Local microcirculatory reflexes and afferent signalling in response to gastric acid challenge.
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Calcitonin Gene-Related Peptide↗
Biomedical subjects
P Holzer
Publications and source records attributed to P Holzer.
Protective effect of cromakalim and diazoxide, and proulcerogenic effect of glibenclamide on indomethacin-induced gastric injury.
We investigated the influences of the K+ channel opening drugs cromakalim and diazoxide and their blocker, glibenclamide, in indomethacin-induced gastric injury in rats. Cromakalim (0.1 and 0.3 mg/kg) and diazoxide (10 and 30 mg/kg) produced dose-dependent gastroprotection at doses that were also effective on the cardiovascular system. Glibenclamide reversed their gastroprotective effects and aggravated indomethacin-induced gastric damage by its own. Cromakalim (10(-9)-10(-5) M) and diazoxide (10(-9)-10(-4) M) relaxed noradrenaline pre-contracted gastric arteries (94.59+/-1.58% and 93.86+/-2.99%, respectively). Their relaxant effects were inhibited by glibenclamide (10(-5) M) but not by indomethacin (10(-5) M) and LG-nitro-L-arginine (10(-4) M). Cromakalim (0.1 and 0.3 mg/kg) did not change gastric mucosal blood flow but increased the gastric mucosal vascular conductance in anaesthetized rats as measured by the hydrogen gas clearance technique. Indomethacin increased myeloperoxidase activity in the gastric mucosa, an effect which was reversed by cromakalim and diazoxide. Glibenclamide abolished their effects on myeloperoxidase activity and, alone, increased this parameter. Additionally, indomethacin caused infiltration of neutrophils which was reduced by cromakalim and diazoxide in a glibenclamide sensitive manner. The effects of cromakalim and diazoxide on mucosal myeloperoxidase activity, neutrophil infiltration and gastric injury correlated with each other. The effects of diazoxide (30 mg/kg) and glibenclamide (10 mg/kg) on blood glucose level were not correlated with their effects on gastric injury. Taken together, K+ channel opening drugs show misoprostol-like protective effects in indomethacin-induced gastric injury which seems to be related to modulation of neutrophil function.
Animals↗
Cannabinoid inhibition of guinea-pig intestinal peristalsis via inhibition of excitatory and activation of inhibitory neural pathways.
Since activation of cannabinoid CB1 receptors inhibits gastrointestinal transit in the mouse, this study analyzed the action of the cannabinoid receptor agonist methanandamide on distension-induced propulsive motility. Peristalsis 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. Methanandamide (0.1-3 microM) inhibited peristalsis as deduced from a concentration-related increase in the peristaltic pressure threshold, an action that was prevented by the CB1 receptor antagonist SR141716A (1 microM) per se, which had no effect on peristalsis. The distension-induced ascending reflex contraction of the circular muscle was likewise depressed by methanandamide in a SR141716A-sensitive manner, whereas indomethacin-induced phasic contractions of the circular muscle were left unchanged by methanandamide. The anti-peristaltic action of methanandamide was inhibited by apamin (0.5 microM), attenuated by N-nitro-L-arginine methyl ester (300 microM) and left unaltered by suramin (300 microM), pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (150 microM) and naloxone (0.5 microM). It is concluded that methanandamide depresses intestinal peristalsis via activation of CB1 receptors on enteric neurons, which results in blockade of excitatory motor pathways and facilitation of inhibitory pathways operating via apamin-sensitive K+ channels and nitric oxide.
Animals↗
Tachykinin receptors are involved in the "local efferent" motor response to capsaicin in the guinea-pig small intestine and oesophagus.
