Affinity Of Alpha 2-adrenergic Receptors Research Articles

Effects of Prenatal Exposure to a Low-Dose of Bisphenol A on Sex Differences in Emotional Behavior and Central Alpha2-Adrenergic Receptor Binding.

Prenatal exposure to bisphenol A (BPA) influences the development of sex differences neurologically and behaviorally across many species of vertebrates. These effects are a consequence of BPA’s estrogenic activity and its ability to act as an endocrine disrupter even, at very low doses. When exposure to BPA occurs during critical periods of development, it can interfere with the normal activity of sex steroids, impacting the fate of neurons, neural connectivity and the development of brain regions sensitive to steroid activity. Among the most sensitive behavioral targets of BPA action are behaviors that are characterized by a sexual dimorphism, especially emotion and anxiety related behaviors, such as the amount of time spent investigating a novel environment, locomotive activity and arousal. Moreover, in some species of rodents, BPA exposure affected males’ sexual behaviors. Interestingly, these behaviors are at least in part modulated by the catecholaminergic system, which has been reported to be a target of BPA action. In the present study we investigated the influence of prenatal exposure of mice to a very low single dose of BPA on emotional and sexual behaviors and on the density and binding characteristics of alpha2 adrenergic receptors. Alpha2 adrenergic receptors are widespread in the central nervous system and they can act as autoreceptors, inhibiting the release of noradrenaline and other neurotransmitters from presynaptic terminals. BPA exposure disrupted sex differences in behavioral responses to a novel environment, but did not affect male mice sexual behavior. Importantly, BPA exposure caused a change in the binding affinity of alpha2 adrenergic receptors in the locus coeruleus and medial preoptic area (mPOA) and it eliminated the sexual dimorphism in the density of the receptors in the mPOA.

Simultaneous quantitation of dexmedetomidine and glucuronide metabolites (G-Dex-1 and G-Dex-2) in human plasma utilizing liquid chromatography with tandem mass spectrometric detection.

Dexmedetomidine (Dex) (Precedex) is a novel lipophilic imidazole derivative with a high affinity for alpha-2 adrenergic receptors, which exhibits sedative, analgesic-sparing, and sympatholytic properties. The pharmacological effects and therapeutic benefits of this drug have drawn continued interest from the medical community. Here we report a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method to simultaneously measure the concentrations of dexmedetomidine and its glucoronide metabolites, G-Dex-1 and G-Dex-2, in human plasma samples. A solid-phase extraction method was developed to effectively extract Dex, G-Dex-1, and G-Dex-2 from plasma matrices. An isocratic chromatographic method was developed to achieve baseline separation of G-Dex-1 and G-Dex-2. The linear dynamic range evaluated was 19.08-1908.56 pg/mL for Dex, 65.17-6518.17 pg/mL for G-Dex-1, and 29.42-2943.28 pg/mL for G-Dex-2. The linear correlation coefficient (r) ranged from 0.9944-0.9979 for Dex, from 0.9966-0.9984 for G-Dex-1, and from 0.9939-0.9966 for G-Dex-2. The intra-assay coefficient of variation (CV) was between 2.5-12.5% for Dex, between 5.2-11.0% for G-Dex-1, and between 3.5-12.1% for G-Dex-2. The inter-assay precision of QC samples give % CV ranges from 6.5-9.3% for Dex, from 7.1-10.6% for G-Dex-1, and from 8.2-10.2% for G-Dex-2. The inter-assay accuracies ranged from 102.0-109.3% for Dex, from 95.4-105.6% for G-Dex-1, and from 98.7-115.0% for G-Dex-2.

Pharmacology of cizolirtine: a new analgesic agent.

