THE EFFECTS OF KF‐4317, A NOVEL COMBINED α‐ and β1‐ADRENORECEPTOR ANTAGONIST, ON THE RAT ISOLATED RIGHT VENTRICLE AND AORTA

The effects of KF‐4317 on the accumulation of radioactivity from [3H]‐noradrenaline, and on the subsequent spontaneous and noradrenergic nerve‐evoked outflow of radioactivity have been investigated in the rat isolated right ventricle. In addition the effects of KF‐4317 on the contractions of the electrically‐driven directly muscle stimulated rat right ventricle to isoprenaline and of the rat isolated aorta to phenylephrine and 5‐hydroxytryptamine are reported. KF‐4317 at 1μM had no effect on the ability of the rat right ventricle to accumulate radioactivity from [3H]‐noradrenaline. The spontaneous outflow of radioactivity, following loading of the ventricle with [3H]‐noradrenaline, was increased by KF‐4317 at 1μM by a cocaine‐insensitive mechanism. KF‐4317 at 1μM had no effect on the noradrenergic nerve‐evoked outflow or radioactivity, and therefore is not an α2‐adrenoreceptor antagonist, but reduced the associated contractile response probably mainly by acting as an antagonist at postjunctional β1‐adrenoreceptors. KF‐4317 caused a parallel rightward shift of the concentration‐response curve of the electrically‐driven directly muscle stimulated rat right ventricle to isoprenaline. However the inhibitory effect, × 9.0 and × 237.2 in the presence of 0.1 and 1μM KF‐4317, was not closely concentration‐related. At 1μM, KF‐4317 also depressed the maximum responses to isoprenaline. This suggests that in addition to β1‐adrenoreceptor antagonism, KF‐4317 probably exerts membrane stabilizing activity. The responses of the rat isolated aorta to phenylephrine were inhibited in a non‐concentration related manner by KF‐4317. Thus the responses were inhibited × 1.8, × 2.7 and × 4.7 in the presence of KF‐4317 at 0.1, 1 and 1μM, respectively. The responses of the aorta to 5‐hydroxytryptamine were inhibited to a small extent by KF‐4317 at 1μM but potentiated to a small degree by KF‐4317 at 10μM. We suggest that KF‐4317 is an antagonist at α1‐adrenoreceptors and 5‐hydroxytryptamine receptors but that it also has an additional postjunctional action, in the rat aorta, to increase the sensitivity to both phenylephrine and 5‐hydroxytryptamine.