Dose-Dependent Cx1-Adrenoceptor Antagonist Activity of the Anti-Arrhythmic Drug, Abanoquil (UK-52,046), Without Reduction in Blood Pressure in Man

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. t P < 0.01 compared with baseline. Dose-dependent oa-adrenoceptor blockade of abanoquil in man 407

Table 2 Dose ratios (PS20 in the presence of antagonist/PS20 in the absence of antagonist) for abanoquil 0.25, 0.5 and 1 mg in 10 subjects. Results are means ± s.d. Time (h) 2 4 8 12 24 48 Abanoquil 0.25 mg 1.4 ± 0.6 1.4 ± 0.4 2.0 ± 0.9 1.6 ± 0.6 1.4 ± 0.6 1.2 ± 0.4 Abanoquil 0.5 mg 2.4 ± 1.8 2.0 ± 0.8 2.4 ± 1.3 2.2 ± 0.6 1.7 ± 0.8 1.2 ± 0.4 Abanoquil 1 mg 3.2 ± 1.9 2.8 ± 1.0 3.4 ± 1.1 3.0 ± 1.0 2.2 ± 1.0 1.4 ± 0.3

0c _ Heart rate = CM response to phenylephrine .-0uo E cnE Individual dose-response curves for the heart rate re- 0 E sponse were not analysed because there was a large variability in the response and on several occasions a cDC-.-0 reduction of 10 beats per minute was not achieved. The Q)C0C._ means of the observations at each phenylephrine dose c 0 )O after each treatment at 4 h are shown in Figure 3. The phenylephrine induced reduction in heart rate appears 60 100 150 200 300 400 600 1000 to be antagonised by abanoquil 0.25, 0.5 and 1 mg in a Phenylephrine dose (,ug min-') dose-dependent manner.

Figure 1 Mean (± s.d.) increase in systolic blood pressure (mm Hg) with phenylephrine 4 h after abanoquil (UK-52,046) 0.25 (e), 0.5 (oJ) and 1 mg (m) and placebo (0) in 10 subjects except where indicated.

Supine blood pressure and heart rate

Abanoquil had no effects on supine systolic or diastolic Diastolic blood pressure response to phenylephrine blood pressure. Supine heart rate was increased (P < (PD1o) 0.01) by all three doses of abanoquil at 8 h post-dosing The pre-treatment mean inter-subject variability of PD10 ranged from 58.1 to 82.6 ,ug min-' and the day to day variability ranged from 54.2 to 76.5 ,g min-'. After treatment with abanoquil 0.25, 0.5 and 1 mg, the diastolic 40 blood pressure response to phenylephrine was of a smaller magnitude than the corresponding systolic blood E 30 pressure response such that generally a rise of 20 mm Hg was not achieved and in some cases, even a rise of 10 20 n~~n= mm Hg was not achieved. Thus several dose-response C curves could not be constructed. Statistical .- evaluation 20 was not carried out because of these missing values C T5~10n~~Peyeprn dos 4 i 9 resulting in unequal numbers at each time point and the (,u large variability. The results reported are therefore 0 based on the evaluable dose-response curves (Table 3). Abanoquil 0.25, 0.5 and 1 mg appeared to increase 30 60 100 150 200 300 400 600 1000 the PD10 from 2 h to approximately 48 h. Figure 2 shows Phenylephrine dose (jIg min-1) the effects at 4 h. There was a dose-dependent increase Figure 2 Mean (± s.d.) increase in diastolic blood pressure in the dose ratio with abanoquil 0.25 mg having a (mm Hg) with phenylephrine 4 h after abanoquil (UK-52,046) maximal dose ratio of 2.2 ± 0.5; 0.5 mg of 9.2 ± 14.4; 0.25 (-), 0.5 (0) and 1 mg (U) and placebo (0) in 10 subjects and 1 mg with 21.9 ± 30.2. except where indicated.

Table 3 Mean infusion rates of phenylephrine (jig min-') required to raise diastolic blood pressure by 10 mm Hg (PD10) before and after dosing with abanoquil 0.25, 0.5 and 1 mg and placebo. The number of subjects analysed is indicated by n. Results are means ± s.d. Time (h) O(n = 6) 2 (n = 7) 4 (n = 7) 8 (n = 6) 12 (n = 7) 24 (n = 5) 48 (n = 7) Abanoquil 0.25 mg 55.6 ± 22.8 125.6 ± 87.2 111.1 ± 61.0 123.9 ± 57.2 103.3 ± 56.2 76.6 ± 17.8 80.3 ± 36.4 Abanoquil 0.5 mg 64.4 ± 15.1 462.4 ± 587.5 170.4 ± 199.8 141.0 ± 66.7 145.0 ± 66.6 92.5 ± 49.4 68.0 ± 23.3 Abanoquil 1 mg 76.5 ± 21.6 1125.4 ± 1440.3 543.7 ± 523.0 686.0 ± 803.5 323.4 ± 110.8 158.8 ± 105.6 91.9 ± 26.4 Placebo 54.2 ± 11.5 58.6 ± 15.5 62.1 ± 17.4 56.6 ± 26.6 54.0 ± 7.8 64.8 ± 18.6 61.2 ± 9.3 408 T. C. K. Tham et al.

