Postsynaptic Alpha 2-adrenoreceptors Research Articles

Case Study: Two Fatal Case Reports of Acute Yohimbine Intoxication

Yohimbine is an alkaloid that has been encountered on the streets as an aphrodisiac, hallucinogen, dietary supplement and erectile dysfunction drug. Yohimbine hydrochloride is an alpha 2-adrenoreceptor antagonist, blocking the pre- and postsynaptic alpha-2 adrenoreceptors and causing an increased release of noradrenaline and dopamine. An average oral dose of 5-15 mg produces a therapeutic whole blood level range of 40-400 ng/mL. Overdoses leading to neurotoxic effects have been seen with blood concentrations up to 5,000 ng/mL. The laboratories from the Maricopa County Medical Examiner and the Los Angeles County Department of Coroner each encountered a case in which yohimbine was identified in whole blood by means of a liquid-liquid basic drug extraction with detection on a GC-MS. Because validated quantitative methods for yohimbine did not exist at either facility, both agencies referred the blood specimens to NMS Labs, Inc. The reference laboratory analyzed the blood specimens with an LC-MS-MS and determined the quantitative values of yohimbine to be 7,400 and 5,400 ng/mL. Given the absence of other significant positive findings and the substantial yohimbine blood concentrations cited, the respective Medical Examiners determined the cause of death to be acute yohimbine intoxication with the mode being an accident. Yohimbine is a rarely encountered drug in medical examiner casework, and interpretation of the results is difficult to assess toward the cause and manner of death without such case studies being described.

Blunted Growth Hormone Response to Clonidine in Patients With Generalized Anxiety Disorder

Patients with panic disorder or depression have abnormal responses to the alpha 2-adrenergic receptor partial agonist clonidine. Evidence linking anxiety to noradrenergic dysfunction and the presence of anxiety symptoms in both depression and panic suggest that abnormal responses to clonidine in these disorders could be due to the anxiety symptoms. To explore a possible link between "nonspecific" anxiety symptoms and abnormal responses to clonidine, patients with DSM-III-defined generalized anxiety disorder were given intravenous infusions of clonidine hydrochloride. Responses of plasma growth hormone, 3-methoxy-4-hydroxyphenylglycol, heart rate, blood pressure, and psychological states were determined in 11 patients with generalized anxiety disorder and 14 healthy subjects. Clonidine produced significantly smaller growth hormone responses in patients than in healthy controls. The two groups did not differ in 3-methoxy-4-hydroxyphenylglycol, heart rate, blood pressure, or psychological responses to clonidine. These results are compared with data from similar studies on patients with panic disorder and depression. The blunting of the growth hormone response to clonidine in all three disorders could be due to the presence of generalized anxiety symptoms. Subsensitivity of postsynaptic alpha 2-adrenoreceptors may be present in all three disorders; however, there are alternative interpretations of growth hormone blunting in response to clonidine. Blunting was observed in DSM-III-defined generalized anxiety disorder, whether or not the DSM-III-R criterion of excessive worry was also present.

Seizure suppression in kindling epilepsy by intrahippocampal locus coeruleus grafts: evidence for an alpha-2-adrenoreceptor mediated mechanism

Intrahippocampal cell suspension grafts, prepared from the locus coeruleus region of rat fetuses, have previously been shown to retard seizure development in rats made hypersensitive to hippocampal kindling by a lesion of the forebrain noradrenergic system. The objective of the present study was to provide evidence that the seizure-suppressant effect elicited by the grafts is mediated via noradrenergic mechanisms. Two groups of rats received 6-hydroxydopamine in the lateral ventricle and then bilateral intrahippocampal locus coeruleus grafts. After 3 months, the grafted animals and a group of normal rats were subjected to hippocampal kindling. One group of grafted animals and the normal rats were injected intraperitoneally with the alpha-2 adrenergic receptor blocker idazoxan before each kindling stimulation. The other grafted rats received vehicle injections. The development of seizures was significantly faster in the grafted and normal rats that had been given idazoxan than in the grafted rats that had not been subjected to alpha-2 receptor blockade. Our data suggest that the seizure-suppressant action exerted by grafts of fetal locus coeruleus in hippocampal kindling is mediated via noradrenergic mechanisms, most likely via activation of postsynaptic alpha-2 adrenoreceptors.