The sensory neuron stimulant drug capsaicin stimulates primary afferent nerve endings in the guinea-pig small intestine, which in turn activate myenteric cholinergic neurons by an unknown mechanism. The tachykinins substance P and neurokinin A are present in primary afferent neurons. This study was performed to assess the possible involvement of endogenous tachykinins acting via neurokinin-1, neurokinin-2 and neurokinin-3 receptors in the contractile effect of capsaicin in the isolated guinea-pig ileum and oesophagus by using the receptor-specific antagonists GR 82334 (3 microM) for neurokinin-1 receptors, MEN 10627 (3 microM; ileum) or MEN 11420 (1 microM; oesophagus) for neurokinin-2 receptors and SR 142801 (0.1 microM) for neurokinin-3 receptors. In the ileum, the peak contraction evoked by capsaicin (2 microM) was not reduced when tachykinin neurokinin-1, neurokinin-2 or neurokinin-3 receptors were blocked separately, whereas an inhibition of neurokinin-3 receptors diminished the area under the curve of the capsaicin response. A combined blockade of neurokinin-1 and neurokinin-3 receptors significantly depressed the effect of capsaicin; the amplitude of the contractile response was 53.3+/-3.7% of the maximal longitudinal spasm in control preparations, whereas in the presence of GR 82334 plus SR 142801 it reached only 27.6+/-5% (P<0.001, Kruskal-Wallis test; n=9 and 10, respectively). Also, the area under the curve of the contractile response to capsaicin was more than 85% lower in the group of preparations treated with GR 82334 plus SR 142801 than in the control group (P<0.001). Including a neurokinin-2 blocker in the combination did not produce any further inhibition. A concomitant tachyphylaxis to substance P (natural neurokinin-1 receptor stimulant) and the neurokinin-3 receptor agonist senktide (5 and 1 microM, respectively) also reduced the contractile effect of capsaicin. In the oesophagus, capsaicin (1 microM) induced biphasic contractions which were strongly inhibited by atropine (1 microM) or capsaicin pretreatment (1 microM for 10 min). Here again, a blockade of tachykinin neurokinin-1, neurokinin-2 or neurokinin-3 receptors separately failed to inhibit the response to capsaicin, whereas a combined blockade of any two tachykinin receptors caused a partial inhibition. The reduction of the contractile effect of capsaicin was strongest when all three tachykinin receptors were blocked. In seven control preparations, peaks for the first and second phases of contraction reached 35.3+/-3.7% and 20+/-3.2% of maximal longitudinal spasm; the corresponding values in the presence of a combination of GR 82334, MEN 11420 and SR 142801 were 7.5+/-0.8% and 9.1+/-2.2%, respectively (n=6, P<0.001 and 0.05, respectively). Tetrodotoxin (0.5 microM) practically abolished the contractile effect of capsaicin in both tissues studied. It is concluded that an interplay of neuronal tachykinin neurokinin-1 and neurokinin-3 receptors (ileum) and neurokinin-1, neurokinin-2 and neurokinin-3 receptors (oesophagus) is involved in the contractile action of capsaicin, probably in mediating excitation of myenteric neurons by tachykinins released from primary afferents. In both tissues, there also seems to be a non-tachykininergic component of the capsaicin-induced contraction.
Animals↗
Stimulant action of pituitary adenylate cyclase-activating peptide on normal and drug-compromised peristalsis in the guinea-pig intestine.
1. Pituitary adenylate cyclase-activating peptide (PACAP) is known to influence the activity of intestinal smooth muscle. This study set out to examine the action of PACAP on normal and drug-inhibited peristalsis and to shed light on its site and mode of action. 2. Peristalsis in isolated segments of the guinea-pig small intestine was elicited by distension through a rise of the intraluminal pressure. Drug-induced motility changes were quantified by alterations of the peristaltic pressure threshold at which aborally moving peristaltic contractions were triggered. 3. PACAP (1-30 nM) stimulated normal peristalsis as deduced from a concentration-related decrease in the peristaltic pressure threshold (maximum decrease by 55%). The peptide's stimulant effect remained intact in segments pre-exposed to apamin (0.5 microM), N-nitro-L-arginine methyl ester (300 microM), naloxone (0.5 microM), atropine (1 microM) plus naloxone (0.5 microM) or hexamethonium (100 microM) plus naloxone (0.5 microM). 4. PACAP (10 nM) restored peristalsis blocked by morphine (10 microM), noradrenaline (1 microM) or N6-cyclopentyladenosine (0.3 microM) and partially reinstated peristalsis blocked by Rp-adenosine-3',5'-cyclic monophosphothioate triethylamine (100 microM) but failed to revive peristalsis blocked by hexamethonium (100 microM) or atropine (1 microM). The peptide's spectrum of properistaltic activity differed from that of naloxone (0.5 microM) and forskolin (0.3 microM). 5. The distension-induced ascending reflex contraction of the circular muscle was facilitated by PACAP (1-30 nM) which itself evoked transient nerve-mediated contractions of intestinal segment preparations. 6. These data show that PACAP stimulates normal peristalsis and counteracts drug-induced peristaltic arrest by a stimulant action on excitatory enteric motor pathways, presumably at the intrinsic sensory neurone level. The action of PACAP seems to involve multiple signalling mechanisms including stimulation of adenylate cyclase.
