Comparative β-blocking activities and electrophysiologic actions of racemic sotalol and its optical isomers in anesthetized dogs

Gomoll, Allen W.; Bartek, M.J.

doi:10.1016/0014-2999(86)90597-2

Cited by 44 publications

(22 citation statements)

References 23 publications

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“…Additionally, d-sotalol was one-to threefold more potent than either l-sotalol or the racemate in inducing AP prolongation (Lathrop, 1985). Other studies demonstrated a weak b-adrenoceptor-blocking activity of d-sotalol compared with l-sotalol (Gomoll and Bartek, 1986;Manley et al, 1986;Tande and Refsum, 1988). Taken together, all these data suggest that the blockade of the b-adrenoceptors by the l-element in dl-sotalol may play a role in the divergent results of d-and dl-sotalol on STV(APD).…”

Section: Lvmms As a Preclinical Model For The Assessment Of Drug-indumentioning

confidence: 94%

Dog left ventricular midmyocardial myocytes for assessment of drug‐induced delayed repolarization: short‐term variability and proarrhythmic potential

Abi‐Gerges

Valentin

Pollard

2010

British J Pharmacology

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Background and purpose: Evaluation of the potential for delayed ventricular repolarization and proarrhythmia by new drugs is essential. We investigated if dog left ventricular midmyocardial myocytes (LVMMs) that can be used as a preclinical model to assess drug effects on action potential duration (APD) and whether in these cells, short-term variability (STV) or triangulation could predict proarrhythmic potential. Experimental approach: Beagle LVMMs and Purkinje fibres (PFs) were used to record APs. Effects of six reference drugs were assessed on APD at 50% (APD50) and 90% (APD90) of repolarization, STV(APD), triangulation (ratio APD90/APD50) and incidence of early afterdepolarizations (EADs) at 1 and 0.5 Hz. Key results: LVMMs provided stable recordings of AP, which were not affected by four sequential additions of dimethyl sulphoxide. Effects of dofetilide, d-sotalol, cisapride, pinacidil and diltiazem, but not of terfenadine, on APD in LVMMs were found to be comparable with those recorded in PFs. LVMMs, but not PFs, exhibited a proarrhythmic response to IKr blockers. Incidence of EADs was not related to differences in AP prolongation or triangulation, but corresponded to beat-to-beat variability of repolarization, here quantified as STV of APD. Conclusions and implications:LVMMs provide a suitable preclinical model to assess the effects of new drugs on APD and also yield additional information about putative indicators of proarrhythmia that add value to an integrated QT/TdP risk assessment. Our findings support the concept that increased STV(APD) may predict drug-induced proarrhythmia.

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Section: Lvmms As a Preclinical Model For The Assessment Of Drug-indumentioning

confidence: 94%

Dog left ventricular midmyocardial myocytes for assessment of drug‐induced delayed repolarization: short‐term variability and proarrhythmic potential

Abi‐Gerges

Valentin

Pollard

2010

British J Pharmacology

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“…This action is attributable primarily to cardiac potassium channel block. 3,20,21,30,32 The effects may be expected to decrease during VF because of a reverse use-dependence. However, the increase in VF cycle length produced by class III antiarrhythmic drugs 12,25 is explained in terms of concomitant increments in refractoriness.…”

Section: Modification Of the Wl During Arrhythmiamentioning

confidence: 99%

Alteration of Ventricular Fibrillation by Flecainide, Verapamil, and Sotalol

et al. 2000

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“…The effects of (+)-and ( -)-sotalol at PZ-adrenoceptors have not been characterized. (*)-Amosulalol is considered to be a nonselective P-adrenoceptor antagonist having pA2 values of 7.60, 7.30, 7.70, and 7.50 at the PI -adrenoceptors of rat right atria,8 guinea o 1993 Wiley-Liss, Inc. pig atria,9 rat jugular vein, lo and rat right ventricle l1 and of 7.04 and 7.90 at the 02-adrenoceptors of the guinea pig tra-chea12 and of the rat aorta,13 respectively. The activity of ( f )-amosulalol at the P1 -adrenoceptors of the rat right ventri-cle14 and the rat atrium and at the P2-adrenoceptors of the guinea pig tracheal2 is predominantly due to the (-)-enantiomer.…”

Section: Introductionmentioning

confidence: 91%

The effects of (±)‐, (+)‐, and (−)‐atenolol, sotalol, and amosulalol on the rat left atria and portal vein

Doggrell

1993

Chirality

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The effects of (+/-)-, (+)-, and (-)-atenolol, sotalol, and amosulalol alone on the rat left atria and portal vein and on the respective beta 1- and beta 2-adrenoceptor-mediated responses to isoprenaline have been determined. (+/-)-Atenolol at 10(-6) M had no effect whereas high concentrations of (+/-)- and (-)-sotalol, 10(-5)-10(-4) M, and (+/-)-, and (-)-amosulalol depressed the response of the rat left atria to cardiac stimulation which indicates membrane stabilizing activity. None of the drugs tested had any effect alone on the rat portal vein. The order of potency as antagonists was (+/-)-amosulalol > (+/-)-atenolol > (+/-)-sotalol at beta 1-adrenoceptors and (+/-)-amosulalol > (+/-)-sotalol > (+/-)-atenolol at beta 2-adrenoceptors. (+/-)-Atenolol and (+/-)-amosulalol are beta 1-selective whereas (+/-)-sotalol is beta 2-selective. For each of the racemic beta-blockers, the beta 1- and beta 2-adrenoceptor blocking activity was predominantly due to the (-)-enantiomer.

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Comparative β-blocking activities and electrophysiologic actions of racemic sotalol and its optical isomers in anesthetized dogs

Cited by 44 publications

References 23 publications

Dog left ventricular midmyocardial myocytes for assessment of drug‐induced delayed repolarization: short‐term variability and proarrhythmic potential

Dog left ventricular midmyocardial myocytes for assessment of drug‐induced delayed repolarization: short‐term variability and proarrhythmic potential

Alteration of Ventricular Fibrillation by Flecainide, Verapamil, and Sotalol

The effects of (±)‐, (+)‐, and (−)‐atenolol, sotalol, and amosulalol on the rat left atria and portal vein

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