Cizolirtine citrate (E-4018) is a new analgesic agent with antinociceptive activity against phenylquinone (ED50 33.7 mg/kg) and acetic acid (ED50 24.4 mg/kg) in mice, against acetic acid in rats (ED50 21.3 mg/kg) and in the plantar test (ED50 26.8 mg/kg). It demonstrated antinociceptive activity in the tail-pinch and tail-flick tests (ED50s of 68.0 and 46.0 mg/kg, respectively), in both phases of the formalin test (ED50 13.8 and 2.31 mg/kg), and in the capsaicin test (ED50 7.14 mg/kg). Cizolirtine does not inhibit prostaglandin biosynthesis, it is not a ligand for opioid receptors, it does not have antiinflammatory or ulcerogenic activity, it has some antipyretic activity and shows no affinity for alpha 2-adrenergic receptors, but its analgesic effect was modified by idazoxan and by desipramine. Recent studies have shown that the analgesic effect of cizolirtine could be related, at least partially, to an inhibition of spinal substance P release.

Radioreceptor binding profile of the atypical antipsychotic olanzapine

The affinities of olanzapine, clozapine, haloperidol, and four potential antipsychotics were compared on binding to the neuronal receptors of a number of neurotransmitters. In both rat tissues and cell lines transfected with human receptors olanzapine had high affinity for dopamine D1, D2, D4, serotonin (5HT)2A, 5HT2C, 5HT3, alpha 1-adrenergic, histamine H1, and five muscarinic receptor subtypes. Olanzapine had lower affinity for alpha 2-adrenergic receptors and relatively low affinity for 5HT1 subtypes, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites. The receptor binding affinities for olanzapine was quite similar in tissues from rat and human brain. The binding profile of olanzapine was comparable to the atypical antipsychotic clozapine, while the binding profiles for haloperidol, resperidone, remoxipride, Org 5222, and seroquel were substantially different from that of clozapine. The receptor binding profile of olanzapine is consistent with the antidopaminergic, antiserotonergic, and antimuscarinic activity observed in animal models and predicts atypical antipsychotic activity in man.

Pressor hormones in elderly hypertensive persons. Racial differences.

The purpose of this study was to examine pressor hormones and platelet alpha 2-adrenergic receptors in elderly unmedicated free-living subjects. Eighty-seven subjects, 70 +/- 5 years old (mean +/- SD), hypertensive or normotensive (blood pressure less than 160/90 mm Hg) were recruited for measurement of blood levels of norepinephrine, epinephrine, and vasopressin, as well as density and affinity of alpha 2-adrenergic receptors from platelet membranes, assessed by maximal binding (Bmax) and dissociation constant (Kd) of rauwolscine. They were separated into white hypertensive (n = 22) or normotensive (n = 41), and black hypertensive (n = 11) or normotensive (n = 13) groups, with similar age distribution throughout and similar blood pressure levels in the hypertensive and normotensive groups. Vasopressin was higher in the black hypertensive than white hypertensive group (1.5 +/- 1.0 vs. 0.7 +/- 0.5 pg/ml, respectively, p less than 0.005), whereas epinephrine correlated inversely with diastolic blood pressure (r = -0.7, p less than 0.02, in the black hypertensive group). Kd was higher in the black normotensive group than in the other groups (1.6 +/- 0.6 vs. 1.0 +/- 0.2, 1.1 +/- 0.3, or 1.0 +/- 0.3 nM in the white normotensive, black hypertensive, or white hypertensive group, respectively, p less than 0.002). Bmax was no different among groups but was significantly correlated with vasopressin levels for the whole group (r = 0.4, p less than 0.0004) although no such correlation existed within the black hypertensive group. The data suggest that various vasoconstrictor systems participate to different extents in the mechanisms generating and sustaining hypertension in elderly white and black subjects.

Noradrenergic receptor binding during sleep-waking states in the rat.

