Actions and mechanisms of action of novel analogues of sotalol on guinea‐pig and rabbit ventricular cells

Abstract

1 The actions and mechanisms of action of novel analogues of sotalol which prolong cardiac action potentials were investigated in guinea-pig and rabbit isolated ventricular cells. 2 In guinea-pig and rabbit cells the compounds significantly prolonged action potential duration at 20% and 90% repolarization levels without affecting resting membrane potential. In guinea-pig but not rabbit cells there was an increase in action potential amplitude and in rabbit cells there was no change in the shape or position of the 'notch' in the action potential. 3 Possible mechanisms of action were studied in more detail in the case of compound II (1-(4-methanesulphonamidophenoxy)-3-(N-methyl 3,4 dichlorophenylethylamino)-2-propanol). Prolongation of action potential duration continued to occur in the presence of nisoldipine, and calcium currents recorded under voltage-clamp conditions were not reduced by compound II (1 pM). Action potential prolongation by compound II was also unaffected in the presence of 10 JiM tetrodotoxin.4 Compound II (1 !M) did not influence IKI assessed from the current during ramp changes in membrane potential (20 mV s') over the range -90 to -10 mV.5 Compound II (1 JLM) blocked time-dependent delayed rectifier potassium current (IK) activated by step depolarizations and recorded as an outward tail following repolarization. When a submaximal concentration (50 nM) was applied there was no change in the apparent reversal potential of IK-6 Submaximal concentrations of compound II were without effect on activation of IK with time at a membrane potential of + 40 mV, and no changes were detected in the time constants of the two components of IK decay over the range of potentials -60 to 0 mV. Compound 11 (50 nM) appeared to cause a small shift in the activation of IK with membrane potential (an apparent shift of approximately 10 mV in the depolarizing direction at the mid-point of the curve). 7 Log dose-response curves for action potential prolongation and for blockade of IK by compound II were similar. The IC50 for compound II was approximately 30 nM. 8 It is concluded that this novel series of compounds prolongs action potential duration, and that in the case of compound II the evidence supports a potent selective effect on the time-dependent potassium current IK, an effect which can account for this prolongation.

Identification of ion-channel modulators that protect against aminoglycoside-induced hair cell death

“…Of the 13 compounds that protect mouse OHCs from gentamicin-induced death, 4 (13087, 13097, 13143, and 13154) are potassium channel blockers (31)(32)(33)(34). Two of these are blockers of K V 7 channels (13097 and 13143), but they do not block the MET channel.…”

The positive inotropic effect of compound II, a novel analogue of sotalol, on guinea‐pig papillary muscles and single ventricular myocytes

“…This concentration was chosen to produce maximal prolongation of the action potential (Connors et al, 1991;1992). There was a consistent increase in force in all preparations of 14 ± 4.6% (mean ± s.e.mean, n = 4; P< 0.05).…”

“…The influence of compound II on action potential duration was studied at 100 nM. The effects on membrane currents (see later) were tested at 1 JIM for consistency with a previous study, (Connors et al, 1992). Both doses of drug give maximal prolongation of the action potential (Connors et al, 1992 Terrar & White, 1989;White & Terrar, 1990a,b the driving force of the electrogenic Na:Ca exchange to extrude Ca2" from the cell.…”

“…The effects on membrane currents (see later) were tested at 1 JIM for consistency with a previous study, (Connors et al, 1992). Both doses of drug give maximal prolongation of the action potential (Connors et al, 1992 Terrar & White, 1989;White & Terrar, 1990a,b the driving force of the electrogenic Na:Ca exchange to extrude Ca2" from the cell. Reduced extrusion of Ca2" may then lead to increased loading of intracellular Ca2" stores allowing a greater Ca2" release by the following action potential (see, Boyett et al, 1993).…”

“…Compound II (1-(4-methanesulphonamidophenoxy)-3-(Nmethyl 3,4,dichlorophenylethylamino)-2-propanol) is an analogue of sotalol which has been shown to prolong cardiac action potentials with a 1000 fold increase in potency, compared with the parent compound, and is devoid of any P-adrenoceptor blocking activity (Connors et al, 1991;1992).…”