Effect of UK‐52,046, an alpha 1‐adrenoceptor antagonist, on baroreflex function in man.

Abstract

1 In a placebo controlled study (six healthy male subjects), the effects of UK-52,046 (0.4 pLg kg-1 i.v.) and prazosin (0.25 mg i.v.) on baroreflex function were compared, at doses which produced antagonism to phenylephrine, but which had no effect on supine blood pressure.2 Baroreflex function [AR-R interval ms mm Hg-1 change in SBP] was assessed following increases in systolic blood pressure (SBP) with phenylephrine and during the Valsalva manoeuvre.3 At these doses neither UK-52,046 nor prazosin had an effect on supine SBP or heart rate; however following prazosin, standing SBPs at 5 s (69.7 ± 7.6 mm Hg) and at 3 min (65.5 ± 11.7 mm Hg) were less than the respective pre-treatment (P < 0.05) values (96.0 + 2.9, 110.3 ± 6.2 mm Hg) and placebo (82.7 ± 5.6, 98.7 ± 11.1 mm Hg). UK-52,046 had no significant effects on standing SBP at 5 s or 3 min. At 5 s, pre-and post-treatment R-R intervals (584 ± 26, 541 ± 27 ms respectively) were not significantly different with prazosin, but at 3 min the post-treatment R-R interval following prazosin (519 ± 17 ms) was less (P < 0.05) than the pre-treatment value (658 ± 36 ms).4 UK-52,046 had no effect on baroreflex sensitivity (12.7 ± 1.3 ms mm Hg'l) compared with placebo (17.9 ± 2.7 ms mm Hg-1). Following prazosin baroreflex sensitivity (9.9 ± 1.5 ms mm Hg-1) was reduced (P < 0.05) compared with both the pre-treatment value (16.6 ± 1.8 ms mm Hg-1) and placebo.5 The results of this study suggest that the different effects of UK-52,046 and prazosin on baroreflex function, standing BP and heart rate may be due to less extensive blockade of peripheral vascular otl-adrenoceptors by UK-52,046.

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

“…The electrophysiological safety of this compound has not been previously documented in man, whereas the haemodynamic findings are in accord with findings in experimental animals (Flores & Sheridan, 1989;Uprichard et al, 1988) and in man McKaigue et al, 1989;Miller et al, 1989). In an experimental model (Aubry et al, 1988), intravenous UK-52,046 caused an elevation of the threshold for adrenaline induced arrhythmias, at no cost to haemodynamic parameters such as heart rate, blood pressure or filling pressure.…”

Duration of action and effect on baroreflex function of the anti-arrhythmic α1 antagonist UK-52,046

“…UK-52,046 did not affect baroreflex function (either slope or intercept) to increases in blood pressure with phenylephrine, confirming results occurring in man (McKaigue et al 1989). However, it did shift the phenylephrine dose response curve to the right on day 1 and day 8 compared with placebo, in keeping with competitive al-antagonism.…”

Functional interaction between nucleus tractus solitarius NK and 5-HT receptors in the inhibition of baroreflex in rats

“…Indeed, by rising blood pressure and then possibly increasing the blood-brain barrier permeability [21], phenylephrine may act on central alpha 1-adrenoceptors, which are reported to inhibit the cardiac baroreflex response [22]. Although the fact that UK-52,046, a potent alpha 1-adrenoceptor antagonist, was found to have no effect on the phenylephrine-induced baroreflex sensitivity [23] does not support this possibility, other means to induce carotid baroreflex (i.e., activation of carotid sinus Table 3 Cardiac baroreflex responses triggered by phenylephrine administration or by aortic nerve stimulation before and after microinjection into the NTS of phenylbiguanide (PBG) alone or after prior local microinjection of GR205171 (GR+PBG) baroreceptors) would be necessary to exclude this hypothetical effect of phenylephrine on the degree of baroreflex bradycardia inhibition induced by NTS NK 1 receptors. It is also important to note that facilitation of cardiac baroreflex by NTS NK 1 receptor activation has also been suggested in other studies.…”