The effects of labetalol (AH 5158) on adrenergic transmission in the cat spleen.
1. The competitive alpha- and beta-adrenoceptor blocking agent labetalol, in concentrations up to 10(-4) M, produced dose-dependent increases in transmitter overflow from the isolated blood perfused spleen of the cat following nerve stimulation at 10 and 30 Hz. 2. At concentrations above 10(-4) M labetol produced a pronounced decrease in transmitter overflow. 3. Labetalol (1.5 X 10(-4) M) increased the recovery of 3H label in the venous blood following the close-arterial infusion of [3H]-(-)-noradrenaline indicating that the drug inhibits uptake of the amine. 4. Both labetalol (3.8 X 10(-5) M) and piperoxan (7.4 X 10(-6) M) produced parallel shifts to the right of the dose-response curves to noradrenaline and oxymetazoline in isolated strips of cat splenic capsule. In this preparation both drugs acted as competitive postsynaptic alpha-adrenoceptor blocking agents. 5. Labetalol (3.3 X 10(-5) M) increased the transmitter overflow following stimulation of the splenic nerves with 200 impulses at 10 Hz. The overflow could be further increased by subsequent addition of piperoxan (7.2 X 10(-6 M). Piperoxan (5.7 X 10(-6) M) alone produced a marked increase in transmitter overflow which could be further increased by subsequent addition of desmethylimipramine (DMI; 3.2 X 10(-5) M). Cocaine (1.5 X 10(-5) M) or DMI (5.4 X 10(-5 M) produced a small increase in transmitter overflow which was not further increased by addition of labetalol (2.8 X 10(-5) M). 6. Labetalol produced a biphasic effect on the responses of the isolated blood perfused spleen of the cat to nerve stimulation. With low doses (up to 10(-4) M) vascular responses were potentiated and with high doses (greater than 10(-4) M) inhibited. The potentiation was related to uptake blockade and the inhibition to decreased transmitter overflow and postsynaptic alpha-adrenoceptor blockade. 7. Labetalol appears to act as a postsynaptic alpha-adrenoceptor antagonist in the isolated blood perfused spleen of the cat with little effect on presynaptic alpha-adrenoceptors. The moderate elevation of transmitter overflow by the drug is related to the inhibitory effect of the drug on neuronal uptake rather than on presynaptic alpha-adrenoceptors.
D000818:Animals; D002415:Cats; D004347:Drug Interactions; D004558:Electric Stimulation; D004983:Ethanolamines / Q000494:pharmacology*; D066298:In Vitro Techniques; D007741:Labetalol / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D010109:Oxymetazoline / Q000494:pharmacology; D010883:Piperoxan / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects / Q000294:innervation* / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects*; D013997:Time Factors
D004983:Ethanolamines; D018377:Neurotransmitter Agents; D010109:Oxymetazoline; D010883:Piperoxan; D007741:Labetalol; D009638:Norepinephrine