Postsynaptic Alpha 2-adrenergic Receptors Research Articles

Alpha-2 adrenergic receptor sensitivity and the mechanism of action of antidepressant therapy. The effect of long-term amitriptyline treatment.

It has been hypothesized that the mechanism of action of antidepressant treatments is related to their ability to decrease the sensitivity of the alpha-2 adrenergic autoreceptor. In order to assess alpha-adrenergic autoreceptor sensitivity, the effects of clonidine, the alpha-2 adrenergic receptor agonist, on plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenethyleneglycol (MHPG), blood pressure (BP) and patient-rated sedation were measured in nine depressed patients before and during amitripytline treatment. Postsynaptic alpha-2 adrenergic receptor sensitivity was assessed by determining the growth hormone (GH) response to clonidine before and during treatment. Amitriptyline significantly attenuated the effects of clonidine on plasma MHPG, standing systolic BP, and sedation, indicating that alpha-2 adrenergic autoreceptors had become subsensitive. In addition, baseline plasma MHPG levels were significantly reduced. Amitriptyline had no effect on the GH response to clonidine.

Postsynaptic alpha-adrenergic receptors potentiate the beta-adrenergic stimulation of pineal serotonin N-acetyltransferase.

The role played by postsynaptic alpha-adrenergic receptors in the stimulation of pineal N-acetyltransferase (EC 2.3.1.5) and [3H]melatonin production was investigated in the rat. In vivo studies indicated that phenylephrine, an alpha-adrenergic agonist, potentiated and prolonged the effects of isoproterenol, a beta-adrenergic agonist. Similar observations were made in organ culture with glands devoid of functional nerve endings. In addition, a combination of 1 microM prazosin, an alpha 1-adrenergic blocking agent, and 1 microM propranolol, a beta-adrenergic blocking agent, was many times more potent then either agent alone in blocking the stimulatory effects of norepinephrine on N-acetyltransferase activity and [3H]melatonin production. These findings establish that norepinephrine acting through alpha- and beta-adrenergic receptors stimulates rat pineal N-acetyltransferase activity and, as a result, the production of melatonin. Apparently, beta-adrenergic activation is an absolute requirement, and an alpha-adrenergic receptor mechanism potentiates beta-adrenergic activation. These findings are significant because they demonstrate alpha-adrenergic potentiation of beta-adrenergic effects. In addition, they indicate that the widely held belief that melatonin production is regulated exclusively by a postsynaptic beta-adrenergic mechanism must be revised.

Catecholamine-mediated constrictor effects of aldosterone on vascular smooth muscle

The possibility that the corticosteroid hormone, aldosterone, might possess direct vasoconstrictor properties was examined in the isolated central ear artery of the New Zealand white rabbit. Aldosterone alone produced only minimal contractile effects in the arterial segments; but following pretreatment of the tissue with desipramine (10 −7M), a blocker of neuronal uptake of norepinephrine, aldosterone concentrations of 10 −6M, 10 −5M, and 10 −4M produced stepwise contractile responses of 0.16 ± 0.03 (SE)g, 0.48 ± .04g, and 1.31 ± 0.06g. The possible involvement of norepinephrine in this action of aldosterone was tested in a series of tissues stored for 2 days at 2°C in Krebsbicarbonate medium so as to deplete endogenous catecholamine stores. Treatment with desipramine followed by aldosterone (10 −4M) now produced an average contraction of only 0.1 ± 0.06g; but if the labile neuronal tissue stores of norepinephrine in these tissues were then replenished by exposure to norepinephrine 10 −7M, contractions of 1.2 ± 0.3g now occurred when desipramine and aldosterone were added. To examine whether aldosterone's action might be due to blockade of extraneuronal norepinephrine uptake (uptake-2), 3H-norepinephrine was added to ear artery tissues exposed to desipramine with or without aldosterone: a significant (P<0.005) decrease of 25% in 3H-norepinephrine uptake occurred in the tissues treated with aldosterone. In further studies, the contractile effects of aldosterone could be prevented by pretreatment with prazosin (10 −7M) or phentolamine (10 −7M); if added after the aldosterone, each of these alpha-blockers completely reversed the contractile responses. Although the physiological relevance of these findings is yet to be fully defined, these studies indicate that the in vitro contractile effects of aldosterone are dependent upon its inhibition of extraneuronal uptake of endogenous norepinephrine; it is likely that the resulting increase in extracellular norepinephrine concentration then produces vasoconstriction by stimulation of post-synaptic alpha-adrenergic receptors.

Postsynaptic localization of alpha 2-adrenergic receptors in rat submandibular gland

Norepinephrine is known to inhibit its own release from presynaptic nerve terminals through alpha 2-adrenergic receptors, which presumably have a presynaptic localization. alpha 2-Adrenergic receptors (as determined by [3H]clonidine binding) appear in rat submandibular gland membranes following reserpine treatment. These alpha 2 receptors seem to be localized postsynaptically, based on the following evidence. (1) Partial destruction of the presynaptic nerve terminals with 6-hydroxydopamine did not decrease the density of alpha 2-adrenergic receptors following subsequent reserpine administration. (2) Duct ligation, which results in atrophy of the gland, markedly decreased the density of the receptors following subsequent reserpine administration. (3) Surgical denervation resulted in the appearance of high levels of alpha 2-adrenergic receptors. (4) The changes in alpha 2 receptors paralleled the changes in postsynaptic beta-adrenergic receptor binding (as determined by [3H]dihydroalprenolol). While these results establish the existence of postsynaptic alpha 2-adrenergic receptors in an innervated tissue, the concomitant presence of a low density of presynaptic alpha 2 receptors has not been eliminated.