ranges for the day to day variability within subjects are 25 small. Abanoquil 0.25, 0.5 and 1 mg administered orally (E demonstrated dose-dependent o1-adrenoceptor ant- XDc-o)a) 1 5 agonist activity as assessed by the phenylephrine o _0 pressor dose-response curves (Sumner etal., 1982, 1987; 0)-.- 10 + Sumner & Elliott, 1987), with effects being seen at 48 h with the 1 mg dose. The long duration of action of

cu et (D 5 abanoquil has confirmed the report by Schafers al. (1989) who found that abanocuil after a single intra- 0 venous dose of 0.5 pLg kg- had oti-adrenoceptor 30 60 100 150 200 300 400 600 1000 antagonist activity which lasted up to 12 h. - Phenylephrine dose (,ug min 1) In this study, there was a difference in the antagonism of the systolic and diastolic pressor responses to Figure 3 Mean (± s.d.) decrease in heart rate (beats min-') with phenylephrine 4 h after abanoquil (UK-52,046) 0.25 (0), phenylephrine after administration of all three doses of 0.5 (o) and 1 mg (-) and placebo (0) in 10 subjects except abanoquil; the diastolic pressor response being antagon- where indicated. ised to a greater extent than the systolic. For example, the maximum systolic dose ratio with abanoquil 1 mg was 3.4 while the corresponding diastolic dose ratio was only (65 ± 8, 64 ± 8, 64 ± 9, 58 ± 6 beats min-1 for 21.9. This effect has been described with prazosin abanoquil 0.25, 0.5, 1 mg and placebo respectively) (Singleton et al., 1982; Tomlinson et al., 1989). Tomlinson (Table 4). et al. (1989) found that at doses having similar effects on the systolic pressor response, abanoquil showed less antagonism of the diastolic pressor response than prazosin. A possible explanation for this effect is that Discussion the diastolic pressor response may be more dependent on peripheral ox-adrenoceptors whereas the systolic This study demonstrated that oral abanoquil 0.25, 0.5 response may have a greater cardiac component due to and 1 mg shifted the phenylephrine systolic and diastolic cardiac oL-adrenoceptors which have inotropic effects pressor dose-response curves to the right in a dose- (Bruckner et al., 1985). Thus, Tomlinson et al. (1989) dependent manner with a possibly larger effect on the suggested that abanoquil when compared with prazosin diastolic than on the systolic pressor response although may have less inhibition of peripheral ot-adrenoceptors the differences were not statistically tested. The maximal at equal levels of cardiac a-adrenoceptor antagonism. effects for abanoquil 0.5 and 1 mg on the systolic pressor Another possible explanation is that abanoquil has a responses were at 2 h post-dosing and for 0.25 mg at larger effect on arteries than on veins and venoconstric- 8 h. The effects lasted up to 24 h for abanoquil 0.5 mg tion caused by phenylephrine increases venous return and 1 mg and were still seen at 48 h after the 1 mg dose and hence cardiac output with the result that the right- while with the 0.25 mg dose there was a trend for its ward shift in the dose-response curve for systolic pressure effect to last for 24 h. Abanoquil at these doses did not was reduced compared with that for diastolic (Singleton affect supine blood pressure but caused a small increase et al., 1982). This possibility would require further in- in supine heart rate. The reproducibility of the method- vestigation by comparing the effects of the drug on veins ology of phenylephrine pressor responses is good as the with that on arteries.

