Evidence Against the Unitary Hypothesis of Agonist and Antagonist Action at Presynaptic Adrenoceptors

Kalsner, Stanley

doi:10.1111/j.1476-5381.1982.tb09308.x

Cited by 28 publications

(16 citation statements)

References 14 publications

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“…Three possibilities arise. Firstly, as suggested by Kalsner (1982b), yohimbine and exogenous noradrenaline may act at different sites to modulate stimulation-evoked overflow of radioactivity, but yohimbine acts at the same sites as the noradrenaline released from the nerve terminals. If this is so, why does yohimbine not block the receptors at which exogenous noradrenaline acts, and what sort of receptors are they?…”

Section: Discussionmentioning

confidence: 99%

“…Recently, however, this concept has been challenged by Kalsner and his associates (see Kalsner, 1982a,b) who have shown that many of the predictions made from this concept do not seem to be substantiated by experimental investigation. Lately Kalsner (1982b) has shown that concentrations of yohimbine that seem to interrupt this inhibitory feedback process (because they enhance the overflow of [3H]-noradrenaline from guinea-pig ureters during transmural stimulation) do not antagonize the ability of exogenously administered, non-radioactive noradrenaline to inhibit the stimulation-evoked overflow of [3H]-noradrenaline. Kalsner concluded that the exogenous noradrenaline and yohimbine act at different sites to modulate the release of neuronal noradrenaline stores, and that these findings do not, therefore, support the unified hypothesis of feedback regulation of transmitter release.…”

Section: Introductionmentioning

confidence: 99%

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Presynaptic α‐adrenoceptors: do exogenous and neuronally released noradrenaline act at different sites?

Baker

Drew

Hilditch

1984

British J Pharmacology

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The effects of dopamine receptor and α‐adrenoceptor agonists and antagonists on the stimulation‐evoked overflow of radioactivity from strips of dog saphenous vein previously loaded with [3H]‐noradrenaline have been examined alone and in combination. In the presence of neuronal and extraneuronal catecholamine uptake inhibitors, noradrenaline (0.1–1 × 10−6 m) and dopamine (0.01–1 × 10−6 m) both inhibited the stimulation‐evoked overflow of radioactivity. Sulpiride (1 × 10−6 m) was without effect and prazosin (1 × 10−7 m) had little effect on stimulation‐evoked overflow but yohimbine enhanced it approximately 2 fold; the effect of yohimbine was similar at concentrations of 1 × 10−7 and 1 × 10−6 m. Sulpiride abolished the inhibitory effect of dopamine on stimulation‐evoked overflow, but was without effect against noradrenaline. When allowance was made for the effects of yohimbine, alone, on overflow, yohimbine (1 × 10−7 m) had no effect against dopamine and minimal effects against noradrenaline. A similar result was obtained when the concentration of yohimbine was increased to 1 × 10−6 m. Prazosin did not antagonize the effect of noradrenaline. In the absence of the uptake inhibitors, clonidine (0.01–1 × 10−5 m) inhibited stimulation‐evoked overflow of radioactivity. Yohimbine (1 × 10−6 m) was without effect on its own and antagonized the effects of clonidine at a concentration of 0.1 × 10−5 m, but not at 0.01 or 1.0 × 10−5 m. These findings suggest that dopamine inhibits overflow by stimulating presynaptic dopamine receptors on the terminals of the noradrenergic nerves supplying the dog saphenous vein. The interaction between yohimbine and noradrenaline is discussed in terms of the current concepts of control of transmitter release mediated via presynaptic α2‐adrenoceptors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Presynaptic α‐adrenoceptors: do exogenous and neuronally released noradrenaline act at different sites?

Baker

Drew

Hilditch

1984

British J Pharmacology

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“…Kalsner, 1979aKalsner, ,b, 1982aHolman & Surprenant, 1980;Blakeley et al, 1982) that the concept of feedback regulation of neurotransmitter release has been prematurely integrated into the corpus of accepted working hypotheses. Several studies in which frequency, pulse number, train length and effector response were systematically altered to determine the experimental predictability of presynaptic theory have brought to light its severe limitations Kalsner 1979a,b;1982c;1983a;Kalsner etal., 1980). Conceptual modifications to the hypothesis, in terms of intermnittent patterns of nodal release (Bevan, Tayo, Rowan & Bevan, 1983), do not resolve its basic shortcomings.…”

Section: Basal Efflux Of Tritiummentioning

confidence: 99%

Yohimbine and prolongation of stimulation pulse duration alter similarly ³H‐transmitter efflux in heart: an alternative to the negative feedback hypothesis

