Α-adrenoceptor Blocking Research Articles

Dualism in the α-adrenoceptor blocking action of dihydroergocristine

Summary Dihydroergocristine, tested on the rat isolated “vas deferens”, was able to antagonize the noradrenaline-induced contraction with competitive (pA 2 = 7.88) and non competitive (pD′ 2 = 6.86) mechanisms. On the rat perfused caudal vein the antagonism towards noradrenaline seems to be mainly non competitive in nature. The non competitive antagonistic action of dihydroergocristine is almost 100 times greater than that of papaverine. The mechanism of this action seems to be independent from mechanisms involving Ca ++ since dihydroergocristine, unlike papaverine, did not antagonize the Ca ++ induced contractions of the rat “vas deferens”.

Responses of the rat anococcygeus muscle to sympathomimetics

1. 1. The effects of methoxamine, noradrenaline, octopamine and tyramine were studied on the rat anococcygeus muscle in vitro. They all contract the muscle concentration-dependently. 2. 2. The following — log EC 50 values were obtained: methoxamine (5.55), noradrenaline (5.15), tyramine (5.05) and octopamine (4.95). The intrinsic activity (α) obtained suggests that they are all true agonists. 3. 3. Reserpine treatment completely abolished tyramine effect and markedly reduced the effects of octopamine and methoxamine. However, guanethidine reduced tyramine—but not octopamine-induced contractions. 4. 4. Phentolamine competitively reduced noradrenaline-induced contractions, however the antagonism of octopamine, tyramine and methoxamine was non-competitive. 5. 5. Pimozide non-competitively antagonized the effect of methoxamine whilst it competitively reduced contractions induced by the other agents. 6. 6. The results indicate that pimozide may also have α-adrenoceptor blocking properties in the anococcygeus muscle.

Effect of guanethidine on α-adrenoceptor blocking potency of phentolamine in vitro

The effect of guanethidine on the α-adrenoceptor blocking property of phentolamine was studied using the rabbit aortic strip and rat vas deferens. The agonists used were noradrenaline (in presence of DOCA and cocaine which block uptake mechanisms) and xylometazone (which is not taken by uptake mechanisms). Guanethidine augmented the responses to noradrenaline and xylometazoline and increased the pA 2 value of phentolamine against both agonist. Increased affinity of α-receptors may be partly responsible for the guanethidine-induced supersensitivity to α-adrenoceptor agonists.

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.

α-Adrenoceptor Blocking Properties of a New Antihypertensive Agent, 2-[4-(n-butyryl)-homopiperazine-1-yl]-4-amino-6,7-dimethoxyquinazoline (E-643)

Postsynaptic α-receptor blocking properties of E-643 were studied in vivo and in vitro and compared with these same properties of phentolamine and phenoxy-benzamine. In anesthetized rats, E-643 (i.v.) attenuated pressor response to adrenaline dose-dependently and an adrenaline-reversal was seen with large doses. The in vivo α-adrenoceptor blocking effect of E-643 was 3.4 times more potent than that of phentolamine. On the other hand, hypotensive action of E-643 was 9.4 times more potent than that of phentolamine. In the isolated rabbit aorta, E-643 blocked noradrenaline-induced contraction of the aorta with a parallel shift of the dose-response curve to the right. The pA2 values for E-643 and phentolamine were 8.60 and 7.65, respectively. The α-blocking effect of E-643 was reversible. E-643 protected α-receptors against irreversible inhibition by phenoxybenzamine. E-643 neither exhibited significant blocking effects on K+-, Ba2+- and angiotensin-induced contractions of the aorta nor caused relaxation of the aorta contracted by Ca2+. These data suggest that E-643 is a specific and competitive inhibitor of noradrenaline at the α-adrenoceptors.

Investigations on the mode of action of a new antihypertensive drug, urapidil, in the isolated rat vas deferens