The effect of UK14,304-18 (an alpha-2 adrenergic agonist) on myocardial blood flow during cardiopulmonary resuscitation

Several recent studies have suggested that adrenergic drugs with peripheral postsynaptic alpha-2 agonist properties increase aortic diastolic pressure (ADP), and thus in the setting of CPR, may improve myocardial blood flow (MBF). This preliminary study investigated the effect of UK14,304-18, a postsynaptic alpha-2 adrenergic agonist on ADP, MBF, myocardial oxygen delivery/utilization (MDO 2/MVO 2), endocardial/epicardial blood flow ratio (EN/EP), coronary sinus oxygen content (C csO 2) and extraction ratio (ER) during CPR. Five swine were instrumented for MBF measurements using tracer microspheres. Catheters were also placed to measure arterial oxygen content (C aO 2) and C csO 2. ADP, MBF, MDO 2/MVO 2, EN/EP, ER, C aO 2 and C csO 2 were measured during normal sinus rhythm (NSR), and during CPR following a 10-min cardiorespiratory arrest. Following this, each animal received 2.0 mg/kg of UK14,304-18 through a right atrial line. ADP, MBF, MDO 2/MVO 2, EN/EP, ER, C aO 2 and C csO 2 were again determined. Defibrillation was then attempted. To determine whether UK14,304-18 improved ADP, MBF and MDO 2 over MVO 2, compared to CPR alone, results were compared using a paired Student t-test. Statistical significance was considered at the P ⩽ 0.05 level. No significant improvement in ADP, MBF, MDO 2 or ER was noted following the administration of UK14,304-18. The lack of improvement in ADP and MBF may be secondary to a centrally acting postsynaptic alpha-2 agonist effect because of disruption of the blood brain barrier following a prolonged cardiac arrest or because of pharmacologically or structurally distinct populations of peripheral postsynaptic alpha-2 adrenoreceptors that develop in this setting. This study suggests that UK14,304-18 does not improve myocardial hemodynamics at these doses during CPR following a 10-min arrest.

Alpha 1- and alpha 2-adrenoreceptor antagonists produce opposing mydriatic effects by a central action.

1. In anaesthetized rats, intravenous administration of alpha 2-adrenoreceptor antagonists yohimbine (0.3-3.0 mg kg-1), idazoxan (0.03-0.3 mg kg-1) and raulwolscine (0.3-3.0 mg kg-1) produced a dose-related inhibition of sciatic nerve-(ScN) mediated reflex pupillary dilation (parasympatho-inhibition). The rank order of potency was idazoxan greater than yohimbine greater than rauwolscine. 2. Under similar experimental conditions, intravenous administration of alpha 1-adrenoreceptor antagonists prazosin (0.03-1.0 mg kg-1), phenoxybenzamine (0.3-3.0 mg kg-1) and corynanthine (0.03-1.0 mg kg-1) produced a dose-dependent potentiation of the reflex mydriasis with the potency order being prazosin greater than corynanthine greater than phenoxybenzamine. Intravenous yohimbine (1.5 mg kg-1) reversed the potentiation caused by the alpha 1-adrenoreceptor antagonists and blocked the reflex mydriasis. 3. Parasympatho-inhibition and mydriasis elicited by hypothalamic stimulation was not affected by the alpha 2-adrenoreceptor antagonists yohimbine (0.3-3.0 mg kg-1), idazoxan (0.03-0.3 mg kg-1) or the alpha 1-adrenoreceptor antagonist prazosin (0.3-1.0 mg kg-1). 4. Microinjection of prazosin (3-30 ng) into the oculomotor nuclear complex (IIIn), produced a dose-related potentiation, whereas microinjection of yohimbine (0.3-3.0 micrograms) produced a dose-related blockade of reflex mydriasis. 5. The above findings support the hypothesis that ascending mechanisms (e.g. afferent ScN) produce inhibition of parasympathetic oculomotor tone to the iris by activation of central postsynaptic alpha 2-adrenoreceptors. Furthermore, these studies demonstrate that alpha 2-adrenoreceptor antagonists block and alpha 1-adrenoreceptor antagonists potentiate the reflex mydriasis. These actions appear to be localized within the pupilloconstrictor regions of the brain (oculomotor nuclear complex).

