Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. In chloralose-anaesthetized cats the centrally induced hypotensive effect of clonidine, and in some cases alpha-methyldopa, was diminished by pretreatment with a variety of tricyclic antidepressants and neuroleptic agents. 2. The interaction is assumed to occur at the central alpha-adrenoreceptors. Clonidine or alpha-methyl-noradrenaline (from alpha-methyldopa) are the agonists, and the aforementioned psychotropic drugs are the antagonists. 3. Psychotropic drugs which are not alpha-receptor blockers, like butyrophenone neuroleptics (pimozide and haloperidol) or benzodiazepine tranquillizers, do not significantly diminsh the centrally induced hypotensive effect of clonidine.
Clin Sci Mol Med Suppl 1976 Dec
PMID:Reduction of the hypotensive effect of clonidine and alpha-methyldopa by various psychotropic drugs. 107 57

1. Effects of imidazole compounds and guanabenz on the stimulus-evoked release of catecholamine (CA) were studied in cultured bovine adrenal chromaffin cells. 2. Clonidine, oxymetazoline, phentolamine, chlorpheniramine, and guanabenz inhibited acetylcholine (ACh)-evoked CA release in a dose-dependent manner, but not high K(+)-evoked release. 3. The inhibition by these compounds was not antagonized by nonimidazole and nonguanidine alpha 2-antagonists (yohimbine and phenoxybenzamine) but was significantly antagonized by tolazoline (imidazole alpha 2-antagonist) and cimetidine (imidazole H2-antagonist). Moreover, tolazoline by itself augmented the ACh-evoked, but not the high K(+)-evoked, CA release. 4. Although chlorpheniramine and cimetidine are antagonists for H1 and H2 histaminergic receptors, the site of action for these compounds in our results seemed to differ from the histamine receptors. 5. These results suggest that the inhibitory action of imidazole compounds and guanabenz on ACh-evoked CA release in adrenal chromaffin cells is mediated through an imidazole receptor. Adrenal chromaffin cells may contain an endogenous clonidine-displacing substance (CDS) which has been found in adrenal gland and brain as an endogenous ligand for imidazole receptors. Thus, CDS may have a regulatory role in the stimulus-secretion coupling in these cells.
Cell Mol Neurobiol 1992 Jun
PMID:Effects of imidazole compounds on catecholamine release in adrenal chromaffin cells. 133 Mar 11

In the presence of SCH 23390, a potent blocker of D1 dopamine receptors, dopamine inhibits adenylate cyclase activity of synaptic plasma membranes isolated from rat striatum. Maximal inhibition corresponds to a 20-25% decrease of basal enzyme activity and is reached with 100 microM dopamine. The apparent IC50 of dopamine is 2.5 microM. The inhibitory effect of dopamine is mimicked by various dopamine receptor agonists with the following rank order of potency: (-)-propylnorapomorphine greater than or equal to bromocriptine greater than (+/-)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene = (-)-apomorphine greater than dopamine greater than LY 171555 greater than l-noradrenaline greater than l-phenylephrine. Clonidine and l-isoproterenol are inactive at 100 microM. Bromocriptine and LY 171555, two agents which stimulate selectively D2 receptors, inhibit striatal adenylate cyclase activity in the absence of SCH 23390. However, bromocriptine behaves like a partial agonist. A variety of neuroleptic drugs antagonize the dopamine inhibition with a rank order of potency which qualitatively correlates with their relative affinity for D2 receptors. l-Sulpiride (EC50 = 210 nM) and (+)-butaclamol (EC50 = 130 nM) are severalfold more potent than d-sulpiride (EC50 = 5 microM) and (-)-butaclamol (EC50 = 10 microM). The inhibitory effect of dopamine on striatal adenylate cyclase activity is dependent on the presence of GTP, with half-maximal inhibition occurring at 1 microM GTP. In the absence of SCH 23390, dopamine stimulates adenylate cyclase activity, reaching a maximum at 1 microM GTP. At higher concentrations of the nucleotide, the dopamine-stimulated enzyme activity decreases, and this decline is antagonized by the D2 receptor blocker l-sulpiride. Guanyl-5'-yl imidodiphosphate, a stable analogue of GTP, has a biphasic effect on the striatal adenylate cyclase activity, inhibiting at low concentration (from 1 to 100 nM) and stimulating at higher concentrations. Selective activation of D2 receptors by LY 171555 does not increase the extent of enzyme inhibition elicited by guanyl-5'-yl imidodiphosphate. Sodium chloride amplifies the inhibition of striatal adenylate cyclase activity by LY 171555 and reduces the potency of the D2 agonist by a factor of 4. The dopamine-inhibited enzyme activity is lost following intrastriatal injection of kainic acid. The results indicate that in rat striatum dopamine inhibits adenylate cyclase activity by acting on postsynaptic dopamine receptors with pharmacological properties of D2 type.
Mol Pharmacol 1985 Aug
PMID:Characterization of dopamine receptors mediating inhibition of adenylate cyclase activity in rat striatum. 241 Jul 69

