Potent Alpha 2-adrenoceptor Antagonist Research Articles

Anti‐angiogenic effects and mechanism of prazosin

Alpha1-adrenoceptors antagonists (doxazosin, terazosin, prazosin) are commonly prescribed for benign prostate hyperplasia and hypertension. Doxazosin and terazosin exhibit anti-angiogenic effects and apoptotic activities against multiple cell types and are potential preventive agents for prostate cancer. Prazosin induces apoptosis in three prostate cancer cell lines. We hypothesized that prazosin, a more potent alpha1-adrenoceptor antagonist with a distinct mechanism, exhibits anti-angiogenic activity. We examined the effect of prazosin on growth and tube formation of human umbilical vascular endothelial cells (HUVECs). We used flow cytometry to assess the effect of prazosin on cell cycle progression and Western blotting to assess its effect on the expression of various apoptotic proteins. Prazosin inhibited the growth of HUVEC with an IC(50) of 6.53 µM and suppressed tube formation in a dose-dependent manner. Unlike prostate cancer cells, prazosin did not arrest cell cycle progression at the G2/M checkpoint. We used rhodamine 123 staining to show that prazosin (20 µM) treatment induced a loss of mitochondrial membrane potential by 12 hr. Prazosin treatment of HUVECs resulted in reduced MCL-1 expression, increased Bad, and Bcl-xL expression, cytochrome c release, and induction of apoptosis via the intrinsic apoptosis pathway. Prazosin induced apoptosis in prostate cancer cells and normal HUVEC cells via different mechanisms. These data suggest that prazosin exhibits anti-angiogenic activity and differentially modulates apoptotic pathways depending on the cell type.

Facilitation of cognitive functions by a specific alpha2-adrenoceptor antagonist, atipamezole.

The present experiments investigated the effects of a specific and potent alpha2-adrenoceptor antagonist, atipamezole (as a stimulator of the noradrenergic system) on cognitive performance in rats. Atipamezole enhanced the acquisition of a linear-arm maze test and also improved the choice accuracy of poorly performing rats in a delayed (20 min) three-choice maze test. Furthermore, atipamezole improved the achievement of a one-trial appetite-maze when injected immediately after teaching, thus having an effect on consolidation. Atipamezole clearly impaired the acquisition of the active avoidance test. The present results indicate that stimulation of noradrenergic system by atipamezole improves the performance of animals in tasks assessing relational learning and memory, possibly affecting attention, short-term memory and the speed of information processing. It has also an effect on a consolidation process unrelated to attentional or motivational mechanisms. In a stressful test. stimulation of noradrenaline release leads to impairment of performance.

The effect of S-(+)-boldine on the alpha 1-adrenoceptor of the guinea-pig aorta.

1. The cardiovascular activity of S-(+)-boldine, an aporphine alkaloid structurally related to papaverine, was determined. The work includes functional studies on guinea-pig isolated aorta contracted with noradrenaline, caffeine, KCl or Ca2+, and on guinea-pig trachea contracted with acetylcholine or histamine. 2. S-(+)-boldine inhibited in a concentration-dependent manner the contractile response evoked by noradrenaline (10 microM) in guinea-pig aorta (IC50 = 1.4 +/- 0.2 microM) while the KCl depolarizing solution (60 mM)- or the Ca2+ (1 mM)-induced contractions were only partially affected by boldine up to 300 microM. In contrast, papaverine relaxed noradrenaline (NA), KCl or Ca2+ induced contractions showing similar IC50 values in all cases. S-(+)-boldine had a greater potency on the contraction elicited by NA whereas papaverine acted in a non-selective manner. 3. S-(+)-boldine was found to be an alpha 1-adrenoceptor blocking agent in guinea-pig aorta as revealed by its competitive antagonism of noradrenaline-induced vasoconstriction (pA2 = 5.64 +/- 0.08), and its potency was compared with that of prazosin (pA2 = 8.56 +/- 0.24), a known potent alpha 1-adrenoceptor antagonist. In contrast, papaverine caused rightward shifts of the NA concentration-response curves with depression of maximal response indicating that it acts as a non-competitive antagonist. 4. Contraction of guinea-pig aorta induced by caffeine (60 mM) in a Ca(2+)-containing Krebs solution was not affected by a 60 min incubation period with different doses of S-(+)-boldine (1-300 microM). Papaverine inhibited partially this caffeine-induced contraction at the maximal dose used (100 microM). 5. Inositol phosphates formation induced by noradrenaline (10 microM) in guinea-pig thoracic aorta was inhibited by S-(+)-boldine (30 microM) but not by papaverine (10 microM). 6. Contractions of guinea-pig trachea caused by acetylcholine (100 microM) or histamine (10 microM) were not modified by S-(+)-boldine (0.1-100 microM). 7. These results provide evidence that S-(+)-boldine, an aporphine alkaloid, has interesting properties as an alpha 1-adrenoceptor blocker in vascular smooth muscle, and acts as a competitive antagonist of the alpha 1-adrenoceptor present in the guinea pig aorta.

