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Oxytocin and its effects on the gastrointestinal tract
Abstract
Oxytocin is released into plasma in response to a meal (Ohlsson et al., 2002) and injection of cholecystokinin (CCK) (Ohlsson et al., 2004a). There are 2 phases in the release after a meal, whereas only one phase after CCK injection. Postprandially, the peak value in oxytocin release comes after the peak level of CCK (Ohlsson et al., 2002). This is in line with the findings in rats, where both parvocellular neurons projecting to the dorsal vagal complex, and magnocellular neurons projecting to the pituitary, secrete oxytocin in response to CCK (Verbalis et al., 1991). Oxytocin and its receptor mRNA is detected by the PCR method in almost all segments of the human gastrointestinal (GI) tract (Monstein et al., 2004). The indirect immunofluorescence approach has shown that oxytocin is expressed in myenteric and submucous ganglia, suggesting that it is important for both GI sensitivity and motility (Ohlsson et al., 2006a). It has not been possible to demonstrate the oxytocin receptor by immunohistochemistry. In human, oxytocin has been shown to stimulate gastric emptying (Hashmoni et al., 1979, Petring 1989) and colonic peristalsis (Ohlsson et al., 2004b). In addition, inhibition of the binding of endogenous oxytocin by the receptor antagonist atosiban delays gastric emptying (Ohlsson et al., 2006b), and diabetics with gastro paresis have impaired oxytocin secretion (Faraj et al., 2008). Despite the stimulatory effect of oxytocin on peristalsis, treatment with nasally administered oxytocin does not improve the stool habits in women with refractory constipation (Ohlsson et al., 2005). In animals, oxytocin exerts divergent effects in different species and segments of the GI tract. Oxytocin is also known to have analgetic and antidepressive effects in rats (Arletti et al., 1995, Petersson et al., 1996), and its plasma levels are found to be decreased in patients suffering from dyspepsia and IBS (Uvnäs-Moberg et al., 1991). Furthermore, children suffering from recurrent abdominal pain exhibit lower plasma levels of oxytocin than healthy controls (Alfven 2004). Interestingly, both depression and fibromylagia are associated with IBS (Lydiard et al., 1993, Sperber et al., 1999), and both of these conditions are also characterised by low plasma levels of oxytocin (Frash et al., 1995, Anderberg et al., 2000). Accordingly, treatment of IBS patients with intravenously (Louvel et al., 1996) or nasally (Ohlsson et al., 2005) administered oxytocin result in the reduction of abdominal pain and reduced depression. The questions remain as to whether oxytocin could be used clinically to improve the suffering of patients with IBS, fibromyalgia and depression by reducing their pain and their depressive mood, or improve gastric emptying in patients suffering from gastro paresis. Further randomised clinical trials are needed to answer these questions.
The study was designed to investigate the effect of estradiol on the excitatory effect of oxytocin (OT) on colon motility. Female Wistar rats were used, and some of them were ovariectomized (OVX) and treated with vehicle or estradiol (E(2)). A plastic balloon made of condom was inserted into colon to monitor the change of colonic pressure in vivo. Longitudinal muscle strips of distal colon were prepared to monitor the spontaneous contraction of colon in vitro. Expression of OT receptor (OTR) was investigated by Western blot analysis. Expression of OTR mRNA was detected by RT-PCR. Immunohistochemistry was used to locate OTR. In OVX rats, pretreatment of E(2) (4-100 microg/kg sc) dose-dependently increased the excitatory effect of OT on colon motility both in vivo and in vitro and increased the expression of OTR and OTR mRNA in colon. Systemic administration of OT excited the colon motility in vivo in rats at perioda of proestrus and estrus but did not influence it at diestrus period, when the concentration of plasma E(2) was lowest in the estrous cycle. Pretreatment of atosiban, the specific OTR antagonist, and TTX, the blocker of voltage-dependent sodium channel on nerve fiber, attenuated the excitatory effect of OT on colon motility. OTR was located in myenteric plexus of colon. These results suggested that E(2) increased the excitatory effect of OT on colon motility by upregulating the expression of OTR in myenteric plexus.
