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)
Doggrell
S A
SA
Hughes
E W
EW
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D044482:Benzeneacetamides; D003042:Cocaine / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010656:Phenylephrine / Q000037:antagonists & inhibitors; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012702:Serotonin Antagonists / Q000494:pharmacology; D014316:Tritium / Q000378:metabolism
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D044482:Benzeneacetamides; D011412:Propanolamines; D012702:Serotonin Antagonists; D014316:Tritium; D010656:Phenylephrine; C039100:KF 4317; D003042:Cocaine; D007545:Isoproterenol