Effects of the putative antidepressant, ABT 200, on the clearance of exogenous norepinephrine in rat cerebellum.

ABT 200 [(RR,SS)-3-phenyl-1-[1',2',3',4'-tetrahydro-5',6'-methylenedioxy- 1'-naphthalenyl-methyl]-pyrrolidine methanesulfonate] is a potent alpha 2-adrenoceptor antagonist (Ki = 1.2 nM) with modest norepinephrine uptake-blocking activity (IC50 = 841 nM) that is currently under clinical evaluation as an antidepressant. The effects of ABT 200, nomifensine (an inhibitor of catecholamine uptake), and rauwolscine (a selective alpha 2-adrenoceptor antagonist) on the clearance of exogenous norepinephrine in the cerebellum of urethane-anesthetized rats was investigated using a vivo electrochemistry. Chronoamperometric recordings were continuously made at 5 Hz using Nafion-coated, single carbon fiber electrodes. When a calibrated amount of norepinephrine was pressure-ejected at 5-min intervals from a micropipette adjacent (290-330 microM) to the electrode, transient and reproducible norepinephrine signals were detected. In response to systemic ABT 200 (30 mg/kg i.p.) or nomifensine (30 mg/kg i.p.), the signals increased in both amplitude and time course, indicating significant inhibition of the norepinephrine transporter. A lower dose (15 mg/kg i.p.) of either ABT 200 or nomifensine had no effect in this paradigm. Local application of ABT 200 (400 microM) or nomifensine (400 microM) prior to pressure-ejection of norepinephrine also significantly increased the amplitude and time course of the norepinephrine signals. In contrast, systemic administration of rauwolscine (30 mg/kg i.p.) or vehicle solution, and local application of vehicle solution, had no effect on the norepinephrine signals. These data indicate that at the higher dose evaluated, both ABT 200 and nomifensine inhibit cerebellar norepinephrine uptake in vivo.

Evidence for activation of both adrenergic and cholinergic nervous pathways by yohimbine, an alpha 2-adrenoceptor antagonist.

Adrenoceptors are involved in the control of the activity of the autonomic nervous system and especially the sympathetic nervous system. Activation of alpha 2-adrenoceptors decreases sympathetic tone whereas their blockade has an opposite effect. However, previous investigations have shown that yohimbine (a potent alpha 2-adrenoceptor antagonist) increases salivary secretion through activation of cholinergic pathways. The aim of the present experiment was to investigate the involvement of both the sympathetic and the parasympathetic system in several pharmacological effects of yohimbine. For this purpose, salivary secretion and various endocrino-metabolic parameters (noradrenaline and insulin secretions, lipomobilization) were evaluated in conscious fasting dogs before and after blockade of either the sympathetic (with the beta-adrenoceptor antagonist agent nadolol) or the parasympathetic (with the anticholinergic agent atropine) systems. Yohimbine alone (0.4 mg.kg-1, i.v.) increased within 5-15 minutes, plasma noradrenaline (600%), insulin levels (300%), free-fatty acids (79%) and salivary secretion (143%). Atropine (0.2 mg.kg-1, i.v.) suppressed yohimbine-induced salivary secretion (90%) but did not significantly modify the yohimbine induced changes in noradrenaline (312%), insulin (277%) and free-fatty acids (102%) plasma levels. Administration of nadolol (1 mg.kg-1, i.v.) did not change the magnitude of the increase in both noradrenaline plasma levels (550%) and salivary secretion (300%) induced by yohimbine. However, nadolol totally blunted the increase in insulin (15%) and free-fatty acids (4%) plasma levels. These results show that yohimbine-induced increase in salivary secretion is a cholinergic effect whereas the increase in insulin and free fatty acids can be explained by an increase in sympathetic tone.(ABSTRACT TRUNCATED AT 250 WORDS)

