Α-adrenoceptor Blocking Activity Research Articles

The alpha-adrenoceptor blocking effect of indoramin on human isolated smooth muscle.

Abstract The pharmacological effects of indoramin, a new hypotensive drug, were studied on human isolated smooth muscle preparations. Indoramin was shown to have a potent α-adrenoceptor blocking activity on specimens of colon, ileum and vein. The blockade fulfilled the established criteria for competitive antagonism of noradrenaline. The mean pA2 values were 6ṁ57 for the circular muscle of the colon, 6ṁ91 for longitudinal muscle of the colon, 6ṁ64 for longitudinal muscle of the ileum and 6ṁ58 for saphenous vein. Indoramin (10−3m) did not reduce acetylcholine-induced contractions of the longitudinal muscle of the colon and ileum.

Anti-Hypertension Effect of Vanylidilol: A Phenylaldehyde α/β-Adrenoceptor Blocker with Endothelium-Dependent and K+ Channels Opening-Associated Vasorelaxant Activities

The antihypertensive effect of vanylidilol, a new α/β-adrenoceptor antagonist with endothelium-dependent and K⁺-channel-opening activities, was investigated in normotensive and hypertensive Wistar rats. Vanylidilol competitively antagonized (–)isoproterenol-induced positive chronotropic effects, inotropic effects, and tracheal relaxation effects in isolated rat right atria, left atria, and guinea pig tracheal strips in a concentration-dependent manner. Vanylidilol’s apparent pA₂ values were 6.36 ± 0.08 (right atria), 6.41 ± 0.07 (left atria), and 6.31 ± 0.06 (trachea). Vanylidilol also produced a competitive antagonism of phenylephrine-induced contraction in the isolated rat aorta with pA₂ values of 6.79 ± 0.18. In the radioligand binding assay, vanylidilol inhibited [³H]CGP-12177 binding to rat ventricle and lung tissues and [³H]prazosin binding to brain membranes with Ki values of 535.17, 2,066.69, and 431.11, respectively. In isolated rat thoracic aorta, vanylidilol’s vasorelaxant effects on phenylephrine (10 µmol/l)-induced contractions were attenuated by removing endothelium and by the presence of L-N^G-nitro arginine methyl ester (L-NAME; 100 µmol/l), methylene blue (10 µmol/l), 1H-[1,2,4]oxadiazolol[4,3,-a] quinoxalin-1-one (ODQ; 10 µmol/l), tetraethylammonium (10 mmol/l), glibenclamide (1 µmol/l), apamin (1 µmol/l), and charybdotoxin (0.1 µmol/l). In addition, vanylidilol, in an equally antagonistic activity, inhibited phenylephrine-induced phasic and tonic contractions. Intravenous vanylidilol further reduced mean blood pressure in pentobarbital-anesthetized normotensive Wistar rats in a dose-dependent manner. The oral administration of vanylidilol to conscious spontaneously hypertensive rats had a long-lasting hypotensive effect on the heart rate and decreased it in a dose-dependent manner. Furthermore, vanylidilol’s vasodilator effect can be attributed in part to the release of NO or NO-related substance from vascular endothelium, while the endothelium-independent mechanism involved in vanylidilol’s relaxation is probably linked to the activation of the K⁺ channels and the α-adrenoceptor blocking activity in these vessels.

A new aspect of view in synthesizing new type β-adrenoceptor blockers with ancillary antioxidant activities

A series of vanilloid-type β-adrenoceptor blockers derived from antioxidant traditional Chinese herbal medicines were synthesized and tested for their antioxidant and adrenoceptor antagonistic activities. They all possessed significant β-adrenoceptor blocking activities under in vitro experiments and radioligand binding assays. In addition, some compounds were further examined in in vivo tests and produced antagonist effects matching that of propranolol and labetalol by measurements of antagonism toward (−)isoproterenol-induced tachycardia and (−)phenylephrine-induced pressor responses in anesthetized rats. Furthermore, all of the compounds had antioxidant effects inherited from their original structures. In conclusion, compound 11 had the most potent β-adrenoceptors blocking activity, 12 and 13 possessed high cardioselectivity, whereas 14, 15 and 16 possessed additional α-adrenoceptor blocking activity and 15 is the most effective antioxidant of all. The antioxidant activity may be due to their α and β unsaturated side chain at position 1 and ortho-substituted methoxy moiety on 4-phenoxyethylamine.