Alpha Adrenergic Stimulation Reduces Cyclic Adenosine 3′,5′-Monophosphate Generation in Rabbit Myometrium by Two Mechanisms1

Rabbit myometrium contains postsynaptic alpha-1, alpha-2, and beta-2 adrenoreceptors. The response to endogenous catecholamines depends on the summation of interactions at these receptors and is influenced by the hormonal environment. Estrogen treatment of ovariectomized rabbits increases the alpha adrenergic contractile response whereas progesterone treatment of estrogen primed animals results in a predominance of the beta adrenergic response, which is inhibition of contractions. Of the receptor subtypes, only the alpha-2 receptor concentration is increased at physiological estrogen concentrations. However, alpha-2 receptors have not been shown to be directly involved in myometrial contraction, which appears to be mediated solely by alpha-1 adrenergic interactions. To test whether alpha-2 receptors might indirectly affect contraction by opposing interactions at the beta receptor, we examined the ability of alpha adrenergic stimulation to reduce myometrial cyclic adenosine 3',5'-monophosphate (cAMP) generation. We find that alpha-2 receptors inhibit myometrial ade adenylate cyclase through the guanine nucleotide regulatory protein, Gi. In addition, we find that activation of alpha-1 receptors also reduces cAMP generation. This interaction, which can be demonstrated in the absence but not the presence of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, does not appear to be mediated through Gi. These findings illustrate the complexity of adrenergic interactions in tissues containing several adrenergic subtypes.

ChemInform Abstract: Differential Blockade of Muscarinic Receptor Subtypes by Polymethylene Tetraamines. Novel Class of Selective Antagonists of Cardiac M‐2 Muscarinic Receptors.

Several N,N'-bis[6-[(2-methoxybenzyl)amino]hexyl]-1, omega-alkanediamine tetrahydrochlorides were synthesized and evaluated for their blocking activity on muscarinic receptors in guinea pig atria and rat ileum and bladder. The results were compared with those obtained for the classical nonselective muscarinic antagonist atropine. It was discovered that optimum activity is associated with an eight-carbon chain (compound 4) in guinea pig atria whereas, in both rat ileum and bladder, the 12-carbon analogue 7 had the highest activity. In addition, polymethylene tetraamines 1-6 displayed high selectivity toward guinea pig atria muscarinic receptors. The discriminatory power of 1-6 was not shared by 7. All the tetraamines were shown to be competitive antagonists of muscarinic receptors. N,N'-Bis[6-[(2-methoxybenzyl)amino]hexyl]-1,8-octanediamine was the most potent and selective toward muscarinic receptors in atria, with a pA2 value of 8.13 and a selectivity ratio (atria vs. ileum or bladder) of ca. 270. At a concentration of 10 microM, tetraamine 4 did not affect histamine and 5-hydroxytryptamine receptors of guinea pig ileum or alpha-adrenoreceptors of guinea pig atria whereas it inhibited postsynaptic alpha-adrenoreceptors of rat vas deferens with a -log K value of 5.23 and nicotinic receptors of frog rectus abdominis with an IC50 value of 0.23 microM. It is concluded that 4 is a novel, powerful, and selective tool in the characterization of muscarinic receptor subtypes.

Influence of urapidil on alpha- and beta-adrenoreceptors in pithed rats.