INFLUENCE OF α1‐ADRENOCEPTOR ANTAGONISM OF KETANSERIN ON THE NATURE OF ITS 5‐HT2 RECEPTOR ANTAGONISM

1. In order to investigate alpha 1-adrenoceptor interactions with 5-HT2 receptors, the effect of ketanserin (which antagonizes both types of the above receptors) on responses to 5-hydroxytryptamine (5-HT) and phenylephrine (PE) was measured in isolated perfused rat tail arteries. 2. Ketanserin was found to be a competitive antagonist at 5-HT2 receptors (pA2 = 9.19) and alpha 1-adrenoceptors (pA2 = 7.52). 3. Ritanserin, an analogue of ketanserin with very weak alpha 1-adrenoceptor antagonist activity, was found to be a potent non-competitive 5-HT2 receptor antagonist. 4. In the presence of the potent alpha 1-adrenoceptor antagonist prazosin, ketanserin was a non-competitive 5-HT2 receptor antagonist. 5. Thus, for ketanserin to exhibit competitive 5-HT2 receptor antagonism, its coexisting alpha 1-adrenoceptor antagonist property appears mandatory.

In vivo pharmacological profile of SL 84.0418, a new selective, peripherally active alpha 2-adrenoceptor antagonist.

SL 84.0418 is a novel pyrrolo-indole derivative with potent and selective alpha 2-adrenoceptor antagonist activity in vitro and anti-hyperglycemic properties in vivo. In the present study we demonstrated that SL 84.0418 and its active (+) enantiomer, SL 86.0715, show a high degree of selectivity for alpha 2-adrenoceptors in vivo, preferentially blocking alpha 2-adrenoceptors in the periphery. While having no effects on basal blood pressure and heart rate, p.o. (3 and 10 mg/kg) or i.v. (0.3 mg/kg) administered SL 84.0418 or SL 86.0715 antagonized the hypertensive responses mediated by postsynaptic vascular alpha 2-adrenoceptors after the administration of UK 14304 or norepinephrine to pithed rats. The (-) enantiomer of SL 84.0418, SL 86.0714, was devoid of alpha 2-adrenoceptor antagonist properties in vivo, while the (+) enantiomer of SL 84.0418, SL 86.0715, showed alpha 2-adrenoceptor antagonist activity similar to that of the racemate. SL 84.0418 (3 mg/kg p.o.) did not modify the centrally mediated hypotensive and bradycardic effects of i.c.v. administered clonidine. Furthermore, in the mouse, SL 84.0418 potently antagonized the hyperglycemic responses to epinephrine or UK 14304, which are mediated by peripheral alpha 2-adrenoceptors, but failed (in doses up to 30 mg/kg i.p.) to antagonize the clonidine-induced hypolocomotion, which is mediated by central alpha 2-adrenoceptors. These results suggest that SL 84.0418 preferentially antagonizes peripheral alpha 2-adrenoceptors. SL 84.0418 administered to pithed rats (3 mg/kg p.o. or 0.3 mg/kg i.v.) did not modify the vasoconstriction induced by cirazoline (effect mediated by alpha 1-adrenoceptors) nor the tachycardia induced by norepinephrine (effect mediated by beta-adrenoceptors).(ABSTRACT TRUNCATED AT 250 WORDS)

Vascular Responsiveness of Rabbit Common Carotid, Renal and Femoral Arteries to α-Adrenoceptor Agonists

