Haemodynamic dose‐response effects of UK‐52,046 in ischaemic disease with or without impaired left ventricular function.

Abstract

1 The haemodynamic effects of a new cardioselective postsynaptic a 1-adrenoceptor antagonist UK-52,046, were evaluated in 25 patients with stable coronary disease, with or without impaired left ventricular function. At rest the haemodynamic effects to two doseresponse regimens were determined. In an initial eight patients 0.125, 0.125 and 0.25 ,ug kg-1 were administered peripherally at 15 min intervals; the haemodynamic measurements were determined between 10 to 15 min after each dose. In a further 17 patients, the dose regimen was doubled yielding a cumulative dose-regimen of 0.25, 0.5 and 1.0 ,ug kg-1. The exercise effects were determined by comparison of measurements during 4 min of supine sub-maximal bicycle exercise at a fixed workload before and after drug treatment.2 At rest, the lower dose regimen of UK-52,046 significantly reduced systemic mean arterial blood pressure (-5 mm Hg; P < 0.05) and increased cardiac index (+ 0.21 min-' m-2, P < 0.01). The higher dose regimen of UK-52,046 reduced systemic mean arterial blood pressure (-7 mm Hg; P < 0.01), pulmonary artery occluded pressure (PAOP) (-2 mm Hg, P < 0.01) and vascular resistance index (-314 dyn s cm-5 M2; P < 0.05) with an increase in heart rate (+ 7%, P < 0.05) and cardiac index (+ 0.2 1 min-' m-2, P < 0.05). 3 During dynamic exercise, low dose UK-52,046 did not change the haemodynamics significantly. High dose UK-52,046 reduced systemic mean arterial blood pressure (-5.9 mm Hg, P < 0.01), PAOP (-8.5 mm Hg, P < 0.01), systemic vascular resistance index (-281 dyn s cm-5 m2, P < 0.01) and increased cardiac index (+0.81 min-' m-2, P < 0.01). Comparing haemodynamic response in patients whose initial PAOP > 18 mm Hg with those below did not demonstrate any apparent difference in haemodynamic response related to the presence or absence of left ventricular functional impairment. 4 Thus, UK-52,046 was haemodynamically safe in coronary artery disease; during exercise-induced heart failure beneficial effects on preload and cardiac pumping activity were evident.

Dose‐dependent alpha 1‐adrenoceptor antagonist activity of the anti‐ arrhythmic drug, abanoquil (UK‐52,046), without reduction in blood pressure in man.

“…They suggested that since diastolic pressor response may be more dependent on peripheral ot-adrenoceptors than the systolic pressor response which has a greater cardiac component, abanoquil may exhibit a smaller peripheral vascular effect than existing ot-adrenoceptor antagonists. In patients with ischaemic heart disease, abanoquil 1 ,ug kg-1 resulted in a small reduction in blood pressure with no adverse haemodynamic effects (Silke et al, 1990). Schafers et al (1989) found that in healthy subjects, intravenous abanoquil in a dose of 0.5 jig kg-' showed a1-adrenoceptor antagonism by inhibiting the pressor response to phenylephrine.…”