Gastrointestinal (GI) dysmotility and autonomic neuropathy are common problems among diabetics with largely unknown aetiology. Many peptides are involved in the autonomic nervous system regulating the GI tract. The aim of this study was to examine if concentrations of oxytocin, cholecystokinin (CCK), gastrin and vasopressin in plasma differ between diabetics with normal function and dysfunction in GI motility.
Nineteen patients with symptoms from the GI tract who had been examined with gastric emptying scintigraphy, oesophageal manometry, and deep-breathing test were included. They further received a fat-rich meal, after which blood samples were collected and plasma frozen until analysed for hormonal concentrations.
There was an increase in postprandial oxytocin plasma concentration in the group with normal gastric emptying (p = 0.015) whereas subjects with delayed gastric emptying had no increased oxytocin secretion (p = 0.114). Both CCK and gastrin levels increased after the meal, with no differences between subjects with normal respective delayed gastric emptying. The concentration of vasopressin did not increase after the meal. In patients with oesophageal dysmotility the basal level of CCK tended to be higher (p = 0.051) and those with autonomic neuropathy had a higher area under the curve (AUC) of gastrin compared to normal subjects (p = 0.007).
Reduced postprandial secretion of oxytocin was found in patients with delayed gastric emptying, CCK secretion was increased in patients with oesophageal dysmotility, and gastrin secretion was increased in patients with autonomic neuropathy. The findings suggest that disturbed peptide secretion may be part of the pathophysiology of digestive complications in diabetics.
Cholecystokinin (CCK) concentrations in plasma have been shown to be significantly higher in colectomised subjects compared to healthy controls. This has been ascribed to reduced inhibition of CCK release from colon. In an earlier study CCK in all but one woman who was colectomised, induced release of oxytocin, a peptide present throughout the gastrointestinal (GI) tract. The aim of this study was thus to examine if colectomised women had a different oxytocin response to CCK compared to healthy controls.
Eleven women, mean age 34.4 +/- 2.3 years, who had undergone colectomy because of ulcerative colitis or constipation were studied. Eleven age-matched healthy women served as controls. All subjects were fasted overnight and given 0.2 microg/kg body weight of CCK-8 i.v. in the morning. Samples were taken ten minutes and immediately before the injection, and 10, 20, 30, 45, 60, 90 and 120 min afterwards. Plasma was collected for measurement of CCK and oxytocin concentrations.
The basal oxytocin and CCK concentrations in plasma were similar in the two groups. Intravenous injection of CCK increased the release of oxytocin from 1.31 +/- 0.12 and 1.64 +/- 0.19 pmol/l to 2.82 +/- 0.35 and 3.26 +/- 0.50 pmol/l in controls and colectomised women, respectively (p < 0.001). Given the short half-life of CCK-8 in plasma, the increased concentration following injection could not be demonstrated in the controls. On the other hand, in colectomised women, an increase of CCK in plasma was observed for up to 20 minutes after the injection, concentrations increasing from 1.00 +/- 0.21 to a maximum of 1.81 +/- 0.26 pmol/l (p < 0.002).
CCK stimulates the release of oxytocin in women. There is no difference in plasma concentrations between colectomised and controls. However, colectomy seems to reduce the metabolic clearance of CCK. The hyperCCKemia in patients who had undergone colectomy is consequently not only dependent on CCK release, but may also depend on reduced clearance.
Oxytocin is released in response to a meal. Further, mRNA for oxytocin and its receptor have been found throughout the gastrointestinal (GI) tract. The aim of this study was therefore to examine whether oxytocin, or the receptor antagonist atosiban, influence the gastric emptying.
Ten healthy volunteers (five men) were examined regarding gastric emptying at three different occasions: once during oxytocin stimulation using a pharmacological dose; once during blockage of the oxytocin receptors (which also blocks the vasopressin receptors) and thereby inhibiting physiological doses of oxytocin; and once during saline infusion. Gastric emptying rate (GER) was assessed and expressed as the percentage reduction in antral cross-sectional area from 15 to 90 min after ingestion of rice pudding. The assessment was performed by real-time ultrasonography. At the same time, the feeling of satiety was registered using visual satiety scores.
Inhibition of the binding of endogenous oxytocin by the receptor antagonist delayed the GER by 37 % compared to saline (p = 0.037). In contrast, infusion of oxytocin in a dosage of 40 mU/min did not affect the GER (p = 0.610). Satiation scores areas in healthy subjects after receiving atosiban or oxytocin did not show any significant differences.
