Effects Of Domperidone Research Articles

Domperidone Stimulates Prolactin Secretion in Rats With Complete Destruction of the Mediobasal Hypothalamus

The main objective of this study was to further elucidate the functional relationship between endogenous dopamine and the prolactin (PRL)-releasing effect of the dopamine antagonists domperidone and haloperidol. We studied the effect of the above dopamine antagonists on the PRL secretion in control and mediobasal hypothalamus (MBH)-lesioned rats. Significant increase in basal plasma PRL levels was detected 7 days after complete surgical destruction of the MBH. Haloperidol injection (0.5 mg/kg, IV) was followed by an increased plasma PRL concentration in the sham-operated animals; however, in the MBH-lesioned rats where the basal PRL levels were high haloperidol failed to produce additional PRL release. In contrast to haloperidol, domperidone (0.1 mg/kg, IV) was able to further elevate the MBH-lesion induced high plasma PRL concentration. Moreover, the change in plasma PRL levels of the MBH-lesioned rats was parallel with that in the sham-lesioned animals after domperidone injections. When haloperidol was given prior to the domperidone injection it did not influence the PRL releasing effect of domperidone in MBH-lesioned animals. The PRL stimulatory effect of domperidone (0.3 mg/kg, IV) in MBH-lesioned rats was antagonized by dopamine (20 μg/kg, IV) and bromocryptine (20 μg/kg, IV). The above results suggest that the stimulatory effect of domperidone on the pituitary PRL secretion is mediated—at least in part—through the pituitary D2 dopamine receptors, but not by the displacement of endogenous dopamine originating from the MBH and reaching the pituitary via portal vessels.

THE PROKINETIC EFFECT OF DOMPERIDONE IN GALLBLADDER—NOT UPON DOPAMINERGIC RECEPTORS

The mechanism of the contractile effect of domperidone on gallbladder smooth muscle has been investigated by using an in-vivo and an in-vitro model. In the in-vivo part of the study 14 healthy males were administered 20mg domperidone or two placebo tablets orally and gallbladder emptying was measured by ultrasonography. The reduction in the gallbladder volume was significant compared to the placebo at 45 and 55min. In the in-vitro part of the study, the gallbladder strips isolated from guinea pigs were field stimulated and 10−6–10−4Mconcentrations of dopamine were administered before electrical field stimulation (EFS) was repeated. Dopamine exerted no significant effect upon the contractions obtained by EFS. The effect of dopamine and domperidone under basal conditions were also explored. Under basal conditions, dopamine neither contracted nor relaxed the gallbladder muscle between 10−6and 10−4Mconcentrations when added directly to the organ bath. Besides, a significant contraction was observed with 10−4Mconcentration of domperidone whereas 10−7, 10−6and 10−5Mconcentrations exerted no effect. This effect of domperidone was thought to be nonspecific but inhibited by 10−6Matropine, 10−5Mpirenzepine and abolished by 10−6Mtetrodotoxin. In summary, domperidone produces a modest contraction in human gallbladder. This effect does not seem to occur upon dopaminergic receptors in guinea pig models.

ニワトリにおける中鎖脂肪によるそ嚢からの飼料通過遅延に及ぼすドンペリドンの効果

The effect of domperidone, a dopamine D2-receptor antagonist, on the forward passage of the crop contents of chicks receiving 20% medium chain or long chain triacylglycerol was studied. Medium chain triacylglycerol significantly delayed the crop emptying of chicks compared with long chain triacylglycerol, though no significant effects were obtained by domperidone treatments. The present result suggested that the involvement of dopaminergic action was negligible in the delayed crop emptying rate induced by medium chain triacylglycerol in chicks.

Acute hypoxic ventilation, carotid body cell division, and dopamine content during early hypoxia in rats

In a previous study, we showed that the acute hypoxic ventilatory response was blunted in anesthetized chronically hypoxic rats and was restored by blockade of the dopamine D2 receptor with domperidone. We now report observations made during 1-8 days of exposure to 10% O2 on the acute hypoxic ventilatory response and the effect of domperidone and relate them to dopamine content and cellular proliferation in the carotid body. Hypoxic exposure caused a parallel shift in the hypoxic response curve to higher levels of ventilation and arterial oxygen saturation. The greatest response occurred on day 1 and was unaffected by domperidone: dopamine content diminished and mitotic activity increased. By 8 days, hypoxic ventilation approached normal and was significantly augmented by domperidone; in the carotid body, dopamine levels had risen above the control level and mitoses had diminished. Thus the increase in ventilation was inversely related to carotid body dopamine content, which was depressed. The possibility of a causal relationship is discussed.