Table 4 Mean (± s.d.) supine systolic and diastolic blood pressure (mm Hg) and heart rate (beats min-') before and after dosing with abanoquil 0.25, 0.5 and 1 mg and placebo in 10 subjects (except where indicated) Time (h) O (n= 9) 1 2 4 6 8 12 24 Systolic blood pressure (mm Hg) Abanoquil 0.25 mg 110.9 ± 8.3 108.9 ± 8.0 107.1 ± 10.0 106.9 ± 9.6 108.3 ± 8.1 106.8 ± 9.2 107.8 ± 10.0 110.4 ± 9.4 Abanoquil 0.5 mg 115.4 ± 7.1 111.2 ± 8.0 107.0 ± 8.2 106.3 ± 5.9 107.3 ± 6.2 106.4 ± 7.0 107.2 ± 6.7 112.5 ± 8.8 Abanoquil 1 mg 113.4 + 9.2 109.8 ± 6.7 107.2 ± 10.2 103.6 ± 7.3 107.3 ± 5.8 104.1 ± 6.5 106.7 ± 7.6 111.1 ± 4.7 Placebo 110.0 ± 9.3 110.5 ± 8.4 108.2 ± 10.6 107.3 ± 9.7 107.8 ± 7.3 106.9 ± 9.8 109.5 ± 10.7 111.3 ± 9.2 Diastolic blood pressure (mm Hg) Abanoquil0.25 mg 67.0 ± 4.0 67.7 ± 8.1 68.1 ± 8.3 67.9 ± 5.6 62.2 ± 3.3 63.9 ± 5.9 67.2 ± 4.6 68.3 ± 4.0 Abanoquil 0.5 mg 70.8 ± 6.4 67.8 ± 5.2 70.2 ± 9.0 65.5 ± 5.4 60.7 ± 4.1 62.7 ± 4.3 65.5 ± 3.2 69.8 ± 7.8 Abanoquil 1 mg 69.8 ± 5.0 68.3 ± 6.1 68.2 ± 7.4 66.1 ± 4.8 62.6 ± 3.7 64.4 ± 5.1 68.1 ± 2.5 70.0 ± 8.4 Placebo 67.9 ± 8.7 70.4 ± 7.6 71.6 ± 9.3 69.2 ± 7.6 64.1 ± 6.8 67.0 ± 6.3 68.2 ± 6.0 68.4 ± 7.7 Heart rate (beats min-) Abanoquil 0.25 mg 63.7 ± 10.2 61.8 ± 9.8 59.6 ± 8.8 61.6 ± 7.2 71.0 ± 9.0 64.7 ± 8.0** 61.7 ± 7.3 65.4 ± 3.4 Abanoquil 0.5 mg 67.2 ± 8.6 63.4 ± 11.1 60.0 ± 8.8 63.8 ± 9.0 69.2 ± 7.7 64.1 ± 7.5** 63.3 ± 6.0 64.0 ± 7.3 Abanoquil 1 mg 61.6 ± 7.8 62.4 ± 9.6 61.1 ± 10.4 65.0 ± 10.6 70.4 ± 14.0 64.5 ± 8.6** 67.0 ± 6.5 66.2 ± 7.3 Placebo 62.2 ± 4.1 60.3 ± 7.9 56.3 ± 6.7 59.2 ± 7.8 65.6 ± 7.9 57.6 ± 6.0 61.0 ± 8.0 61.5 ± 8.6 **P < 0.01 vs placebo. Dose-dependent a-adrenoceptor blockade of abanoquil in man 409

The present study showed that abanoquil 0.25, 0.5 12 h post-placebo when compared with baseline; this and 1 mg did not affect supine blood pressure while there would have occurred at approximately 18.00 and 22.00 h. is a small increase in heart rate at 8 h post-dosing. These This observation has not been previously described in findings are different from those of Tomlinson et al. man. Possible explanations include increased sensitivity (1989) who showed that intravenous abanoquil 0.8 ,ug of vascular responsiveness to a-adrenoceptor agonists kg-1 which has an approximately equivalent dose ratio in the evening or diurnal variation in the number of ac- (3.4, 95% confidence interval 2.2-5.3) to that of oral adrenoceptors and may account for the effects on supine abanoquil 1 mg (3.4, s.d. 1.1), reduced supine systolic heart rate at 8 h post-dosing. (8.5 mm Hg) and diastolic pressures with an increase in In conclusion, oral abanoquil 0.25, 0.5 and 1 mg heart rate although prazosin caused a larger reduction demonstrated dose-dependent ol-adrenoceptor ant- in supine diastolic pressure. However, Harron et al. agonist activity with effects lasting for 24 to 48 h. There (1989) also did not show any change in supine blood was no effect on supine blood pressure but there was pressure after intravenous abanoquil 0.8 pg kg-' a small increase in heart rate at 8 h post-dosing. This although unlike our study they found no change in would suggest that abanoquil at these doses has marked supine heart rate. It would not be possible to deduce the oL1-adrenoceptor antagonist activity with no effects on mechanism of action for the increased heart rate from supine blood pressure and minimal effects on heart rate. our study but it may reflect a reflex tachycardia from peripheral vasodilatation. This study demonstrated a variability in the vascular The study was supported by a grant from Pfizer Central ot-adrenoceptor mediated response with time over a Research. We also would like to thank Dr James G. Riddell 24 h period because the phenylephrine induced systolic for his support and helpful comments and Dr Barbara pressor response, PS20 was significantly lower at 8 and McDermott for her statistical guidance.

References

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