Animals↗
Different receptors mediating the inhibitory action of exogenous ATP and endogenously released purines on guinea-pig intestinal peristalsis.
1 Adenosine 5'-triphosphate (ATP) is an enteric neurotransmitter which acts at purine receptors on intestinal nerve and muscle. This study set out to shed light on the receptor mechanisms by which exogenous and endogenous ATP influences intestinal peristalsis. 2 Peristalsis in isolated segments of the guinea-pig small intestine was triggered by a perfusion-induced rise of the intraluminal pressure. Motor changes were quantified by alterations of the peristaltic pressure threshold (PPT) at which propulsive muscle contractions were elicited. 3 ATP (>/= 3 microM) increased PPT and abolished peristalsis at concentrations of 100-300 microM. Adenosine 5'-O-2-thiodiphosphate (ADPbetaS, 3-100 microM) was more potent, whereas alpha,beta-methylene ATP (alpha,beta-meATP, 3-100 microM) was less potent, than ATP in depressing peristalsis. 4 8-Phenyltheophylline (10 microM) attenuated the anti-peristaltic effect of 10 and 30 microM ATP but not that of higher ATP concentrations. Apamin (0.5 microM) counteracted the ability of ATP, ADPbetaS and alpha,beta-meATP to enhance PPT. Suramin (300 microM) and pyridoxal phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS, 150 microM) antagonized the inhibitory effect of alpha,beta-meATP on peristalsis but did not alter the effect of ATP and ADPbetaS. 5 PPADS (50-150 microM) reduced PPT by as much as 50%. This stimulant effect on peristalsis was prevented by suramin (300 microM) but left unaltered by apamin (0.5 microM) and NG-nitro-L-arginine methyl ester (300 microM). 6 These data show that exogenous and endogenous ATP inhibits intestinal peristalsis via different apamin-sensitive purinoceptor mechanisms. Exogenous ATP depresses peristalsis mostly via suramin- and PPADS-insensitive P2 receptors, whereas endogenous purines act via P2 receptors sensitive to both suramin and PPADS.
Adenosine Diphosphate↗
Effect of angiotensin II and telmisartan, an angiotensin1 receptor antagonist, on rat gastric mucosal blood flow.
BACKGROUND: Angiotensin II (ATII) has been suggested to contribute to shock-induced dysfunction of the gastric circulation. AIM: To substantiate this conjecture, the effects on gastric mucosal haemodynamics and the hyperaemic response to acid back-diffusion of ATII and the angiotensin AT1 receptor antagonist, telmisartan, were examined in normal rats and in animals subjected to haemorrhage. METHODS: Gastric mucosal blood flow in phenobarbital-anaesthetized rats was recorded with the hydrogen clearance technique, and acid back-diffusion was induced by perfusing the stomach with ethanol (25%) in HCl (0.05 M). RESULTS: Intravenous infusion of ATII (0.3-10 nmol/min/kg) led to dose-dependent hypertension and a reduction of blood flow and vascular conductance in the gastric mucosa. The gastric hyperaemia caused by acid back-diffusion was attenuated by ATII (1 nmol/min/kg). These effects of ATII were antagonized by intravenous injection of telmisartan (1-10 mg/kg) which per se caused hypotension and dilated the gastric mucosal vasculature, but did not modify the gastric mucosal hyperaemia evoked by acid back-diffusion. Hypotension induced by haemorrhage (1.3 mL blood per 100 g body weight) failed to alter the hyperaemia due to acid back-diffusion, but caused gastric mucosal vasoconstriction, an effect that was left unaffected by telmisartan. CONCLUSIONS: ATII constricts the rat gastric microvasculature via an action involving AT1 receptors. The effects of telmisartan indicate that endogenous ATII contributes to the homeostatic regulation of gastric vascular tone but does not compromise the ability of the gastric microvasculature to react to influxing acid. These results negate the concept that ATII contributes to the gastric vascular perturbances in haemorrhagic shock.
Angiotensin II↗
Intestinal motor depression by 7-nitroindazole through an action unrelated to nitric oxide synthase inhibition.