Is α-adrenoceptor blockade responsible for atropine flush?

Toxic amounts of atropine usually, and therapeutic doses occasionally, dilate cutaneous blood vessels, especially those in the blush area (atropine flush). However, the mechanism of this anomalous vascular response is unknown. We, therefore, investigated this action of atropine not only in functional but also in binding studies with isolated rat aorta and brain, respectively. Endothelium-denuded rat thoracic aortic rings were contracted with norepinephrine, U46619 (9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F 2α, thromboxane A 2 receptor agonist) and KCl, and the relaxation in response to atropine was recorded. The norepinephrine-, but not the U46619- or KCl-mediated contraction was relaxed by atropine. Atropine caused a rightward parallel shift of the phenylephrine concentration-contraction curve with a pA 2 value of 6.57 (slope 0.58), but did not affect the concentration-contraction curve for U46619. In rat cerebral cortex homogenates, atropine displaced [ 3H]prazosin binding with a K i value of 1.21 μM, while phentolamine and clonidine displaced [ 3H]prazosin with K i values of 3.33 nM and 0.19 μM, respectively. These results suggest that even though atropine has low affinity for the α-adrenoceptor, it possesses characteristics similar to those of a competitive ligand for the α-adrenoceptor. Thus, atropine, especially at high concentrations, has direct α-adrenoceptor blocking activity, which may account, at least in part, for atropine flush.

The pharmacology of vesamicol: An inhibitor of the vesicular acetylcholine transporter

1. 1. Vesamicol (2-[4-phenylpiperidino] cyclohexanol) inhibits the transport of acetylcholine into synaptic vesicles in cholinergic nerve terminals. 2. 2. Recent pharmacological studies of the effects of vesamicol on skeletal neuromuscular transmission have revealed a pattern of activity for the compound consistent with the neurochemical observation of the mechanism of action of the compound. 3. 3. Pharmacological manipulation of vesicular acetylcholine transport has been used to investigate the recycling and mobilization of synaptic vesicles within cholinergic nerve terminals. 4. 4. In addition to its effects on vesicular acetylcholine transport, vesamicol also possesses some sodium channel and α-adrenoceptor blocking activity. 5. 5. Vesamicol clearly represents a unique tool for investigating presynaptic mechanisms in cholinergic nerve terminals.

α-Adrenoceptor blocking properties of vesamicol

The side-effects of vesamicol, an inhibitor of acetylcholine storage, on α 1- and α 2-adrenoceptors have been studied in the isolated rat vas deferens. Antagonism of α 1-adrenoceptors was determined from the ability of vesamicol to reduce contractions elicited by exogenous noradrenaline. Antagonism of α 2-adrenoceptors was determined from the ability of vesamicol to block the inhibitory effects of the α 2-adrenoceptor agonist clonidine on electrically evoked twitches. In the absence of noradrenaline uptake block, (−) vesamicol, the isomer active at cholinergic synapses, produced a leftward shift of the noradrenaline concentration-effect curve. This effect was abolished by desipramine suggesting that it is due to an ability of (−)-vesamicol to block uptake 1. In the presence of noradrenaline uptake blockers, (−)-vesamicol produced a competitive, non-selective block of both α 2- and α 2adrenoceptors with a K d of around 40 μM (pA 2 4.4). ( + )-Vesamicol, the isomer that has no activity at cholinergic synapses, was equipotent with the (−)-isomer for blocking α 2 adrenoceptors. In addition to its α-adrenoceptor antagonist activity, (−)-vesamicol augmented the maximum response of the tissue to exogenous and endogenous noradrenaline. This study was unable to determine the exact nature of this effect. We suggest that the α-adrenoceptor blocking activity of vesamicol is a function of the phenylpiperidino moiety of the molecule.

P-597 - α-Adrenoceptor blocking activity of enantiomers of dobutamine in the rat ventricular myocardium.