Urapidil (6-{3-[4-(o-methoxyphenyl)-1-piperazinyl]-propylamino}-1,3-dimethyluracil), phentolamine (both 10 −8–10 −5 M), yohimbine (10 −7 M), and clonidine (10 −6–10 −5 M) competitively antagonized the effect of noradrenaline on postsynaptic α-adrenoceptors in organ bath-suspended rat vas deferens, yielding pA 2 values of 7.02, 7.64, 6.48 and 5.81, respectively, whereas xylazine (BAY 1470) was ineffective as an antagonist. In contrast to clonidine and xylazine, urapidil did not exert α-adrenoceptor agonist properties at the postsynaptic level in this preparation. Stimulation of presynaptic α-adrenoceptors by urapidil, clonidine and xylazine was assessed by inhibition of twitch contractions of the superfused rat vas deferens in response to intramural nerve stimulation. Inhibition of contraction caused by these drugs was reversed by phentolamine and yohimbine, indicating that they were presynaptic in origin. The presynaptic α-adrenoceptor antagonist activity of urapidil and phentolamine was quantitatively determined by studying the effects of increasing concentrations of these compounds on clonidine dose-response curves in the vas deferens after electrical stimulation. The inhibitory effect of clonidine could be competitively blocked by phentolamine (10 −7–10 −6 M), whereas urapidil (10 −5−3 × 10 −4 M) elicited partial agonism on presynaptic α-adrenoceptors which was apparent from the dose-response curves revealing competitive dualism. The pA 2 value for phentolamine and urapidil against clonidine was 7.97 and 5.11, respectively. These results indicate that, with respect to pre- and postsynaptic α-adrenoceptors, the action of urapidil is complex but suggests a primary presynaptic stimulatory site of action at doses similar to those of clinidine, but with an apparent intrinsic activity of 0.52. The α-adrenoceptor blocking potency of urapidil at the postsynaptic site was 4–8 times weaker than that of phentolamine, whereas antagonism at the presynaptic level was negligible.

Interactions between clonidine and alpha-adrenoceptor blocking drugs on the tachycardic response to stimulation of the cardiac nerve in dogs.

In pentobarbital-treated dogs clonidine (10 micrograms/kg) reduced the increase in heart rate caused by electrical stimulation of the cardiac nerve (1-10 Hz). We studied the actions of six alpha-adrenoceptor blocking drugs. Yohimbine (0.3 mg/kg) and phentolamine (1 mg/kg) potentiated the effects of nerve stimulation and antagonized the inhibitory effects of clonidine. Piperoxan (1 mg/kg) increased the response to nerve stimulation but antagonized the effects of clonidine only at the lowest frequency of stimulation. Thymoxamine (1 mg/kg) and prazosin at high doses (1 mg/kg) also antagonized the effects of clonidine but failed to increase the positive chronotropic response to stimulation of the cardiac nerve. AR-C239, a new and potent alpha-adrenoceptor blocking agent, changed neither the response to nerve stimulation nor the inhibitory effect of clonidine. The effects of all these drugs were observed at doses which reduced or reversed the pressor response to adrenaline. Therefore, our results afford further evidence for a dissimilarity between postsynaptic and presynaptic alpha-adrenoceptors in the dog. In addition, they show that the failure of an alpha-adrenoceptor blocking compound to increase the response to nerve stimulation does not necessarily indicate a lack of presynaptic alpha-adrenoceptor blockade.

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.

Comparative effects of clozapine and α-adrenoceptor blocking drugs on regional noradrenaline metabolism in rat brain

Clozapine increased brain noradrenaline (NA) metabolism, as indicated by changes in 3-methoxy-4-hydroxy-phenylglycol sulfate content, in brain regions corresponding to the predominance of α- over β-receptors, i.e., hypothalamus, medulla, midbrain and cortex, but not corpus striatum or cerebellum. Phenoxybenzamine had a stronger effect in the hypothalamus than did clozapine, but did not change cortical NA metabolism within a 60 min treatment time; however, cortical NA metabolism was increased 150 min after phenoxybenzamine. The delayed effect of phenoxybenzamine may be due to either a poor affinity for some central receptors or a slow rate of entry into certain brain regions. Thioridazine and the benzodioxane, dibozane, had regional effects similar to clozapine. The similarity between clozapine and dibozane in their effects on regional brain NA metabolism may reflect a preference for presynaptic α-receptors. It is unlikely that the antipsychotic activity of clozapine is related to a specific adrenolytic effect, but may reflect the combined activity of this drug on several transmitter systems.

Double‐blind trial of indoramin in digital artery disease.