Oxytocin and/or vasopressin seem to be regulators of gastric emptying during physiological conditions, since the receptor antagonist atosiban delayed the GER. However, the actual pharmacological dose of oxytocin in this study had no effect. The effect of oxytocin and vasopressin on GI motility has to be further evaluated.
Abstract The effect of systemically-administered Cholecystokinin octapeptide (CCK) on hypothalamic oxytocin, vasopressin, and corticotropin-releasing hormone neurons was studied by analysis of c-fos antigen expression in immunocytochemically-characterized neurons in the supraoptic and paraventricular nuclei. CCK (100mug/kg intraperitoneally) caused a marked increase in nuclear c-fos immunocytochemical staining, which peaked at 60 to 90 min after injection. C-fos expression was found in most magnocellular oxytocin neurons in the supraoptic nucleus and in all magnocellular subdivisions of the paraventricular nucleus, but in no vasopressin neurons in either area. C-fos expression was also found in several parvocellular subdivisions of the paraventricular nucleus: in oxytocin neurons within the medial and lateral, but not the dorsal, parvocellular subdivisions, and in corticotropin-releasing hormone neurons in the medial parvocellular subdivision. Injection of lower doses of CCK showed that c-fos expression closely paralleled the pattern of pituitary oxytocin secretion in response to CCK, with a threshold for activation at 1 mug/kg, near maximal responses by 10 mug/kg, and maximal responses by 100 mug/kg. These studies demonstrate that the pattern of c-fos expression in hypothalamic magnocellular neurons following systemic CCK administration mirrors the neurosecretory response of these neurons, both with regard to specificity for the peptides secreted as well as intensity of secretion. They also demonstrate that systemic CCK administration activates c-fos expression in parvocellular oxytocin and corticotropin-releasing hormone neurons, and therefore likely causes secretion of oxytocin and corticotropin-releasing hormone within the brain at the terminal fields of these neurons.
In conscious dog deamino-dicarba-oxytocin strongly stimulated a spike activity in the uterus which was more prolonged than that after oxytocin. Both oxytocin and deamino-dicarba-oxytocin inhibited the tone and peristaltic contractions of stomach and small intestines in starving dogs, eliminated the spike discharges, reduced the basic electrical rhythm frequency of the stomach and accelerated the propagation velocity of the slow waves in the small intestine. Only oxytocin, but not its deamino-analogue, reduced the pulse frequency and inhibited the spontaneous contractions of muscle strips isolated from the guinea pig stomach and portal vein.
A study is made of the effect of synthetic oxytocin on the mechanograms and electromyograms of the stomach and small intestines of 11 wakeful and 7 chloralose-anaesthesized dogs. Oxytocin was administered intravenously in doses of 0.5 to 2.0 IU/kg for the anaesthesized dogs. The mechanograms were recorded by means of the balloon-kymographic method, the electromyograms-by silver macroelectrodes implanted in the muscle wall. In all animals oxytocin decreased the tone and abolished the peristaltic contractions and the spike-potentials in the stomach and in the intestines for 8 to 15 min. This effect of oxytocin is not eliminated by adreno-, cholino- and gangliolytics. Besides these changes, oxytocin administered in wakeful dogs reduces two or three times the frequency of the basic electric rhythm (BER) in the stomach from 10 s to 3 min and increases the propagation of BER in the small intestine from 10 s to 10 min. The effect of oxytocin on gastric and intestinal BER is eliminated by cholinolytics and gangliolytics and it is not manifested in the small pouch of Heindenhein. A direct myogenic mechanism of oxytocin effect on the activity of the gastro-intestinal smooth muscle is discussed, as well as the effect mediated by vagal nerves and cholinergic receptors.
