Irmgard Lippe - Academia.edu (original) (raw)
Papers by Irmgard Lippe
Toxicologic Pathology, 1989
The adrenal cortex is the target of a surprisingly large number of exogenous chemicals. Until rec... more The adrenal cortex is the target of a surprisingly large number of exogenous chemicals. Until recently, the toxic action of these chemicals was discovered serendipitously. Following our observations that acrylonitrile, cystearnine or pyrazole induces hemorrhagic adrenocortical necrosis in the rat, we recently recognized a structure-activity correlation which predicts the adrenocorticolytic property of alkyl chemicals, i.e., 2-3carbons with double or triple bonds and with nucleophilic terminal radicals (e.g., -CN, -SHY -NH2). On the basis of our results obtained with electron microscopic, histochemical and biochemical studies as well as those of others, we propose the following sequence of events in the pathogenesis of chemically induced adrenocortical necrosis: 1) Depletion of glutathione and increased dopamine concentration in the adrenals; 2) Endothelial damage and rupture of capillary walls in the adrenal cortex due to either direct attack by the chemicals (metabolites) and/or released monoamines; 3) Retrograde embolization of medullary tissue fragments into the cortical capillaries; 4) Enhanced destruction of cortical vascular walls with subsequent platelet aggregation, fibrin deposition which is often associated with a systemic drop in platelet counts, and changes in blood coagulation; 5 ) Escape of plasma and cellular elements of blood into extravascular spaces and damage of adrenocortical parenchymal cells; and 6) Hemorrhage and necrosis in the adrenal cortex. This pathogenetic sequence was investigated in detail with acrylonitrile, and studied in various aspects with thioguanine, cysteamine and pyrazole.
Naunyn Schmiedeberg S Archives of Pharmacology, 1989
- This study investigated a possible involvement of protein kinase C (PKC) in the substance P-in... more 1) This study investigated a possible involvement of protein kinase C (PKC) in the substance P-induced contraction of the longitudinal muscle of the guinea-pig isolated ileum.
Naunyn Schmied Arch Pharmacol, 1985
The effect of substance P on the metabolism of membrane phosphoinositides and the possible role o... more The effect of substance P on the metabolism of membrane phosphoinositides and the possible role of this effect in the contractile response to substance P was investigated in longitudinal muscle strips obtained from the guinea-pig small intestine and prelabelled with [3H] inositol. Substance P (2.2 microM) failed to change significantly the tissue content of phosphoinositides but caused an accumulation of their water-soluble hydrolysis products, inositol bisphosphate (InsP2) and inositol monophosphate (InsP). These experiments were carried out in the presence of Li+ (12 mM), since only under these conditions could an accumulation of InsP2 be observed. The rate at which InsP2 and InsP accumulated was highest during the first 0.5 min of exposure to substance P (2.2 microM) and then decreased rapidly. Thus, the rate of inositol phosphate accumulation paralleled the time course of the contractile response to substance P. The magnitude of inositol phosphate accumulation was related to the concentration of substance P (22 nM-22 microM). The substance P-induced accumulation of InsP2 and InsP was not reduced when muscle strips had been incubated in Ca2+-free medium, for a time period sufficient to deplete the intracellular Ca2+ store which can be released by substance P, or in Ca2+-free medium containing high [K+]. These findings are compatible with the concept that hydrolysis of membrane phosphoinositides is a mechanism that links substance P receptor activation to contraction but further work is needed to establish a causal relationship.
