Depression of peripheral chemosensitivity by a dopaminergic mechanism in patients with obstructive sleep apnoea syndrome.
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In the present study, respiratory drives to chemical stimuli and peripheral chemosensitivity were evaluated in patients with obstructive sleep apnoea (OSAS). The effects of oral administration of domperidone, a selective dopamine D2-receptor antagonist, were also examined, to study the respiratory effects of endogenous dopamine on peripheral chemoreceptors. Sixteen patients with OSAS and nine normal control subjects were studied. Respiratory responses to hypercapnia and hypoxia were measured using the rebreathing method and isocapnic progressive hypoxia method, respectively. The hypoxic withdrawal test, which measures the decrease in ventilation caused by two breaths of 100% O2 under mild hypercapnic hypoxic conditions (end-tidal oxygen and carbon dioxide tensions approximately 8.0 kPa and 5.3-6.7 kPa, respectively), was used to evaluate peripheral chemosensitivity. In the patients with OSAS, ventilatory responses to hypercapnia and hypoxia were significantly decreased compared with those of control subjects. Hypoxic withdrawal tests showed that peripheral chemosensitivity was significantly lower in patients with OSAS than in normal subjects. Hypercapnic ventilatory response and peripheral chemosensitivity were enhanced by administration of domperidone in the patients with OSAS, although no changes in either of these were observed in the control subjects. The hypoxic ventilatory response and peripheral chemosensitivity in the patients with OSAS were each significantly correlated with severity of hypoxia during sleep. These findings suggest that peripheral chemosensitivity in patients with obstructive sleep apnoea syndrome may be decreased as a result of abnormality in dopaminergic mechanisms and that the reduced chemosensitivity observed in patients with obstructive sleep apnoea syndrome may affect the severity of hypoxia during sleep. (+info)
Effects of long-term application of dopamine HCl on dopamine agonist-induced cAMP production in rat renal cortex.
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AIM: To study the effects of long-term application of dopamine HCl (DA) on the functional changes of dopamine receptor subtypes coupled to adenyl cyclase in rat renal cortex. METHODS: cAMP levels were measured by radioimmunoassay as an index of dopamine receptor function. RESULTS: Injection of DA (30 mg.kg-1.d-1, i.p. 30 d) reduced the fenoldopam (Fen) (100 mumol.L-1)-induced increments of cAMP production from the control group of +1.26 +/- 0.04 to the DA-treated group of +0.63 +/- 0.22 nmol.min-1/g tissue and the propyl-butyl-dopamine (PBDA) (100 mumol.L-1)-induced decrements of cAMP production in the presence of Sch-23390 (Sch) from the control group of -0.38 +/- 0.18 to the DA-treated group of -0.11 +/- 0.08 nmol.min-1/g tissue with, however, comparable percentile changes for the 2 groups. Sch blocked both Fen- and PBDA-induced increase in cAMP production, while domperidone (Dom) blocked the decreasing effects of PBDA on cAMP accumulation in the presence of Sch. CONCLUSION: Long-term application of DA produced a marked "down regulation" of both DA1 and DA2 receptors in rat renal cortex with, however, the responsiveness of the remaining receptors unchanged. (+info)
Calcium channels involved in the inhibition of acetylcholine release by presynaptic muscarinic receptors in rat striatum.
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1. The mechanism of the inhibitory action of presynaptic muscarinic receptors on the release of acetylcholine from striatal cholinergic neurons is not known. We investigated how the electrically stimulated release of [3H]-acetylcholine from superfused rat striatal slices and its inhibition by carbachol are affected by specific inhibitors of voltage-operated calcium channels of the L-type (nifedipine), N-type (omega-conotoxin GVIA) and P/Q-type (omega-agatoxin IVA). 2. The evoked release of [3H]-acetylcholine was not diminished by nifedipine but was lowered by omega-conotoxin GVIA and by omega-agatoxin IVA, indicating that both the N- and the P/Q-type (but not the L-type) channels are involved in the release. The N-type channels were responsible for approximately two thirds of the release. The release was >97% blocked when both omega-toxins acted together. 3. The inhibition of [3H]-acetylcholine release by carbachol was not substantially affected by the blockade of the L- or P/Q-type channels. It was diminished but not eliminated by the blockade of the N-type channels. 4. In experiments on slices in which cholinesterases had been inhibited by paraoxon, inhibition of [3H]-acetylcholine release by endogenous acetylcholine accumulating in the tissue could be demonstrated by the enhancement of the release after the addition of atropine. The inhibition was higher in slices with functional N-type than with functional P/Q-type channels. 5. We conclude that both the N- and the P/Q-type calcium channels contribute to the stimulation-evoked release of acetylcholine in rat striatum, that the quantitative contribution of the N-type channels is higher, and that the inhibitory muscarinic receptors are more closely coupled with the N-type than with the P/Q-type calcium channels. (+info)
Role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in the control of prolactin, growth hormone and gonadotropin secretion in prepubertal rats.
