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Because the high-affinity state of dopamine D2 receptors, D2(High), is the functional state of D2, and because the proportion of D2 receptors in the high-affinity state correlates with dopamine behavioral supersensitivity, the present study was designed to determine the affinities of antiparkinson dopamine agonists at the D2(High) site by means of competition with [3H]domperidone. In contrast to [125I]iodosulpride or [3H]spiperone, which are not sensitive to low concentrations of dopamine agonists, [3H]domperidone readily reveals dissociation constants (K(i)) for antiparkinson agonists at D2(High) and D3(High) receptors. The K(i) values for the human cloned D2(High) and D3(High) receptors, respectively, were 19 and 9 nM for pramipexole, 0.24 and 0.6 nM for +PHNO, 0.7 and 1.3 nM for bromocriptine, 0.5 and 2.6 nM for apomorphine, and 0.09 and 0.25 nM for (-)N-propylnorapomorphine. After correcting for the fraction of drug bound to plasma proteins, the known clinical concentrations in plasma or plasma water of these drugs, including pramipexole and +PHNO, are sufficient to occupy and activate the high-affinity state of D2, D2(High), in treating Parkinson's disease. The D3(High) receptors are less selectively occupied by +PHNO, bromocriptine, apomorphine, and -NPA.
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Mammalian hair growth is cyclic, with hair-producing follicles alternating between active (anagen) and quiescent (telogen) phases. The timing of hair cycles is advanced in prolactin receptor (PRLR) knockout mice, suggesting that prolactin has a role in regulating follicle cycling. In this study, the relationship between profiles of circulating prolactin and the first post-natal hair growth cycle was examined in female Balb/c mice. Prolactin was found to increase at 3 weeks of age, prior to the onset of anagen 1 week later. Expression of PRLR mRNA in skin increased fourfold during early anagen. This was followed by upregulation of prolactin mRNA, also expressed in the skin. Pharmacological suppression of pituitary prolactin advanced dorsal hair growth by 3.5 days. Normal hair cycling was restored by replacement with exogenous prolactin for 3 days. Increasing the duration of prolactin treatment further retarded entry into anagen. However, prolactin treatments, which began after follicles had entered anagen at 26 days of age, did not alter the subsequent progression of the hair cycle. Skin from PRLR-deficient mice grafted onto endocrine-normal hosts underwent more rapid hair cycling than comparable wild-type grafts, with reduced duration of the telogen phase. These experiments demonstrate that prolactin regulates the timing of hair growth cycles in mice via a direct effect on the skin, rather than solely via the modulation of other endocrine factors.
The relationship between symptom improvement (SI) and acceleration of gastric emptying (GE) for different drugs used in the treatment of idiopathic and diabetic gastroparesis is uncertain. In this paper we examined the study-specific correlations between SI and GE, and we performed a meta-regression analysis of the association across multiple studies.
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A low dose of dopamine (1 microgram/min/kg) infused for 3 h, which is without systemic hemodynamic effects in normal subjects, increased the renal blood flow and renal production of prostacyclin (PGI2). This action was blocked by metoclopramide as well as by either of two cyclooxygenase (CO) blockers, but effects were not altered by administration of the alpha 1 blocker prazosin. Much of the effect of dopamine (DA) is apparently via the DA1 receptor, since fenoldopam (0.1 microgram/min/kg) reproduced these actions. However, although fenoldopam increased glomerular filtration rate and urinary Na+, CO blockers were without effect. In contrast neither DA or fenoldopam infusions changed either renal blood flow or PGI2 in a group of patients with essential hypertension. Renin secretion was shown to be increased via DA1 receptor activation both in humans and rat renal tissue. The DA2 receptor may also play a role since domperidone can reduce renal blood flow.