Nitric oxide (NO) is a cotransmitter of inhibitory motor neurons of the enteric nervous system. This study examined the effect of 7-nitroindazole (7-NI), an inhibitor of neuronal NO synthase (NOS), on intestinal peristalsis and muscle activity and compared 7-NI with N(G)-nitro-L-arginine methyl ester (L-NAME), a nonselective inhibitor of NOS isoforms. Peristalsis in isolated segments of the guinea pig small intestine was triggered by a perfusion-induced rise of the intraluminal pressure. While L-NAME (10-300 micromol/l) lowered the peristaltic pressure threshold (PPT) at which propulsive muscle contractions were elicited, 7-NI (10-300 micromol/l) caused a concentration-related increase in PPT. L-Arginine (1-3 mmol/l) failed to reverse peristaltic motor depression evoked by 7-NI but annulled the L-NAME-evoked stimulation of peristalsis. Drugs which stimulated peristalsis, such as L-NAME, naloxone, apamin and suramin plus pyridoxal phosphate-6-azophenyl-2'-4'-disulphonic acid counteracted the inhibitory effect of submaximally effective concentrations of 7-NI on peristalsis. 7-NI (100-300 micromol/l) inhibited circular muscle contractions evoked by cholecystokinin octapeptide, the NK(1) receptor agonist GR-73,632 and indomethacin whereas L-NAME (100-300 micromol/l) failed to inhibit any drug-evoked contraction. These data show that 7-NI, unlike L-NAME, inhibits circular muscle contractions of the gut and depresses intestinal peristalsis. It is concluded that the inhibitory motor action of 7-NI is unrelated to inhibition of neuronal NOS and arises from depression of smooth muscle activity.
Animals↗
Mediation by 5_hydroxytryptamine of the femoral vasoconstriction induced by acid challenge of the rat gastric mucosa.
1. Gastric mucosal barrier disruption in the presence of luminal acid causes femoral vasoconstriction via a pathway that appears to be stimulated by messengers generated in the injured gastric mucosa. This study was undertaken to analyse the gastric factors that are responsible for the femoral vasoconstrictor response. 2. Gastric mucosal barrier disruption in the presence of luminal acid was induced by perfusing the stomach of urethane-anaesthetized rats with ethanol (15 %) in 0.01-0.15 M HCl. Blood flow in the left gastric and right femoral artery was estimated by the ultrasonic transit time shift technique. 3. Gastric perfusion of ethanol in HCl caused loss of H+ ions from the gastric lumen, decreased the HCO3- concentration in hepatic portal vein blood, induced macroscopic histological damage to the gastric mucosa, dilated the left gastric artery and constricted the femoral artery. These responses were related to the HCl concentration in the ethanol-containing perfusion medium. 4. The femoral vasoconstriction was also seen when, instead of ethanol, taurocholate (20 mM) was used to disrupt the gastric mucosal barrier in the presence of 0.15 M HCl. 5. The femoral vasoconstriction evoked by gastric perfusion of ethanol in HCl was left unaltered by pharmacological blockade of gastrin and histamine receptors. In contrast, the 5-hydroxytryptamine 5-HT1/2 receptor antagonist methiothepin, but not the 5-HT2A receptor antagonist ketanserin or the 5-HT3 receptor antagonist granisetron, inhibited the ability of both 5-hydroxytryptamine and gastric acid back-diffusion to constrict the femoral artery. 6. Gastric acid back-diffusion caused release of 5-hydroxytryptamine into the gastric lumen, which was related to the HCl concentration in the ethanol-containing perfusion medium. 7. These data show that femoral vasoconstriction evoked by gastric mucosal barrier disruption depends on back-diffusion of acid into the mucosa. The acid-induced damage results in release of 5-hydroxytryptamine from the gastric mucosa, and the pathway leading to constriction of the femoral artery involves 5-hydroxytryptamine acting via 5-HT1/2 receptors as a messenger molecule.
Animals↗
Gastric acid-evoked c-fos messenger RNA expression in rat brainstem is signaled by capsaicin-resistant vagal afferents.