Interaction of the effects of domperidone and sub-anaesthetic concentrations of isoflurane on the immediate and sustained hypoxic ventilatory response in humans

Twenty normal male subjects with brisk hypoxic ventilatory responses were recruited and ventilatory responses to sustained isocapnic hypoxia (SaO2 80.4 (SD 1.3)% for 20 min) were studied on separate days under four conditions: hypoxia alone, with or without domperidone, and 0.1 MAC of end-tidal isoflurane, with or without domperidone. Ventilatory variables were subjected to analysis of variance with estimation of the effects of isoflurane and domperidone, and their interaction. Isoflurane reduced the initial increase in ventilation significantly by 3.12 (95% confidence limits 1.69, 4.55) litre min-1 (P < 0.05) and domperidone increased the initial increase in ventilation by 1.78 (0.35, 3.21) litre min-1 (P < 0.05). Neither isoflurane nor domperidone affected the subsequent ventilatory decline. No interaction was found between these agents. These results confirm that 0.1 MAC of isoflurane suppressed the initial hypoxic ventilatory response but not the subsequent ventilatory decline when hypoxia was sustained. Domperidone offset the suppressive effect of isoflurane on the hypoxic ventilatory response but no interaction was detected.

Differential effects of bromopride and domperidone on cholinesterase activity in rat tissues

Bromopride (BRO) and domperidone (DOMP) are dopamine D2 blocking agents used in gastroenterology clinics because of their anti emetic effect as well as their central and peripheral actions of increasing gastrointestinal motor activity. The rationale for these experiments was to compare BRO- and DOMP-effects on plasma, brain, and intestinal cholinesterase activity in vitro. BRO and DOMP effects on cholinesterase activity in plasma, striatum, duodenum and ileum of adult male rats were measured for drug concentrations ranging from 0.006 to 3.134 microM for BRO and from 0.006 to 125 microM for DOMP. The results demonstrate that both BRO and DOMP can inhibit cholinesterase activity in all tissues studied, with DOMP being more potent than BRO in plasma and intestinal tissues. These data suggest the existence of a cholinergic mechanism of action for these dopamine blocking agents.

Possible role of dopamine in ventilatory acclimatization to high altitude

Ventilatory acclimatization to high altitude is accompanied by increased hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses which may reflect increased carotid body chemosensitivity. Dopamine is an inhibitory neuromodulator of the carotid body and its activity may be reduced by hypoxic exposure. To determine whether decreased dopaminergic activity could account for the increased chemosensitivity of acclimatization, we examined the response to peripheral dopamine receptor (D 2) blockade with domperidone on HVR and HCVR in awake cats before and after exposure to simulated altitude of 14000 ft for 2 days. During anesthesia, we also examined the effects of domperidone on carotid body responses to hypoxia and hypercapnia in acclimatized and low altitude cats. Two days' exposure to hypobaric hypoxia produced an increase in HVR and HCVR. Before acclimatization, domperidone augmented HVR and HCVR, but there was no effect after acclimatization. In anesthetized low altitude cats, domperidone increased carotid body responses to hypoxia and hypercapnia, but had no effect in acclimatized cats. These results indicate that decreased endogenous dopaminergic activity may contribute to increased ventilatory and chemoreceptor responsiveness to hypoxia and hypercapnia during hypoxic ventilatory acclimatization.