Problems of the Gastrointestinal Tract in Anesthesia, the Perioperative Period, and Intensive Care, 1999
Neuropharmacology, 1998
The tachykinins substance P and neurokinin A are excitatory cotransmitters of cholinergic enteric... more The tachykinins substance P and neurokinin A are excitatory cotransmitters of cholinergic enteric neurons, their actions being mediated by NK1, NK2 and NK3 receptors. This study examined which of these receptors are part of the neural circuitry of peristalsis. Peristaltic propulsion in luminally perfused segments of the guinea-pig isolated ileum was elicited by a rise of the intraluminal pressure. The pressure threshold at which peristaltic contractions were triggered was used to quantify drug effects on peristalsis, inhibition of peristalsis being reflected by an increase in the pressure threshold. The NK1, NK2 and NK3 receptor antagonists SR-140333, SR-48968 and SR-142 801 (each at 0.1 microM), respectively, had little effect on peristaltic activity as long as cholinergic transmission was left intact. However, both the NK1 and NK2 receptor antagonist (each at 0.1 microM) abolished peristalsis after cholinergic transmission via muscarinic receptors had been blocked by atropine (1 m...
Regulatory Peptides, 1989
Afferent neuron-mediated gastric mucosal protection has been suggested to result from the local r... more Afferent neuron-mediated gastric mucosal protection has been suggested to result from the local release of vasodilator peptides such as calcitonin gene-related peptide (CGRP) from afferent nerve endings within the stomach. The present study, therefore, examined whether rat alpha-CGRP, administered via different routes, is able to protect against mucosal injury induced by gastric perfusion with 25% ethanol or acidified aspirin (25 mM, pH 1.5) in urethane-anesthetized rats. Close arterial infusion of CGRP (15 pmol/min) to the stomach, via a catheter placed in the abdominal aorta proximal to the celiac artery, significantly reduced gross mucosal damage caused by ethanol and aspirin whereas mean arterial blood pressure (BP) was not altered. Intravenous infusion of CGRP (50 pmol/min) did not affect aspirin-induced mucosal injury but significantly enhanced ethanol-induced lesion formation. Intravenous CGRP (50 pmol/min) also lowered BP and increased the gastric clearance of [14C]aminopyrine, an indirect measure of gastric mucosal blood flow while basal gastric output of acid and bicarbonate was not altered. Intragastric administration of CGRP (260 nM) significantly inhibited aspirin-induced mucosal damage but did not influence damage in response to ethanol. BP, gastric clearance of [14C]aminopyrine, and gastric output of acid and bicarbonate remained unaltered by intragastric CGRP. These data indicate that only close arterial administration of CGRP to the rat stomach, at doses devoid of a systemic hypotensive effect, is able to protect against both ethanol- and aspirin-induced mucosal damage. As this route of administration closely resembles local release of the peptide in the stomach, CGRP may be considered as a candidate mediator of afferent nerve-induced gastric mucosal protection.
Pharmacology, 2009
Portal hypertension is associated with splanchnic vasodilation which is claimed responsible for t... more Portal hypertension is associated with splanchnic vasodilation which is claimed responsible for the maintenance of chronically elevated portal pressure. Vasopressin analogues are used in the treatment of acute variceal bleeding, since they effectively reduce splanchnic blood flow and portal pressure. Dehydration stimulates the release of endogenous vasopressin release. Here we compared the effects of deprivation of drinking water for 18 h with those of vasopressin infusion on mesenteric hemodynamics in portal vein-ligated (PVL) and sham-operated (SHAM) rats. Blood flow in the superior mesenteric artery was measured with the ultrasonic transit time shift technique. Deprivation of drinking water had no hemodynamic effects in SHAM rats, but completely reversed the mesenteric hyperemia and portal hypertension in PVL rats to figures measured in SHAM rats, without altering blood pressure. Similarly, intravenous infusion of low doses of arginine vasopressin (1-10 pmol/min) selectively reduced mesenteric blood flow in PVL rats but had little effect in SHAM rats. These data suggest that control of water balance or aquaretic drugs might have beneficial effects on splanchnic hemodynamics and portal pressure in advanced liver disease, possibly by stimulating endogenous vasopressin release.
