The Effects of Piperoxan on Uptake of Noradrenaline and Overflow of Transmitter in the Isolated Blood Perfused Spleen of the Cat

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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. At concentrations above 10−4 M labetalol produced a pronounced decrease in transmitter overflow. 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. 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. 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). 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. 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.

Section: Stabilization Oftransmitter Overflowmentioning

confidence: 88%

Section: Stabilization Oftransmitter Overflowmentioning

confidence: 99%

Section: Stabilization Oftransmitter Overflowmentioning

confidence: 99%

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The Effects of Labetalol (Ah 5158) on Adrenergic Transmission in the Cat Spleen

Blakeley

Summers

1977

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“…Sensitization of mechanical responses to sympathetic nerve stimulation by phenoxybenzamine and other adrenoceptor antagonists has been observed in a number of preparations with predominantly 13-receptors and also in certain tissues with 2-receptor mediated responses, such as the vas deferens, pulmonary artery, and spleen (Kirpekar & Cervoni, 1963;Burn & Gibbons, 1964;Langer, Adler-Graschinsky & Giorgi, 1977;Blakeley & Summers, 1978). This is interpreted by proponents of the presynaptic receptor hypothesis to represent the anticipated consequences of blockade by the antagonists of the presynaptic negative feedback system (e.g.…”

Section: Discussionmentioning

confidence: 99%

Single Pulse Stimulation of Guinea‐pig Vas Deferens and the Presynaptic Receptor Hypothesis

Kalsner

1979

I The effect of phenoxybenzamine on the efflux of [3H]-noradrenaline and the mechanical response to single pulse excitation of superfused guinea-pig vas deferens was determined to examine the validity of the currently accepted hypothesis of a presynaptic negative feedback system on adrenergic nerve terminals.2 The adrenoceptor antagonist enhanced both the outflow of tritium and the mechanical response to single pulse stimulation. The efflux of labelled material and the responses to 4 pulses were also enhanced, as expected. 3 Blockade of neuronal and extraneuronal uptake did not by itself increase nerve-induced outflow or the mechanical response nor did it prevent phenoxybenzamine from doing so. 4 The present observations cannot be accommodated within the framework of a hypothesis that proposes that the enhancement of response and tritium efflux by phenoxybenzamine results from blockade of a feedback system whereby noradrenaline released by previous impulses inhibits its own subsequent release.

“…The most effective displacers of binding in the kidney such as naphazoline, phentolamine, yohimbine and piperoxane also tend to be those drugs which interact preferentially with presynaptic a-adrenoceptors (Drew, 1976;Starke, 1977;Blakeley & Summers, 1978) whereas drugs such as phenylephrine, prazosin and labetalol which are poor (Starke, 1977;Cambridge, Davey & Massingham, 1977;Blakeley & Summers, 1977). However, there are a few anomalies, in particular the imidazoline a-adrenoceptor agonist, oxymetazoline, which is a powerful inhibitor of transmitter release (Starke, 1977) but which is a relatively poor displacer of [3H]-clonidine binding in the kidney.…”

Section: Discussionmentioning

confidence: 99%

THE CHARACTERISTICS OF [³H]‐CLONIDINE BINDING TO ANα‐ADRENOCEPTOR IN MEMBRANES FROM GUINEA‐PIG KIDNEY

Jarrott

Louis

Summers

1979

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[3H]‐clonidine binds to membranes prepared from guinea‐pig kidney. At 25°C the binding is rapid and saturable. Scatchard analysis of the binding data showed that the Kd for [3H]‐clonidine binding in kidney membranes is 8.54 nM and the density of binding sites 12.5 pmol/g wet wt. tissue. Hill plots of the binding data showed that there were no cooperative site interactions associated with binding. [3H]‐clonidine binding could be displaced by drugs, the most potent being drugs with a high affinity for the α‐adrenoceptor. The neuroleptic drugs (+)‐butaclamol, ds‐clopenthixol and ds‐flupen‐thixol at high concentration also displaced [3H]‐clonidine binding. Drugs acting as agonists or antagonists of β‐adrenoceptors, histamine receptors, acetylcholine receptors as well as prostaglandins E1 E2, Flα and F2α, angiotensin II, arginine vasopressin, naloxone, nalorphine and pargyline had little effect on binding. It is likely that the binding site labelled by [3H]‐clonidine in guinea‐pig kidney membranes is an α‐adrenoceptor similar in some pharmacological aspects to an a2‐adrenoceptor.