Differential effects of bromopride and domperidone on cholinesterase activity in rat tissues

Bromopride (BRO) and domperidone (DOMP) are dopamine D2 blocking agents used in gastroenterology clinics because of their anti emetic effect as well as their central and peripheral actions of increasing gastrointestinal motor activity. The rationale for these experiments was to compare BRO- and DOMP-effects on plama brain, and intestinal cholinesterase activity in vitro. BRO- and DOMP effects on cholinesterase activity in plasma, striatum, duodenum and ileum of adult male rats were measured for drug concentrations ranging from 0.006 to 3.134 μM for BRO and from 0.006 to 125 μM for DOMP. The results demonstrate that both BRO and DOMP can inhibit cholinesterase activity in all tissues studied, with DOMP being more potent than BRO in plasma and intestinal tissues. These data suggest the existence of a cholinergic mechanism of action for these dopamine blocking agents.

Effects of dopaminergic blockade upon carotid chemosensory activity and its hypoxia-induced excitation

The effects of domperidone, antagonist of D 2 receptors, on arterial chemoreceptor activity were studied in spontaneously breathing and pentobarbitone anesthetized cats, in which recordings of chemosensory impulse activity were obtained simultaneously from both cut carotid (sinus) nerves. Intravenous injections of domperidone 50 μg/kg produced a maintained increase in the basal frequency of chemosensory discharges, after which hyperoxic tests (breathing 100% O 2 for 30 s) evoked larger falls in the rate of chemosensory impulses. Chemosensory responses evoked by hypoxic hypoxia (100% N 2 tests) and by cytotoxic hypoxia (i.v. injections of NaCN) reached higher impulse rates after domperidone treatment. The effects of domperidone reveal that a resting release of dopamine from glomus cells maintains a low level of basal chemosensory activity under normoxic conditions. Domperidone turns off such restraining dopaminergic control and enhances the transient chemosensory responses to hypoxic stimuli. Present data support a modulatory role for dopamine within the chemoreceptor process, but not its participation as excitatory transmitter between glomus cells and sensory nerve endings.

Effects of domperidone on neonatal and adult carotid chemoreceptors in the cat.

It has been postulated that the weak carotid chemoreceptor responses of neonatal mammals may be due to inhibition produced by high levels of endogenous dopamine release or exaggerated sensitivity to dopaminergic inhibition. This was studied by measuring the effect of domperidone, a selective dopamine D2-receptor antagonist, on the carotid chemoreceptor response to O2 and CO2 in anesthetized neonatal and adult cats. The animals were exposed to four levels of isocapnic O2 (arterial PO2 of approximately 35-45, 55-65, 80-90, > 300 Torr) and four levels of isoxic CO2 (end-tidal PCO2 of approximately 21, 40, 58, and 78 Torr) before and after D2-receptor blockade. Whole nerve activity was recorded from the carotid sinus nerve (CSN). Both neonatal and adult cats increase CSN activity during hypoxia and hypercapnia (P < 0.001). Domperidone caused an increase in CSN activity at all O2 levels in adults (P < 0.01) but only during hypoxia in neonates (P < 0.001). Domperidone caused an increase in CSN activity during normo- and hypercapnia in adults but only during hypercapnia in neonates (P < 0.001). Domperidone approximately doubled an index of hypoxic sensitivity in the normoxia-hypoxia range (100 to 40 Torr) in the neonatal group but had little effect on sensitivity to hypoxia in adults. We conclude that the inhibitory role of endogenous dopamine in the carotid chemoreceptors changes with postnatal development.

Cardiovascular reflexes in Parkinson's disease: effect of domperidone and apomorphine.

Cardiovascular reflexes were evaluated in 18 patients with idiopathic Parkinson's disease who had a Hoehn & Yahr score of III-IV. The effect of apomorphine and domperidone on blood pressure, heart rate, R-R interval variation, and the Valsalva ratio were studied. Autonomic dysfunction was not found in the patients and there were no differences between subgroups of patients on different treatments. Apomorphine altered cardiovascular reflexes to a greater degree in patients who received the drug for the first time than in chronically treated patients. The changes were antagonized by domperidone, a peripheral dopamine receptor antagonist. Apomorphine treated patients who were receiving long-term domperidone had similar abnormalities of cardiovascular reflexes to those who had been able to withdraw it.