Naunyn-Schmiedebergs Archives of Pharmacology, 1985
The effect of substance P on the metabolism of membrane phosphoinositides and the possible role o... more The effect of substance P on the metabolism of membrane phosphoinositides and the possible role of this effect in the contractile response to substance P was investigated in longitudinal muscle strips obtained from the guinea-pig small intestine and prelabelled with [3H] inositol. Substance P (2.2 microM) failed to change significantly the tissue content of phosphoinositides but caused an accumulation of their water-soluble hydrolysis products, inositol bisphosphate (InsP2) and inositol monophosphate (InsP). These experiments were carried out in the presence of Li+ (12 mM), since only under these conditions could an accumulation of InsP2 be observed. The rate at which InsP2 and InsP accumulated was highest during the first 0.5 min of exposure to substance P (2.2 microM) and then decreased rapidly. Thus, the rate of inositol phosphate accumulation paralleled the time course of the contractile response to substance P. The magnitude of inositol phosphate accumulation was related to the concentration of substance P (22 nM-22 microM). The substance P-induced accumulation of InsP2 and InsP was not reduced when muscle strips had been incubated in Ca2+-free medium, for a time period sufficient to deplete the intracellular Ca2+ store which can be released by substance P, or in Ca2+-free medium containing high [K+]. These findings are compatible with the concept that hydrolysis of membrane phosphoinositides is a mechanism that links substance P receptor activation to contraction but further work is needed to establish a causal relationship.
Naunyn-Schmiedeberg's Archives of Pharmacology, 2004
- This study investigated a possible involvement of protein kinase C (PKC) in the substance P-in... more 1) This study investigated a possible involvement of protein kinase C (PKC) in the substance P-induced contraction of the longitudinal muscle of the guinea-pig isolated ileum.
![Research paper thumbnail of Effect of the tachykinin antagonist, [abetd-Pro4, abetd-Trp7,9,10] substance P-(4?11), on tachykinin- and histamine-induced inositol phosphate generation in intestinal smooth muscle](https://attachments.academia-assets.com/47434959/thumbnails/1.jpg)
](Naunyn-Schmiedeberg's Archives of Pharmacology, 1987
1. The effect of the tachykinin antagonist, 9,10] substance P-(4-11), on inositol phosphate accum... more 1. The effect of the tachykinin antagonist, 9,10] substance P-(4-11), on inositol phosphate accumulation produced by tachykinins and by histamine in strips of longitudinal muscle from the guinea-pig small intestine was investigated in the presence of 12 mM Li +.
Gastroenterology, 2000
Background : CB receptors have been implicated in inflammation and pain. CB receptor agonists are... more Background : CB receptors have been implicated in inflammation and pain. CB receptor agonists are potent vasodilators in different vascular preparations, but the mechanism of action is unclear. We investigated the effect of methanandamide, a CB receptor agonist, on the gastric vasculature of the rat stomach in vitro. In particular, we addressed the possibility that methanandamide activated capsaicin-sensitive afferent neurons which are known to release vasoactive substances upon stimulation. Methods: The rat isolated stomach was perfused via the left gastric artery with oxygenated Krebs solution by means of a peristaltic pump. Vasoconstrictor responses were recorded by an increase in intravascular pressure. The lumen of the stomach was filled with 5 ml of saline, gastric contractions being recorded by an increase in intraluminal pressure. The vasculature was precontracted by continuous infusion of methoxamine (10 ILM). Results: Vascular perfusion ofrnethanandarnide (2 or 20 ILM) and capsaicin (0.2 or 2 ILM) caused significant concentration-dependent relaxation of the precontracted va~culature\{lut ha\i no effect on gastric muscle activity. The vasorelaxant activity of n1I:thanandamide was significantly counteracted by the canna-
European Journal of Pharmacology, 1985
P. HOLZER and I.TH. LIPPE, The inhibitory effect of neurotensin on the motor activity of rabbit i... more P. HOLZER and I.TH. LIPPE, The inhibitory effect of neurotensin on the motor activity of rabbit ileum: dependence on the ionic environment, European J. Pharmacol. 117 (1985) 329-335. The possible ionic mechanisms underlying the inhibitory effect of neurotensin on the spontaneous phasic contractions of the longitudinal muscle of the isolated rabbit ileum were studied by varying the ionic environment. Neurotensin (0.06-60 nM) reduced and abolished the phasic contractions in a concentration-dependent manner. The effect of neurotensin was transient, and the phasic contractions began to recover after 1-3 min although neurotensin was not washed out. The response to neurotensin was very sensitive to alterations in the ionic composition of the bath medium. The changes in the effect of neurotensin brought about by changes in [Na+], [K+], Ca2+], and [C1 ] suggest that neurotensin hyperpolarizes the smooth muscle. In addition, the effect of combined changes in [Ca 2+] and [CI ] points to a specific role of these ions in the action of neurotensin.