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Excitatory amino acids, such as glutamate, constitute a major transmitter system in the control of hypothalamic-pituitary secretion. Different subtypes of glutamate receptors, such as NMDA (N-methyl-d-aspartic acid) and KA (kainate) receptors, are involved in the control of anterior pituitary secretion. Other receptor subtypes, such as AMPA (activated by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and metabotropic receptors, have been identified, although their role in the control of neuroendocrine function remains largely unknown. Recent reports have demonstrated the involvement of AMPA receptors in the control of the steroid-induced luteinizing hormone (LH) surge in female and growth hormone (GH) secretion in male rats. The aim of this study was to assess the potential role of AMPA receptors in the control of GH, prolactin (PRL), LH and follicle-stimulating hormone (FSH) secretion in prepubertal 23-day-old rats. To this end, prepubertal female rats were injected with AMPA (2.5 or 5 mg/kg i.p.) or the antagonist of AMPA receptors 1,2,3,4-tetrahydro-6-nitro-2, 3-dioxo-benzo (f) quinoxaline-7-sulfonamide (NBQX; 0.25 or 0.50 mg/kg i.p.). Serum LH and FSH concentrations and hypothalamic LH-releasing hormone (LHRH) content remained unchanged after AMPA or NBQX administration. In contrast, serum PRL levels significantly decreased 15, 30 and 60 min after i.p. administration of AMPA and increased 120 min after NBQX treatment, whereas serum GH levels increased after AMPA treatment and decreased after NBQX administration. Considering that AMPA has been shown to activate a subset of kainate receptors, its effects were compared with those elicited by 2.5 mg/kg KA in prepubertal female rats. At this age, however, KA was unable to reproduce the effects of AMPA on PRL and GH secretion, thus suggesting that the actions observed after AMPA administration were carried out specifically through AMPA receptors. In addition, as the effects of AMPA on LH secretion in adult females have been proved to be steroid-dependent, the effects of AMPA (2.5 mg/kg) and NBQX (0.5 mg/kg) were tested in prepubertal animals with different gonadal backgrounds, i.e. intact males, and intact and ovariectomized (OVX) females. The effects of AMPA in prepubertal females appeared to be modulated by ovarian secretion, as the inhibition of PRL secretion disappeared and LH secretion was partially suppressed by AMPA in OVX animals whereas the stimulatory effect on GH release was enhanced by ovariectomy. Furthermore, in male rats, AMPA administration significantly decreased PRL secretion and increased serum GH levels, the amplitude of the GH response being higher than in prepubertal females. To ascertain the pituitary component for the reported actions of AMPA, hemi-pituitaries of male rats were incubated in the presence of AMPA (10(-8)-10(-6) M). The results obtained showed no effect of AMPA on PRL, GH and gonadotropin secretion in vitro. Finally, we investigated the involvement of the dopaminergic (DA) system in the inhibitory action of AMPA on PRL secretion. Pre-treatment of prepubertal female rats with a dopamine receptor antagonist (domperidone: 1 mg/kg) resulted in the blockage of AMPA-mediated inhibition of PRL secretion, thus suggesting that this action is probably mediated by an increase in DA activity. In conclusion, we provide evidence for the physiological role of AMPA receptors in the control of PRL and GH secretion in prepubertal rats. In contrast, our data cast doubts on the involvement of AMPA receptors in the regulation of gonadotropin secretion at this age. The effects of AMPA reported herein were not mediated through activation of kainate receptors and were probably exerted at the hypothalamic or suprahypothalamic levels. In addition, we show that ovarian secretion actively modulates the effects of AMPA receptor activation on anterior pituitary secretion in prepubertal female rats. (+info)
In vivo evidence that endogenous dopamine modulates sympathetic activity in man.