The stainless steel cannula inserting method was used to observe vascular effects of alpha-adrenoceptor agonists, phenylephrine (PE), methoxamine (ME), clonidine (CL) and xylazine (XY), on the isolated, perfused rabbit common carotid, renal and femoral arteries. PE and ME induced a dose-dependent vasoconstriction that was readily suppressed by treatment with bunazosin, an alpha 1-adrenoceptor blocker. CL induced a constriction only in common carotid arteries, and this was readily suppressed by bunazosin. In preparations preconstricted by phenylephrine, CL and XY dose-dependently induced vasodilations in the 3 types of arteries, and these vasodilations were not modified by a potent alpha 2-adrenoceptor antagonist, midaglizole. In preparations preconstricted by prostaglandin F2 alpha, CL and and XY did not produce any significant vasodilation, but CL induced a vasoconstriction in common carotid arteries that was completely blocked by bunazosin. Thus, it is concluded that: 1) alpha 1-adrenoceptors are functionally predominant in rabbit peripheral arteries, 2) the alpha 2-adrenoceptor agonist-induced vasodilation may be due to an antagonistic action towards alpha 1-mediated constrictions, and 3) clonidine has alpha 1-adrenoceptor stimulating properties in rabbit common carotid artery but not in renal and femoral arteries.

Presynaptic alpha 2-adrenoceptor-mediated modulation of norepinephrine release from vascular adrenergic neurons in reduced renal mass salt hypertensive rats.

The present study was designed to investigate the presynaptic alpha 2-adrenoceptor function to inhibit norepinephrine (NE) release in blood vessels of reduced renal mass salt hypertensive rats (Na-loaded HT). Isolated perfused mesenteric vasculatures were prepared from Na-loaded HT and normotensive control rats (NT-control), and the NE release and vascular responsiveness were examined. Periarterial nerve stimulation caused a significantly greater release of NE and pressor responses in Na-loaded HT than in NT-control. Yohimbine, a potent alpha 2-adrenoceptor antagonist, demonstrated the facilitatory effects on NE release during nerve stimulation. The effects were significantly attenuated in Na-loaded HT compared with NT-control. These results demonstrate that vascular sympathetic nervous activity might be enhanced in Na-loaded HT. Furthermore, the increased NE release from vascular adrenergic neurons in Na-loaded HT could partially depend on impaired presynaptic alpha 2-adrenoceptor-mediated modulation, which might contribute to the pathogenesis and maintenance of this form of salt-dependent hypertension.

INVESTIGATIONS INTO INTERACTIONS BETWEEN DOXAZOSIN AND ENALAPRILAT AT α1‐ADRENOCEPTORS IN ANAESTHETIZED RATS

1. In anaesthetized intact Sprague-Dawley rats, the angiotensin-converting enzyme inhibitor enalaprilat, 1 mg/kg, had no significant effect on the pressor responses to the alpha 1-adrenoceptor agonist phenylephrine (PE). Doxazosin 1 mg kg was found to be a potent alpha 1-adrenoceptor antagonist. 2. The combination of enalaprilat 1 mg/kg plus doxazosin 1 mg/kg was 3.3-fold more potent in antagonizing alpha 1-adrenoceptors than doxazosin 1 mg/kg alone. 3. After treatment of rats with deoxycorticosterone acetate (DOCA) twice weekly for 5 weeks, the alpha 1-adrenoceptor antagonist action of doxazosin in anaesthetized rats was not potentiated by enalaprilat 1 mg/kg. 4. Since DOCA treatment suppresses renin activity, these findings strongly support the hypothesis that angiotensin II can modulate the functional activity of alpha 1-adrenoceptor in vascular smooth muscle.