Twenty-four individuals with functional disorders of the gastrointestinal tract participated in the study. Symptoms from the upper and lower gastrointestinal tract were recorded by means of a self-administered questionnaire before, 3 months and 3 yr after participation in group therapy. Blood was sampled from the patients while they were subjected to three different provocations (a friendly greeting, a food stimulus and a stress stimulus). Ten subjects without gastrointestinal symptoms participated in an identical experiment. Gastrin, somatostatin and oxytocin levels were measured with radioimmunoassay. Both gastrin and somatostatin levels were influenced by the provocations and by the greeting and the stress stimulus in particular. In principle, the controls tended to react with a parasympathetic response pattern following the interactive stimuli, whereas the individuals with functional disorders of the gastrointestinal tract reacted with an activation of the sympathetic nervous system. Somatostatin levels were significantly higher and oxytocin levels lower in patients than in controls and gastrin levels tended to be higher in patients than in controls. Most individuals reported both gastric as well as intestinal symptoms. Gastrin levels correlated positively with total symptom level and somatostatin levels with intestinal symptoms scores reported by the patients.
Extracellular recordings were made from vasopressin (AVP) and oxytocin (OXT)-secreting cells in the paraventricular nucleus (PVN) of the hypothalamus in rats anesthetized with urethane-chloralose to determine the effects of electrical stimulation of vagal gastric nerves and gastric distension on their activity. Electrical stimulation of gastric branches of the vagus nerves inhibited 5 and excited 10 of 32 phasically firing neurosecretory cells. Approximately one third of the phasically firing neurosecretory cells (9 out of 29 cells) were transiently inhibited by gastric distension; an effect which was completely abolished by bilateral cervical vagotomy. In contrast, gastric nerve stimulation excited 45 of 72 non-phasically firing paraventricular cells. Thirteen of 77 non-phasically firing cells tested were excited by gastric distension. We conclude that there are some sensory afferent inputs originating from gastric receptors and transmitted by gastric vagal afferents which inhibit the activity of AVP-secreting neurons in the PVN although other inputs excite the cells. Similar inputs also excite some of the putative OXT-secreting neurons in the PVN.
Both human and guinea pig gallbladder strips were tonically contracted by supramaximal concentrations of histamine in vitro. Guinea pig gallbladder strips were also tonically contracted by potassium, with no spontaneous relaxation after 5 min. The amplitude of the contractions caused by histamine decreased spontaneously only by 34 +/- (SD) 10% after 5 min in guinea pig strips and by 25 +/- 7% after 5 min in human strips. Both oxytocin and 8-l-lysine-vasopressin dose-dependently relaxed almost completely contractions caused by histamine and potassium in guinea pigs. In humans, only 8-l-lysine-vasopressin decreased the amplitude of histamine contractions. In both species, neither oxytocin nor 8-l-lysine-vasopressin affected the basal tone of strips.
Synthetic oxytocin (OT) was infused iv in four men at 3 mU/min, and the rate was doubled every 90 min for a total of three infusion periods. The mean (+/- SEM) OT MCR was 16.4 +/- 1.7 ml/kg X min and was independent of the rate of infusion. A method for measuring OT in urine was developed using an octadecasilyl-silica column for extraction of the hormone. The extracted residue was reconstituted in potassium phosphate buffer, pH 7.4, for RIA. The minimum detectable level of OT in urine was 0.2 microU/ml (defined as a bound to free ratio of approximately 90%). The mean recovery of OT was 77 +/- 2%. The mean (+/- SEM) concentration of endogenous OT in urine was 10.2 +/- 1.4 microU/ml. Endogenous OT in urine eluted from a reverse phase high pressure liquid chromatography column as a single peak of OT immunoreactivity in the position of synthetic OT. Urinary OT excretion during infusion of synthetic OT was linearly correlated with plasma OT concentration whether calculated as microunits of urinary OT per mg creatinine (r = 0.89) or urinary OT per min (r = 0.93). Mean urinary fractional clearance of OT (OT clearance/creatinine clearance) was 3.6% renal clearance of OT (5.5 ml/min or 0.43% of MCR). Thus, OT MCR was constant over a wide range of physiological plasma OT levels and was similar to MCR in pregnant women studied previously in this laboratory. Less than 1% of OT was cleared in urine. This study defines the relationship between urinary and plasma OT during steady state infusion of physiological concentrations of the hormone and indicates that measurements of OT in urine by RIA may prove helpful for pharmacokinetic and physiological studies of OT-related events in humans.