Several investigators have shown that incubating unstirred platelets with epinephrine blunts subsequent aggregation when the platelets are stirred. Using aspirin-treated platelets, we further characterized this desensitization of alpha 2-adrenergic receptor-initiated aggregation. Desensitization occurred with a t1/2 of 3-6 min and was maximal at 20-30 min, at which time the initial rate of aggregation and its maximal extent were about half that of control platelets. When we preincubated platelets with epinephrine, and then added phentolamine to block the alpha 2-receptors, ADP-initiated aggregation occurred normally. Thus, the desensitization of epinephrine-initiated aggregation was not associated with a generalized impairment of aggregation. At concentrations too low to initiate aggregation, epinephrine is known to potentiate aggregation initiated by other agents. Clonidine also acts at alpha 2-receptors to potentiate aggregation initiated by other agents, but it does not initiate aggregation by itself. Preincubating clonidine with platelets for 30 min abolished its potentiating effect on ADP-initiated aggregation. Thus, the ability of alpha 2-receptors to both potentiate and initiate aggregation desensitizes after a brief preincubation with agonist. We performed several types of experiments to investigate the mechanism of this desensitization. Platelet alpha 2-receptors are coupled to an inhibition of adenylate cyclase. We found, however, that alpha 2-mediated inhibition of prostaglandin E1-stimulated cAMP accumulation occurred normally in desensitized platelets. Similarly, epinephrine inhibited basal adenylate cyclase activity normally in membranes prepared from desensitized platelets. In membranes prepared from desensitized platelets, epinephrine competed normally for [3H]rauwolscine binding, and this competition was modulated normally by guanine nucleotides. Thus, the properties of the alpha 2-receptors, as measured in radioligand binding experiments, were unchanged by densensitization. In conclusion, desensitization of alpha 2-adrenergic receptor-mediated aggregation occurs without change in the alpha 2-adrenergic receptors or in their coupling to an inhibition of adenylate cyclase.
Mol Pharmacol 1986 Jan
PMID:Desensitization of epinephrine-initiated platelet aggregation does not alter binding to the alpha 2-adrenergic receptor or receptor coupling to adenylate cyclase. 241 46

We compared the pharmacological properties of the alpha 2-adrenergic radioligand [3H]idazoxan with those of [3H]rauwolscine in rat and [3H]yohimbine in human renal cortical membranes. The density of "specific" [3H]idazoxan binding sites (defined by 100 microM tolazoline) was twice as high as that of [3H]rauwolscine in rat kidney and four times as high as that of [3H]yohimbine in human kidney. A variety of structurally different drugs fully competed for specific [3H]rauwolscine and [3H]yohimbine binding, with affinities appropriate for the interaction with alpha 2-adrenergic receptors. Specific [3H]idazoxan binding, however, was only partially competed for by the catecholamines epinephrine and norepinephrine in both tissues. Thus, [3H]idazoxan labels both alpha 2-adrenergic receptors and a nonadrenergic site. Clonidine, B-HT 920, moxonidine, phentolamine, prazosin, yohimbine, dopamine, and serotonin also could not compete for this site. However, UK 14,304, guanabenz, indanidine, tolazoline, oxymetazoline, and SK&F 104,078 competed for the additional [3H]idazoxan sites with affinities similar to those at alpha 2-adrenergic receptors. [3H]idazoxan binding substantially in excess of [3H]rauwolscine or [3H]yohimbine binding was also found in human platelets, myometrium, and erythroleukemia (HEL) cells but not in three cell lines lacking alpha 2-receptors (MDCK, BC3H1, and Jurkat cells). Although we have been unsuccessful thus far in defining the precise nature of the additional [3H]idazoxan binding sites, we hypothesize that these sites may be closely affiliated with alpha 2-adrenergic receptors but clearly distinct from the catecholamine binding site of the receptor. The results indicate that care must be taken in the use of [3H]idazoxan or drugs that are recognized at its nonadrenergic site when studying alpha 2-adrenergic effects and receptor subtypes.
Mol Pharmacol 1989 Mar
PMID:[3H]idazoxan and some other alpha 2-adrenergic drugs also bind with high affinity to a nonadrenergic site. 256 31

