Studies with abanoquil (UK‐52,046) a novel quinoline alpha 1‐ adrenoceptor antagonist: II. Duration of action, pharmacokinetics and concentration‐effect relationships in normotensive subjects.

Abstract

3 Despite evidence of substantial oxl-adrenoceptor antagonism abanoquil had no significant effect on blood pressure, supine and erect, but there were small and statistically significant increments in heart rate.4 The degree of ol-adrenoceptor antagonism was related to whole blood concentrations abanoquil: the PD-ratios of phenylephrine pressor responses performed at 1, 6, and 12 h post dosing were significantly correlated with log drug concentrations (r = 0.57 for systolic (P < 0.05) and r = 0.78 for diastolic blood pressure (P < 0.005). 5 In conclusion, abanoquil produced significant oal-adrenoceptor antagonism which was related to circulating drug concentrations. The absence of other significant cardiovascular effects suggests that abanoquil warrants further clinical study as an antiarrhythmic agent.

Studies with abanoquil (UK‐52,046) a novel quinoline alpha 1‐ adrenoceptor antagonist: I. Effects on blood pressure, heart rate and pressor responsiveness in normotensive subjects.

“…In the dose-finding study, substantial 2-3 fold rightward shifts of phenylephrine pressor dose-responses were obtained with abanoquil at a dose of 0.4 ,ug kg-'. These rightward shifts of the phenylephrine pressor response curves are indicative of an antagonist effect on human oal-adrenoceptors and are consistent with the results of the earlier animal studies (Aubry et al, 1988) and with the results from other human studies (Schafers et al, 1991;Tomlinson et al, 1989).…”

“…Despite this evidence of significant a1-adrenoceptor blockade, abanoquil had no significant effect on supine blood pressure and, more importantly, on erect blood pressure and there was only an associated slight acceleration of heart rate. Similar results were obtained in a second series of studies with 0.5 ,ug kg-1 (Schafers et al, 1991) in which neither supine nor erect blood pressure showed any significant reductions despite the presence of an effective and relatively long lasting (12 h) antagonism of phenylephrine pressor responses. Thus, abanoquil, which is a quinoline derivative, appears to show some haemodynamic differences from the 'conventional' quinazoline derivative a1-adrenoceptor antagonists, prazosin and doxazosin.…”

“…These slight increases in both supine and erect heart rate appear to be consistent phenomena: although statistical significance was not achieved in this (dose finding) study with 0.4 ,ug kg-l it was achieved for both supine and erect heart rate in the follow-up series of studies involving an i.v. dose of 0.5 j±g kg-' (Schafers et al, 1991). The results of the atenolol study also lend some support to this interpretation since concomitant ,-adrenoceptor blockade (and attenuation of any baroreflex-mediated increase in heart rate) apparently 'unmasked' a vasodilating effect of abanoquil leading to a fall in blood pressure additional to that produced by atenolol alone.…”