablation of surface epithelial cells in the interfoveolar regions, and cells in the gastric pits remained grossly normal. Exposure to the barrier breaker ethanol (15%) in the presence of 0.05 M HCl caused extensive ablation of the surface epithelium. There were many focal areas in which the honeycomb structure of the lamina propria was exposed and the basal lamina was removed. Gastric mucosal damage progressed further when the luminal HCl concentration was raised to 0.15 M in the presence of ethanol (15%). In this instance, extensive areas with deep erosions and vast areas of deep-reaching ablation of the epithelium and basal lamina were observed. Ultrastructurally, there was extensive damage to the endothelium of capillaries lying underneath denuded areas of the gastric mucosa, the injured capillaries containing erythrocyte ghosts and thrombocyte aggregates. The data suggest that the integrity of the junctional complex, basolateral membrane, and basal lamina forms the morphologic basis of the functional gastric acid barrier. Once these structures are disrupted or ablated to an appreciable extent, damage forms in the mucosal microvasculature, and injury progresses to deeper layers of the mucosa.

Animals↗
PubMed1995

Visceral vasodilatation and somatic vasoconstriction evoked by acid challenge of the rat gastric mucosa: diversity of mechanisms.

1. Acid back-diffusion through a disrupted gastric mucosal barrier increases blood flow to the stomach without any change in systemic blood pressure. This study was undertaken to examine the gastric acid-evoked changes in blood flow in a number of visceral and somatic arterial beds and to elucidate the mechanisms which lead to the regionally diverse haemodynamic responses. 2. The gastric mucosa of urethane-anaesthetized rats was challenged with acid by perfusing the stomach with ethanol (15%, to disrupt the gastric mucosal barrier) in 0.15 M HCl. Blood flow was estimated by laser Doppler flowmetry, the hydrogen clearance method or the ultrasonic transit time shift technique. 3. Gastric acid challenge increased blood flow in the gastric mucosa and left gastric artery while blood flow in the femoral artery and skin declined. 4. Afferent nerve stimulation by intragastric administration of capsaicin enhanced blood flow in the left gastric artery but did not diminish blood flow in the femoral artery when compared with the vehicle. 5. The gastric acid-evoked dilatation of the left gastric artery was depressed by acute extrinsic denervation of the stomach, capsaicin-induced ablation of afferent neurones or hexamethonium-induced blockade of autonomic ganglionic transmission. 6. The gastric acid-induced constriction of the femoral artery was attenuated by acute extrinsic denervation of the stomach but left unaltered by capsaicin, hexamethonium, guanethidine, indomethacin, telmisartan (an angiotensin II antagonist), [d(CH2)5(1), Tyr(Me)2, Arg8]-vasopressin (a vasopressin antagonist), bosentan (an endothelin antagonist) and acute ligation of the blood vessels to the adrenal glands. 7. These data show that acid challenge of the gastric mucosa elicits visceral vasodilatation and somatic vasoconstriction via divergent mechanisms. The gastric hyperaemia is brought about by extrinsic vasodilator nerves, whereas the reduction of somatic blood flow seems to be mediated by non-neural, probably humoral, vasoconstrictor messengers that remain to be identified.

Animals↗
PubMed1995

Activity of SR 142801 at peripheral tachykinin receptors.

The pharmacological profile of the novel tachykinin NK3 receptor antagonist SR 142801, ((S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl) propyl)-4-phenylpiperidin-4-yl)-N-methylacetamide), was studied at tachykinin NK1, NK2 and NK3 receptors, in several in vitro bioassays. In the guinea-pig isolated ileum longitudinal muscle preparation, SR 142801 (10 nM-1 microM) caused an insurmountable antagonism of tachykinin NK3 receptor-mediated contractions produced by senktide (apparent pKB = 9.27). The blockade induced by SR 142801 was essentially irreversible, since it was not removed by washout (up to 2 h) and was increased by prolonging the incubation from 15 to 120 min. SR 142801 showed similar antagonist potency at rat tachykinin NK3 receptors (portal vein) and rabbit tachykinin NK2 receptors (pulmonary artery) (pKB = 7.49 and 7.66, respectively), whereas it was distinctly less potent at hamster tachykinin NK2 receptors (trachea; pKB = 6.84) and inactive at guinea-pig tachykinin NK1 receptors (ileum, longitudinal muscle). In the guinea-pig whole ileum SR 142801 (100 nM) did not affect the contraction produced by capsaicin (1 microM). The combined SR 142801 pretreatment and tachyphylaxis of neuronal CGRP (calcitonin gene-related peptide) receptors produced a slight (about 25%), but significant reduction of the response to capsaicin, suggesting that tachykinin NK3 receptors play a minor role in capsaicin-induced neuronal excitation of afferent nerves in the guinea-pig ileum.

Analysis of Variance↗
PubMed1995

Paralytic ileus in a fetus-neonate after maternal intake of benzodiazepine.

Paralytic ileus of the small bowel was diagnosed in a fetus at 32 weeks' gestation after referral because of polyhydramnios. The mother had taken clonazepam, a benzodiazepine, and carbamazepine during the entire pregnancy for epilepsy. All known causes for the ileus were ruled out and at 20 months the boy has developed normally. We conclude that maternal anticonvulsant drug intake was very likely the cause of the paralytic ileus. This side-effect is known in experimental and clinical pharmacology but has not yet been described in human fetuses.

Adult↗