Inhibition of Adrenaline‐induced Platelet Aggregation by the Α‐adrenoceptor Blocking Drug Benextramine

Belleau, B.; Benfey, B. G.; Melchiorre, Carlo; Montambault, M

doi:10.1111/j.1476-5381.1982.tb09214.x

Cited by 6 publications

(2 citation statements)

References 15 publications

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“…3). In addition, we found, as did Belleau et al (1982), that quinidine antagonized platelet aggregation initiated by epinephrine working through a 2 -adrenergic receptors, but did not block aggregation initiation by adenosine diphosphate (ADP) working through distinct receptors (Fig. 4).…”

Section: Discussionsupporting

confidence: 56%

Quinidine is a competitive antagonist at alpha 1- and alpha 2-adrenergic receptors.

Motulsky¹,

Maisel²,

Snavely³

et al. 1984

Circulation Research

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SUMMARY. Although quinidine is known to have antiadrenergic effects in the cardiovascular system, the precise mechanism by which it exerts these effects is not well defined. We asked whether quinidine binds directly to adrenergic receptors. Radioligand-binding assays were used to identify <*i -adrenergic receptors ([ 3 H]prazosin-binding sites) on membranes prepared from rat heart and kidney, a 2 -adrenergic receptor ([ 3 H]yohimbine-binding sites) on human platelets and rat kidney membranes, and /3-adrenergic receptors ([ 125 I]iodocyanopindolol-binding sites) on rat heart and kidney membranes. Although it did not effectively compete for binding to /3-adrenergic receptors, quinidine competed for binding to <*i-and a 2 -adrenergic receptors and yielded equilibrium dissociation constants of 0.3-3 /*M. TWO other antiarrhythmic agents, lidocaine and procainamide, did not compete for binding to a-adrenergic receptors. Further experiments demonstrated that the interactions of quinidine with the cardiac c*i-and platelet a 2 -adrenergic receptors were competitive and reversible. We conclude that that antiadrenergic actions of quinidine can be explained by occupancy and competitive blockade of «i-and a 2 -adrenergic receptors. (Circ Res 55: 376-381, 1984) THE antiarrhythmic drug quinidine appears to act by multiple mechanisms. In addition to its wellknown direct effects on myocardial excitability, conduction velocity, and contractility, quinidine also has indirect effects on the cardiovascular system, including anticholinergic and antiadrenergic actions (c.f. Nelson, 1928;Hiatt, 1950;James and Nadeau, 1967, Schmid et al., 1974;Mirro et al., 1980;Toda et al., 1981, Caldwell et al., 1983. The anticholinergic effects on the heart appear to result from blockade of muscarinic receptors (Mirro et al., 1980), but the mechanism by which quinidine exerts its antiadrenergic actions has not been clearly defined. There are many possibilities, including a nonspecific "local anesthetic* or "membrane-stabilizing" effect, an interaction with receptor-linked ion channels, or a direct blockade at adrenergic receptors. With the availability of radioligand-binding techniques, one can test whether quinidine acts to block adrenergic response by binding to receptors. We report here results of radioligand-binding studies examining the interaction of quinidine and other antiarrhythmic agents with adrenergic receptors in heart, kidney, and platelets. Methods Tissue PreparationHeart Left ventricles were excised from adult Sprague-Dawley rats and were homogenized using a Brinkman Polytron at setting 8 for 15 seconds. After filtering through 200 /tm Nitex mesh, the homogenate was centrifuged at 8000 g for 10 minutes. The supernatant extract was discarded, and the pellet was washed once and stored at -70° until used. The final suspension was 0.5-2.0 mg protein/ml. The buffer used for washing membranes, as well as in the binding experiments, consisted of 50 HIM Tris HCI, 8 irtM MgCl 2 , 0.5 mM EGTA at pH 7.5 KidneyRenal membranes were p...

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Section: Discussionsupporting

confidence: 56%

Quinidine is a competitive antagonist at alpha 1- and alpha 2-adrenergic receptors.

Motulsky¹,

Maisel²,

Snavely³

et al. 1984

Circulation Research

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“…Benextramine has been known to irreversibly bind to ␣ 2 -adrenoceptors (Melchiorre, 1981;Belleau et al, 1982b;Lew and Angus, 1984;Hieble et al, 1985;Timmermans et al, 1985;Taouis et al, 1987;McKernan et al, 1988;Brink et al, 2000;Umland et al, 2001), 5-HT 1A -serotonergic receptors (Stanton and Beer, 1997), H 2 -histaminergic receptors (Belleau et al, 1982a), and neuropeptide Y receptors (Melchiorre et al, 1994). Present knowledge regarding the mechanism of action of benextramine is limited to the observations from predominantly radioligand binding studies, and it is generally assumed that benextramine irreversibly inactivates the ligand (primary or syntopic) binding sites at these receptors.…”

mentioning

confidence: 99%

Phenoxybenzamine and Benextramine, but Not 4-Diphenylacetoxy-N-[2-chloroethyl]piperidine Hydrochloride, Display Irreversible Noncompetitive Antagonism at G Protein-Coupled Receptors

Bodenstein¹,

Venter²,

Brink³

2005

J Pharmacol Exp Ther

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Many irreversible antagonists have been shown to inactivate G protein-coupled receptors (GPCRs) and used to study agonists and spare receptors. Presumably, they bind to primary (agonist) binding sites on the GPCR, although noncompetitive mechanisms of antagonism have been demonstrated but not thoroughly investigated. We studied noncompetitive antagonism by phenoxybenzamine and benextramine at ␣ 2A -adrenoceptors in stably transfected Chinese hamster ovary cells, benextramine and 4-diphenylacetoxy-N-[2-chloroethyl]piperidine hydrochloride (4-DAMP mustard) at endogenous muscarinic acetylcholine (mACh) receptors in human neuroblastoma SH-SY5Y cells, and benextramine at serotonin 5-HT 2A

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Two long acting α-adrenoceptor blocking drugs: benextramine and phenoxybenzamine

Benfey

1982

Trends in Pharmacological Sciences

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Inhibition of Adrenaline‐induced Platelet Aggregation by the Α‐adrenoceptor Blocking Drug Benextramine

Cited by 6 publications

References 15 publications

Quinidine is a competitive antagonist at alpha 1- and alpha 2-adrenergic receptors.

Quinidine is a competitive antagonist at alpha 1- and alpha 2-adrenergic receptors.

Phenoxybenzamine and Benextramine, but Not 4-Diphenylacetoxy-N-[2-chloroethyl]piperidine Hydrochloride, Display Irreversible Noncompetitive Antagonism at G Protein-Coupled Receptors

Two long acting α-adrenoceptor blocking drugs: benextramine and phenoxybenzamine

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