Insulin secretion from isolated rat islets of Langerhans in the presence of 4 mM glucose averaged 2.26 +/- 0.20 (S.E.M.) ng/islet per 90 min and was significantly (P less than 0.001; n = 30) increased to 3.28 +/- 0.21 ng/islet per 90 min by the covalent alpha-adrenoceptor antagonist benextramine (10 microM). Glucose (20 mM) also increased the secretion rate (to 6.24 +/- 6.0 ng/islet per 90 min) but, under these conditions, the response was not further enhanced by benextramine. Clonidine and noradrenaline (1 nM-10 microM) each caused dose-dependent inhibition of glucose-induced insulin secretion which was maximal at 1 microM. Benextramine, when added simultaneously with the agonist, relieved, in a dose-dependent manner, the inhibition of secretion induced by either clonidine or noradrenaline with similar sensitivity. Even after a 30-min preincubation with benextramine the antagonist failed to differentiate between noradrenaline, adrenaline and clonidine with respect to inhibition of insulin secretion. In contrast to its effects on adrenergic responses, short-term treatment with benextramine did not significantly affect muscarinic-cholinergic receptor-mediated 45Ca2+ efflux from rat islets of Langerhans perifused in Ca2+-depleted medium. These data suggest that benextramine does not differentiate between clonidine and noradrenaline in rat islets of Langerhans but that it does show preference for alpha-adrenoceptors in this tissue.
J Mol Endocrinol 1989 Mar
PMID:Effects of benextramine on the adrenergic inhibition of insulin secretion in isolated rat pancreatic islets. 257 May 93

Endothelium-derived relaxing factors (EDRFs) have been previously shown to exert an inhibitory influence on the contractile effects of alpha-adrenoceptor agonists in vascular smooth muscle. alpha 2-Adrenoceptor agonists such as clonidine have been reported to be particularly susceptible to this effect, and it has been suggested that clonidine acts on alpha 2 receptors on endothelial cells to stimulate the release of EDRF. EDRF release is known to be accompanied by increased levels of cGMP in many blood vessels, and it is suggested that cGMP exerts an inhibitory influence on the smooth muscle cells, which tends to counteract the contractile effect of the clonidine. This hypothesis was tested in isolated rings of rat aorta and mesenteric artery using the cGMP lowering agent, 6-anilino-5,8-quinolinedione (LY83583). LY83583 markedly decreased resting levels of cGMP in these vascular preparations and completely prevented both the relaxation and the cGMP elevation normally caused by acetylcholine in rat aorta with intact endothelium. These effects of LY83583 are identical to those observed after mechanical disruption of the endothelium. LY83583 also enhanced the contractile responses to norepinephrine and particularly to clonidine in both aorta and mesenteric artery. The effects of LY83583 on contractile responses to both alpha-adrenoceptor agonists were reversed by low concentrations of 8-bromo-cGMP. Clonidine did not increase cGMP levels in vascular preparations with intact endothelia, in the presence or absence of LY83583. Thus, enhanced release of EDRF by clonidine did not appear to be responsible for the inhibition of its contractile effects observed in the presence of intact endothelial cells. Our results suggest instead that this endothelium-dependent inhibition is due to spontaneous release of EDRF, which results in tonic elevation of cGMP in the vascular smooth muscle. This tonic elevation of cGMP exerts a more marked inhibitory effect against contractions induced by the partial agonist, clonidine, than it does against contractions induced by a full agonist, norepinephrine.
Mol Pharmacol 1987 Jul
PMID:Evidence that cGMP is the mediator of endothelium-dependent inhibition of contractile responses of rat arteries to alpha-adrenoceptor stimulation. 288 38

