Allosteric Modulation of [3H]Nitrendipine Binding to Cardiac and Cerebral Cortex Membranes by Amiodarone

Nokin, Pierre; Clinet, M.; Swillens, Stéphane; Delisée, Chantal; Meysmans, L; Chatelain, Pierre

doi:10.1097/00005344-198609000-00025

Cited by 26 publications

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“…The possibility of AM effects at the membrane level is suggested by the fact that AM has been reported to behave as a Ca2+ channel blocker in cardiac cells (9,26) or as a potent inhibitor of [3H]nitrendipine binding to rat heart and cerebral cortex membranes (10). Furthermore, AM has been shown specifically to decrease TSH-stimulated adenylate cyclase activity, to inhibit [3H]-2-deoxyglucose uptake in response to TSH, to reduce carbachol or TSH-stimulated increase in [Ca2+]¡ in dog thyroid cells (19) and to alter Ca2+ binding properties of brain calmodulin (27).…”

Section: Effects Of Amiodarone (Am)mentioning

confidence: 99%

“…For example, the antiarrhythmic activity of AM is presumed to involve inhibition of currents flowing through several types of ion channels, and electrophysiological studies have shown that AM modulates Ca + channel currents in guinea pig ventricular cells (9). In addition, pharmacological studies have demon¬ strated that AM exerts competitive inhibition on [3H]nitrendipine binding to cardiac and cerebral cortex membranes by acting at a site in allosteric interaction with the 1,4-dihydropyridine (DHP) binding site associated with calcium channels (10).…”

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confidence: 99%

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Dihydropyridine-like effects of amiodarone and desethylamiodarone on thyrotropin secretion and intracellular calcium concentration in rat pituitary

Roussel

Grazzini²,

Guipponi³

et al. 1995

European Journal of Endocrinology

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Amiodarone (AM) and its major metabolite desethylamiodarone (DEA) are structurally similar to biologically active thyroid hormones. Amiodarone therapy is frequently associated with impairment of thyrotropic function, whose mechanisms are still controversial. Besides its effect on nuclear thyroid hormone binding. AM is able to displace dihydropyridine (DH) binding on membrane preparations from several tissues. By perifusing rat pituitary fragments and measuring thyrotropin (TSH) release we examined: the effect of AM on Ca(2+)-dependent and DHP-sensitive potentiation of the TSH response to thyrotropin-releasing hormone (TRH) induced by either triiodothyronine (T3, perifused for only 30 min before a TRH pulse) or by the prepro-TRH peptide 160-169 (PS4); and the effect of DEA on TRH-induced TSH response in the presence or absence of the DHP nifedipine. We show that AM reverses T3 or PS4 potentiation of the TSH response to TRH; this effect is specific because AM does not modify ionomycin potentiation of that response. In contrast, DEA significantly potentiates the TSH response to TRH and the DHP nifedipine reverses that potentiation. We also tested whether AM would change the acute T3-induced increase in intracellular Ca2+ concentration by measuring intracellular Ca2+ ([Ca2+])i with fura-2 imaging on primary cultures of pituitary cells. We show that AM reverses the effect of T3 on [Ca2+]i as well as the PS4-induced increase in [Ca2+]i. In contrast, DEA increases [Ca2+]i and nifedipine reverses this effect. Our results suggest that AM and DEA display DHP-like effects on TRH-induced TSH release, behaving either as a Ca2+ channel blocker (AM) or as a Ca2+ channel agonist (DEA).

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Section: Effects Of Amiodarone (Am)mentioning

confidence: 99%

mentioning

confidence: 99%

Dihydropyridine-like effects of amiodarone and desethylamiodarone on thyrotropin secretion and intracellular calcium concentration in rat pituitary