The interaction of urapidil with pre- and postsynaptic alpha-adrenoreceptors and with postsynaptic beta-adrenoreceptors was studied in pithed normotensive rats and compared to the effects of clonidine, prazosin, and atenolol. I.v. injection of urapidil did not substantially change blood pressure, while clonidine raised blood pressure. Urapidil dose-dependently antagonized the pressor effects of the alpha 1-agonist L-phenylephrine (pDR2 6.8) and of the alpha 2-agonist azepexole (pDR2 5.2). Compared to urapidil, prazosin was a more potent antagonist of phenylephrine at postsynaptic vascular alpha 1-adrenoreceptors (pDR2 8.7) and of azepexole at alpha 2-adrenoreceptors (pDR2 5.6). Urapidil inhibited the tachycardia produced by discontinuous or continuous electrical stimulation of the thoracic spinal outflows (ID50 4.8 and 27.2 mumol/kg, respectively). In contrast to the inhibitory action of clonidine (ID50 0.039 and 0.023 mumol/kg, respectively), the inhibition by urapidil was not reversed by the selective alpha 2-antagonist rauwolscine (10 mumol/kg). Prazosin did not change stimulation-evoked tachycardia but atenolol caused pronounced inhibition (ID50 0.158 mumol/kg, discontinuous stimulation). Urapidil dose-dependently antagonized the tachycardic effect of isoprenaline at beta 1-adrenoreceptors (pDR2 5.1) but also exhibited intrinsic activity by increasing basal heart rate (maximum effect of urapidil was 30% of that of isoprenaline). Urapidil did not change the vasodilatory beta 2-adrenoreceptor-mediated effect of isoprenaline. The results suggest that urapidil is an antagonist at postsynaptic vascular alpha 1- and alpha 2-adrenoreceptors, with a greater potency against alpha 1-adrenoreceptors. An agonistic interaction of urapidil with presynaptic alpha 2-adrenoreceptors could not be demonstrated in pithed rats. Instead, the inhibition by urapidil of stimulation-evoked tachycardia could be accounted for by its beta 1-adrenoreceptor antagonistic effect.

Interactions of levamisole with some autonomic drugs on guinea-pig vas deferens.

The effects of levamisole on responses to various agonists were studied in guinea-pig vas deferens. Levamisole did not itself exhibit any contractile or relaxant effect on guinea-pig vas deferens but in the presence of levamisole the concentration-response curve of noradrenaline (NA) was shifted to the left and the maximal response was increased. Responses to field-stimulation at 5 and 10 Hz were potentiated by levamisole. Cocaine and denervation caused potentiation of NA responses and these enhanced responses remained unchanged in the presence of levamisole. Acetylcholine (ACh) responses were potentiated by levamisole whereas responses to histamine, KCl and methoxamine remained unaltered. These results suggest that levamisole does not have any action at postsynaptic alpha-adrenoreceptors. The increased responses to NA and ACh in the presence of levamisole may be due to its uptake1, blocking and anticholinesterase activities respectively.

Clonidine-induced sedation in rats: evidence for mediation by postsynaptic alpha 2-adrenoreceptors.

The effect of low doses of clonidine on exploration and motility was investigated in rats after destruction of central noradrenergic systems by 6-hydroxydopamine (6-OHDA) or DSP-4. In accordance with previous results, clonidine decreased exploration and motility in control animals. This sedative effect of clonidine was potentiated in animals that suffered selective and extensive depletions of brain NA as a result of neonatal treatment with 6-OHDA. Depletion of NA by administration of DSP-4 to adult animals did not influence clonidine's sedative effects. Yohimbine, but not phentolamine, antagonized clonidine-induced hypomotility both in control and in neonatal 6-OHDA treated groups. The results suggest that clonidine-induced sedation is mediated by postsynaptic alpha 2-adrenoreceptors.

Presynaptic dopamine receptors mediate the inhibitory action of dopamine agonists on stimulation-evoked pressor responses in the rat.

