THE EFFECTS OF LABETALOL (AH 5158) ON ADRENERGIC TRANSMISSION IN THE CAT SPLEEN

1 The competitive α‐ and β‐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 labetalol produced a pronounced decrease in transmitter overflow. 3 Labetalol (1.5 × 10−4M) 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 × 10−5 M) and piperoxan (7.4 × 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 α‐adrenoceptor blocking agents. 5 Labetalol (3.3 × 10−5M) 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 × 10−6M). Piperoxan (5.7 × 10−6M) alone produced a marked increase in transmitter overflow which could be further increased by subsequent addition of desmethylimipramine (DMI; 3.2 × 10−5M). Cocaine (1.5 × 10−5M) or DMI (5.4 × 10−5M) produced a small increase in transmitter overflow which was not further increased by addition of labetalol (2.8 × 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 10−4M) vascular responses were potentiated and with high doses (greater than 10−4M) inhibited. The potentiation was related to uptake blockade and the inhibition to decreased transmitter overflow and postsynaptic α‐adrenoceptor blockade. 7 Labetalol appears to act as a postsynaptic α‐adrenoceptor antagonist in the isolated blood perfused spleen of the cat with little effect on presynaptic α‐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 α‐adrenoceptors.