Prolactin responses to domperidone in chronic schizophrenia

The prolactin response to 20 mg of domperidone, a peripheral dopamine receptor antagonist, was evaluated in a group of 17 male, drug-free, elderly, chronic schizophrenic patients and 8 age-matched male normal control subjects. Both groups of subjects were receiving a variety of nonpsychotropic medications not known to affect the prolactin response to dopamine receptor antagonists. Basal plasma prolactin levels did not differ between the two groups. However, the prolactin response following domperidone was significantly greater in the schizophrenic patients, although plasma domperidone levels did not differ between the two groups. This effect is opposite to the previously reported effect of domperidone in young schizophrenic patients compared with age-matched control subjects (Nerozzi, 1990). The prolactin response to domperidone was markedly smaller in the old compared with the young normal control subjects, whereas the young and old schizophrenic patients had identical responses. Possible explanations for these results are considered, especially the possibility of abnormalities in the release of dopamine and pituitary D 2 dopamine receptors in the elderly schizophrenic patients compared with age-matched normal control subjects.

Mechanism for the gastrokinetic action of domperidone: In vitro studies in guinea pigs

To test the hypothesis that domperidone stimulates gastric muscle contraction by antagonizing the inhibitory effects of dopamine on postsynaptic cholinergic neurons in the myenteric plexus, the effects of dopamine on circular muscle from the body of the guinea pig stomach were examined. Dopamine inhibited circular muscle contraction evoked by electric field stimulation in a dose-related manner. The threshold dose was 10−6 mol/L and half-maximal inhibition occurred at 10−5 mol/L. Preincubation of muscle contraction with atropine or tetrodotoxin abolished the contractile response to electric field stimulation, indicating mediation via a cholinergic pathway. The adrenergic antagonists phentolamine and propranolol and the DA1 antagonist SCH 23390 were ineffective in antagonizing the action of dopamine. In contrast, the DA2 antagonist domperidone blocked the inhibitory effect of dopamine on electric field stimulation-mediated contractions. Schild analysis showed a Ki of 3 × 10−8 mol/L and a slope of unity. In addition, it was shown that dopamine inhibited veratridine-evoked release of [3H]acetylcholine from the gastric myenteric plexus in a doserelated manner (median effective dose, 5.2 × 10−5 mol/L). Tetrodotoxin abolished [3H]acetylcholine release evoked by veratridine, but hexamethonium had no effect. Domperidone, but not SCH 23390, antagonized the inhibitory action of dopamine. Pretreatment with pertussis toxin blocked the action of dopamine to inhibit evoked release of [3H]acetylcholine. These observations indicate that dopamine inhibits gastric muscle contraction evoked by electric field stimulation by inhibiting cholinergic transmission. This is mediated by DA2 receptors located on the postganglionic cholinergic neurons, and the pathway involves a pertussis toxin—sensitive G protein. The DA2-receptor antagonist domperidone antagonizes the inhibitory effect of dopamine, resulting in stimulation of gastric muscle contraction. This provides a mechanism for the gastrokinetic effect of domperidone.

A Comparison of Bromopride and Domperidone Effects on Rat Conditioned Avoidance and Motor Activity

Acute intraperitoneal administration of bromopride (BRO) and domperidone (DOMP), two dopamine D2 blockers used as antiemetics in gastroenterology, were tested in male rats for effects on motor activity and on active and inhibitory conditioned behaviour. BRO dose-dependently depressed ambulation and rearing, impairing the performance of active conditioned avoidance (CAR) even when injected prior to the retention session. It also impaired inhibitory avoidance responses (IAR). All these effects were dose-dependent. DOMP was ineffective at modifying any of the above described parameters. These results suggest that BRO exerts neuroleptic effects which are neither mediated by actions on peripheral dopamine receptors nor by increased prolactin levels. These data also suggest that DOMP is a more appropriate drug for gastroenterology.