The pharmacology of fluparoxan: a selective α2‐adrenoceptor antagonist

1. This paper describes the pharmacology of the novel alpha 2-adrenoceptor antagonist fluparoxan (GR 50360) which is currently being studied clinically as a potential anti-depressant. Idazoxan and yohimbine were included in many studies for comparison. 2. In the rat isolated, field-stimulated vas deferens and the guinea-pig isolated, field-stimulated ileum preparations, fluparoxan was a reversible competitive antagonist of the inhibitory responses to the alpha 2-adrenoceptor agonist UK-14304 with pKB values of 7.87 and 7.89 respectively. In the rat isolated anococcygeus muscle, fluparoxan was a much weaker competitive antagonist of the contractile response to the alpha 1-adrenoceptor agonist phenylephrine with a pKB of 4.45 giving an alpha 2: alpha 1-adrenoceptor selectivity ratio of greater than 2500. 3. In the conscious mouse, fluparoxan (0.2-3.0 mg kg-1) was effective by the oral route and of similar potency to idazoxan in preventing clonidine-induced hypothermia and antinociception. In the rat, UK-14304-induced hypothermia (ED50 = 1.4 mg kg-1, p.o. or 0.5 mg kg-1, i.v.) and rotarod impairment (ED50 = 1.1 mg kg-1 p.o. or 1.3 mg kg-1, i.v.) were antagonized by fluparoxan. Fluparoxan, 0.67-6 mg kg-1, p.o., also prevented UK-14304-induced sedation and bradycardia in the dog. 4. In specificity studies fluparoxan had low or no affinity for a wide range of neurotransmitter receptor sites at concentrations up to at least 1 x 10(-5) M. It displayed weak affinity for 5-HT1A (pIC50 = 5.9) and 5-HT1B (pKi = 5.5) binding sites in rat brain. 5. We conclude that fluparoxan is a highly selective and potent alpha 2-adrenoceptor antagonist. The density of rat brain [3H]-dihydroalprenolol binding sites was reduced by 26% when fluparoxan was administered chronically for 6 days at a dose of 12 mg kg- 1 orally twice daily. The down-regulation of beta-adrenoceptors by fluparoxan is consistent with its antidepressant potential.

Identification of human platelet a2‐adrenoceptors with a new antagonist [3H]‐RX821002, a 2‐methoxy derivative of idazoxan

1. The binding of a new alpha 2-adrenoceptor antagonist, [3H]-RX821002 (2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline), was investigated in human platelet membranes and compared with [3H]-yohimbine binding parameters. 2. Analysis of kinetic data revealed association and dissociation time courses consistent with a simple biomolecular reaction. Saturation isotherms showed that [3H]-RX821002 labelled a higher total number of alpha 2-binding sites (224 +/- 31 vs 168 +/- 24 fmol mg-1 protein) than [3H]-yohimbine and with higher affinity (Kd: 0.92 +/- 0.06 vs 1.51 +/- 0.08 nM). Moreover [3H]-RX821002 exhibited a lower percentage of nonspecific binding 3. The difference in total binding is due to a better labelling of the alpha 2-adrenoceptors in the low affinity state by [3H]-RX821002 since the labelled receptors number in high affinity state was identical with the two radioligands. 4. [3H]-RX821002 binding displayed a specificity similar to that obtained with [3H]-yohimbine. The potency of various compounds acting on adrenoceptors was: yohimbine greater than oxymetazoline greater than UK14304 greater than (-)-adrenaline greater than prazosin greater than or equal to (+)-adrenaline greater than isoprenaline. This order of potency is classical for an alpha 2A-adrenoceptor. 5. RX821002 is a more potent alpha 2-adrenoceptor antagonist than yohimbine on adrenaline-induced platelet aggregation. 6. These results indicate that [3H]-RX821002 is a suitable ligand for the identification of human platelet alpha 2-adrenoceptors.

SL 84.0418: a new, potent and selective alpha-2 adrenoceptor antagonist with peripheral activity

SL 84.0418: a new, potent and selective alpha-2 adrenoceptor antagonist with peripheral activity