It was recently shown that the number of muscarinic receptors in the rat pons undergoes short-term changes which are related to sleep-waking states and may thus play a role in determining their time course. In this study we investigated whether also noradrenergic receptors change in relation to polygraphically documented wakefulness (W), synchronized (S) and desynchronized sleep (D). Brain noradrenergic systems are deeply involved in the control of vigilance states, and a new hypothesis about the function of D has suggested that adrenoceptors would be desensitized or downregulated during W and upregulated during D. We examined the number of alpha 1-, alpha 2- and beta-adrenergic receptors in the forebrain and the cerebellum, and the number and affinity of alpha 2-receptors in a brainstem region including the locus coeruleus. The results indicate that the number of alpha 1-, alpha 2- and beta-adrenergic receptors does not change in relation to sleep-waking states either in the forebrain or in the cerebellum, and that the number and the affinity of alpha 2-adrenergic receptors in the brainstem are stable as well.

How does salt raise blood pressure? A hypothesis.

Existing data in the literature indicate that alpha 2-adrenergic receptor agonists have a profound hypotensive action, that sodium attenuates the affinity of alpha 2-adrenergic receptors for agonists, that the location of these receptors in the central nervous system is mainly at the sites of cardiovascular regulation, and that these sites exert a constant tonic inhibition of sympathetic vasoconstrictor tone. This article proposes the theory that sodium exerts its hypertensive action by decreasing the state of affinity of the alpha 2-adrenergic receptors of the central nervous system for locally occurring agonist neurotransmitters, which results in disinhibition of sympathoinhibitory neurons and leads to the hyperadrenergic state characteristic of salt-induced hypertension.

Role of alpha-2 adrenergic affinity in the action of a non-sedative antispasticity agent.

Muscle hypertonus of central origin can be effectively reversed by either dopamine agonists or alpha-adrenergic antagonists. Because of its efficacy in reversing reserpine rigidity (a syndrome resembling Parkinsonism), SKF-7265 was examined to determine whether its action was mediated through alpha-adrenergic or dopaminergic receptors. The pharmacologic blocking activity of SKF-7265 was assessed by measuring blockade of the cardiovascular agonist responses induced by norepinephrine, epinephrine, isoproterenol, acetylcholine and histamine. The binding affinity of SKF-7265 was determined by displacement of 3H-spiperone from rat corpus striatum tissue and 3H-clonidine and 3H-WB-4101 displacement from rat cerebral cortical tissue. Using the cardiovascular responses, SKF-7265 was devoid of beta-adrenergic or cholinergic blocking effects and did not produce any behavioral or reflex deficits in awake animals. Receptor binding studies showed that SKF-7265 had equal affinity for alpha-1 and alpha-2 adrenergic receptors and little affinity for dopamine receptors. It is concluded that the efficacy which has been reported for the SKF-7265 induced reversal of reserpine rigidity and its potential value as an antispasticity agent may be attributed to its relatively high affinity for alpha-2 adrenergic receptors.

Adrenergic receptors in human and experimental pheochromocytoma.

Radioligand binding to adrenergic receptors has become an important technique for identification and quantitation of these receptors. In this article we review our recent findings using subtype-selective radioligands for studying alpha 1 (e.g., [3H]prazosin) and alpha 2 (e.g. [3H]yohimbine) receptors in human platelets and rat renal cortical membranes, and we report new results on changes in adrenergic receptors of patients and animals with pheochromocytoma. Five patients with pheochromocytoma were tested prior to surgery. The number of alpha 2-adrenergic receptors on platelets from these patients and the affinity of these receptors for [3H]yohimbine were similar to values for control subjects. In rats with a transplantable pheochromocytoma we found a 50-fold increase in plasma norepinephrine levels. The number of renal cortical beta-adrenergic receptors (identified using [125I]iodohydroxybenzylpindolol) and alpha 1-adrenergic receptors were decreased while the number of alpha 2-adrenergic receptors did not change. Receptor affinities for radioligands were unaltered in animals with pheochromocytoma. These findings indicate that pheochromocytoma is associated with selective decreases in the number of renal beta- and alpha 1-adrenergic receptors without changing alpha 2-adrenergic receptor number or affinity. Furthermore, the number and affinity of alpha 2-adrenergic receptors are not altered in platelets of patients with pheochromocytoma. We conclude that down regulation (an agonist-mediated decrease in receptor number) occurs in vivo for some, but not all, types of adrenergic receptors.