British Journal of Clinical PharmacologyVolume 6, Issue 1 p. 88-91 Free Access Double-blind trial of indoramin in digital artery disease. P Robson, P RobsonSearch for more papers by this authorV Pearce, V PearceSearch for more papers by this authorAC Antcliff, AC AntcliffSearch for more papers by this authorM Hamilton, M HamiltonSearch for more papers by this author P Robson, P RobsonSearch for more papers by this authorV Pearce, V PearceSearch for more papers by this authorAC Antcliff, AC AntcliffSearch for more papers by this authorM Hamilton, M HamiltonSearch for more papers by this author First published: July 1978 https://doi.org/10.1111/j.1365-2125.1978.tb01688.xCitations: 3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References ALPS, B.J., HILL, M., JOHNSON, E.S. & WILSON, A.B. (1970). Autonomic blocking properties of Wy 21901. Br. J. Pharmac., 40, 153P. ALPS, B.J., HILL, M., JOHNSON, E.S. & WILSON, A.B. (1972). Quantitative analysis on isolated organs of the autonomic blocking properties of indoramin hydrochloride (Wy 21901). Br. J. Pharmac., 44, 52– 62. ANTCLIFF, A.C., BOUHOUTSOS, J., MARTIN, P. & MORRIS, T. (1974). A plethysmographic study of the effect of tetranicotinoylfructose (Bradilan) on digital blood flow in primary and secondary Raynaud's phenomenon. Angiology, 25, 312– 316. COLLIS, M.G. & ALPS, B.J. (1973). The evaluation of the α-adrenoceptor blocking action of indoramin phentolamine and thymoxamine on the rat and guinea-pig isolated mesenteric vasculature and aortic spiral preparations. J. Pharm. Pharmac., 25, 621– 628. FARES, C.M. & MILLIKEN, J.C. (1974). The effect of parenteral indoramin on peripheral blood flow in patients with Raynaud's disease or atherosclerosis associated with intermittent claudication. Curr. med. Res. Opin., 2, 57– 62. ROWELL, N.R. (1972). Lupus erythematosus scleroderma and dermatomyositis. In Textbook of Dermatology, ed. A. Rook, D.S. Wilkinson & F.J.G. Ebing, chapter 36 p. 1061. Oxford: Blackwell Scientific. ROYDS, R.B. & LOCKHART, J.D.F. (1972). The effect of indoramin on muscle blood flow and skin temperature in man. 5th International Congress on Pharmacology.. ROYDS, R.B. & LOCKHART, J.D.F. (1974). The effect of indoramin on peripheral blood flow. Br. J. clin. Pharmac., 1, 13– 17. Citing Literature Volume6, Issue1July 1978Pages 88-91 ReferencesRelatedInformation

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.

Paradoxical sleep inhibition by central alpha-adrenoceptor stimulant clonidine antagonized by alpha-receptor blocker yohimbine

In cats clonidine produces sedation and dose dependent inhibition of paradoxical sleep (PS). With 10 μg/kg PS is suppressed for ca. 8 hours. The α-adrenoceptor blocking drug yohimbine (2mg/kg) increases arousal and antagonizes the PS depressing effect of clonidine. This implies that the impact of clonidine on PS is due to its stimulating effect on central α-receptors. This interpretation, however, does not resolve the current controversy, whether noradrenaline (NA) is a positive or a negative factor in PS control. Stimulation of post-synaptic α-receptors may mimic the action of liberated NA, while stimulation of presynaptic receptors inhibits NA-liberation. Both clonidine and yohimbine are claimed to have a predominance of action on the presynaptic side. Definitive conclusions, however, would require more data about the central receptors, and the timing and balance of the agonist and antagonist actions envolved. Also central adrenaline receptors and interactions with the 5-HT system may complicate the situation.

Specific α-adrenoceptor blocking effect of droperidol on isolated smooth muscles

The present study was conducted so as to obtain more insight into the controversies concerning the α-adrenoceptor blocking properties of droperidol, a short-acting neuroleptic agent used in neuroleptanalgesia. The effect of droperidol on the vasoconstriction induced by norepinephrine, sympathetic nerve stimulation, histamine and potassium ions was studied on isolated, perfused ear arteries; its effect on norepinephrine-induced contraction was studied on isolated aorta, spleen and vas deferens. In addition, the onset and duration of action of droperidol was studied. Low doses of droperidol inhibit the vasoconstriction induced by norepinephrine and sympathetic nerve stimulation in the ear artery of the rabbit (3.3 × 10 −9 M and 1.3 × 10 −8 M respectively). At similar low doses, droperidol inhibits norepinephrine-induced contractions in the other tissues studied and has a potency comparable to that of phentolamine; its action is rapid in onset and of short duration. High doses of droperidol (10 −6 M) also inhibit the vasoconstriction of the ear artery induced by histamine and by potassium ions. These findings indicate that at low doses, droperidol has specific and competitive α-adrenoceptor blocking effects.