The intermittent reports concerning metabolic actions of neurohypophysial extracts or hormones encouraged us to study the effect of these substances on the function of the endocrine pancreas. A surprisingly small amount of neural lobe (NL) extract (0.025 NL eq/ml) stimulated a 425% increase in the release of glucagon from islets isolated from the pancreas of the rat. Gel filtration of the extract produced an elution profile of glucagon-releasing activity that was superimposable on the profiles of oxytocin (OT) and arginine vasopressin (AVP). Synthetic OT and AVP each elicited a concentration-dependent stimulation of glucagon release but failed to influence insulin release in medium 199 containing 5.6 mM glucose. They were effective at 0.2 ng/ml (+55%, +50%) and produced a striking increase (five- to sevenfold) at 20 ng/ml. The response to each peptide was greatly diminished in the presence of a higher concentration of glucose (11 mM). The lysine, desamino-, and 1,6-aminosuberyl analogues of vasopressin, vasotocin, and AVP are equipotent peptides, whereas the desglycinamide analogue, pressinoic acid, and angiotensin II were inactive. Injection of AVP (1 microgram iv) produced a rapid increase in peripheral glucagon (+185% in 5 min). The response to injection of OT was less rapid (+105% in 15 min), but in each case elevation of insulin was also observed. Our results provide evidence that OT and AVP can act directly on the endocrine pancreas and may help explain previous reports of metabolic actions of these peptides.
Oxytocin binding sites were detected by autoradiography on films and emulsion-coated sections in the spinal cord of adult and postnatal rats from C8 to L2, using a highly selective 125I-labelled oxytocin antagonist. Oxytocin binding sites were detected on all transverse sections in the dorsal horn, where labelling was scattered over laminae I and II. The autonomic areas, i.e. the intermediolateral cell column, the central grey (lamina X) and the nucleus intercalatus were labelled. Binding in the intermediolateral cell column was most frequently observed on sections from T9 to T11 in adult and T7 to T8 in postnatal rats. In this location, oxytocin binding sites were highly concentrated on cell bodies of putative sympathetic preganglionic neurons; however, not all of these cells were labelled. Diffuse labelling occurred on the dorsal part of the central grey, mainly between T8 and L2. Isolated labelled cells belonging to the nucleus intercalatus were scattered between the central canal and the intermediolateral cell column. In addition, oxytocin binding sites were found on some motoneurons of the lateral group of T12-T13, but only in postnatal rats. The distribution of oxytocin binding sites in the rat spinal cord coincides with that of the oxytocin innervation and strongly suggests a modulatory role of this peptide in sensory and autonomic functions.
Oxytocin, intraperitoneally injected to 26-month-old male rats 60 min before testing, significantly improved social memory (at doses of 3 and 6 ng/kg) and reduced the duration of immobility in the behavioral despair test (at doses of 50 and 500 micrograms/kg). These results are in agreement with previous data obtained in adult rats and indicate that aging does not compromise the social memory improving and antidepressant-like activities of oxytocin.
To study the effects of oxytocin on both spontaneous phasic contractions and K ⁺ outward currents (I K ) of the so-called 'non-target' smooth muscle cells, physiological concentrations of oxytocin ranging between 10 ⁻¹² mol/l and 10 ⁻⁸ mol/l were applied to smooth muscle preparations and single voltage-clamped cells isolated from the circular layer of the guinea-pig gastric antrum. Oxytocin (10 ⁻¹² mol/l to 10 ⁻⁸ mol/l) suppressed, in a dose-dependent manner, the tetrodotoxin- and atropine-resistant spontaneous phasic contractions and shifted rightward the dose–response curves of 10 ⁻⁷ mol/l charybdotoxin and 10 ⁻³ mol/l BaCl 2 . In cells with preloaded intracellular Ca ²⁺ stores, oxytocin (10 ⁻¹² mol/l to 10 ⁻⁹ mol/l) caused a dose-dependent activation of the charybdotoxin-blockable non-inactivating component of I K (I K(s1) ) of single voltage-clamped cells, which was accompanied by hyperpolarization of the cell membranes. ⁸ Lys-vasopressin and ⁸ arg-vasopressin failed to mimic the effects of oxytocin on both contraction and K ⁺ currents. Further, the oxytocin-induced activation of I K(s1) was effectively antagonized by 5× 10 ⁻⁸ mol/l U-73122 or 5× 10 ⁻⁶ mol/l 2-nitro-4-carboxyphenyl N,N-diphenylcarbamate (inhibitors of the cell membrane phospholipase C), as well as by intracellularly applied heparin (selective inhibitor of inositol-1,4,5-trisphosphate (IP 3 )-induced Ca ²⁺ release channels). In cells incubated in the absence of Ca ²⁺ entry throughout the study, oxytocin (10 ⁻⁹ mol/l) caused a slight and transient increase of I K(s1) amplitudes. Neither ryanodine (10 ⁻⁶ mol/l nor cyclopiazonic acid (10 ⁻⁶ mol/l) were able to restore the I K -activating effect of oxytocin in these cells.