Roussel

Grazzini²,

Guipponi³

et al. 1995

European Journal of Endocrinology

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“…Furthermore, SR 33557 was a potent antagonist of the effects of Bay K 8644. DHPs have been shown to antagonize competitively the effects of Bay K 8644, whereas verapamil and diltiazem non-competitively antagonize contractile effects and diphenylpiperidines are highly potent antagonists which depress the maximum response (Spedding & Berg, 1984;Spedding, 1985a,b (Chatelain et al, 1991;SolRolland et al, 1991 (Schmid et al, 1989;Sol-Rolland et al, 1991) and cardiac sarcolemmal membranes (Chatelain et al, 1991 (Murphy et al, 1983), amiodarone (Nokin et al, 1986) and fluspirilene (Qar et al, 1987 (Spedding, 1985a;Tytgat et al, 1988), and extremely high concentrations present in the membrane due to its high partition coefficient (Mason et al, 1991). The membrane concentration arising from aqueous concentrations around 1 ILM (likely to be nearer 1 mM in the membrane) would give rise to many non-selective effects.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, the observation that the inhibition of [3H]nitrendipine binding by SR 33557 could be fully reversed by D-cis-diltiazem was evidence for a distinct site of action for SR 33557. This allosteric interaction has been used to differentiate the site of action of several calcium antagonists such as prenylamine (Murphy et al, 1983), amiodarone (Nokin et al, 1986) and fluspirilene (Qar et al, 1987). However, in these previous studies where diltiazem has been used to reverse the inhibition of [3H]-DHP binding, reversal curves have been generated only in the presence of one concentration of calcium antagonist.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel calcium antagonist binding site in rat brain by SR 33557

Kenny¹,

Fraser²,

Spedding

1993

British J Pharmacology

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1 In K+-depolarized taenia preparations from guinea-pig caecum SR 33557 was a potent antagonist of Ca2"-induced contractions and antagonized the effect of the calcium channel activator Bay K 8644.2 SR 33557 displayed high affinity (pKi 9.54 ± 0.04, nH 1.01) for the [3H]-( ± )-PN 200-110 binding site in rat cerebral cortex membranes. In the presence of 5 mM Ca2" this affinity was reduced (pKl 8.82 ± 0.01, nH 1.05) whilst the affinity of nitrendipine was unaffected by this concentration of Ca2". Cd2+ > Ca2+ >Mn2+ >Mg2+ > Na+. 7 We propose that SR 33557 labels a distinct site in rat cerebral cortex. The coupling between the SR 33557 and DHP site appears to be very close, resulting in apparently competitive interactions in some experimental protocols but can be revealed as negatively allosteric in other circumstances.

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“…Both compounds block potassium currents but are non-selective in their action. Sotalol is also a non-specific adrenoceptor blocker (Singh et al 1987) while amiodarone has been shown to block both sodium (Sheldon et al 1989) and calcium channels (Nokin et al 1986). …”

Section: Introductionmentioning

confidence: 99%

Inhibition by Compound II, a sotalol analogue, of delayed rectifier current (iK) in rabbit isolated sino-atrial node cells

Lei

Brown

1998

Naunyn-Schmiedeberg's Arch Pharmacol

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The effects of Compound II, a sotalol analogue, on spontaneous electrical activity and on three membrane currents (the delayed rectifier current, iK, the long-lasting inward calcium current, i(Ca,L) and hyperpolarization activated inward current, i(f)) were investigated in rabbit isolated sino-atrial node cells by whole cell clamp with amphotericin-permeabilised patches. A submaximal concentration of Compound II (50 nM) had a significant effect on the time and voltage dependent activation of iK and caused a positive shift of the iK activation curve. As well as blocking i(Kr), it caused some degree of block of i(Ks). Block of iK by Compound II was found to be concentration dependent with an IC50 of approximately 40 nM. 1 microM Compound II nearly completely blocked iK without significantly affecting the peak current or I/V relationships of i(Ca,L) or i(f). 50 nM Compound II caused a significant prolongation of APD100 and of cycle length. It also decreased diastolic depolarization rate without significantly affecting MDP and action potential amplitude. It is concluded that Compound II, a sotalol analogue, slows spontaneous activity of isolated rabbit SA node cells through a selective inhibition of iK.

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Allosteric Modulation of [3H]Nitrendipine Binding to Cardiac and Cerebral Cortex Membranes by Amiodarone

Cited by 26 publications

References 0 publications

Dihydropyridine-like effects of amiodarone and desethylamiodarone on thyrotropin secretion and intracellular calcium concentration in rat pituitary

Dihydropyridine-like effects of amiodarone and desethylamiodarone on thyrotropin secretion and intracellular calcium concentration in rat pituitary

Identification of a novel calcium antagonist binding site in rat brain by SR 33557

Inhibition by Compound II, a sotalol analogue, of delayed rectifier current (iK) in rabbit isolated sino-atrial node cells

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