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Dopamine receptors type 2 (D2)-like receptor blockers cause an increase in the norepinephrine response to intense physical exercise. However, during intense physical exercise, D2-like antagonists also cause an increase in the epinephrine response, which itself might cause an increase in plasma norepinephrine through the activation of beta2 presynaptic receptors. Therefore, we evaluated the effect of domperidone, a D2-like antagonist, on the norepinephrine response to physical exercise in 6 Addison patients (3 were adrenalectomized and 3 had adrenal tuberculosis). In these patients, the norepinephrine increase observed during exercise was significantly higher after the administration of domperidone than a placebo (F=4,328; P<0.001). Because peripheral plasma norepinephrine does not reflect the sympathetic tone to the heart accurately, we evaluated the effect of domperidone administration (20 mg orally) on the sympathovagal balance, which was measured by the ratio between the high- and low-frequency components of heart rate variability, in 9 normal volunteers in the supine and sitting positions. When compared with placebo, domperidone caused a significant increase in the low/high frequency ratio (P<0.05) in the sitting position without modifying basal and stimulated norepinephrine plasma levels or blood pressure. These data support a role for endogenous dopamine in modulating norepinephrine release by human sympathetic nerves in vivo. (+info)
Inhibition of myocardial inward rectifier potassium current by propylbutyldopamine.
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AIM: To study the effects of propylbutyldopamine (PBDA) on the inward rectifier potassium current (Ik1). METHODS: The quasi-steady state current-voltage relationship from the isolated guinea pig ventricular cells were measured using whole-cell patch-clamp techniques with a slow ramp depolarization (8 mV.s-1). RESULTS: PBDA 5, 50, and 100 mumol.L-1 concentration-dependently reduced the inward rectifier potassium current. PBDA blocked Ik1 in guinea pig ventricular cells. The effect of PBDA was not blocked by the selective dopamine D2-receptor blocker, domperidone. CONCLUSION: PBDA inhibited Ik1 directly, independent of the dopamine D2-receptor. (+info)
Cholinergic dopamine release from the in vitro rabbit carotid body.
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The aim of this study was to test whether cholinergic mechanisms regulate dopamine (DA) release from the carotid body (CB) and interact with DA D(2) autoreceptors. One hundred forty-two CBs from adult rabbits were infused in vitro in a surviving medium bubbled with O(2) (Bairam A, Marchal F, Cottet-Emard JM, Basson H, Pequignot JM, Hascoet JM, and Lahiri S. J Appl Physiol 80: 20-24, 1996). CB DA content and release were measured after 1 h of exposure to various treatments: control, cholinergic agonist (0.1-50 microM carbachol), full muscarinic antagonist (1 and 10 microM atropine), antagonists of M(1) and M(2) muscarinic receptors (1 and 10 microM pirenzepine and 10 microM AFDX-116, respectively), and the DA D(2) receptor antagonist domperidone (1 microM), alone and with carbachol (1 microM). Compared with control, the release of DA was significantly increased by carbachol (1-50 microM), AFDX-116, and domperidone and decreased by atropine (10 microM) and pirenzepine (10 microM). The effects of domperidone and carbachol were not significantly different but were clearly additive. It is concluded that, in the rabbit CB, M(1) and M(2) muscarinic receptor subtypes may be involved in the control of DA release, in addition to the DA D(2) autoreceptors. (+info)
Domperidone should not be considered a no-risk alternative to cisapride in the treatment of gastrointestinal motility disorders.
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BACKGROUND: Several cases of QT prolongation and ventricular tachyarrhythmia have been reported with domperidone, a gastrokinetic and antiemetic agent available worldwide but still under investigation in the United States. Although electrolyte disturbances such as hypokalemia could account for some of these events, we hypothesized that domperidone may have unsuspected electrophysiological effects predisposing some patients to proarrhythmia. METHODS AND RESULTS: Studies were undertaken in 9 isolated guinea pig hearts, which demonstrated reverse use-dependent prolongation of cardiac repolarization by 100 nmol/L domperidone. Action potential duration increased 27% from baseline with domperidone (from 114+/-3 to 145+/-2 ms) during pacing at a cycle length of 250 ms, and a 9% increase (from 97+/-2 to 106+/-3 ms) was seen with pacing at a cycle length of 150 ms. Experiments in human ether-a-go-go-related gene (HERG)-transfected Chinese hamster ovary cells (n=32) demonstrated a concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current. The tail current decreased by 50% at 162 nmol/L domperidone. CONCLUSIONS: Domperidone possesses cardiac electrophysiological effects similar to those of cisapride and class III antiarrhythmic drugs. These effects are observed at clinically relevant concentrations of the drug. Therefore, domperidone should not be considered a no-risk alternative to cisapride, a drug that was recently withdrawn from the US market. (+info)