Negative chronotropic effect of a novel class III antiarrhythmic drug, UK‐68,798, devoid of β‐blocking action on isolated guinea‐pig atria

Abstract

1 The chronotropic effects of a novel class III antiarrhythmic drug, 798, and the ,6-adrenoceptor blocker, propranolol, for comparison, were studied on spontaneously beating right atria isolated from guinea-pigs in the absence and presence of increasing concentrations of isoprenaline (10 10-10-4 M).2 UK-68,798 (10-9-10-M) decreased spontaneous atrial rate by 6-21%. Propranolol (10-81-106M) also had a negative but significantly smaller chronotropic effect. 3 UK-68,798 dose-dependently reduced the maximal positive chronotropic effect induced by isoprenaline, but without significantly shifting the concentration-response curve for isoprenaline in a parallel fashion. A pD'2 value of 5.88 was obtained. As expected, propranolol displayed a competitive inhibition with a pA2 value of 8.21. 4 The results demonstrate a negative chronotropic effect of UK-68,798, which is not associated with a fJ-adrenoceptor blocking action. We suggest that the negative chronotropic effect is linked with potassium channel blockade and thereby the class III antiarrhythmic action of UK-68,798.

Selective IK blockade as an antiarrhythmic mechanism: effects of UK66,914 on ischaemia and reperfusion arrhythmias in rat and rabbit hearts

“…The higher concentration of drug (1.0 1M) also caused slight bradycardia, in accordance with other studies in vitro (Tande et al, 1990;Yang et al, 1991) Taken together, the rat and rabbit data indicate that for UK66,914 to inhibit reperfusion-induced VF, IK blockade and associated QT prolongation are necessary and sufficient. Lack of protective action in rat is not merely negative evidence since, should protection have been observed then this would have falsified the IK hypothesis by indicating that a non-specific mechanism is sufficient to explain the protective action of the drug, and IK block (which does not occur in the rat ventricle) unnecessary.…”

Role of the Na+–H+exchanger (NHE1) in heart muscle function during transient acidosis. A study in papillary muscles from rat and guinea pig hearts

“…Ventricular papillary muscle preparations were dissected and mounted horizontally in a 5-mL tissue chamber while superfused with bicarbonate solution (5 mL/min) at 37°C. The composition (Yang et al 1991) of the bicarbonate solution was (in mmol/L): K + , 5.0; Na + , 141.2; Ca 2+ , 2.0; Mg 2+ , 1.0; Cl -, 131.0; H 2 PO 4 -, 1.2; HCO 3 -, 20.0; and glucose, 10. This solution was continuously gassed with 95% O 2 -5% CO 2 (pH 7.4).…”

Acidification alters Antiarrhythmic Drug Blockade of the ether‐a‐go‐go‐related Gene (HERG) Channels

“…Dofetilide, a methanesulfonanilide and a class III antiarrhythmic agent, is known to be a potent and selective I kr /HERG blocker and this property is believed to account for dofetilide's ability to suppress cardiac arrhythmias (Yang et al 1991 & 1992). Noticeably, while most drugs lose their efficacy against arrhythmias associated with myocardial ischaemia and reperfusion, dofetilide remains effective under such situations (Yang et al 1991 & 1992). This property is of paramount importance considering that these arrhythmias are often life‐threatening and can lead to sudden cardiac death.…”