Pharmacological characterization of B-HT 933 (2-amino-6-ethyl-4,5,7,8,-tetrahydro-6H-oxazolo-[5,4-d]-azepindihydrochloride) as a hypotensive agent of the "clonidine-type".

The hypotensive action of a new compound, B-HT 933 (2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo-[5,4-d]-azepin) was characterized to be of the “clonidine-type” by the use of 6 pharmacological test procedures. (1) Intravenous injection of the substance elicited a typical cardiovascular reaction pattern of initial hypertension, followed by hypotension with bradycardia and decreased cardiac output. (2) A direct α-adrenoceptor stimulation at peripheral vascular sites was demonstrated by a hypertensive action in spinal rats. (3) A central nervous site of action was shown as 30 μg/kg injected intracisternally (i.ci.) lowered blood pressure and heart rate in cats, but the same dose i.v. was practically ineffective. (4) The decrease in sympathetic activity was revealed by a decrease in preganglionic splanchnic nerve discharges in cats. (5) The drug facilitated the vagally-mediated baroreceptor reflex as shown by the increase in reflex bradycardia following i.v. angiotensin injection in dogs. (6) The involvement of central nervous α-adrenoceptors was suggested because the α-adrenoceptor blocking drug piperoxan antagonized the facilitation of the baroreceptor reflex induced by B-HT 933. Furthermore, the drug facilitated the flexor reflex in rats with spinal section at midthoracic level. These results were unexpected as the chemical structure of B-HT 933 differs considerably from hitherto known substances of the “clonidine-type”.

Secretory responses to sympathetic stimulation of the cat's salivary glands in a state of resting secretion.

The secretory effect of sympathetic stimulation on the cat's submaxillary gland was augmented greatly when studied against a background of slow secretion evoked by parasympathetic stimulation at a low frequency and imitating the slow resting secretion normally present in the waking state. The sympathetic secretory threshold was markedly lowered, and even at low frequencies sympathetic stimulation caused a large, well-maintained response. After an alpha-adrenoceptor blocking drug sympathetic stimulation alone lost its secretory effect, but during resting secretion part of the accelerating effect was found to remain; this effect was elicited via beta-adrenoceptors. A marked secretory effect of sympathetic stimulation was also obtained during resting secretion in the parotid gland, where the sympathetic secretory effect is normally very small.

The α-adrenoceptor blocking effects of a new benzodioxane

Journal Article The α-adrenoceptor blocking effects of a new benzodioxane Get access D R Mottram, D R Mottram Department of Pharmacology, School of Pharmacy, Liverpool Polytechnic, Liverpool L3 3AF, U.K. Search for other works by this author on: Oxford Academic Google Scholar H Kapur H Kapur Department of Pharmacology, School of Pharmacy, Liverpool Polytechnic, Liverpool L3 3AF, U.K. Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 27, Issue 4, April 1975, Pages 295–296, https://doi.org/10.1111/j.2042-7158.1975.tb10707.x Published: 12 April 2011 Article history Received: 22 November 1974 Published: 12 April 2011

Venoconstrictor effect of dihydroergotamine in superficial hand veins.

The effect of dihydroergotamine on superficial veins of the hand has been investigated in healthy volunteers. The compliance of the veins was assessed by measurement of their diameter at a standard congestion pressure. Direct local infusion into the vein under study of 0.4 µg and 2.0 µg dihydroergotamine reduced venous compliance by 15±5% and 30±3%, respectively. Local infusion of phentolamine 20 µg, an α-adrenoceptor blocking drug, did not affect venous compliance, but markedly inhibited the venoconstrictor effect of dihydroergotamine 2 µg. It was concluded that the venoconstrictor effect of dihydroergotamine demonstrated in this experiment was mainly due to α-adrenoceptor stimulation. Venous compliance also decreased after oral administration of dihydroergotamine 10 mg; after 150 min, venous diameter was reduced by 30±5%.

Further observations on the experimental antidysrhythmic activity of indoramin hydrochloride.

Abstract Indoramin showed potent activity in reversing severe myocardial conduction disorders and ventricular fibrillation induced by hypothermia, and protected against the precipitation of electrically-induced ventricular fibrillation at low doses in pentobarbitone-anaesthetized cats. It would appear that the α-adrenoceptor blocking and local anaesthetic membrane stabilizing properties of indoramin are responsible for the mechanisms by which these dysrhythmias are reversed as they are with those induced by ouabain and adrenaline, previously described.