The pharmacology of carvedilol

Carvedilol is a potent antihypertensive agent with a dual mechanism of action. At relatively low concentrations it is a competitive beta-adrenoceptor antagonist and a vasodilator, whereas at higher concentrations it is also a calcium channel antagonist. The antihypertensive activity of carvedilol is characterized by a decrease in peripheral vascular resistance, resulting from the vasodilator activity of the compound, with no reflex tachycardia, as a result of beta-adrenoceptor blockade. The antihypertensive activity of carvedilol is associated with an apparent "renal sparing" effect in that the reduction in mean arterial blood pressure does not compromise renal blood flow or urinary sodium excretion. Studies on the mechanism of action of carvedilol indicate that the compound is a potent competitive antagonist of beta 1- and beta 2-adrenoceptors with a dissociation constant (KB) of 0.9 nM at both beta-adrenoceptor subtypes. Carvedilol is also a potent alpha 1-adrenoceptor antagonist (KB = 11 nM), which accounts for most, if not all, of the vasodilating response produced by the compound. At concentrations above 1 microM, carvedilol is a calcium channel antagonist. This activity can be demonstrated in vivo at doses that represent the higher end of the antihypertensive dose-response curve. Although the calcium-channel blocking activity of carvedilol may not contribute to the antihypertensive activity of the compound, it may play a prominent role in certain peripheral vascular beds, such as the cutaneous circulation, where marked increases in blood flow are observed. The data indicate that carvedilol is an antihypertensive agent that is both a beta-adrenoceptor antagonist and a vasodilator.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological Analysis of Vasodilator Responses to Alpha2-Adrenoceptor Agonists in Isolated Rat Common Carotid Arteries

Using the cannula inserting method, vasodilator responses to alpha2-adrenoceptor agonists (clonidine, guanabenz, DJ7141 and xylazine) were investigated in isolated and perfused rat common carotid arteries. Alpha2-adrenoceptor agonists dose-dependently induced a vasodilation in preparations preconstricted by noradrenaline. The potencies were in the order of clonidine>guanabenz>DJ-7141≥xylazine. Removal of the endothelium inhibited ACh-induced vasodilation, but not the alpha2-agonist-induced dilation. Atropine treatment inhibited ACh-induced vasodilation, but not the alpha2-agonist-induced dilation. Alpha2-agonist-induced dilations were not modified by beta-blockade, which significantly suppressed isoprenaline-induced vasodilations. The potent alpha2-adrenoceptor antagonist DG5128 did not influence the alpha2-agonist-induced vasodilation. In preparations preconstricted by PGF2α, clonidine and xylazine never induced a vasodilation, and clonidine frequently induced vasoconstrictions that were completely blocked by bunazosin. It is concluded that alpha2-adrenoceptor agonist-induced vasodilation is independent from the existence of the endothelium, and that it is not related to vascular beta- and alpha2-adrenoceptors and muscarinic receptors, suggesting that the alpha2-adrenoceptor agonist-induced vasodilation is due to an antagonistic activity towards the vascular alpha1-adrenoceptors.

AN IN VITRO STUDY OF INTERACTIONS BETWEEN DOXAZOSIN AND ENALAPRILAT AT VASCULAR α1‐ADRENOCEPTORS

1. Isolated perfused male Sprague-Dawley rat tail artery segments were used to investigate interactions between the alpha-1-adrenoceptor antagonist, doxazosin, and the angiotensin converting enzyme (ACE) inhibitor, enalaprilat, using phenylephrine (PE) as the alpha 1-adrenoceptor agonist. 2. In concentrations of up to 10(-5) mol/L, enalaprilat had no effect on arterial responses to PE. 3. Doxazosin produced a concentration-dependent competitive alpha 1-adrenoceptor antagonism, yielding a mean pA2 value of 8.72. 4. In the continuous presence of 10(-6) mol/L enalaprilat, doxazosin with a pA2 value of 9.10 was a 2.4-fold more potent alpha 1-adrenoceptor antagonist than in the absence of enalaprilat. 5. These results are interpreted to indicate that endogenously produced angiotensin II can modulate the activity of alpha 1-adrenoceptors in vascular smooth muscle.

Effect of CH-38083, a selective antagonist of alpha 2-adrenoceptors, on renal sympathetic function

The effects of 7,8-(methylenedioxi)-14-α-hydroxyalloberbane HCl (CH-38083), a structurally new, selective and potent alpha 2-adrenoceptor antagonist, and of idazoxan, were studied on both the spontaneous activity of the postganglionic sympathetic renal nerve and on the clonidine- or xylazineinduced inhibitory action in anaesthetized cats. The drug CH-38083 (30–200 μg/kg, i.v.) caused a sustained increase of the sympathetic activity and blood pressure. Larger doses of idazoxan (200–500 μg/kg, i.v.) were needed to induce similar effects. Both antagonists were effective in antagonizing the sympathoinhibitory effect of clonidine or xylazine. The excitatory response to selective alpha 2-adrenoceptor antagonists suggests that the sympathetic output undergoes tonic inhibition due to a permanent alpha 2-adrenoceptor stimulation.

