Adrenergic presynaptic receptors: an overextended hypothesis?

Kalsner, Stanley; Suleiman, Mohamad Zaini; Dobson, Robert E.

doi:10.1111/j.2042-7158.1980.tb12914.x

Cited by 22 publications

(16 citation statements)

References 20 publications

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“…It appears from the present study and from several other recent studies (Kalsner, 1979a,b;1980a,b;Chan & Kalsner, 1979a,b;Kalsner & Chan, 1979;Kalsner, Suleiman & Dobson, 1980;Kalsner, 1981) that a model of perineuronal regulating sites identified as a-and P-negative and positive feedback systems is not a satisfactory explanation for the available experimental data.…”

Section: Spontaneous Effluxcontrasting

confidence: 51%

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

Kalsner

1982

British J Pharmacology

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The concept that presynaptic receptors regulate noradrenergic transmitter release via a system of inhibitory receptors mediating negative feedback relies on a supposed association between increases in stimulation‐induced efflux of [3H]‐noradrenaline by antagonists and blockade by them of the inhibitory effects of exogenous noradrenaline. It was shown in guinea‐pig ureter, that yohimbine (3 × 10−7 m), a presumed selective presynaptic antagonist, increased transmitter efflux substantially at 1 Hz and 5 Hz with 100 pulses, purportedly representing antagonism of the inhibitory effect of locally released noradrenaline but did not reduce the inhibitory effect of exogenous noradrenaline (1.8 × 10−6 m or 1.8 × 10−7 m) except in one case. Additionally, the inhibitory effect of oxymetazoline (1.0 × 10−7m or 1.0 × 10−8m) on stimulation‐induced efflux was in no way antagonized by yohimbine (3 × 10−7 m). It is concluded that the increased efflux of [3H]‐noradrenaline produced by antagonists and the decreased efflux produced by exogenous agonists may represent actions at different loci and that the hypothesis of presynaptic feedback regulatory sites is still not substantiated.

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Section: Spontaneous Effluxcontrasting

confidence: 51%

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

Kalsner

1982

British J Pharmacology

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“…It has been suggested that drugs which are selective postsynaptic aradrenoceptor antagonists (such as indoramin and prazosin) are less likely to increase heart rate in clinical use, as the negative feedback inhibition of NA release mediated by presynaptic a2-adrenoceptors is left intact (Hoffman & Lefkowitz, 1980). Numerous studies have demonstrated in vitro the role of the a2-adrenoceptors in the regulation of NA release (Lokhandwala & Buckley, 1976;Langer, 1977;Yamaguchi et al, 1977;Lefevre-Borg et al, 1978), although the degree of regulation may be limited in extent (Drew, 1980;Reid & Hamilton, 1980;Angus & Korner, 1980;Kalsner et al, 1980). The selectivity of an antagonist for al-or a2-adrenoceptors may vary between different species and it is not always possible to demonstrate differential a-adrenoceptor blockade in vivo (Commarato et al, 1977;Atkins & Nicolosi, 1979).…”

Section: Discussionmentioning

confidence: 99%

Differential blockade of alpha‐adrenoceptors by indoramin.

Nicholls¹,

O'Connor²,

Harron³

et al. 1984

Brit J Clinical Pharma

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1 The effect of equihypotensive single oral doses of indoramin (mean dose 67 mg), phenoxybenzamine (mean dose 50 mg), hydralazine (mean dose 133 mg) and placebo on arterial pressure and heart rate in the supine and standing position was studied in six normal volunteers. Observations were made before and at 2 and 4 h after drug administration.2 Plasma noradrenaline (NA) was measured at each time interval in the supine position, and after 4 min of standing. Plasma renin activity (PRA) was measured at each time interval after 30 min in the standing position. 3 The three active drugs reduced systolic arterial pressure in the standing position to a similar extent (indoramin, -24 mm Hg; phenoxybenzamine, -23.4 mm Hg; hydralazine, -30.4 mm Hg). The maximum effect of indoramin and phenoxybenzamine was observed at 4 h, and of hydralazine at 2 h after drug administration. 4 The reductions of arterial pressure in the standing position were accompanied by increases in heart rate, plasma NA and PRA. Small increases were observed after indoramin (heart rate, + 9.2 beats min-'; plasma NA, + 126 pg/ml; PRA, + 0.33 ng angiotensin 1 ml-' h-1), greater increases after phenoxybenzamine (heart rate, + 20; plasma NA, + 210; PRA, + 0.47), and the greatest increases after hydralazine (heart rate, + 26; plasma NA, + 250; PRA, + 1.16). 5 In the supine position, indoramin and phenoxybenzamine produced no effect on arterial pressure, heart rate or plasma NA. Hydralazine produced small reductions in diastolic pressure, which were accompanied by an increase in heart rate of 25.5 beats min (P < 0.01 when compared to placebo) and in plasma NA of 223 pg ml-'(P < 0.05). 6 Plasma NA, PRA and heart rate increased together and may be regarded as three interdependent indices of sympathetic activity. 7 Indoramin reduced the degree of increase of plasma NA, PRA and heart rate per unit fall in pressure, when compared to phenoxybenzamine and hydralazine. The effect of phenoxybenzamine and hydralazine on the degree of increase was similar. 8 The results are consistent with the hypothesis that indoramin produces selective postsynaptic al-adrenoceptor blockade in man, and therefore produces relatively less tachycardia and NA increase than does a non-selective a-adrenoceptor antagonist (phenoxybenzamine) or an arteriolar vasodilator (hydralazine).Keywords indoramin phenoxybenzamine hydralazine a-adrenoceptors 719 720 D. P. Nicholls et al.

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“…1, glucose 7.8 and disodium edetate 0.03 mM). Left atria were removed, bisected from base to apex as previously described (Furchgott, Garcia, Wakade & Cervoni, 1971;Kalsner, Suleiman & Dobson, 1980) and incubated for 60 min in 4.0 ml of continuously oxygenated Krebs solution containing (-)- [7,8-3H]-noradrenaline (10 jiCi ml-l, 7.6-10.0 x 10-7 M) at 37°C. Following incubation the tissues were briefly washed with fresh Krebs solution and then mounted under 1 g tension between platinum electrodes in a superfusion apparatus.…”

Section: Tissue Preparationmentioning

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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Adrenergic presynaptic receptors: an overextended hypothesis?

Cited by 22 publications

References 20 publications

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

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

Differential blockade of alpha‐adrenoceptors by indoramin.

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

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Adrenergic presynaptic receptors: an overextended hypothesis?

Cited by 22 publications

References 20 publications

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

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

Differential blockade of alpha‐adrenoceptors by indoramin.

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

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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