The data obtained suggest (i) that selective oxytocin receptors are present on the membranes of guinea-pig antral smooth muscle cells, (ii) that the oxytocin-related relaxation may result from the activation of Ca ²⁺ -sensitive K ⁺ conductivity via activation of IP 3 -induced release of C a from the submembrane located cisternae of the sarcoplasmic reticulum Ca ²⁺ stores and (iii) in turn, this evokes a non-inactivating component of I K , hyperpolarizing the cell membrane.
European Journal of Endocrinology 136 531–538
The effects of oxytocin (OT) on gastric emptying and plasma levels of cholecystokinin (CCK) were studied in male rats. Gastrointestinal motility was assessed in rats 15 min after intragastric instillation of a test meal containing charcoal and Na2(51)CrO4. Gastric emptying was determined by measuring the amount of radiolabeled chromium contained in the small intestine as a percentage of the initial amount received. Blood samples were collected for OT and CCK radioimmunoassay. After administration of OT (0.2-0.8 mg x kg(-1)), gastric emptying was inhibited, whereas plasma concentrations of OT and CCK were increased in a dose-dependent manner. Atosiban, an oxytocin receptor antagonist, effectively attenuated the OT-induced inhibition of gastric emptying. However, administration of atosiban alone had no effect on gastric emptying. Devazepide (3 mg x kg(-1)), a selective CCKA receptor antagonist, effectively attenuated the OT-induced inhibition of gastric emptying. L-365, 260, a selective CCKB receptor antagonist, did not alter the OT-induced inhibition of gastric emptying. These results suggest that OT inhibits gastric emptying in male rats via a mechanism involving CCK stimulation and CCKA receptor activation.
The effects of oxytocin (OT) on gastric emptying, gastrointestinal transit, and plasma levels of cholecystokinin (CCK) were studied in female rats. Gastrointestinal motility was assessed in rats 15 min after intragastric instillation of a test meal containing charcoal and Na(2)(51)CrO(4). Gastric emptying was determined by measuring the amount of radiolabeled chromium contained in the small intestine as a percentage of the initial amount received. Gastrointestinal transit was evaluated by calculating the geometric center of distribution of the radiolabeled marker. Blood samples were collected for CCK radioimmunoassay. After administration of OT (0.2-0.8 mg/kg), gastric emptying and gastrointestinal transit were inhibited, whereas the plasma concentration of CCK was increased in a dose-dependent manner. Atosiban, an oxytocin receptor antagonist, effectively attenuated the OT- induced inhibition of gastric emptying and gastrointestinal transit. However, administration of atosiban alone had no effect on gastric emptying and gastrointestinal transit. The selective CCK(1) receptor antagonists, devazepide and lorglumide, effectively attenuated the OT-induced inhibition of gastric emptying and gastrointestinal transit. L-365, 260, a selective CCK(2) receptor antagonist, did not alter the OT-induced inhibition of gastric emptying and gastrointestinal transit. These results suggest that OT inhibits gastric emptying and gastrointestinal transit in female rats via a mechanism involving CCK stimulation and CCK(1) receptor activation.