P-597 - α-Adrenoceptor blocking activity of enantiomers of dobutamine in the rat ventricular myocardium.

Effects of benzylic hydroxyl substitution on the α-adrenoceptor blocking activity of tolazoline

The R(−)- and S(+)-enantiomers of α-hydroxytolazoline, the benzylic hydroxy-substiuted derivative of the α-adrenoceptor antagonist, tolazoline, were evaluated at α 1- and α 2-adrenoceptors in canine saphenous vein. Benzylic hydroxyl substitution of tolazoline in either the R(−) or S(+) configuration significantly decreased affinity at both α 1- and α 2-adrenoceptors. Differences in affinity between the R(−)- and S(+)-enantiomers were small, which is characteristic of imidazolines, but in marked contrast to phenethylamines where enantiomeric differences are large. The rank order of affinities at α 1- and α 2-adrenoceptors is tolazoline > S(+)- α-hydroxytolazoline = R(−)- α-hydroxytolazoline, which is different from that order predicted by the Easson-Stedman hypothesis (i.e., R(−) > S(+) = desoxy). The findings support our contention that phenethylamines and imidazolines interact differently with α-adrenoceptors.

B-HT 958 — An antagonist at α2-adrenoceptors and an agonist at dopamine autoreceptors in the brain

B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo[5,4-d]azepine), a compound chemically related to clonidine-like drugs of the azepine type, was described previously as a mixed agonist-antagonist at peripheral α2-adrenoceptor sites. In the present experiments the actions B-HT 958 on brain noradrenergic and dopaminergic mechanisms were examined using behavioural, pharmacological and biochemical methods. (i) In the dog, intracisternally injected B-HT 958 (300 μg/kg) abolished the reflex bradycardia facilitated by the α2-agonist B-HT 920 (10 μg/kg i.ci.). (ii) In the whole mouse brain as well as in the rat hypothalamus and neocortex, but not in the hippocampus, amaygdala and nucleus accumbens B-HT 958 (5–20 mg/kg s.c.) accelerated the α-methyltyrosine (α-MT)-induced disappearance of noradrenaline. (iii) B-HT 958 decreased in a dose-dependent manner the exploratory activity of mice (ED50: 6.3 mg/kg s.c.) and slightly enhanced the motor activity of reserpine-treated mice only in high doses. (iv) B-HT 958 (20 mg/kg s.c.) lowered the level of homovanillic acid in the striatum and nucleus accumbens and dose dependently (1–20 mg/kg) slowed the α-MT-induced disappearance of dopamine in these 2 brain regions of the rat as well as in the whole mouse brain. (v) The γ-butyrolactone-induced increase in DOPA levels was effectively antagonized by B-HT 958 (1 and 5 mg/kg s.c.) in the rat striatum and nucleus accumbens. These behavioural, pharmacological and biochemical observations indicate that B-HT 958 possesses central α-adrenoceptor blocking activity and exerts a strong agonistic effect on brain dopamine autoreceptors.

P-196) - α-Adrenoceptor blocking activity of histamine H2-receptor antagonists, ranitidine, cimetidine and metiamide, in isolated guinea pig heart

P-196) - α-Adrenoceptor blocking activity of histamine H2-receptor antagonists, ranitidine, cimetidine and metiamide, in isolated guinea pig heart

On the assessment of the potency of antagonists using the rat isolated anococcygeus muscle

The conditions required for assessing the potencies of antagonists of muscarinic and at α-adrenoceptors have been examined using contractility studies with the rat anococcygeus muscle. Physostigmine (5 × 10 −7 M) and atropine (10 −8 −10 −7 M) had no effect on the responses to noradrenaline. The responses to acetylcholine were potentiated by physostigmine and inhibited by atropine. Physostigmine and atropine increased the slopes of the concentration-response curves to acetylcholine. In the presence of physostigmine, atropine at 10 −8M inhibited the responses without altering the slopes of the concentration-response curves to acetylcholine. The responses to acetylcholine were potentiated by cocaine (greater than 10 −6M) and inhibited by phentolamine (10 −6M). Cocaine (10 −6-5 × 10 −6M) potentiated and phentolamine (10 −7−10 −6M) inhibited the responses to noradrenaline. The slopes of the concentration-response curves to noradrenaline were increased by cocaine at 5 × 10 −6M, but not at 10 −6−2 × 10 −6M, and by phentolamine. In the presence of cocaine (10 −6M), phentolamine (10 −7−5 × 10 −7M) inhibited the responses and increased the slopes of the concentration-response curves to noradrenaline. These results illustrate that, in the rat anococcygeus muscle, it is possible to assess the potency of muscarinic antagonists with the method described. However, in this tissue, α-adrenoceptor blocking activity cannot be determined with noradrenaline as the agonist in the presence of cocaine.