Kalsner

1983

British J Pharmacology

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1 The hypothesis of negative feedback regulation of noradrenaline release was studied in guineapig left atrial halves mounted in vitro. 2 Tissues were transmurally stimulated with 30, 100 or 300 pulses at 2 Hz with pulse durations ranging from 50 lts to 2,000 yts, and the efflux of 3H-transmitter determined.3 The efflux of tritium increased with increasing pulse duration as was anticipated, but the effects of supposed presynaptic antagonism by yohimbine were opposite to expectations for a negative feedback system. The magnification of efflux by yohimbine, compared to untreated controls was less rather than more as stimulation-induced transmitter efflux climbed with increases in pulse duration, and with all other parameters of stimulation held constant. 4 It is concluded that the neuronal effect of yohimbine is not linked to negative feedback or to any other system sensing the perineuronal concentration of previously released transmitter. 5 Analysis of the effects on tritium efflux of yohimbine and of prolongation of the stimulation pulse duration, reveals a similarity in the way that they promote transmitter release. Yohimbine increased efflux to approximately the same value at all pulse durations between 50 and 1,000 lis and the value reached was equivalent to that obtained in untreated atria during stimulation with very long pulses (2,000 pjs duration). It is suggested that yohimbine prolongs the outward current attributable to the efflux of potassium from axon terminals, and by this means prolongs depolarization and the period of transmitter release.6 Tetraethylammonium (TEA), a quaternary ion known to plug potassium efflux channels, had an effect on transmitter efflux that was, in some ways, similar to that of yohimbine but of greater magnitude. The present findings provide, for the first time, an alternative to the hypothesis of negative feedback, that might explain the presynaptic effects of adrenoceptor antagonists and possibly other compounds.

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“…It is a little over 10 years since the presence of questioned (Baker et al, 1984; presynaptic adrenoceptors on sympathetic nerve 1979; Kalsner, 1979Kalsner, , 1980aKalsner, , b, 1981Kalsner, ,1982; Kalsner endings was proposed (Starke, 1972;Kirpekar et & Chan, 1979). Evidence that these receptors al., 1973;Langer, 1974).…”

Section: Introductionmentioning

confidence: 99%

The physiological and pharmacological role of presynaptic alpha‐ and beta‐adrenoceptors in man.

Brown¹,

Struthers²,

Burrin³

et al. 1985

Brit J Clinical Pharma

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1 Two studies were performed each in six normal volunteers in order to find evidence of either a physiological or pharmacological role of presynaptic ax-and presynaptic P-adrenoceptors in man.2 In Study 1 subjects received a 60 min infusion of guanfacine 3 mg (a2-adrenoceptor agonist) preceded by either idazoxan (oL2-adrenoceptor antagonist) or vehicle. 3 Guanfacine reduced plasma noradrenaline concentration by approximately 30% and this fall was not antagonised by the a2-receptor antagonist. The 30-fold increase in plasma growth hormone, measured as a marker of the central action of guanfacine, was almost completely blocked by idazoxan. 4 A comparison of the drug concentrations of idazoxan and guanfacine, together with their relative affinities for c.2-adrenoceptors, suggested that the idazoxan could not block the peripheral actions of guanfacine and that these were responsible for the fall in plasma noradrenaline concentration. 5 In Study 2 adrenaline 0.05 ,ug kg-1 min--was infused for 80 min preceded by either idazoxan or vehicle. 6 After vehicle, adrenaline caused no change in plasma noradrenaline concentration whereas it rose approximately 25% after administration of idazoxan. This was probably due to unmasking of presynaptic f-adrenoceptor stimulation by adrenaline when the opposing inhibitory autoreceptor was blocked.

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Evidence Against the Unitary Hypothesis of Agonist and Antagonist Action at Presynaptic Adrenoceptors

Cited by 28 publications

References 14 publications

Presynaptic α‐adrenoceptors: do exogenous and neuronally released noradrenaline act at different sites?

Presynaptic α‐adrenoceptors: do exogenous and neuronally released noradrenaline act at different sites?

Yohimbine and prolongation of stimulation pulse duration alter similarly ³H‐transmitter efflux in heart: an alternative to the negative feedback hypothesis

The physiological and pharmacological role of presynaptic alpha‐ and beta‐adrenoceptors in man.

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Evidence Against the Unitary Hypothesis of Agonist and Antagonist Action at Presynaptic Adrenoceptors

Cited by 28 publications

References 14 publications

Presynaptic α‐adrenoceptors: do exogenous and neuronally released noradrenaline act at different sites?

Presynaptic α‐adrenoceptors: do exogenous and neuronally released noradrenaline act at different sites?

Yohimbine and prolongation of stimulation pulse duration alter similarly 3H‐transmitter efflux in heart: an alternative to the negative feedback hypothesis

The physiological and pharmacological role of presynaptic alpha‐ and beta‐adrenoceptors in man.

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Product

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Yohimbine and prolongation of stimulation pulse duration alter similarly ³H‐transmitter efflux in heart: an alternative to the negative feedback hypothesis