The effects of the dopamine agonists TL-99, M-7 (N, N-dimethyl analogues of aminotetralins) and N, N-dinpropyldopamine (NNPD) on stimulation-evoked pressor responses and tachycardia in pithed Sprague-Dawley rats were investigated when pressor responses to the compounds per se had subsided. Various antagonists were used to characterise the effects of the dopamine agonists. 2 M-7 (3 micrograms/kg i.v.), and NNPD (1 mg/kg i.v.), but not TL-99 (1-30 micrograms/kg i.v.), inhibited pressor responses evoked by low frequency electrical stimulation of the spinal cord in the pithed rat. 3 M-7 (3 micrograms/kg i.v.), but neither NNPD (1 mg/kg i.v.) nor TL-99 (1-30 micrograms/kg), inhibited tachycardia evoked by low frequency electrical stimulation of the spinal cord in the pithed rat. 4 The inhibition of stimulation-evoked pressor responses by M-7 and NNPD was prevented by pimozide, metoclopramide and sulpiride but not by yohimibine, atropine, cimetidine or propranolol. 5 The inhibition of stimulation-evoked tachycardia by M-7 was prevented by yohimbine (and to a certain extent by sulpiride) but not pimozide, metoclopramide, atropine or cimetidine. 6 Pressor responses elicited by TL-99, M-7 and NNPD were selective antagonised by yohimbine, but not by prazosin, indicating that these responses were mediated by stimulation of vascular postsynaptic alpha 2-adrenoreceptors. 7 This study demonstrates that, in the rat, presynaptic dopamine receptors exist on sympathetic pre- or postganglionic nerve endings to blood vessels, but not on sympathetic pre- or postganglionic nerve endings to the heart, where inhibition by M-7 of stimulation-evoked tachycardia is mediated by stimulation of presynaptic alpha 2-adrenoreceptors.

The effects of intravenous 6-hydroxydopamine on peripheral alpha-adrenoreceptors.

1 Peripheral alpha-adrenoreceptor-mediated responses were studied in conscious intact rabbits and in animals pretreated with intravenous 6-hydroxydopamine (50 mg/kg). 2 Treatment caused a large decrease in noradrenaline in plasma and peripheral tissue but only small falls in blood pressure. 3. There was a shift to the left in pressor dose-response curves to the alpha 1-adrenoreceptor agonist phenylephrine and the mixed alpha 1/alpha 2-adrenoreceptor agonist noradrenaline in 6-hydroxydopamine-pretreated animals. The alpha 1-adrenoreceptor antagonist prazosin was less effective at blocking the phenylephrine pressor response in these animals. 4 There was no change in pressor responses to the alpha 2-adrenoreceptor selective agonists clonidine and guanabenz and alpha-adrenoreceptor antagonists were equally effective at blocking this pressor response in 6-hydroxydopamine-pretreated and in intact rabbits. 5 In conscious animals 6-hydroxydopamine pretreatment causes alteration in responses mediated by postsynaptic alpha 1-but not postsynaptic alpha 2-adrenoreceptors. These changes may help maintain blood pressure in the 6-hydroxydopamine treated rabbits.

Impairment by nifedipine of vasopressor responses to stimulation of postsynaptic alpha 2-adrenoreceptors in ganglion--blocked rabbits. Further evidence for the selective inhibition of postsynaptic alpha 2-adrenoreceptor-induced pressor responses by calcium antagonists.

1 After ganglionic blockade and bilateral vagotomy, vasopressor responses induced by activation of postsynaptic alpha 1- and alpha 2-adrenoreceptors were elicited in the intact circulatory system of rabbits. 2 The hypertensive effects of the selective stimulating agents methoxamine (alpha 1-agonist) and B-HT 920 (alpha 2-agonist) were effectively antagonized by the adrenoreceptor antagonists prazosin and yohimbine, respectively. These findings confirm the existence of two types of postsynaptic alpha-adrenoreceptors (alpha 1- and alpha 2-type) in vascular smooth muscle of rabbits. 3 The calcium antagonistic drug nifedipine did not affect the maximal increase in diastolic pressure brought about by methoxamine, whereas it strongly inhibited the hypertensive effects of B-HT 920. 4 It is concluded that this confirmation of the selective inhibition of postjunctional alpha 2-adrenoreceptor-mediated vasopressor responses by a calcium antagonistic drug, such as nifedipine, indicates that this activity constitutes a general phenomenon. This finding supports the hypothesis that an influx of extracellular calcium is necessary for the vasoconstriction mediated by postsynaptic alpha 2-adrenoreceptors.