European Journal of Pharmacology, 1989
R 59022, a compound which causes the accumulation of diacylglycerol by inhibition of the enzyme d... more R 59022, a compound which causes the accumulation of diacylglycerol by inhibition of the enzyme diacylglycerol kinase, was tested for its effect on stimulated motor activity of the longitudinal muscle from the guinea-pig ileum. Motor responses to histamine were very potently inhibited by R 59022 (greater than or equal to 0.03 microM), which confirms its known activity as a histamine receptor antagonist. Contractions elicited by acetylcholine, substance P, or K+ depolarization were also concentration dependently depressed by R 59022 (1-30 microM); further analysis showed that substance P was antagonized in a non-competitive manner. R 59022 was significantly more active to block the tonic than the phasic component of the contractile response to K+ depolarization. The Ca2+-induced activation of the contractile apparatus in chemically skinned muscle strips was depressed by similar concentrations of R 59022 (3-30 microM). These data indicate that R 59022 suppresses the contractile activity of intestinal smooth muscle at an intracellular site of action but it is not yet clear whether this action can be accounted for by the accumulation of diacylglycerol and subsequent stimulation of protein kinase C.
European Journal of Pharmacology, 1983
British Journal of Pharmacology, 1992
1 The possible participation of prostacyclin and nitric oxide (NO) in the gastric mucosal hyperae... more 1 The possible participation of prostacyclin and nitric oxide (NO) in the gastric mucosal hyperaemic response to acid back-diffusion through a disrupted gastric mucosal barrier was examined. The experiments were carried out on anaesthetized rats in which acid back-diffusion was elicited by gastric perfusion with dilute ethanol in 0.15 M HCl and gastric mucosal blood flow (MBF) was measured by the hydrogen gas clearance technique.
British Journal of Pharmacology, 1987
British Journal of Pharmacology, 1984
1 The contraction of the longitudinal muscle of the guinea-pig isolated ileum in response to subs... more 1 The contraction of the longitudinal muscle of the guinea-pig isolated ileum in response to substance P (SP) in high [K+] medium and in Ca2+-free solution which contained EGTA has been investigated in order to examine whether excitation-contraction coupling involves the release of Ca2+ from an intracellular store. 2 In tissues contracted by K+, high concentrations of SP (>0.1 lM) were still capable of causing a slight, transient contraction.
Annals of the New York Academy of Sciences, 1992
It is well established that the vascular system of the gastrointestinal tract is innervated by bo... more It is well established that the vascular system of the gastrointestinal tract is innervated by both sympathetic vasoconstrictor and parasympathetic vasodilator neurons.' Besides this autonomic innervation, splanchnic blood vessels receive a dense supply by fibers of primary afferent (sensory) neurons, many of which contain calcitonin gene-related peptide (CGRP).2 There is evidence that these afferent neurons participate in the regulation of blood flow and possibly other vascular functions in the gastrointestinal tract. Apart from perceiving and transmitting information to the central nervous system and giving rise to reflex changes in the cardiovascular system, peptidergic sensory neurons have been recognized to act as "effector" neurons to control vascular and other local tissue function^.^ This local control function is exerted by the release of peptide transmitters including CGRP from the peripheral terminals of sensory neurons. Historically, this role was first portrayed by the finding that stimulation of the peripheral ends of cut dorsal roots induced vasodilatation in the skin area supplied by the respective neuron^.^ "Antidromic vasodilatation," as this response is commonly called, can be observed in many tissues including the gastrointestinal tract. The present article reviews the possible role of CGRP and CGRP-immunoreactive sensory neurons in the control of blood flow in the splanchnic vascular bed.