Our recent study indicated that, in the dorsal motor nucleus of the vagus (DMV), the N-methyl-D-aspartic acid (NMDA) receptor-nitric oxide (NO)-cGMP pathway participated in the regulation of gallbladder motility in rabbits. Oxytocin (OT) is involved as a neurotransmitter in autonomic regulation. The aim of the present experiments is to investigate the effect of OT microinjected into DMV on the gallbladder motility and the involvement of NMDA receptor-NO-cGMP pathway. A frog bladder connected with transducer was inserted into the gallbladder to record the gallbladder pressure. Microinjection of OT (10-50 nmol/L, 100 nl) dose dependently increased the strength of gallbladder phasic contraction. The excitatory effect of OT (10 nmol/L, 100 nl) was completely abolished by atosiban (10 mmol/L, 100 nl), the specific OT receptor antagonist, but was not influenced by [deamino-Pen(1), O-Me-Tyr(2),Arg(8)]-vasopressin (10 mmol/L, 100 nl), the V(1) receptor antagonist. Pretreatment of ketamine (10 mmol/L, 100 nl), the NMDA receptor antagonist, suppressed the gallbladder motor response to OT; but pretreatment of 6-Cyaon-7-Nitroquinoxaline-2,3-(1H,4H)-Dione (CNQX; 10 mmol/L, 100 nl), the non-NMDA receptor antagonist, did not affect it. Pretreatment of L-NAME (10 mmol/L, 100 nl), the nitric oxide synthase (NOS) inhibitor, or methyl blue (10 mmol/L, 100 nl), the guanylyl cyclase inhibitor, inhibited the excitatory effect of OT on gallbladder motility. Hence, we deduced that the microinjection of OT into the DMV enhanced the gallbladder motility through binding specific OT receptors and activating the NMDA receptor-NO-cGMP pathway.
Vasopressin and oxytocin are closely related peptides, and both exert effects on the gastrointestinal function. In the present study, we wanted to map the expression of vasopressin receptor mRNAs (V1a, V1b/V3, and V2) in nontumorous tissue biopsy specimens of human gastrointestinal tract and surrounding tissues.
Total and polyA+ RNAs were isolated from human tissue biopsy specimens using an automated nucleic acid extractor and, subsequently, converted into single-stranded cDNA. Semi-nested PCR amplifications were carried out, using gene-specific V1a, V1b/V3, and V2 receptor primers. The PCR amplicons were partially sequenced to confirm their identity.
The present study demonstrated the expression of vasopressin receptor mRNAs in human gastrointestinal tract, pancreas, kidney, lung, brain, and ovary. The expression pattern varied between different parts of the gastrointestinal tract. In the colon ascendens, V1a receptor mRNA expression could not be detected in 3 out of 4 analyzed tissue biopsy specimens. On the other hand, all the vasopressin receptor mRNAs were expressed in all colon transversum biopsy samples.
V1a, V1b/V3, and V2 receptor mRNAs are widely expressed throughout human gastrointestinal tract and surrounding tissues. The data obtained provide information for further mapping and determination of the physiological role of the vasopressin receptor mRNA expression in normal and tumorous tissues.
These experiments were performed to study the effect of oxytocin (OT) and it's specific receptor on gallbladder motility in rabbits. The fasted New Zealand white rabbits (2.0-2.5 kg) were anaesthetized by urethane (1 g/kg). The gallbladder pressure was recorded continuously to monitor the gallbladder motility. Systemic OT (0.01, 0.02, 0.04 mg/kg, iv) did not affect the gallbladder pressure, but dose-dependently increased the frequency of phasic contraction. Five min after OT administration (0.04 mg/kg, iv), the strength of phasic contraction increased to 0.23 +/- 0.08 mmHg/min (P < 0.01, n = 6). The gallbladder motility returned to normal 15 min later after OT treatment. Intravenous injection of atosiban (0.04 mg/kg, iv), an OT receptor antagonist, decreased the strength of gallbladder phasic contraction but did not affect gallbladder pressure. Pretreatment of atosiban (0.04 mg/kg, iv) completely abolished the systemic OT effect on gallbladder. Vasopressin (VP) (0.1 - 0.5 IU/kg, iv) dose-dependently decrease the gallbladder pressure but did not affect the phasic contraction. MK-329 (0.4 mg/kg, iv), the CCK-A receptor antagonist, L-365, 260 (0.4 mg/kg, iv), the CCK-B receptor antagonist and atropine (0.2 mg/kg, iv), the M receptor antagonist, did not affect the OT effect on gallbladder motility. We suggest that endogenous OT regulates gallbladder phasic contraction through specific OT receptor. This effect is independent of the peripheral CCK and M receptors.