The effect of temperature elevation on the cerebrovascular response to noradrenaline and 5‐hydroxytryptamine

Fever frequently complicates stroke and subarachnoid haemorrhage. A transient rise in transmitter monoamine levels of plasma and cerebrospinal fluid occurs in these diseases. The present study demonstrates an enhanced vasoconstrictor response of cerebral vessels to noradrenaline-but not 5-hydroxytryptamine-following a rise in temperature. The augmented response is more likely due to an impaired inactivation (re-uptake) of the amine than to an altered sensitivity of the post-synaptic alpha-adrenergic receptor, since it could be reproduced by pretreatment with cocaine. The finding indicates that it may be important to combat fever in these patients.

Chronic L-DOPA treatment of mice: a behavioural and biochemical study.

Mice were pretreated once daily with L-DOPA (200 mg/kg) plus benserazide (B) (50 mg/kg) for ten days and challenged with various doses of L-DOPA + B on the first, fourth or sixteenth days of withdrawal. L-DOPA + B-pretreated mice were more sensitive the locomotor stimulant effect of L-DOPA + B challenge one and four days, but not sixteen days after withdrawal. The enhanced response was most marked on the first day of withdrawal. Other mice, pretreated once daily with B (50 mg/kg), responded one day after the tenth dose with a slightly enhanced response to L-DOPA + B challenge compared to the response to vehicle-pretreated animals. Moreover, vehicle-pretreated mice challenged with B alone, were significantly less active than those challenged with vehicle. On the first day of withdrawal, the L-DOPA + B-pretreated animals were supersensitive to locomotor stimulant effects of apomorphine but subsensitive to dexamphetamine (Bailey et al., 1979). On the fourth day of withdrawal, there were no differences in the responses of the L-DOPA + B-pretreated mice compared to the vehicle-pretreated mice, to apomorphine or apomorphine plus clonidine, but L-DOPA + B-pretreated mice were still subsensitive to the locomotor stimulant effects of dexamphetamine. Clonidine produced a dose-dependent, but similar, degree of hypothermia in both pretreatment groups. On the first and fourth days of withdrawal L-DOPA + B-pretreated mice exhibited higher brain levels of dopamine (DA) and DOPA than vehicle-pretreated mice in response to an acute dose of L-DOPA + B. The biochemical results suggest that the enhanced locomotor response to L-DOPA + B in L-DOPA + B-pretreated mice is probably dependent on changes in the amount of L-DOPA (and DA) available in the brain. Moreover, it is not ruled out that some of the effects of L-DOPA + B pretreatment were due to the B alone. Some of the enhanced response to L-DOPA + B on the first day of withdrawal may have been dependent on the same mechanism as that underlying the apparent supersensitivity to apomorphine. The subsensitive response to dexamphetamine would appear to be independent of changes in post-synaptic DA and alpha-adrenergic receptor sensitivity.

Regulation of the postsynaptic alpha-adrenergic receptor in rat mesenteric artery. Effects of chemical sympathectomy and epinephrine treatment.

Regulation of the postsynaptic alpha-adrenergic receptor in rat mesenteric artery. Effects of chemical sympathectomy and epinephrine treatment.

Characterization of postsynaptic alpha-adrenergic receptors by [3H]-dihydroergocryptine binding in muscular arteries from the rat mesentery.

Alpha-adrenergic receptors are likely to be important determinants of the effects of catecholamines on vascular resistance. To study the alpha-adrenergic receptor in muscular arteries of the type that determine vascular resistance, we characterized and quantitated alpha-adrenergic receptors in a particulate fraction of the highly reactive, richly innervated arteries of the rat mesentery. With the ligand [3H]-dihydroergocryptine ([3H]-DHEC), specific binding (displaceable by 5 microM phentolamine) is saturable. There is a single class of binding sites with a dissociation constant (Kd) of 2.9 nM and a maximal binding capacity of 68 fmoles of [3H]-DHEC per mg of particulate fraction protein. Catecholamines compete for [3H]-DHEC binding stereospecifically and with the alpha-adrenergic potency series of (-)epinephrine greater than (-)norepinephrine greater than (-)isoproterenol. Binding is rapid (t 1/2 less than or equal to 2 mins) and rapidly reversible (t 1/2 less than or equal to 2 mins). Inhibition of [3H]-DHEC binding by the alpha-adrenergic antagonist phentolamine (Kd = 3.0 nM) is much greater than by the beta-adrenergic antagonist propranolol (Kd = 8200 nM). The alpha 1-selective antagonist prazosin (Kd = 63 nM) is 20 times more potent in competing for [3H]-DHEC binding than is the alpha 2-selective antagonist yohimbine (Kd = 1250 nM), thus suggesting that the alpha-adrenergic receptor identified is predominantly of the alpha 1 subtype that is responsible for vascular smooth muscle contraction. This extension of radioligand binding techniques to highly innervated muscular arteries of the type contributing to vascular resistance will allow the study of the role of the vascular alpha-adrenergic receptor in various physiologic states and models of hypertension.

