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.

Abstract

1 Abanoquil (UK 52,046) is a novel, quinoline-derivative, oxl-adrenoceptor antagonist which, on the basis of animal studies, possesses antiarrhythmic activity at doses which have little or no effect on blood pressure. 2 In two placebo-controlled, double-blind, crossover studies the cX1-adrenoceptor antagonist activity (phenylephrine pressor responses) and the effects on blood pressure and heart rate (in the presence and absence of concomitant 13-adrencoeptor blockade) have been investigated in healthy, normotensive subjects following the intravenous administration (i.v.) of abanoquil.3 In the first study, abanoquil at a dose of 0.4 ,ug kg-' i.v. (as a bolus or by increments) produced significant cx1-adrenoceptor antagonism (with rightward shifts of more than two-fold in the phenylephrine pressor dose-response curves) but no significant effects on supine or erect blood pressure and heart rate.4 In the second study, a dose of 0.5 ,ug kg-' i.v. had no significant effect on supine or erect blood pressure but pre-treatment with atenolol promoted a small fall in erect blood pressure without causing significant orthostatic hypotension. 5 In conclusion, significant ao1-adrenoceptor antagonism without marked reflex tachycardia or profound postural hypotension suggest that abanoquil has a different haemodynamic profile from that of 'classical' peripheral a1l-adrenoceptor antagonists.

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.

“…This study confirms and extends the results of previous studies with abanoquil (Schafers et al, 1991) with rightward shifts of the phenylephrine dose-responses, maximal at 1 h but detectable for up to 12 h after a single intravenous dose. The preliminary pharmacokinetic analysis suggests that the whole blood concentration-time profile of intravenous abanoquil is most appropriately described by a two-compartment model as has previously been found for both prazosin and doxazosin (Meredith et al, 1985), with a mean terminal elimination half-life of around 6 h. In the studies with prazosin and doxazosin the measured blood concentrations were around 10 ng ml-' i.e.…”

“…The results of preliminary studies in man have been consistent with those of animal studies in suggesting that abanoquil (UK-52,046) (4-amino-6-7-dimethoxy-2 -(1,2,3,4 -tetrahydro -6,7 -dimethoxyisoquinol -2 -yl) quinoline methanesulphonate) may have a relative selectivity for cardiac rather than peripheral vascular xl-adrenoceptors (Aubry et al, 1988;Schafers et al, 1991;Uprichard et al, 1988). Thus, although 'conven-tional' oxl-adrenoceptor antagonist drugs (e.g.…”

“…Thus, if peripheral arterial vasodilatation induces a compensatory increase in heart rate, a fall in blood pressure may not be detectable in young, healthy subjects. The results of our previous study (Schafers et al, 1991) seem to support such an interpretation to some extent, since concomitant ,-adrenoceptor blockade with atenolol apparently 'unmasked' a vasodilating effect of abanoquil leading to a reduction in blood pressure. However, although there have been slight and statistically significant increases in both supine and erect heart rate consistent with compensatory baroreflex mediated increase in sympathetic nervous system activity, there also consistently has been an early and transient rise in supine heart rate within 10-15 min of intravenous dosing and it is noteworthy that ,B-adrenoceptor blocker treatment with atenolol did not prevent this increase (Schafers et al, 1991).…”

Cardiopulmonary and sedative effects of the peripheral α2-adrenoceptor antagonist MK 0467 administered intravenously or intramuscularly concurrently with medetomidine in dogs

“…In another study, 12 investigators used a higher dose of MK 0467 and found an increase in CI and Do 2 with no deleterious effects. In the present study, we chose not to evaluate administration of MK 0467 alone on the basis of results of other studies 4,12,16,17 and in recognition of the fact that the only anticipated clinical use of the receptor antagonist would be in conjunction with the α 2 -adrenoceptor agonist.…”

Differential vascular α1‐adrenoceptor antagonism by tamsulosin and terazosin

“…The classical method for analysis of receptor antagonism in vivo is the administration of increasing doses of agonist with measurement of shifts in the dose‐response curve in the presence of antagonist. For studies of α 1 ‐adrenoceptor antagonists this usually involves the agonist phenylephrine with measurements of DBP elevations as an indicator of arterial vasoconstriction [ 25–28]. When standard therapeutic doses of tamsulosin (0.4 mg) and terazosin (5 mg) were given to fasting, healthy subjects, the extent of inhibition of DBP responses at several time points was so pronounced, especially for terazosin, that shifts of the phenylephrine dose‐response curve could not formally be calculated.…”