Comparison of the effects of labetalol and SCH 19927, the R1R isomer of labetalol, on the rat isolated right ventricle and aorta.
The effects of labetalol and its R1R isomer, SCH 19927, on the accumulation of radioactivity from [3H]-noradrenaline, and on the subsequent spontaneous and nerve-evoked outflow of radioactivity have been investigated in the rat isolated right ventricle. In addition, the effect of these agents on the contractions of the electrically-driven rat right ventricle to isoprenaline and of the rat isolated aorta to phenylephrine and 5-hydroxytryptamine are reported. Labetalol and SCH 19927 (both at 10(-6)M) inhibited the accumulation of radioactivity from [3H]-noradrenaline by 26 and 37%, respectively. The spontaneous outflow of radioactivity, following loading of the ventricle with [3H]-noradrenaline, was increased by labetalol and SCH 19927 (both at 10(-6)M) by a cocaine and idazoxan-insensitive mechanism. The nerve-evoked outflow of radioactivity was increased by labetalol and SCH 19927 (both at 10(-6)M). The ability of labetalol and SCH 19927, to increase nerve-evoked outflow was maintained in the presence of cocaine (10(-5)M) or idazoxan (10(-7)M) but reversed in the presence of cocaine and idazoxan. It is suggested that labetalol and its R1R isomer act both to inhibit neuronal uptake of noradrenaline and as antagonists at prejunctional alpha 2-adrenoreceptors. Labetalol and SCH 19927 reduced the contractile responses associated with the nerve-evoked outflow of radioactivity probably mainly by acting as antagonists at postjunctional beta 1-adrenoreceptors. The contractile responses of the electrically-driven rat right ventricle to isoprenaline were inhibited by labetalol and SCH 19927. SCH 12297 (pA2 = 8.9) was 4 times more potent than labetalol (pA2 = 8.3) as a beta 1-adrenoreceptor antagonist. The ability of labetalol and SCH 19927 at greater than or equal to 10(-7)M to depress maximal responses to isoprenaline may represent membrane stabilizing activity. The contractile responses of rat aorta to phenylephrine were inhibited by labetalol and SCH 19927. Labetalol (pA2 = 7.5) was 4X more potent than SCH 19927 (pA2 = 6.9) as an alpha 1-adrenoreceptor antagonist. SCH 19927 and labetalol had no effect on contractile responses to 5-hydroxytryptamine.
D000818:Animals; D001011:Aorta / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D019329:Idazoxan; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D007741:Labetalol / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009638:Norepinephrine / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000494:pharmacology; D013237:Stereoisomerism; D014661:Vasoconstriction / Q000187:drug effects*
D004146:Dioxanes; D010656:Phenylephrine; D012701:Serotonin; D003042:Cocaine; D007545:Isoproterenol; D007741:Labetalol; D009638:Norepinephrine; D019329:Idazoxan