Effects of the myocardial‐selective α₁‐adrenoceptor antagonist UK‐52046 and atenolol, alone and in combination, on experimental cardiac arrhythmias in dogs

Abstract

Adrenaline‐induced arrhythmias in anaesthetized dogs respired with halothane were attenuated in 3 groups of 6 dogs by either UK‐52046, 3.8 ± 1.4μgkg−1 (mean ± s.e.mean), atenolol 14.6 ± 2.1 μgkg−1, or a combination containing equal amounts of the two drugs of 0.36 ± 0.1 μgkg−1. The pressor response to adrenaline was reduced (P < 0.01) by UK‐52046 but not by atenolol or the combination of both drugs. In a group of 6 dogs with multiventricular ectopic beats 24 h after coronary artery ligation (CAL), UK‐52046, 32μgkg−1, increased the number of sinus beats in each 5min period from 137 ± 47 to 662 ± 99 (P < 0.01); this was associated with a significant (P < 0.01) fall in blood pressure. Atenolol in doses of up to 800μg kg−1 had no effect. UK‐52046, 3.7 ± 1.4μgkg−1, prevented adrenaline‐induced arrhythmias 3–4 days after CAL in 6/6 conscious dogs; atenolol in doses of up to 100μgkg−1 produced an 84.4 ± 7.4% reduction in the number of ventricular ectopic beats. A combination containing 3.7 ± 1.1 μgkg−1 of each drug prevented the arrhythmia in 6/6 dogs. The pressor response to adrenaline was attenuated (P < 0.05) by UK‐52046, but resting blood pressure was unaffected by the different treatments. An increase (P < 0.01) in heart rate was associated with both UK‐52046 and the combination. Neither UK‐52046 (doses up to 64μgkg−1) nor atenolol (up to 800μgkg−1) had any effect upon ouabain‐induced arrhythmias in 2 groups of 6 anaesthetized dogs. In a study of the early (1a/1b) arrhythmias of acute myocardial ischaemia, the total number of ventricular ectopic beats occurring within 30min of CAL was not reduced by 4μgkg−1 UK‐52046 but fell (P < 0.01 compared with placebo) after 8μgkg−1 [median values with ranges for placebo, 4μgkg−1 and 8μgkg−1 respectively 190 (4–674), 246 (9–1204) and 12 (1–154)]. Both doses of UK‐52046 were associated with significant falls in blood pressure. The arrhythmias produced by programmed electrical stimulation were studied in 2 groups of 6 conscious dogs, 7–30 days after CAL. With placebo, 4/6 dogs remained unchanged and 2 died: UK‐52046 prevented arrhythmias in 2/6, 2 remained unchanged and 2 died (P = 0.29). Compared with placebo, blood pressure fell with doses greater than 4μgkg−1. These results indicate antiarrhythmic effects of UK‐52046 in a number of experimental models and suggest an enhanced role of α‐receptors in the genesis of ischaemia‐related arrhythmias. In several of the models used, UK‐52046 produced haemodynamic changes in keeping with peripheral α‐adrenoceptor antagonism.

An acute study of the electrophysiological and haemodynamic effects of intravenous UK‐52,046, a novel alpha 1‐adrenoceptor antagonist.

“…A new agent, UK-52,046 (4-amino-6,7-dimethoxy-2-(1,2,3,4-tetrahydro-6,7-dimethoxyisoquinol-2-yl) quinoline methanesulphonate), is a potent ao -adrenoceptor antagonist which shows little vasodilator activity in doses which are antiarrhythmic in experimentally induced ischaemia (Aubrey et Uprichard et al, 1988). The purpose of this study, which was performed in a non-ischaemic setting, was to examine the acute electrophysiological and haemodynamic effects of UK-52,046 given intravenously in man.…”

“…Antagonists to these receptors have been shown capable of restoring sinus rhythm after experimentally induced arrhythmias, but their clinical use has been hampered by the hypotensive effects of these compounds (Sheridan et al, 1980). A new agent, UK-52,046 (4-amino-6,7dimethoxy-2-(1,2,3,4-tetrahydro-6,7-dimethoxyisoquinol-2-yl) quinoline methanesulphonate), is a potent ao -adrenoceptor antagonist which shows little vasodilator activity in doses which are antiarrhythmic in experimentally induced ischaemia (Aubrey et al, 1988;Uprichard et al, 1988). The purpose of this study, which was performed in a non-ischaemic setting, was to examine the acute electrophysiological and haemodynamic effects of UK-52,046 given intravenously in man.…”

Enhanced α‐adrenoceptor responsiveness and receptor number during global ischaemia in the Langendorff perfused rat heart

“…*e ventricular chronotropic responses to a-It has been suggested that where myocardial ischaemia is lation were potentiated during periods of localised to small regions, local c-adrenoceptor mediated pro--hanism for the enhanced a-adrenoceptor longation of action potential duration may combine with fiy be explained at least partially, by an adrenoceptor-mediated shortening of action potential sity of [3H]-prazosin binding sites in the duration in areas of normal coronary flow, to produce the indicating an increase in the number of electrical inhomogeneity suitable for the emergence of ven-)ceptors. Such an increase in the density of tricular arrhythmias (Uprichard et al, 1988). If this is correct, ding sites induced by ischaemia has been the ischaemia-induced increase in a-adrenoceptor responsivee cat Crafford, ness may not be an important factor in the genesis of arrhyth-1988) and the dog heart (Mukherjee et al, mias in a model of global ischaemia, where a-mediated nge can be demonstrated in the guinea-pig prolongation of action potential duration may be more 1l., 1985), although the number of ventricu-uniform.…”

“…The -sponses to phenylephrine were enhanced. increase in a-adrenoceptor responsiveness therefore, does not ous in vivo studies in the cat (Sheridan et (Uprichard et al, 1988). If this is correct, ding sites induced by ischaemia has been the ischaemia-induced increase in a-adrenoceptor responsivee cat (Corr et (1984) could not demonstrate a proring myocardial ischaemia in the rat.…”

Dose‐dependent alpha 1‐adrenoceptor antagonist activity of the anti‐ arrhythmic drug, abanoquil (UK‐52,046), without reduction in blood pressure in man.

“…Abanoquil ,7-di-methoxy-2-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinol-2-yl) quinoline methanesulphonate)) is a novel otl-adrenoceptor antagonist which has marked anti-arrhythmic activity in animals at doses which have minimal impact on systemic blood pressure (Aubry et al, 1988;Uprichard et al, 1988). Abanoquil is a more potent otl-adrenoceptor antagonist with regard to its effect on phenylephrine induced pressor responses than prazosin at doses that do not reduce blood pressure (Spiers et al, 1991), but unlike prazosin, it has no effect on baroreflex sensitivity in animals (Spiers et al, 1991) and man (McKaigue & Harron, 1990).…”