Pharmacological Research Communications, 1988
Toxicologic Pathology, 1989
The adrenal cortex is the target of a surprisingly large number of exogenous chemicals. Until rec... more The adrenal cortex is the target of a surprisingly large number of exogenous chemicals. Until recently, the toxic action of these chemicals was discovered serendipitously. Following our observations that acrylonitrile, cystearnine or pyrazole induces hemorrhagic adrenocortical necrosis in the rat, we recently recognized a structure-activity correlation which predicts the adrenocorticolytic property of alkyl chemicals, i.e., 2-3carbons with double or triple bonds and with nucleophilic terminal radicals (e.g., -CN, -SHY -NH2). On the basis of our results obtained with electron microscopic, histochemical and biochemical studies as well as those of others, we propose the following sequence of events in the pathogenesis of chemically induced adrenocortical necrosis: 1) Depletion of glutathione and increased dopamine concentration in the adrenals; 2) Endothelial damage and rupture of capillary walls in the adrenal cortex due to either direct attack by the chemicals (metabolites) and/or released monoamines; 3) Retrograde embolization of medullary tissue fragments into the cortical capillaries; 4) Enhanced destruction of cortical vascular walls with subsequent platelet aggregation, fibrin deposition which is often associated with a systemic drop in platelet counts, and changes in blood coagulation; 5 ) Escape of plasma and cellular elements of blood into extravascular spaces and damage of adrenocortical parenchymal cells; and 6) Hemorrhage and necrosis in the adrenal cortex. This pathogenetic sequence was investigated in detail with acrylonitrile, and studied in various aspects with thioguanine, cysteamine and pyrazole.
Naunyn Schmiedeberg S Archives of Pharmacology, 1989
- This study investigated a possible involvement of protein kinase C (PKC) in the substance P-in... more 1) This study investigated a possible involvement of protein kinase C (PKC) in the substance P-induced contraction of the longitudinal muscle of the guinea-pig isolated ileum.
Naunyn Schmied Arch Pharmacol, 1985
The effect of substance P on the metabolism of membrane phosphoinositides and the possible role o... more The effect of substance P on the metabolism of membrane phosphoinositides and the possible role of this effect in the contractile response to substance P was investigated in longitudinal muscle strips obtained from the guinea-pig small intestine and prelabelled with [3H] inositol. Substance P (2.2 microM) failed to change significantly the tissue content of phosphoinositides but caused an accumulation of their water-soluble hydrolysis products, inositol bisphosphate (InsP2) and inositol monophosphate (InsP). These experiments were carried out in the presence of Li+ (12 mM), since only under these conditions could an accumulation of InsP2 be observed. The rate at which InsP2 and InsP accumulated was highest during the first 0.5 min of exposure to substance P (2.2 microM) and then decreased rapidly. Thus, the rate of inositol phosphate accumulation paralleled the time course of the contractile response to substance P. The magnitude of inositol phosphate accumulation was related to the concentration of substance P (22 nM-22 microM). The substance P-induced accumulation of InsP2 and InsP was not reduced when muscle strips had been incubated in Ca2+-free medium, for a time period sufficient to deplete the intracellular Ca2+ store which can be released by substance P, or in Ca2+-free medium containing high [K+]. These findings are compatible with the concept that hydrolysis of membrane phosphoinositides is a mechanism that links substance P receptor activation to contraction but further work is needed to establish a causal relationship.
