Interactions of D600 (methoxyverapamil) and local anesthetics with rat brain α-adrenergic and muscarinic receptors

Fairhurst, Alan S.; Whittaker, Michael; Ehlert, Frederick J.

doi:10.1016/0006-2952(80)90323-8

Cited by 123 publications

(22 citation statements)

References 16 publications

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“…Nearly identical results have been observed for another antiarrhythmic agent, verapamil (Cavey et al, 1977;Glossman and Hornung, 1980;Fairhurst et al, 1980;Atlas and Adler, 1981;Barnathan et al, 1982;Karliner et al, 1982;Motulsky et al, 1983a). Conceivably, quinidine and verapamil may bind to similar regions on the distinct receptors.…”

Section: Discussionsupporting

confidence: 63%

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: 63%

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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“…We have also shown that diltiazem blocks [3H]-mepyramine binding to membrane preparations from the porcine aorta at high concentrations (Ki = 114piM) (Matsumoto et al, 1989). Ca2"-antagonists inhibit the binding of several agonists to specific binding sites (Fairhurst et al, 1980;Glossman & Hornung, 1980;Barnathan et al, 1982;Karliner et al, 1982;Nayler et al, 1982;Motulsky et al, 1983). Thus, inhibition of the receptor-mediated Ca2+-release from intracellular store sites seen with very high concentrations of diltiazem (around 10-M) may be due to competitive binding to receptor-sites.…”

Section: Discussionmentioning

confidence: 74%

Effects of diltiazem on calcium concentrations in the cytosol and on force of contractions in porcine coronary arterial strips

Hirano

Kobayashi

Abe

et al. 1990

British J Pharmacology

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“…In addition to blocking calcium channels, methoxyverapamil (D-600) has a moderate affinity for (xadrenoceptors (Fairhurst et al, 1980). It is likely that verapamil also exhibits some affinity for a-adrenoceptors.…”

Section: Isolated Tissues Andpatient Materialsmentioning

confidence: 99%

Relationship between the stereoselective negative inotropic effects of verapamil enantiomers and their binding to putative calcium channels in human heart

Ferry

Glossmann

Kaumann

1985

British J Pharmacology

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Ventricular preparations from patients with mitral disease and hypertrophic obstructive cardiomyopathy (HOCM) were set up to contract isometrically. Ventricular membrane particles were also prepared and putative calcium channels were labelled with [3H]‐nimodipine. Positive staircase was induced by varying the rate of stimulation of isolated strips from 6 min−1 to 120 min−1 in the presence of 6–60 μm (—)‐adrenaline or (—)‐noradrenaline. (—)‐Verapamil 3–5 μm or (+)‐verapamil 20–30 μm reversed the force‐frequency relationship (i.e. caused negative staircase) in preparations from patients with mitral disease or HOCM. In subendocardial strips of ventricular septum from 5 patients with HOCM paced at 60 min−1, both (—)‐verapamil and (+)‐verapamil caused cardiodepression. Half‐maximal cardiodepression was observed with 0.4 μm (—)‐verapamil and with 3 μm (+)‐verapamil. [3H]‐nimodipine bound to ventricular membrane particles in a saturable, reversible fashion to a high affinity site with an equilibrium dissociation constant of 0.23 nm. The density of these sites was 95 fmol mg−1 of membrane protein. Binding of the tritiated 1,4‐dihydropyridine was stereoselectively inhibited by 1,4‐dihydropyridine enantiomers and nifedipine. (—)‐Verapamil and (+)‐verapamil inhibited high affinity [3H]‐nimodipine binding in a negative heterotropic allosteric manner with (—)‐verapamil being 5 times more potent than (+)‐verapamil on an IC50 basis. At a given [3H]‐nimodipine concentration, (+)‐verapamil inhibited a greater fraction of specific [3H]‐nimodipine binding. The allosteric mode of (+)‐verapamil inhibition of [3H]‐nimodipine binding was confirmed by kinetic studies. (—)‐Verapamil shifted (+)‐verapamil‐binding inhibition curves to the right in an apparently competitive fashion. The inversion of staircase caused by both verapamil enantiomers suggests that they cause a use‐dependent channel blockade. The similar potency ratios for binding and for cardiodepression are indicative of a common locus of action for both verapamil enantiomers within the calcium channel.

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Interactions of D600 (methoxyverapamil) and local anesthetics with rat brain α-adrenergic and muscarinic receptors

Cited by 123 publications

References 16 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.

Effects of diltiazem on calcium concentrations in the cytosol and on force of contractions in porcine coronary arterial strips

Relationship between the stereoselective negative inotropic effects of verapamil enantiomers and their binding to putative calcium channels in human heart

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