Dose-Dependent Cx1-Adrenoceptor Antagonist Activity of the Anti-Arrhythmic Drug, Abanoquil (UK-52,046), Without Reduction in Blood Pressure in Man
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Br. J. clin. Pharmac. (1992), 33, 405-409 Dose-dependent cx1-adrenoceptor antagonist activity of the anti-arrhythmic drug, abanoquil (UK-52,046), without reduction in blood pressure in man TONY C. K. THAM, SUZANNE GUY, ROBIN G. SHANKS & DEAN W. G. HARRON Department of Therapeutics and Pharmacology, The Queen's University of Belfast, Belfast, Northern Ireland 1 The dose-dependency of the co1-adrenoceptor antagonist activity of the anti-arrhythmic abanoquil (UK-52,046) was investigated in 10 healthy male subjects who received serially increasing infusions of phenylephrine before and 2, 4, 8, 12, 24 and 48 h after single oral doses of abanoquil 0.25, 0.5 and 1 mg and placebo in a double-blind randomised manner. 2 The doses of phenylephrine required to increase systolic BP by 20 mm Hg (PS20) were calculated using a quadratic fit to the individual dose-response curves. 3 Abanoquil 0.25, 0.5 and 1 mg increased the PS20 in a dose-dependent manner with effects which were maximal at 2 to 8 h and lasted for 24 to 48 h (P < 0.05). Maximal dose ratios were: abanoquil 0.25 mg 2.0 ± 0.9, 0.5 mg 2.4 ± 1.3, 1 mg 3.4 ± 1.1. 4 No change occurred in supine BP but a small increase (P < 0.01) occurred in supine HR 8 h post-dosing (64 ± 9, 58 ± 6 beats min-1 for abanoquil 1 mg and placebo respectively). 5 Therefore abanoquil 0.25, 0.5 and 1 mg showed dose-dependent otl-adrenoceptor antagonist activity with no effect on supine BP. Keywords cx-adrenoceptor antagonist UK-52,046 abanoquil dose-response phenylephrine Introduction There is evidence for a major role of adrenergic stimula- blood pressure (Aubry et al., 1988; Uprichard et al., tion in the genesis of fatal arrhythmias secondary to 1988). Abanoquil is a more potent otl-adrenoceptor ischaemia and reperfusion which may be due to an antagonist with regard to its effect on phenylephrine increase in ot-adrenergic receptors (Culling et al., 1987; induced pressor responses than prazosin at doses that do Sheridan et al., 1980). ot-adrenoceptor stimulation not reduce blood pressure (Spiers et al., 1991), but during reperfusion also appears to enhance myocardial unlike prazosin, it has no effect on baroreflex sensitivity calcium uptake potentially contributing to both malignant in animals (Spiers et al., 1991) and man (McKaigue & arrhythmias and myocardial cell damage (Corr & Sharma, Harron, 1990). Tomlinson et al. (1989) demonstrated 1984). a-adrenoceptor antagonists such as prazosin and that there was a lesser inhibition of the phenylephrine phentolamine have been shown to protect against diastolic pressor response curves following abanoquil ischaemically-induced or reperfusion arrhythmias in 0.8 ,ug kg-' compared with prazosin 16 ,ug kg-' at equal animals (Sheridan et al., 1980; Williams et al., 1982). levels of systolic ot-adrenoceptor antagonism. They However, the hypotensive actions of these agents have suggested that since diastolic pressor response may be limited their potential clinical application in acute more dependent on peripheral ot-adrenoceptors than myocardial infarction or post-thrombolysis. the systolic pressor response which has a greater cardiac Abanoquil (UK-52,046 (4-amino-6,7-di-methoxy-2- component, abanoquil may exhibit a smaller peripheral (1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinol-2-yl) quino- vascular effect than existing ot-adrenoceptor antagonists. line methanesulphonate)) is a novel otl-adrenoceptor In patients with ischaemic heart disease, abanoquil 1 ,ug antagonist which has marked anti-arrhythmic activity in kg- 1 resulted in a small reduction in blood pressure with animals at doses which have minimal impact on systemic no adverse haemodynamic effects (Silke et al., 1990). Correspondence: Dr D. W. G. Harron, Department of Therapeutics and Pharmacology, Whitla Medical Building, The Queen's University of Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland 405 406 T. C. K. Tham et al. Schafers et al. (1989) found that in healthy subjects, described above. Supine heart rate and blood pressure intravenous abanoquil in a dose of 0.5 jig kg-' showed were measured after 15 min rest before each set of a1-adrenoceptor antagonism by inhibiting the pressor phenylephrine infusions and also at 1 and 6 h post- response to phenylephrine. However, the effects of oral dosing. administration have not been studied. For each subject, individual dose-response curves for The objectives of this study were to determine the the changes induced by phenylephrine were