BACKGROUND & AIMS: Gastric acid is known to contribute to ulcer pain, but the mechanisms of gastric chemonociception are poorly understood. This study set out to investigate the pathways and mechanisms by which gastric acid challenge is signaled to the brain. METHODS: Neuronal excitation in the rat brainstem and spinal cord after intragastric administration of HCl (0.35-0.7 mol/L) was examined by in situ hybridization autoradiography for the immediate early gene c-fos. RESULTS: Gastric acid challenge did not induce c-fos transcription in the spinal cord but caused many neurons in the nucleus tractus solitarii and area postrema to express c-fos messenger RNA (mRNA). The HCl concentration-dependent excitation of medullary neurons was in part associated with behavioral manifestations of pain but not directly related to the acid-induced injury and contraction of the stomach. Subdiaphragmatic vagotomy suppressed the c-fos mRNA response to intragastric acid, and morphine inhibited it in a naloxone-reversible manner, whereas pretreatment of rats with capsaicin was without effect. CONCLUSIONS: Gastric acid challenge is signaled to the brainstem, but not the spinal cord, through vagal afferents that are sensitive to acid but resistant to capsaicin. It is hypothesized that the gastric acid-induced c-fos transcription in the brainstem is related to gastric chemonociception.
Afferent Pathways↗
Neural emergency system in the stomach.
The maintenance of gastric mucosal integrity depends on the rapid alarm of protective mechanisms in the face of pending injury. Afferent neurons of extrinsic origin constitute an emergency system that is called into operation when the gastric mucosa is endangered by acid and other noxious chemicals. The function of these chemoceptive afferents can be manipulated selectively and explored with the excitotoxin capsaicin. Most of the homeostatic actions of capsaicin-sensitive afferents are brought about by peptides released from their peripheral endings in the gastric wall. When stimulated, chemoceptive afferents enhance gastric blood flow and activate hyperemia-dependent and hyperemia-independent mechanisms of protection and repair. In the rodent stomach, these local regulatory roles of sensory neurons are mediated by calcitonin gene-related peptide acting via calcitonin gene-related peptide 1 receptors and neurokinin A acting via neurokinin 2 receptors, with both peptides using nitric oxide as their common messenger. In addition, capsaicin-sensitive neurons form the afferent arc of autonomic reflexes that control secretory and motor functions of the stomach. The pathophysiological potential of the neural emergency system is best portrayed by the gastric hyperemic response to acid backdiffusion, which is signaled by afferent nerve fibers. This mechanism limits damage to the surface of the mucosa and creates favorable conditions for rapid restitution and healing of the wounded mucosa.
Animals↗
Tachykinin NK1 and NK2 receptor-mediated control of peristaltic propulsion in the guinea-pig small intestine in vitro.
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 microM) and peristalsis rescued by naloxone (0.5 microM). When cholinergic transmission via nicotinic receptors was suppressed by hexamethonium (100 microM) and peristalsis restored by naloxone (0.5 microM), only the NK2 receptor antagonist (0.1 microM) was able to attenuate peristaltic performance as deduced from a rise of the peristaltic pressure threshold by 106%. The NK3 receptor antagonist (0.1 microM) lacked a major influence on peristalsis under any experimental condition. It is concluded that tachykinins acting via NK1 and NK2 receptors sustain intestinal peristalsis when cholinergic neuroneuronal and neuromuscular transmission via muscarinic receptors has been suppressed. NK2 receptors help maintaining peristalsis once cholinergic neuroneuronal transmission via nicotinic receptors has been blocked, whereas NK3 receptors play little role in the neural pathways of peristalsis.
Animals↗
Neurogenic vasodilatation and plasma leakage in the skin.
1. Primary afferent nerve fibers control cutaneous blood flow and vascular permeability by releasing vasoactive peptides. These vascular reactions and the additional recruitment of leukocytes are commonly embodied in the term neurogenic inflammation. 2. Calcitonin gene-related peptide (CGRP) acting via CGRP1 receptors is the principal transmitter of neurogenic dilatation of arterioles whereas substance P (SP) and neurokinin A (NKA) acting via NK1 receptors mediate the increase in venular permeability. 3. Neurogenic vasodilatation and plasma protein leakage play a role in inflammation because many inflammatory and immune mediators including interleukin-1 beta, nitric oxide, prostanoids, protons, bradykinin, histamine, and 5-hydroxytryptamine can stimulate peptidergic afferent nerve fibers or enhance their excitability. 4. Neurogenic inflammatory reactions can be suppressed by alpha 2-adrenoceptor agonists, histamine acting via H1 receptors, 5-hydroxytryptamine acting via 5-HT1B receptors, opioid peptides, and somatostatin through prejunctional inhibition of peptide release from vasoactive afferent nerve fibers. CGRP, SP, and NKA receptor antagonists are powerful pharmacological tools to inhibit neurogenic inflammation at the postjunctional level. 5. Imbalance between the facilitatory and inhibitory influences on afferent nerve activity has a bearing on chronic inflammatory disease. Impaired nerve function represents a deficit in skin homeostasis while neuronal overactivity is a factor in allergic and hyperreactive disorders of the skin.