Problems of the Gastrointestinal Tract in Anesthesia, the Perioperative Period, and Intensive Care, 1999
Neuropharmacology, 1998
The tachykinins substance P and neurokinin A are excitatory cotransmitters of cholinergic enteric... more The tachykinins substance P and neurokinin A are excitatory cotransmitters of cholinergic enteric neurons, their actions being mediated by NK1, NK2 and NK3 receptors. This study examined which of these receptors are part of the neural circuitry of peristalsis. Peristaltic propulsion in luminally perfused segments of the guinea-pig isolated ileum was elicited by a rise of the intraluminal pressure. The pressure threshold at which peristaltic contractions were triggered was used to quantify drug effects on peristalsis, inhibition of peristalsis being reflected by an increase in the pressure threshold. The NK1, NK2 and NK3 receptor antagonists SR-140333, SR-48968 and SR-142 801 (each at 0.1 microM), respectively, had little effect on peristaltic activity as long as cholinergic transmission was left intact. However, both the NK1 and NK2 receptor antagonist (each at 0.1 microM) abolished peristalsis after cholinergic transmission via muscarinic receptors had been blocked by atropine (1 m...
Regulatory Peptides, 1989
Afferent neuron-mediated gastric mucosal protection has been suggested to result from the local r... more Afferent neuron-mediated gastric mucosal protection has been suggested to result from the local release of vasodilator peptides such as calcitonin gene-related peptide (CGRP) from afferent nerve endings within the stomach. The present study, therefore, examined whether rat alpha-CGRP, administered via different routes, is able to protect against mucosal injury induced by gastric perfusion with 25% ethanol or acidified aspirin (25 mM, pH 1.5) in urethane-anesthetized rats. Close arterial infusion of CGRP (15 pmol/min) to the stomach, via a catheter placed in the abdominal aorta proximal to the celiac artery, significantly reduced gross mucosal damage caused by ethanol and aspirin whereas mean arterial blood pressure (BP) was not altered. Intravenous infusion of CGRP (50 pmol/min) did not affect aspirin-induced mucosal injury but significantly enhanced ethanol-induced lesion formation. Intravenous CGRP (50 pmol/min) also lowered BP and increased the gastric clearance of [14C]aminopyrine, an indirect measure of gastric mucosal blood flow while basal gastric output of acid and bicarbonate was not altered. Intragastric administration of CGRP (260 nM) significantly inhibited aspirin-induced mucosal damage but did not influence damage in response to ethanol. BP, gastric clearance of [14C]aminopyrine, and gastric output of acid and bicarbonate remained unaltered by intragastric CGRP. These data indicate that only close arterial administration of CGRP to the rat stomach, at doses devoid of a systemic hypotensive effect, is able to protect against both ethanol- and aspirin-induced mucosal damage. As this route of administration closely resembles local release of the peptide in the stomach, CGRP may be considered as a candidate mediator of afferent nerve-induced gastric mucosal protection.
Pharmacology, 2009
Portal hypertension is associated with splanchnic vasodilation which is claimed responsible for t... more Portal hypertension is associated with splanchnic vasodilation which is claimed responsible for the maintenance of chronically elevated portal pressure. Vasopressin analogues are used in the treatment of acute variceal bleeding, since they effectively reduce splanchnic blood flow and portal pressure. Dehydration stimulates the release of endogenous vasopressin release. Here we compared the effects of deprivation of drinking water for 18 h with those of vasopressin infusion on mesenteric hemodynamics in portal vein-ligated (PVL) and sham-operated (SHAM) rats. Blood flow in the superior mesenteric artery was measured with the ultrasonic transit time shift technique. Deprivation of drinking water had no hemodynamic effects in SHAM rats, but completely reversed the mesenteric hyperemia and portal hypertension in PVL rats to figures measured in SHAM rats, without altering blood pressure. Similarly, intravenous infusion of low doses of arginine vasopressin (1-10 pmol/min) selectively reduced mesenteric blood flow in PVL rats but had little effect in SHAM rats. These data suggest that control of water balance or aquaretic drugs might have beneficial effects on splanchnic hemodynamics and portal pressure in advanced liver disease, possibly by stimulating endogenous vasopressin release.