analysed by phenylephrine induced ot1-adrenoceptor antagonist a non-linear quadratic fit (non-linear regression pro- dose-response relationship over the anticipated thera- gramme of SPSS-PC (V3.0)). From the individual peutic dose range of abanoquil 0.25 to 1 mg and to quadratic equations, the following indices were calcu- evaluate its duration of effect in man. lated: the dose of phenylephrine required to increase systolic blood pressure by 20 mm Hg (PS20) and the dose of phenylephrine required to increase diastolic blood pressure by 10 mm Hg (PD10). Dose ratios from the ratio of these values in the presence and absence of Methods abanoquil were calculated. PS20, supine heart rate and blood pressure at each The study was approved by the Research Ethics Com- time point were analysed by repeated measures analysis mittee of the Queen's University of Belfast. Ten healthy of variance (MANOVA Programme of SPSS-X (V2.0)) male volunteers (age 22 ± 2 years, mean weight 72.3 + followed by Dunnett's test for multiple means com- 7.2 kg) participated in the study after giving a full written parison, comparing treatments with placebo (Winer, consent. Having abstained from caffeine for at least 8 h 1971). A P value of less than 0.05 was taken as statistically and after a light breakfast, the subjects presented at the significant. Results are expressed as means ± s.d. same time at weekly intervals. An intravenous infusion of saline was commenced into a forearm vein. After resting supine for 15 min, baseline measurements of heart rate (five consecutive R-R intervals on an ECG rhythm strip) and blood pressure (Hawksley random Results zero sphygmomanometer; diastolic blood pressure was taken at Korotkoff phase 4) as a mean of two observa- All 10 subjects completed the study without any untoward tions were made. Phenylephrine hydrochloride 40 jig effects. min-' was then infused using an infusion pump (B Braun Perfusor VI). When the initial dose of pheny- Systolic blood pressure response to phenylephrine (PS20) lephrine 40 ,ug min-' had been running for 4 min, heart rate and blood pressure were measured. After running The pre-treatment mean inter-subject variability of PS20 for 8 min, the rate of infusion of phenylephrine was then ranged from 92.4 to 173.3 ,ug min-' and the dar to day increased to 60 ,ug min-' and 4 min later, the same variability ranged from 108.0 to 127.8 ,ug min- . There observations were repeated and the infusion increased were no significant effects on pre-drug PS20 between again after 8 min. The rate of infusion was increased treatments. Abanoquil 0.5 and 1 mg increased PS20, gradually instead of being doubled in order to prevent with maximal effects occurring at 2 to 8 h (P < 0.05). The an excessively rapid rise in blood pressure. Serial doses effects lasted for 24 h with abanoquil 0.5 mg (P < 0.01) of phenylephrine through the range 40, 60, 100, 150, and were present at 48 h with abanoquil 1 mg (P < 0.01). 200, 300, 400, 600, 1000 and 1500 ,ug min- 1 were infused With abanoquil 0.25 mg there were trends towards an in the same manner until the systolic blood pressure increase in PS20 from 2 to 24 h, a significant increase increased by 30 mm Hg from baseline or the diastolic however occurred at 8 h post-dosing only (Table 1, blood pressure exceeded 110 mm Hg or the subject Figure 1). could not tolerate the effects of phenylephrine. Single There was a dose-dependent increase in the dose ratio oral doses of abanoquil 0.25, 0.5 and 1 mg or placebo with abanoquil 0.25 mg having a maximal dose ratio of were administered in a double-blind randomised manner 2.0 ± 0.9; 0.5 mg of 2.4 ± 1.3; and 1 mg of 3.4 ± 1.1 separated by at least 1 week until each subject received (Table 2). all the doses. Phenylephrine infusions were then per- The PS20 for placebo was lower at 8 and 12 h when formed at 2, 4, 8, 12, 24 and 48 h post-dosing as compared with its baseline (pre-drug) values (P < 0.05). Table 1 Mean infusion rates of phenylephrine (,ug min-') required to raise systolic blood pressure by 20 mm Hg (PS20) before and after dosing with abanoquil 0.25, 0.5 and 1 mg and placebo in 10 volunteers. Results are means ± s.d. Time (h) 0 2 4 8 12 24 48 Abanoquil 0.25 mg 112.4 ± 43.0 142.6 ± 76.8 151.7 ± 65.9 164.8 ± 74.6* 114.5 ± 64.1 131.6 ± 63.5 123.3 ± 47.7 Abanoquil 0.5 mg 127.8 ± 25.2 233.0 ± 173.4* 219.3 ± 123.5** 191.3 ± 112.0** 164.6 ± 73.6** 155.1 ± 58.6** 126.2 ± 41.0 Abanoquil 1 mg 114.0 ± 24.0 294.8 ± 157.3** 288.5 ± 127.4** 268.7 ± 80.8** 212.4 ± 81.5** 197.2 ± 74.9** 146.8 ± 31.3** Placebo 108.0 ± 27.6 98.3 ± 21.9 103.5 ± 19.2 81.4 ± 15.3t 71.1 ± 16.Ot 95.6 ± 23.5 103.7 ± 17.8 * P < 0.05 and ** P < 0.01 compared with placebo.