The effect of repeated electroconvulsive shock (ECS) treatment and chronic LiCl feeding on calcium-dependent, K+-evoked release of [3H] norepinephrine from rat cortical vesicular preparation was studied. There was no significant effect of either acute or repeated ECS treatment on [3H]norepinephrine release in cortical vesicles obtained from animals treated for either 1 or 10 days. Release of norepinephrine was examined over a range of CaCl2 concentrations. Clonidine effectively inhibited release of [3H]norepinephrine in cortical vesicles obtained from control and ECS-treated animals. K+-evoked release of [3H]norepinephrine at low (0.2 mM) and high (1.0 mM) CaCl2 concentrations was significantly increased in cortical vesicles obtained from LiCl-treated animals. Clonidine effectively inhibited release of [3H]norepinephrine in cortical vesicles obtained from both control and LiCl-fed animals. These results suggest a possible common mechanism of action of antidepressant drug therapy on presynaptic release of norepinephrine from nerve terminals.
Cell Mol Neurobiol 1983 Sep
PMID:The effect of repeated electroconvulsive shock treatment and chronic lithium feeding on the release of norepinephrine from rat cortical vesicular preparations. 632 93

In situ hybridization for the norepinephrine transporter (NET) was performed in rats receiving short-term (2 days) treatment with either an alpha-2 (alpha 2) receptor agonist (clonidine) or antagonist (yohimbine) followed by saline or desipramine (DMI). The 'saline' group received intraperitoneal injections of either clonidine, yohimbine or saline followed by an injection of saline. The 'DMI' group received intraperitoneal injections of either clonidine, yohimbine or saline followed by an injection of DMI. Dosages given were clonidine (0.10 mg/kg), yohimbine (0.5 mg/kg) and DMI (10 mg/kg). In the 'saline' group, the clonidine/saline animals had significantly less NET mRNA expression compared to the saline/saline animals. In the 'DMI' group an attentuation of the DMI-induced increase in NET mRNA was observed in the clonidine/DMI animals compared to the saline/DMI animals. In both treatment groups, administration of yohimbine did not alter the expression of NET mRNA compared to the appropriate control animals. These findings suggest that the DMI-induced increase in NET mRNA is not mediated via alpha 2 receptors for, although clonidine attenuates DMI's effect, there is no reciprocal enhancement with the alpha 2 antagonist yohimbine. Clonidine's attenuation of DMI's effect may occur via the imidazole receptor as clonidine is an agonist at the imidazole receptor but yohimbine has no known activity at it. Additional studies are needed to clarify the mechanism of the DMI-induced increase in NET mRNA and to correlate changes in NET mRNA with transporter expression at the synaptic membrane.
Brain Res Mol Brain Res 1994 Dec
PMID:Desipramine-induced increase in norepinephrine transporter mRNA is not mediated via alpha 2 receptors. 789 21

The population of alpha 1-adrenoceptor subtypes functionally mediating contraction in response to phenylephrine was examined in rat thoracic aorta and tail arteries. In thoracic aorta, chloroethylclonidine (CEC), which alkylates the alpha 1B and alpha 1D subtypes, shifted the concentration-response curve for phenylephrine substantially to the right without reduction in maximum contraction. The pA2 value (7.8) for 5-methylurapidil was consistent with the values reported for alpha 1D subtype, but was higher than those in tissues in which the alpha 1B subtype is dominant. In tail arteries, CEC did not shift the concentration-response curve for phenylephrine, but somewhat inhibited the maximum contraction. Schild analysis for 5-methylurapidil yielded a straight line with a slope significantly less than unity. Prazosin antagonized phenylephrine-induced contraction of tail arteries in a competitive manner with a pA2 value of 8.5, consistent with values for alpha 1L subtype. Clonidine relaxed the active tone induced by phenylephrine in both thoracic aorta and tail arteries, but quite different responses to clonidine by the two tissues were observed. After pretreatment with CEC, the relaxation induced by clonidine was abolished in thoracic aorta, but not in tail arteries. These results suggest that alpha 1D-and alpha 1L-adrenoceptors are mainly present in thoracic aorta and tail arteries, respectively. This difference in the populations of alpha 1-adrenoceptor subtypes may be related to regional differences in the modes of relaxant action of clonidine.
Res Commun Mol Pathol Pharmacol 1996 Apr
PMID:Further characterization of antagonism by alpha 2-adrenoceptor agonists of contractions induced by alpha 1-adrenoceptor agonists. 873 26


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