The effect of domperidone on the electrical response of cockroach salivary gland acinar cells

The effects of domperidone on the electrical response of the cockroach salivary gland to applied dopamine and to nerve stimulation have been investigated. Dopamine and nerve stimulation induced a hyperpolarization of the salivary gland acinar cells, which was occasionally followed by a depolarization. At 1 and 10 μM domperidone had no effect on the responses; however, at higher concentrations domperidone (50 and 100 μM) potentiated the hyperpolarization induced by both dopamine and nerve stimulation. Domperidone (50 μM) also potentiated the hyperpolarization induced by 5-HT. Thus the potentiation probably results from a post synaptic action independent of either the dopamine or 5-hydroxytryptamine receptor. In addition, domperidone (50 and 100 μM) had two delayed effects: one, presynaptic, led to a reduction in the response to nerve stimulation; the other, postsynaptic, led to the abolition of the depolarizing phase of the response.

Carotid body chemoreceptor response to prolonged hypoxia in the rabbit: effects of domperidone and propranolol.

1. The discharge of single afferent chemoreceptor fibres was recorded from the cut sinus nerve over periods of 60 or 90 min of constant, isocapnic hypoxia (arterial O2 pressure, Pa,O2, 3.13-5.25 kPa), in twenty anaesthetized rabbits, after dividing the sympathetic supply to the carotid body. 2. Under control conditions, discharge after 60 min of hypoxia adapted to a mean (S.E.M.) of 71.95 (2.75)% of that attained at 5 min of hypoxia in twenty-three hypoxic experiments. This adaptation was more pronounced when Pa,O2 was lower than 4 kPa (30 Torr). 3. Domperidone (1 mg kg-1 bolus + 1 mg kg-1 h-1 infusion I.V.), increased normoxic afferent discharge by a mean of 142%. In ten experiments, discharge after 60 min of hypoxia adapted to a mean (S.E.M.) of 56.22 (+/- 3.40)% of that attained at 5 min of hypoxia which was significantly different from control hypoxic runs (P = 0.006). 4. In seven experiments propranolol (1 mg kg-1 bolus + 1 mg kg-1 h-1 infusion I.V.) did not affect the normoxic discharge. The mean adaptation of discharge after 60 min of hypoxia was to 77.43 (3.97)% of discharge attained at 5 min of hypoxia, which was not significantly different from control hypoxic runs (P = 0.34). 5. Under control conditions plasma [K+] increased steadily during 60 min of hypoxia, in fourteen experiments, from a mean of 2.76 (0.14) to 2.85 (0.12) mmol l-1 but this was not significant (P = 0.21). Domperidone (n = 6) did not affect plasma [K+] at any time, but after propranolol (n = 6) it increased by a mean (S.E.M.) of 0.39 (0.09) mmol l-1 (P = 0.01) in normoxia and by a further 0.62 (0.28) mmol l-1 (P = 0.08) at 60 min of hypoxia. 6. The results suggest that the adaptation of chemoreceptor discharge to hypoxia in the rabbit is not mediated by changes in plasma [K+]; in addition, endogenous dopamine, but not noradrenaline, contributes to the maintenance of chemoreceptor discharge in prolonged hypoxia.

Effects of domperidone and medroxyprogesterone acetate on ventilation in man

If endogenous dopamine acts as an inhibitory neurotransmitter in the carotid bodies in man, domperidone (DP), a selective dopamine D-2 receptor antagonist should stimulate carotid bodies and augment ventilation. Furthermore, the combination of a central ventilatory stimulant, medroxyprogesterone acetate (MPA), with a peripheral ventilatory stimulant, DP, may produce an additive/synergistic ventilatory effect. We conducted a double-blind, placebo-controlled (P), cross-over trial comparing MPA 20 mg three times daily (TID) and DP (20 mg TID) alone and together in 8 healthy male human subjects. Drug effects were measured after 7 days, and a two-week drug washout period was allowed. MPA significantly increased alveolar ventilation (V̇ a), and slopes of hypercapnic and hypoxic ventilatory responses. Domperidone alone significantly increased the slope of the hypoxic response; however, V̇ a and Pa CO 2 did not change significantly. The combination of MPA and DP resulted in ventilatory changes similar to MPA alone. We conclude that in man endogenous dopamine acts as a modulator of chemoreception during hypoxemia, but plays no major role tonically in control of ventilation during normoxemia and normocapnia. Lack of additive effect with combined DP and MPA suggests that these drugs may share the same final common pathway in the process of chemoreception.