Dissociation of the effects of alpha 1-adrenergic blockade on blood pressure and renin release in patients with essential hypertension.

Prazosin, a selective antagonist of postsynaptic alpha-adrenoreceptors, was used to investigate the influence mediated by the juxtaglomerular alpha-adrenoreceptors on renin release in man. We studied, in seven patients with essential hypertension, the acute effects of 0.25 mg prazosin, given intravenously, on blood pressure and plasma renin activity, the degree of alpha-blockade induced by the drug being assessed by comparing the increments in blood pressure following a test dose of phenylephrine before and after prazosin administration. We also measured the increments in plasma renin activity in response to beta-adrenergic stimulus consisting of an isoproterenol challenge, before and during the prazosin induced alpha blockade. Prazosin infusion caused, within 20 min, a marked reduction of the pressor response to phenylephrine, a significant increment in plasma renin activity, and no change in blood pressure. The increments in renin in response to isoproterenol were significantly greater, both in absolute and percent values, after rather than before prazosin. These results indicate that the increase in renin during systemic alpha 1-adrenoreceptor blockade may be independent of the fall in blood pressure and support the view that the juxtaglomerular alpha 1-adrenoreceptors participate in the regulation of renin release with an inhibitory action, which antagonizes the stimulating influence of the beta-adrenoreceptors.

Antagonism of pre and postsynaptic alpha-adrenoreceptors by BE 2254 (HEAT) and prazosin.

1 The alpha-adrenoreceptor blocking effects of BE 2254 and prazosin have been studied in the pithed rat and guinea-pig ileum preparations. 2 BE 2254 was a competitive and potent antagonist of NA, Phenylephrine (PE) or stimulation-induced vasoconstriction in the pithed rat, but only exerted a weak antagonism of postsynaptic alpha 2-adrenoreceptor vasoconstriction induced by N,N-diMe-6,7-diOHATN (TL 99) or azepexole (BHT 933). The potency of BE 2254 against NA-induced vasoconstriction was markedly reduced by pretreatment with prazosin and propranolol. The antagonist effects of BE 2254 against TL 99-induced vasoconstriction was not altered by these pretreatments. Prazosin was without effect at postsynaptic alpha 2-adrenoreceptors. Neither antagonist blocked the pressor responses to angiotensin II (A II) nor the tachycardia-induced by exogenous NA, indicating specificity for alpha 2-adrenoreceptors. 3 BE 2254 was a potent antagonist of TL99-induced cardioinhibition (presynaptic alpha 2-adrenoreceptor effects) in the pithed rat, but may not act as a competitive antagonist in this preparation. Prazosin was without antagonist effect in this preparation. 4 In the transmurally stimulated guinea-pig ileum, BE 2254 was a potent antagonist of TL99, or clonidine-induced inhibition of the twitch response (presynaptic alpha 2-adrenoreceptor effects), but did not antagonize the effects of morphine. Prazosin was again without effect. 5 It was concluded that BE 2254 is a potent antagonist at presynaptic alpha 2-adrenoreceptors in vitro and in vivo, and at postsynaptic alpha 1-adrenoreceptors in vivo, but has only weak activity at vascular postsynaptic alpha 2-adrenoreceptors in the pithed rat. The differences in potency of BE 2254 in the pithed rat at pre- and postsynaptic alpha 2-adrenoreceptors suggests that these alpha-adrenoreceptor sub-types may differ.

Effects of chronic prazosin treatment on the renin-angiotensin-aldosterone system in man.