Actions of serotonin antagonists on dog coronary artery

Serotonin released from platelets may initiate coronary vasopasm in patients with variant angina. If this hypothesis is correct, serotonin antagonists without constrictor activity may be useful in this form of angina. We have investigated drugs classified as serotonin antagonists on dog circumflex coronary artery ring segments in vitro. Ergotamine, dihydroergotamine, bromocriptine, lisuride, ergometrine, ketanserin, trazodone, cyproheptadine and pizotifen caused non-competitive antagonism of serotonin concentration-response curves. In addition, ketanserin, trazodone, bromocriptine and pizotifen inhibited noradrenaline responses in concentrations similar to those required for serotonin antagonism. All drugs with the exception of ketanserin, cyproheptadine and pizotifen showed some degree of intrinsic constrictor activity. Methysergide antagonized responses to serotonin competitively but also constricted the coronary artery. The lack of a silent competitive serotonin antagonist precludes a definite characterization of coronary serotonin receptors at this time. However, the profile of activity observed for the antagonist drugs in the coronary artery differs from that seen in other vascular tissues. Of the drugs tested, ketanserin may be the most useful in variant angina since it is a potent 5HT antagonist, lacks agonist activity and has α-adrenoceptor blocking activity.

Evaluation of peripheral dopamine receptor and α-adrenoceptor blocking activity of sulpiride

The effect of sulpiride, a dopamine receptor antagonist, on peripheral α-adrenoceptors and dopamine receptors was determined. Positive chronotropic responses to cardioaccelerator nerve stimulation in pentobarbital-anesthetized dogs were potentiated by 1.0 and 2.0 mg/kg but not by 0.5 mg/kg intravenous sulpiride. This effect persisted after neuronal uptake blockade with desipramine, but was prevented by α 2-adrenoceptor blockade with yohimbine. Positive chronotropic effects of intravenous norepinephrine were unchanged by sulpiride, suggesting that sympathetic nerve function was facilitated via a presynaptic mechanism. Since yohimbine prevented the facilitatory action of sulpiride, an analysis of the ability of sulpiride to antagonize α-adrenoceptors was made. The reduction in stimulus-induced tachycardia caused by the α 2-adrenoceptor agonist tramazoline was significantly antagonized by sulpiride. Furthermore, while sulpiride did not antagonize the pressor effect of the α 1-adrenoceptor agonist phenylephrine, it significantly attenuated the increases in blood pressure produced by tramazoline. The α 2-adrenoceptor blocking action of sulpiride lasted for approximately 15 min at 1.0 mg/kg and for 90 min at 2.0 mg/kg. In additional experiments, it was determined that the dopamine receptor-mediated bradycardic and hypotensive effects of N,N-di-n-propyldopamine were antagonized for at least 2 h by 0.1, 0.5 and 1.0 mg/kg sulpiride. These studies establish that peripheral neuronal and vascular dopamine receptors may be antagonized by sulpiride without affecting α-adrenergic mechanisms. However, at doses of 1.0 mg/kg and higher, sulpiride facilitates sympathetic nerve function via a preferential antagonism of α 2-adrenoceptors.

Isolation and structure of aaptamine a novel heteroaromatic substance possessing α-blocking activity from the sea sponge [formula omitted][formula omitted

A novel heteroaromatic substance, aaptamine possessing an α-adrenoceptor blocking activity has been isolated from the tropical sea sponge Aaptos aaptos and its structure has been determined to be 1 on the basis of spectral data and chemical degradation.