Tricyclic antidepressants and imidazolines as inhibitors of the alpha-adrenergic receptor mediated stimulation of phosphatidylinositol turnover in rat pineal gland

In intact rat pineal glands in vitro, norepinephrine stimulates the incorporation of 32P into phosphatidylinositol through post-synaptic alpha-adrenergic receptors. This response is inhibited by tricyclic antidepressants and imidazolines. Both amitriptyline and oxymetazoline displace the dose-response curve for norepinephrine to the right in a parallel manner indicative of a competitive mode of inhibition by these two classes of drugs.

Noradrenergic transmission and female sexual behavior of guinea pigs

Treatment with the dopamine beta-hydroxylase (DBH) inhibitor U-14,624 (50, 100, or 150 mg/kg) blocked the induction of lordosis behavior by estradiol benzoate (EB) and progesterone (P) in overiectomized guinea pigs. After treatment with U-14,624 (100 mg/kg), norepinephrine (NE) content of medial basal hypothalamus, preoptic area and cortex was reduced (by 55%) and dopamine (DA) content of medial basal hypothalamus was increased (by 155%) during the period when females treated with EB and P normally display lordosis. Treatment with the NE receptor stimulator clonidine (1.0 mg/kg) restored lordosis behavior in females treated with EB, P, and U-14,624 (100 mg/kg), but the putative DA and serotonin (5-HT) receptor blockers pimozide (1.0 mg/kg) and methysergide (20.0 mg/kg) were ineffective in this respect. Thus, inhibition of lordosis after treatment with U-14,624 appeared to be attributable primarily to a reduction in NE neurotransmission, rather than to an increase in DA or 5-HT activity. Because clonidine induced lordosis in females treated with EB, P, and U-14,624, it seemed unlikely that the facilitatory effects of clonidine on lordosis were mediated by activation of presynaptic alpha-adrenergic receptors (i.e. inhibitory NE autoreceptors) rather than by postsynaptic alpha-receptors. In addition, pretreatment with the postsynaptic alpha-adrenergic antagonist phenoxybenzamine (20.0 mg/kg) blocked the facilitation of lordosis by clonidine (1.0 mg/kg) in females primed with EB alone and with EB plus P. Thus, the facilitatory effects of clonidine on lordosis appear to be mediated by activation of postsynaptic alpha-adrenergic (i.e. NE) receptors. The results of this study provide further evidence that NE neurotransmission facilitates the expression of female sexual behavior in guinea pigs.

Prazosin in the diagnosis and treatment of pheochromocytoma

In a patient with paraganglioma, severe hypertension due to high levels of plasma norepinephrine was easily controlled with prazosin hydrochloride, 6 to 8 mg/day for 19 days before surgery. A prolonged antihypertensive response to the first two 1-mg doses suggested the presence of pheochromocytoma. This experience dramatizes the remarkable effectiveness of prazosin as a postsynaptic alpha-adrenergic receptor blocker and invites further trials of the drug for both the diagnosis and treatment of pheochromocytoma.

Differences in postsynaptic α‐Adrenoceptor Populations Between Isolated Cat Urethra and Various Other Isolated Tissues.

This study was undertaken with the aim of determining whether the postsynaptic alpha-adrenergic receptor population of the cat urethra differed from that of other isolated tissues (rabbit aorta and rat vas deferens) and if so the possibility of selectively affect these receptors. For this purpose the substances 2-methylammonio-1-(spiro[cyclopentane-1,1'-indene]-3'-yl)ethanol (KABI 2023), noradrenaline (NA) and dopamine (DA) were used. KABI 2023 and NA acted as full agonists on all three tissues investigated. DA was a full agonist on the vas deferens but was almost inactive on urethra. The contractile response of urethra to KABI 2023 was of an alpha-adrenergic nature, as it could be blocked with phentolamine. Compared with NA, KABI 2023 showed a 10 times higher selectivity for the receptors of urethra than for those of aorta. Affinity constants (log KB) for phentolamine and haloperidol with use of the various agonists were estimated. The affinity of phentolamine was found to be significantly different when using NA and KABI 2023 as agonists on the urethra but not on the aorta. Corresponding findings were obtained with haloperidol. On the vas deferens a greater difference in log KB values than that on the urethra was found. On the basis of the results, it is suggested that the population of postsynaptic alpha-adrenoceptors in the urethra (cat) differs from that in the aorta (rabbit). On the vas deferens a heterogenicity of postsynaptic receptors seem to exist which makes the interpretation of the results more difficult on this organ. In the presence of phentolamine and haloperidol the maximum responses to NA were potentiated on the aorta and vas deferens, but not on the urethra. Investigations to evaluate this difference are now in progress.