The effects of chronic prazosin treatment (3 mg/day for three weeks) on plasma renin activity (PRA) and plasma aldosterone (PA) levels were evaluated in 12 hypertensive patients, under conditions of metabolic balance. After three weeks of drug administration no significant change occurred in PRA as well as PA levels, with respect to pretreatment values, both in basal conditions and following 2 hours of ambulation. No change was observed in heart rate, while a fall in both systolic (P less than 0.02) and diastolic (P less than 0.05) blood pressure occurred in supine as well as in deambulation-stimulating condition. A mild increase in body weight (P less than 0.05) and a decrease in serum sodium (P less than 0.05) was induced by prazosin treatment. These findings are in keeping with the pharmacologic properties of prazosin, which is a selective blocker of postsynaptic alpha adrenoreceptors and therefore lowers vascular resistance without reflex sympathetic overactivity. The moderate volume expansion after prazosin does not appear to be aldosterone mediated.

Mini-review. The postsynaptic alpha 2-adrenoreceptor.

The discovery of postsynaptic alpha 2-adrenoreceptors with the drug specificities of presynaptic alpha 2-adrenoreceptors has contributed to a refinement of the classification of alpha-adrenoreceptors. postsynaptic alpha 2-adrenoreceptors have been identified by pharmacological means and with the aid of direct radioligand-receptor binding studies. The evidence for the existence of this class of alpha 2-adrenoreceptors in the brain and in vascular smooth muscle is particularly strong. Central postsynaptic alpha 2-adrenoreceptors play a major part in the hypotensive action of centrally acting antihypertensive drugs such as clonidine and alpha-methyl-DOPA. Vascular smooth muscle cells contain postsynaptic alpha 2-adrenoreceptors which mediate vasoconstriction, like the more classical alpha 1-adrenoreceptors. The simultaneous occurrence of contractile alpha 1- and alpha 2-adrenoreceptors in vascular smooth muscle offers a simple model for the characterization of alpha-adrenoreceptor agonists and antagonists. At present, highly selective agonists of alpha 2-adrenoreceptors have been found. These new compounds may be useful for the classification of other alpha-adrenoreceptor populations. It has been suggested that the vascular postsynaptic alpha 2-adrenoreceptor might be located at extrasynaptic sites. Accordingly, adrenaline released by the adrenal medulla would be the endogenous stimulant. Finally, observations have been made in vivo indicating that a transmembrane influx of calcium ions is necessary for linking the drug-induced activation of these alpha 2-adrenoreceptors to vasoconstriction.

Gonadotropin-releasing hormone surge: possible modulation through postsynaptic alpha-adrenoreceptors and two pharmacologically distinct dopamine receptors.

We have studied modulation of the release of gonadotropin-releasing hormone (GnRH) by central monoaminergic neurons. The test system was the GnRH surge that occurs at 1700 h on day 32 in female rats injected on day 30 with PMS gonadotropin (PMSG). The release of GnRH, measured by RIA of pituitary stalk blood, was correlated with the release of LH, measured by RIA of external jugular venous blood. All blood samples were collected under Althesin (alphaxalone plus alphadolone acetate) anesthesia. The heights of the PMSG-induced surges of GnRH and LH were reduced in animals which had been injected with either αmethyl-p-tyrosine (an inhibitor of tyrosine hydroxylase), or diethyldithiocarbamate or fusaric acid (inhibitors of dopamine-β-hydroxylase). The action of all three inhibitors was reversed by administering dihydroxyphenylserine, and the inhibitory action of diethyldithiocarbamate was potentiated by L-dopa, The height of the PMSG-induced LH surge was reduced by phenoxybenzamine, but was not affected by ph...

Evaluation of the selectivity of alpha-adrenoreceptor blocking drugs for postsynaptic alpha 1- and alpha 2-adrenoreceptors in a simple animal model.