Attenuation of ethanol intoxication by alpha-2 adrenoceptor antagonists

The interaction of a highly potent and selective alpha-2 adrenoceptor antagonist, atipamezole with ethanol was investigated in tests assessing a number of ethanol's behavioral effects. Atipamezole antagonized ethanol's effects on directed exploration in a holeboard test, reduced observer-rated intoxication and also reduced the duration of loss of righting reflex caused by ethanol. Similar effects were produced by another alpha-2 adrenoceptor antagonist idazoxan. The magnitude of the effects was comparable to that produced in the same animal models by the imidazodiazepine Ro 15-4513, which antagonizes ethanol by an action at central benzodiazepine receptors. Whereas Ro 15-4513 possesses marked behavioral effects on its own, atipamezole is comparatively inactive in all paradigms so far tested. The data suggest that alpha-2 adrenoceptors can play an important role in modulating the intoxicating effects of ethanol.

Possible mechanism of acetaldehyde-induced noradrenaline release from sympathetic nerve terminals in isolated blood vessels.

1. Vasoconstrictor responses to acetaldehyde were investigated in isolated and perfused canine intermediate auricular (ear) arteries. 2. Single injections of small doses of acetaldehyde (1-3 mumol) induced vasoconstriction in a dose-related manner and showed no tachyphylaxis. On the other hand, large doses of acetaldehyde (10-30 mumol) frequently caused tachyphylaxis when injected at 10 min intervals. 3. After tyramine treatment, constrictions induced by a large dose of acetaldehyde were consistently restored temporarily. 4. The acetaldehyde-induced vasoconstriction was inhibited by bunazosin, a potent alpha 1-adrenoceptor antagonist. 5. A small dose of imipramine blocked tyramine-induced vasoconstriction, but had no significant influence on noradrenaline (NA)-induced constrictions, and caused slight potentiation of acetaldehyde-induced constrictions. 6. Hydrocortisone treatment did not modify tyramine-induced vasoconstrictions and slightly suppressed NA- and acetaldehyde-induced constrictions but not significantly. 7. It is suggested that acetaldehyde causes a release of NA from a NA store of the sympathetic nerve terminals which is different from the tyramine-sensitive NA store, and that the acetaldehyde-sensitive NA store may be readily filled up with NA from the tyramine-sensitive store.

Pharmacological Studies on the Selectivity of HV-723, a New Alpha-1 Adrenoceptor Antagonist

The pharmacological profile of a new aipha-1 adrenoceptor antagonist, α-ethyl - 3,4,5 - trimethoxy - α - (3 - ((2 - (2 - methoxyphenoxy) ethyl) amino)propyl) benzene-acetonitrile fumarate (HV-723), was studied in vitro. In dog mesenteric arteries, HV-723, prazosin and yohimbine competitively inhibited noradrenaline-induced contraction: the pA2 value of HV-723 (9.37) was apparently larger than that of prazosin (8.22) and yohimbine (7.18). However, HV-723 showed no or only a slight inhibition on the contractile responses to 5-HT, KCl and prostaglandin F2α HV-723 also showed potent alpha-1 adrenoceptor antagonist activity in the dog mesenteric and saphenous veins. However, HV-723 showed little antagonist activity on the pre- and postsynaptic alpha-2 adrenoceptors, beta-1 and beta-2 adrenoceptors and muscarinic receptors. HV-723 also inhibited the sympathetic contraction induced by electrical transmural stimulation in the dog mesenteric arteries, and the inhibition of HV-723 was about 10 times more potent than that of prazosin. However, 3H-noradrenaline release evoked by electrical stimulation was not influenced by HV-723. These results clearly show that HV-723 is a potent and selective alpha-1 adrenoceptor antagonist.