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Administration of LY171555 (1 mg/kg i.v.) decreased mean arterial pressure (MAP) and heart rate in both pentobarbital- and urethane-anesthesized Sprague-Dawley rats. The depressor response to LY171555 in pentobarbital-anesthetized rats was sustained for at least 30 min, but in urethane-anesthetized rats lasted only approximately 3 min after LY171555 injection. In pentobarbital-anesthetized rats, pretreatment with domperidone (0.5 mg/kg) or metoclopramide (5 mg/kg) attenuated the depressor action of LY171555, whereas pretreatment with d(CH2)5Tyr(Me)arginine vasopressin (AVP) (10 micrograms/kg) only delayed the recovery phase of the depressor response to LY171555. In contrast, LY171555 administered to urethane-anesthetized rats after domperidone pretreatment induced a pressor response which was blocked completely by d(CH2)5Tyr(Me)AVP. Metoclopramide pretreatment in urethane-anesthetized rats prevented the decreases in MAP and heart rate induced by LY171555, whereas pretreatment with d(CH2)5Tyr(Me)AVP delayed the recovery phase of the depressor response. Pretreatment with d(CH2)5Tyr(Me)AVP per se decreased basal MAP in the urethane-anesthetized group, but not in pentobarbital-anesthetized rats. Basal plasma norepinephrine, epinephrine and AVP levels were higher in urethane-anesthetized rats than in the pentobarbital-anesthetized group. LY171555 administration decreased plasma norepinephrine without altering plasma epinephrine in both groups and induced a significant increase in plasma AVP which was greater in the urethane-anesthetized rats than in pentobarbital-anesthetized animals. These results suggest that LY171555 decreases MAP and heart rate in anesthetized rats by inhibiting norepinephrine release from nerve endings through the peripheral dopamine D2 receptor and that the time course of the depressor response may be altered by LY171555-induced AVP release, the magnitude of which appears to be dependent on the anesthetic agent.
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cAMP levels were measured by radioimmunoassay as an index of dopamine receptor function.
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To confirm the identity of the major metabolites of domperidone and to characterize the cytochrome P450s (CYPs) involved in their formation.
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To evaluate the relationship between the onset of peptic ulcer and gastric emptying, some factors which were thought to regulate gastric emptying, i.e. the stage of the ulcer, the location of the ulcer and gastric acidity were studied in cases of gastric ulcer with deformed stomach and were proven to have little influence on gastric emptying. Further, the main cause of delayed gastric emptying was revealed to be the deformity itself, because the shortening of the distance from the gastric angle to the pyloric ring at the lesser curvature (sac-shaped stomach) and the indentation of the corpus ventriculi (hourglass-shaped stomach) significantly delayed gastric emptying. Moreover, it was found that the healing of gastric ulcer was delayed in cases of deformed stomach with delayed gastric emptying when the ulcer was at an active stage. Therefore the improvement of gastric emptying by some methods was thought to be necessary to promote ulcer healing and prevent ulcer recurrence in gastric ulcer patients who had a deformed stomach.
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The MEDLINE database (1,946 to present) was searched, and only controlled trials or trials with an established effective comparator that compared both SI and GE were included.
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To study protection effect of Xuanfudaizhetang on reflux esophagitis in rats.
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Domperidone in pure form and in a number of pharmaceutical formulations (Motilium) has been determined in 0.5-N sulphuric acid by employing first-derivative at 294 nm and zero-order at 284 nm spectrophotometric modes. The results obtained by utilizing the first derivative procedure were 99.98 +/- 0.47, 101.70 +/- 0.53, 101.70 +/- 0.53 and 101.15 +/- 1.23 for the tablets, oral suspension, drops and suppositories respectively. In a similar way the results obtained for the zero order technique were 105.38 +/- 1.01, 101.70 +/- 2.57, 108.56 +/- 1.16 and 102.23 +/- 3.37 in the order. The standard addition method was adopted to evaluate the accuracy of the first derivative spectrophotometric mode.
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Fatigue is seen in many medical conditions. Patients with gastroparesis may complain of fatigue.