1 The increase of diastolic pressure of pithed, normotensive rats was determined after i.v. administration of the alpha-adrenoreceptor agonists L-phenylephrine and B-HT 933. 2 alpha-Adrenoreceptor antagonists varied widely in their relative inhibitory effects towards either L-phenylephrine- or B-HT 933-induced vasoconstrictor responses. Prazosin displayed the highest affinity for the postsynaptic alpha-adrenoreceptor triggered by L-phenylephrine. The rank order of potency was further: phenotlamine greater than dihydroergotamine greater than clozapine greater than corynanthine greater than azapetine greater than yohimbine greater than piperoxan greater than tolazoline greater than mainserin greater than rauwolscine. On the other hand, the rank order of potency towards B-HT 933 was: dihydroergotamine greater than rauwolscine greater than yohimbine greater than phentolamine greater than piperoxan greater than prazosin greater than tolazoline greater than mainserin greater than corynanthine greater than azapetine greater than clozapine. These data are in general agreement with the classification of alpha 1-(triggered by L-phenylephrine) and alpha 2-(triggered by B-HT 933) adrenoreceptors. Both populations are present postsynaptically in vascular smooth muscle of the pithed rat and are involved in vasoconstriction. 3 The ratio of KB post alpha 2/KB post alpha 1 was calculated as a measure of selectivity for either alpha-adrenoreceptor site. The alpha-adrenoreceptor antagonists used cover a 20,000-fold range of activity ratios. The antagonists most selective for either type were prazosin (alpha 1) and rauwolscine (alpha 2). The selectivity of the alpha-adrenoreceptor antagonists for postsynaptic alpha 1- and alpha 2-adrenoreceptors in the intact circulatory system of the pithed rat is comparable with the reported selectivity of these blocking agents for alpha 1 (postsynaptic)- and alpha 2(presynaptic)-adrenoreceptors in the rabbit isolated pulmonary artery. 4 It is concluded that two distinct types of postsynaptic alpha-adrenoreceptors participate in vasoconstriction in the pithed rat. Apart from the classical alpha 1-adrenoreceptor, vascular smooth muscle of the pithed rat contains postsynaptic alpha 2-adrenoreceptors resembling those previously found mainly presynaptically. The presence of separate classes of postsynaptic alpha 1- and alpha 2-adrenoreceptors in the intact circulatory system of the pithed rat offers the possibility to use this relatively simple animal model as an in vivo test system for the pharmacological characterization of alpha-adrenoreceptors agonists and antagonists.

Potentiation of startle response by d- and l-amphetamine: the possible involvement of pre- and postsynaptic alpha-adrenoreceptors and other transmitter systems in the modulation of a tactile startle response.

The startle response to a metered puff of air was investigated in mice treated with d- and l-amphetamine and a range of drugs acting on central transmitter systems. d-Amphetamine produced a dose-related increase in startle response amplitude (SRA). l-Amphetamine was approximately twice as potent as d-amphetamine while apomorphine was without effect. Noradrenaline and alpha-methyl noradrenaline intracerebroventricularly (ICV), and clonidine IP, all tended to reduce control SRA but potentiated the effect of d-amphetamine. Apomorphine IP had no effect on control SRA or on the effect of d-amphetamine. Phenoxybenzamine, phentolamine and piperoxane reduced d-amphetamine potentiation at doses which had no significant effect on control SRA. Higher doses of phenoxybenzamine and phentolamine reduced control SRA. Yohimbine enhanced the effect of d-amphetamine but reduced control SRA. dl-Propranolol, d-propranolol and sotalol (MJ 1999) did not affect d-amphetamine potentiation. Pimozide was without effect on control SRA but caused a late potentiation of the effect of d-amphetamine. H44/68 and FLA 63 reduced d-amphetamine potentiation. Both 5-hydroxytryptamine (5-HT) ICV and p-chlorophenylalanine potentiated the effect of d-amphetamine. The predominant effect of arecoline, physostigmine and carbachol was also to potentiate d-amphetamine. Atropine enhanced and hyoscine reduced d-amphetamine potentiation. The results are discussed in terms of involvement in the startle response of a noradrenergic synapse possessing receptors resembling peripheral pre- and postsynaptic alpha-adrenoreceptors. Cholinergic and 5-HT systems may also be involved.