The assessment of pre- and postsynaptic α-adrenoceptor blocking activity of drugs using the rat anococcygeus muscle

The possibility of using contractility studies with the rat anococcygeus muscle to assess the pre- and postsynaptic α-adrenoceptor blocking activity of agents has been examined. Following 6-hydroxydopamine incubation (10 −3M for 3 hours) of the tissue, phentolamine (5 × 10 −8 and 5 × 10 −7 M), prazosin (5 × 10 −9, 10 −8 and 5 × 10 −8 M) and yohimbine (5 × 10 −7 and 5 × 10 −6 M) had no effect on the magnitude of the maximal responses to exogenously applied (−)-noradrenaline and to acetylcholine. The submaximal responses to (−)-noradrenaline, but not to acetylcholine, were inhibited by these agents. Under these conditions it was possible to assess the postsynaptic α-adrenoceptor blocking activity of these agents: Prazosin > Phentolamine > Yohimbine. In the presence of nortriptyline (10 −6M), the responses to field stimulation at low frequencies were potentiated and the responses to (−)-noradrenaline were unaltered by phentolamine (5 × 10 −9 M) and yohimbine (5 × 10 −7 M). The responses to field stimulation and to (−)-noradrenaline were inhibited and unaltered by ≥ 10 −9 and 10 −10M prazosin, respectively. It is suggested that it is possible to detect presynaptic α-adrenoceptor blocking activity using the methods described but not to assess the potency of agents in this aspect; this matter is further discussed.

β-adrenoceptor and cardiovascular effects of MJ 13105 (Bucindolol) in anesthetized dogs and rats

This report describes the β-adrenoceptor blocking and cardiovascular activity of MJ 13105 (Bucindolol), an indolyl-tert-butyl substituted phenoxypropanolamine. Increases in heart rate elicited by (a) isoproterenol, (b) stellate ganglion stimulation, and (c) bilateral carotid occlusion were antagonized to the same extent (80%) by a dose as low as 30 μg/kg, i.v. MJ 13105 blocked isoproterenol-induced vasodilator responses in the canine hindlimb. Intra-arterial infusions of MJ 13105 effected dose-dependent decreases in perfusion pressure, which persisted even in the presence of prior β-adrenoceptor blockade. Intravenous administration of MJ 13105 lowered mean arterial blood pressure and total peripheral resistance, and increased heart rate and right ventricular contractile force in the open chest, anesthetized dog. The vasodilator response to MJ 13105 persisted and may have been enhanced following propranolol. In vivo, MJ 13105 demonstrated weak α-adrenoceptor blocking activity in both rat and dog. Inhibition of the α-mediated vasoconstriction was more apparent if phenylephrine, rather than norepinephrine was the agonist. MJ 13105 exhibited intrinsic sympathomimetic activity at β 1-receptors, although its maximum capacity to increase heart rate was less than that of pindolol. Plasma renin activity of anesthetized dogs was elevated following administration of MJ 13105, an effect that was attenuated by propranolol. Oral administration lowered blood pressure of SHR and DOCA-salt hypertensive rats and renal hypertensive dogs, with a concomitant decrease in heart rate of rats and an increase in heart rate of dogs.

The interaction between prazosin and clonidine at α-adrenoceptors in rats and cats

In pithed rats prazosin (10μg/kg, i.v.) caused a prolonged antagonism of the hypertensive response to clonidine and (−)-noradrenaline, probably due to inhibition of vascular, postsynaptic α-adrenoceptors. The clonidine-induced reduction of the tachycardia evoked in pithed rats by electrical stimulation of cardiac sympathetic nerve fibres was antagonized by piperoxan and less effectively by prazosin, thus suggesting that prazosin displays a modest degree of cardiac presynaptic α-adrenoceptor blocking activity apart from its predominantly postsynaptic affinity. Prazosin (1 mg/kg, i.p.) significantly affected the hypotensive effect of clinidine (2 and 6 μg/kg, i.v.), but not the bradycardia induced by clonidine in pentobarbitone-anaesthetized, normotensive rats. Prazosin proved to be an effective hypotensive drug in anaesthetized cats. This action was peripheral as no central nervous origin could be demonstrated. Prazosin in low doses significantly reduced the central hypotensive effect of clonidine (1 μg/kg), injected into the left vertebral artery of chloralose-anaesthethized cats. Since the intravenous pretreatment with low doses of prazosin did not alter the central hypotensive response to clonidine, the interaction was likely to have occured within the brain-stem. Presumably, postsynaptic α-adrenoceptors in the brain, similarly to those in the periphery are inhibited by prazpsin, thereby preventing the central hypotensive effect of clonidine. It is submitted that clonidine and prazosin should not be combined in antihypertensive therapy in patients.