Naunyn-Schmiedebergs Archives of Pharmacology, 1985
The effect of substance P on the metabolism of membrane phosphoinositides and the possible role o... more The effect of substance P on the metabolism of membrane phosphoinositides and the possible role of this effect in the contractile response to substance P was investigated in longitudinal muscle strips obtained from the guinea-pig small intestine and prelabelled with [3H] inositol. Substance P (2.2 microM) failed to change significantly the tissue content of phosphoinositides but caused an accumulation of their water-soluble hydrolysis products, inositol bisphosphate (InsP2) and inositol monophosphate (InsP). These experiments were carried out in the presence of Li+ (12 mM), since only under these conditions could an accumulation of InsP2 be observed. The rate at which InsP2 and InsP accumulated was highest during the first 0.5 min of exposure to substance P (2.2 microM) and then decreased rapidly. Thus, the rate of inositol phosphate accumulation paralleled the time course of the contractile response to substance P. The magnitude of inositol phosphate accumulation was related to the concentration of substance P (22 nM-22 microM). The substance P-induced accumulation of InsP2 and InsP was not reduced when muscle strips had been incubated in Ca2+-free medium, for a time period sufficient to deplete the intracellular Ca2+ store which can be released by substance P, or in Ca2+-free medium containing high [K+]. These findings are compatible with the concept that hydrolysis of membrane phosphoinositides is a mechanism that links substance P receptor activation to contraction but further work is needed to establish a causal relationship.
Naunyn-Schmiedeberg's Archives of Pharmacology, 2004
- This study investigated a possible involvement of protein kinase C (PKC) in the substance P-in... more 1) This study investigated a possible involvement of protein kinase C (PKC) in the substance P-induced contraction of the longitudinal muscle of the guinea-pig isolated ileum.
Naunyn-Schmiedeberg's Archives of Pharmacology, 1987
1. The effect of the tachykinin antagonist, 9,10] substance P-(4-11), on inositol phosphate accum... more 1. The effect of the tachykinin antagonist, 9,10] substance P-(4-11), on inositol phosphate accumulation produced by tachykinins and by histamine in strips of longitudinal muscle from the guinea-pig small intestine was investigated in the presence of 12 mM Li +.
Gastroenterology, 2000
Background : CB receptors have been implicated in inflammation and pain. CB receptor agonists are... more Background : CB receptors have been implicated in inflammation and pain. CB receptor agonists are potent vasodilators in different vascular preparations, but the mechanism of action is unclear. We investigated the effect of methanandamide, a CB receptor agonist, on the gastric vasculature of the rat stomach in vitro. In particular, we addressed the possibility that methanandamide activated capsaicin-sensitive afferent neurons which are known to release vasoactive substances upon stimulation. Methods: The rat isolated stomach was perfused via the left gastric artery with oxygenated Krebs solution by means of a peristaltic pump. Vasoconstrictor responses were recorded by an increase in intravascular pressure. The lumen of the stomach was filled with 5 ml of saline, gastric contractions being recorded by an increase in intraluminal pressure. The vasculature was precontracted by continuous infusion of methoxamine (10 ILM). Results: Vascular perfusion ofrnethanandarnide (2 or 20 ILM) and capsaicin (0.2 or 2 ILM) caused significant concentration-dependent relaxation of the precontracted va~culature\{lut ha\i no effect on gastric muscle activity. The vasorelaxant activity of n1I:thanandamide was significantly counteracted by the canna-
European Journal of Pharmacology, 1985
P. HOLZER and I.TH. LIPPE, The inhibitory effect of neurotensin on the motor activity of rabbit i... more P. HOLZER and I.TH. LIPPE, The inhibitory effect of neurotensin on the motor activity of rabbit ileum: dependence on the ionic environment, European J. Pharmacol. 117 (1985) 329-335. The possible ionic mechanisms underlying the inhibitory effect of neurotensin on the spontaneous phasic contractions of the longitudinal muscle of the isolated rabbit ileum were studied by varying the ionic environment. Neurotensin (0.06-60 nM) reduced and abolished the phasic contractions in a concentration-dependent manner. The effect of neurotensin was transient, and the phasic contractions began to recover after 1-3 min although neurotensin was not washed out. The response to neurotensin was very sensitive to alterations in the ionic composition of the bath medium. The changes in the effect of neurotensin brought about by changes in [Na+], [K+], Ca2+], and [C1 ] suggest that neurotensin hyperpolarizes the smooth muscle. In addition, the effect of combined changes in [Ca 2+] and [CI ] points to a specific role of these ions in the action of neurotensin.