Animals↗
Dissociation of dorsal root ganglion neurons into afferent and efferent-like neurons.
Although the textbook function of dorsal root ganglion neurons is to signal information to the brain, a group of C-fibre and some A delta-fibre afferents have the capacity to release peptide transmitters from their peripheral terminations and thereby to regulate vascular and other tissue activities. Depending on the species under study, vasoactive dorsal root ganglion neurons in the skin belong to heat nociceptors or a subclass of polymodal nociceptors, and it has been a matter of long-standing discussion how the local effector role of dorsal root ganglion neurons is related to their afferent function. The observation that local vascular regulation may take place independently of nociception has commonly been explained by a number of transductional differences between peripheral peptide release and afferent nerve activity. However, the view that it is only one population of dorsal root ganglion neurons that can work in either mode is increasingly challenged, and after consideration of the available information we hypothesize that some dorsal root ganglion neurons are specialized in controlling peripheral effector mechanisms but have no role in sensation. These local effector neurons represent a novel class of autonomic neurons that lack a preganglionic input, but operate in an efferent-like mode after stimulation by internal or external stimuli.
Afferent Pathways↗
Lack of effect of a selective vasopressin V1A receptor antagonist SR 49,059, on potentiation by vasopressin of adrenoceptor-mediated pressor responses in the rat mesenteric arterial bed.
The vasopressin receptor subtype involved in the enhancement by vasopressin of adrenoceptor-mediated vasoconstriction was investigated in rat isolated perfused mesenteric arteries. [Arg8]vasopressin (1-10 nM) dose-dependently increased the perfusion pressure and enhanced the pressor response to the adrenoceptor agonist methoxamine (40 nmol) or electrical stimulation of periarterial nerves (16 Hz), at the concentration of 10 nM of [Arg8]vasopressin up to 4 and 3 fold, respectively. During prolonged exposure (45 min) the direct vasoconstrictor effect of [Arg8]vasopressin (10 nM) rapidly declined whereas the potentiation of methoxamine-induced vasoconstriction was maintained. The selective vasopressin V1A receptor antagonist SR 49,059 (1-3 nM) and the non-selective V1A/B and oxytocin receptor antagonist [deamino-Pen1,Tyr(Me)2,Arg8]vasopressin (15-45 nM) inhibited the direct vasoconstrictor action of [Arg8]vasopressin but had no effect on the enhancement of the pressor response to methoxamine or electrical stimulation. The V1B receptor agonist [deamino-Cys1,beta-(3-pyridyl)-D-Ala2,Arg8]vasopressin (100-1000 nM) and the V2 receptor agonist [deamino-Cys1,D-Arg8]vasopressin (1-10 nM) were devoid of any pressor activity and did not potentiate methoxamine-evoked vasoconstriction. In contrast, [1-triglycyl,Lys8]vasopressin (100 - 1000 nM) potentiated the methoxamine responses without per se inducing vasoconstriction. In arteries precontracted with methoxamine (7.5 microM) pressor responses to [Arg8]vasopressin (3-10 nM) were not inhibited by a dose of SR 49,059 (3 nM) which abolished the peptide's vasoconstrictor effect under control conditions. These data show that the direct vasoconstrictor effect of [Arg8]vasopressin is mediated by V1A receptors while the enhancement of adrenoceptor-mediated pressor responses is insensitive to V1A, V1B, and oxytocin receptor antagonists and is not mimicked by selective agonists of V1B and V2 receptors. In conclusion, an unusual interaction of vasopressin with V1A receptors, or even the existence of a novel receptor subtype, has to be considered.
Animals↗
Differential regulation of mesenteric and femoral blood flow in the rat as revealed by computerized data acquisition and evaluation.