Cardiac muscarinic blocking and atropinic blocking effects of a tetramine disulfide and alpha-adrenoceptor blocking activity.

Since many alpha-adrenoceptor blocking drugs were known to have muscarinic blocking activity, BHC, a newly synthesized tetramine disulfide with alpha-adrenoceptor blocking activity, and two of its analogs were tested for muscarinic blocking activity in the isolated guinea pig atrium and ileum. BHC had muscarinic blocking activity. Its potency was higher in the atrium than in the ileum. The cardiac muscarinic blocking potency of the analog that contained carbon atoms instead of sulfur atoms was similar to that of BHC. Lower concentrations of the drugs antagonized inotropic effects of acetylcholine competitively, but higher concentrations had a smaller effect than expected for competitive antagonism. In the atrium BHC competitively inhibited the muscarinic blocking effect of atropine. Its atropinic blocking potency was similar to the muscarinic blocking potency. Quinidine and gallamine also had muscarinic blocking and atropinic blocking effects in the atrium but were about 10 times less potent than BHC.

Antagonism by mianserin and classical α-adrenoceptor blocking drugs of some cardiovascular and behavioral effects of clonidine

Antagonism of pressor responses to sympathetic outflow stimulation and α-adrenoceptor agonists in pithed spontaneously hypertensive rats was used to estimate postsynaptic α-adrenoceptor blocking activity of mianserin, phentolamine, phenoxybenzamine, piperoxan and yohimbine. Estimation of presynaptic α-adrenoceptor blocking activity of these drugs was obtained by studying their ability to antagonize clonidine-induced suppression of positive chronotropic responses to sympathetic outflow stimulation. In this manner, evidence was obtained that mianserin causes selective presynaptic α-adrenoceptor blockade. Mianserin, piperoxan and yohimbine antagonized clonidine-induced avoidance blockade or hypotension in spontaneously hypertensive rats, but methysergide, phenoxybenzamine and phentolamine were ineffective. These results suggest that mianserin may antagonize the central effects of clonidine by blockade of noradrenergic presynaptic or autoreceptors and possibly explain the antidepressant effect of mianserin as due to indirect activation of central noradrenergic neurons.

The neuromuscular and other blocking actions of 4,17a-dimethyl-4,17a-diaza-d-homo-5α-androstane dimethiodide (HS-342) in the anaesthetized cat

I.G. MARSHALL, D. PAUL and H. SINGH, The neuromuscular and other blocking actions of 4.17a-dimethyl-4, 17a-diaza-d-homo-5α-androstane dimethiodide (HS-342) in the anaesthetized cat, European J. Phannacol. 22 (1973) 129–134. The effects of the newly-synthesized bisquaternary ammonium steroidal compound 4,17a-dimethyl-4,17a-diazad-honio-5α-androstane dimethiodide (HS-342) have been studied on the tibialis anterior and soleus muscles, the nictitating membrane and the responses of the heart rate to vagal stimulation in the chloralose-anaesthetized cat. HS-342 exhibited potent neuromuscular blocking activity, possessing slightly less activity than tubocurarine. In contrast to tubocurarine, HS-342 exhibited a short duration of action (one-third of that of tubocurarine) and rapid onset of action. The neuromuscular blockade was of the non.-depolarizing type, and was reversed by anticholinesterase agents. HS-342 also possessed a ganglion-blocking action and a selective atropine-like action at the cardiac vagus neuroeffector junction, but no adrenergic neurone or α-adrenoceptor blocking activity. The predominant cardiovascular side effect of HS-342 was a depressor action, which is probably due to the ganglion blocking activity of the compound.