European Journal of Pharmacology, 1989
R 59022, a compound which causes the accumulation of diacylglycerol by inhibition of the enzyme d... more R 59022, a compound which causes the accumulation of diacylglycerol by inhibition of the enzyme diacylglycerol kinase, was tested for its effect on stimulated motor activity of the longitudinal muscle from the guinea-pig ileum. Motor responses to histamine were very potently inhibited by R 59022 (greater than or equal to 0.03 microM), which confirms its known activity as a histamine receptor antagonist. Contractions elicited by acetylcholine, substance P, or K+ depolarization were also concentration dependently depressed by R 59022 (1-30 microM); further analysis showed that substance P was antagonized in a non-competitive manner. R 59022 was significantly more active to block the tonic than the phasic component of the contractile response to K+ depolarization. The Ca2+-induced activation of the contractile apparatus in chemically skinned muscle strips was depressed by similar concentrations of R 59022 (3-30 microM). These data indicate that R 59022 suppresses the contractile activity of intestinal smooth muscle at an intracellular site of action but it is not yet clear whether this action can be accounted for by the accumulation of diacylglycerol and subsequent stimulation of protein kinase C.
European Journal of Pharmacology, 1983
British Journal of Pharmacology, 1992
1 The possible participation of prostacyclin and nitric oxide (NO) in the gastric mucosal hyperae... more 1 The possible participation of prostacyclin and nitric oxide (NO) in the gastric mucosal hyperaemic response to acid back-diffusion through a disrupted gastric mucosal barrier was examined. The experiments were carried out on anaesthetized rats in which acid back-diffusion was elicited by gastric perfusion with dilute ethanol in 0.15 M HCl and gastric mucosal blood flow (MBF) was measured by the hydrogen gas clearance technique.
British Journal of Pharmacology, 1987
British Journal of Pharmacology, 1984
1 The contraction of the longitudinal muscle of the guinea-pig isolated ileum in response to subs... more 1 The contraction of the longitudinal muscle of the guinea-pig isolated ileum in response to substance P (SP) in high [K+] medium and in Ca2+-free solution which contained EGTA has been investigated in order to examine whether excitation-contraction coupling involves the release of Ca2+ from an intracellular store. 2 In tissues contracted by K+, high concentrations of SP (>0.1 lM) were still capable of causing a slight, transient contraction.
Annals of the New York Academy of Sciences, 1992
It is well established that the vascular system of the gastrointestinal tract is innervated by bo... more It is well established that the vascular system of the gastrointestinal tract is innervated by both sympathetic vasoconstrictor and parasympathetic vasodilator neurons.' Besides this autonomic innervation, splanchnic blood vessels receive a dense supply by fibers of primary afferent (sensory) neurons, many of which contain calcitonin gene-related peptide (CGRP).2 There is evidence that these afferent neurons participate in the regulation of blood flow and possibly other vascular functions in the gastrointestinal tract. Apart from perceiving and transmitting information to the central nervous system and giving rise to reflex changes in the cardiovascular system, peptidergic sensory neurons have been recognized to act as "effector" neurons to control vascular and other local tissue function^.^ This local control function is exerted by the release of peptide transmitters including CGRP from the peripheral terminals of sensory neurons. Historically, this role was first portrayed by the finding that stimulation of the peripheral ends of cut dorsal roots induced vasodilatation in the skin area supplied by the respective neuron^.^ "Antidromic vasodilatation," as this response is commonly called, can be observed in many tissues including the gastrointestinal tract. The present article reviews the possible role of CGRP and CGRP-immunoreactive sensory neurons in the control of blood flow in the splanchnic vascular bed.
Pharmacological Research Communications, 1988