Dopaminergic antagonists prevent long-term maintenance of posttetanic LTP in the CA1 region of rat hippocampal slices

The involvement of dopaminergic mechanisms in the induction and maintenance of posttetanic long-term potentiation (LTP) was investigated on CA1 cells of rat hippocampal slices. The presence of the dopamine receptor blocker domperidone in a concentration of 1 μM during tetanization with 3 trains of 100 impulses (100 Hz) and a train interval of 10 min influences neither the synaptic transmission nor the induction of LTP. However, the potentiation of both the population spike and the population EPSP gradually decreases, thus significantly differing from control LTP about 4 h after initiation and reaching the level of non-tetanized controls about 7–8 after tetanization. The simultaneous presence of 1 μM apomorphine during tetanization abolishes this effect of domperidone indicating the specific dopaminolytic nature of its action. Also the presence of the dopamine antagonists sulpiride and flupenthixol, respectively, in a concentration of 1 μM during tetanization likewise prevents the occurrence of the LTP maintenance. The determination of [ 14C]dopamine in 2 min fractions from the superfused slices after preloading during a preincubation period revealed that a low frequency stimulation of the Schaffer collaterals with 0.33 Hz does not influence the spontaneous efflux of dopamine, whereas the tetanization with an impulse train of 100 Hz produces a significantly enhanced release. The observations suggest that dopaminergwhereas the tetanization with an impulse train of 100 Hz produces a significantly enhanced release. The observations suggest that dopaminergic influences during and immediately after tetanization at least additionally contribute to the induction of postsynaptic mechanisms subserving a late, long-lasting maintenance of potentiation. The results also support the assumed existence of different subsequent stages of LTP.

The effect of domperidone on theophylline disposition in the rat

The effect of domperidone (2 mg kg-1) on the pharmacokinetics of a single oral dose of theophylline (25 mg kg-1) was studied in the rat. Theophylline concentrations were measured serially for 12 h using an HPLC technique. Domperidone did not have any significant effect on any of the four parameters studied: peak plasma levels (Cpmax), the time these were attained (tmax), elimination half-life (t1/2) and area under the plasma concentration-time curve (AUC). Our data preliminarily suggests that domperidone may be safely coadministered with theophylline but clearly further studies in patients or relevant animal models of gastric motility disturbances are needed to reliably rule out any potential interaction between these agents.

Effects of central and peripheral dopamine antagonism on aldosterone secretion: evidence for adrenal mechanism.

Both domperidone (DOMP) and metoclopramide (MCP) are D2 receptor antagonists, MCP being a central and peripheral dopamine antagonist, whereas DOMP is exclusively a peripheral antagonist. MCP, but not DOMP, has been shown to stimulate aldosterone production. To elucidate whether aldosterone stimulation by dopamine antagonism is centrally mediated, we injected DOMP (28 micrograms/kg body wt) via a cannula into the third ventricle in Sprague-Dawley rats. Plasma aldosterone and renin concentration were measured before and 15 min after the injection. Centrally administered DOMP resulted in an increment in plasma aldosterone (23.8 +/- 7.4 ng/dl) that was not significantly greater than that induced by vehicle alone (15.8 +/- 4.5 ng/dl). This increase was inhibited by pretreatment with dexamethasone (100 micrograms three times daily) and attenuated by captopril (1 mg/kg ip) but not by L-beta-3,4-dihydroxyphenylalanine (30 mg/kg), thus reflecting a stress effect. Similarly, central administration of MCP (21 micrograms/kg) resulted in a significant rise in plasma aldosterone. This increase, however, was eliminated by pretreatment with dexamethasone and attenuated by captopril. Peripherally administered DOMP (280 micrograms/kg) had no effect on plasma aldosterone. The effect of DOMP and MCP on aldosterone secretion by freshly obtained adrenal capsules was also tested. Angiotensin II and MCP, but not DOMP, induced a dose-dependent increase in aldosterone secretion, with a maximal increment (15.7 +/- 5.8 ng.mg capsular protein-1.10 min-1; 50% increase) with MCP at 10(-7) M (P less than 0.01 compared with controls). Dopamine completely inhibited this MCP-induced rise in aldosterone release.(ABSTRACT TRUNCATED AT 250 WORDS)