1. A set-up for computerized acquisition and evaluation of haemodynamic data was constructed. Blood flow (BF) in the superior mesenteric and femoral artery of urethane-anaesthetized rats was measured with the ultrasonic transit time shift technique. The signals for arterial blood pressure and BF were fed into a personal computer via an analogue-digital converter. Mean arterial blood pressure, heart rate and vascular conductance (CV) were calculated on-line. For subsequent analysis of the data, algorithms were programmed to filter the data, and to determine average and peak values for each parameter. 2. Systemic hypertension induced by phenylephrine (3-300 nmol kg-1), angiotensin II (0.1-3.0 nmol kg-1) and arginine vasopressin (0.03-1.0 nmol kg-1) was accompanied by constriction of the mesenteric artery. In contrast, the femoral artery responded to phenylephrine with constriction, to angiotensin II with dilatation and to arginine vasopressin with dilation followed by constriction. The haemodynamic effects of endothelin-1 (0.03-3.0 nmol kg-1) were generally biphasic, the initial hypotension being associated with dilatation, and the delayed hypertension being accompanied by constriction of both the mesenteric and femoral arterial bed. 3. Terbutaline (3-1.0 nmol kg-1) and calcitonin gene-related peptide (0.03-1 nmol kg-1) caused systemic hypotension along with mesenteric and femoral vasodilatation. 4. Telmisartan (1 mg kg-1), an angiotensin AT1 receptor antagonist, dilated the mesenteric artery, but had no effect on femoral VC. In contrast, the alpha 1-adrenoceptor antagonist prazosin (0.1 mg kg-1), dilated the femoral artery without altering mesenteric VC. Similarly, the beta-adrenoceptor antagonist propranolol (1 mg kg-1) had no effect on mesenteric VC, but constricted the femoral arterial bed. 5. These data demonstrate that the haemodynamic effects of exogenously administered drugs can widely differ between the mesenteric and femoral arterial beds of urethane-anaesthetized rats. Furthermore, vascular tone of these two arterial beds in maintained by different vasoconstrictor systems. While the femoral artery is mainly under adrenergic control, the renin-angiotensin axis is predominant in the mesenteric arterial bed. In addition, this study also demonstrates that computerized analysis enables quick and accurate estimation of haemodynamic drug effects, and is superior to 'by hand' evaluation of peak changes in the functional diameter of the vascular bed under study.
Angiotensin II↗
Intraluminal capsaicin does not affect fluid and electrolyte absorption in the human jejunum but does cause pain.
BACKGROUND: Stimulation of sensory nerves with capsaicin regulates ion transport in the small intestine in animal experiments. AIM: To investigate whether sensory nerves that are stimulated by capsaicin administration influence fluid and electrolyte absorption in the human jejunum in vivo. METHOD: Intestinal perfusion studies were performed in 12 healthy subjects using a four lumen tube with a proximal occlusion balloon and a plasma-like electrolyte solution. After an initial control period, 5 (n = 3), 10 (n = 8), or 50 (n = 1) micrograms/ml capsaicin was added to the perfusate, and this was followed by a final control period. Rates of absorption of water, sodium, potassium, chloride, and bicarbonate were determined in a 30 cm segment of jejunum using a non-absorbable volume marker. RESULTS: At all three concentrations of capsaicin there were no significant changes in water and electrolyte absorption as compared with control periods. Two subjects who received 10 micrograms/ml and the subject receiving 50 micrograms/ml experienced crampy abdominal pain. CONCLUSION: The results do not support the hypothesis that capsaicin sensitive afferent nerves are involved in the physiological regulation of net absorption or secretion across the human jejunal mucosa. Chemical stimulation of these nerves, however, gives rise to abdominal pain.
Adult↗
Neural injury, repair, and adaptation in the GI tract. II. The elusive action of capsaicin on the vagus nerve.
Capsaicin is an excitotoxin for primary afferent neurons, and perivagal administration of capsaicin is frequently used to ablate afferent fibers from the vagus nerve in an attempt to elucidate the role of afferent fibers in gastrointestinal (GI) regulation. However, this method has recently been called into question by research demonstrating that the molecular target of capsaicin on spinal and trigeminal afferents, vanilloid receptor subtype 1 (VR1), is absent from vagal afferents. Although some concerns about selectivity exist, the available information suggests that perineural capsaicin defunctionalizes afferent neurons of the vagus nerve by acting on a vanilloid receptor subtype that is structurally different from VR1.
Afferent Pathways↗