The effects of KF-4317, a novel combined alpha- and beta 1-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 1 microM 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 1 microM by a cocaine-insensitive mechanism. KF-4317 at 1 microM had no effect on the noradrenergic nerve-evoked outflow or radioactivity, and therefore is not an alpha 2-adrenoreceptor antagonist, but reduced the associated contractile response probably mainly by acting as an antagonist at postjunctional beta 1-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, X9.0 and X237.2 in the presence of 0.1 and 1 microM KF-4317, was not closely concentration-related. At 1 microM, KF-4317 also depressed the maximum responses to isoprenaline. This suggests that in addition to beta 1-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.(ABSTRACT TRUNCATED AT 250 WORDS)