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

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1The hypothesis of negative feedback regulation of transmitter release was examined in a range of tissues obtained from three species. 2 Tissues were transmurally stimulated with 100 pulses at 2 Hz with pulse durations from 50 ps to 5,000 jis, and the efflux of [3H]-noradrenaline determined. 3 The stimulation-induced efflux of tritium increased with increasing pulse duration, but yohimbine, a prototypal 12-antagonist had an effect which was consistently contrary to expectations for a negative feedback system. Enhancement of efflux by the antagonist, supposedly correlated directly with the extent of ongoing auto-inhibition, became smaller rather than larger as the stimulationinduced efflux rose with increases in pulse duration, with all other parameters of stimulation maintained constant. Similar findings were obtained in rat spleen with the haloalkylamine antagonist, phenoxybenzamine. 4 It is concluded that the presynaptic effects of adrenoceptor antagonists do not involve a negative feedback function nor do they relate, in any detectable way, to the extracellular concentration of transmitter. 5 The effects on stimulation-induced tritium efflux of yohimbine, phenoxybenzamine and enlargment of the pulse duration, in a variety of tissues, support the previously described hypothesis of a common action to enhance efflux. The antagonists increased efflux to approximately the same value between 50 and 1,000 As pulse durations and that value was equivalent to that obtained in each given tissue with pulses of 1,000-2,000 Is in the absence of the antagonist. 6 Tetraethylammonium, an inhibitor of stimulation-induced potassium efflux from nerves had an effect on transmitter efflux in rat spleen essentially like that of the adrenoceptor antagonists. These findings provide further support for an alternative to the hypothesis of negative feedback. Yohimbine and other presynaptic antagonists may prolong the period of potassium efflux from nerve varicosities, and by this means prolong depolarization and the associated period of transmitter release, rather than act by disrupting an ongoing system sensing and responding to fluctuations in extracellular transmitter levels.

Section: Tetraethylammonium and Effluxsupporting

confidence: 75%

Section: Stimulation-induced Effluxmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A hypothesis to explain the presynaptic effects of adrenoceptor antagonists

Kalsner

Quillan

1984

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“…Ej.ps are found to increase in amplitude (Bennett & Florin, 1975) & Kalsner, 1979), and independent of the stimulus pulse duration (Kalsner, 1983). When the stimulation frequency is kept very low there is no facilitation and the persistence of free transmitter between stimuli will be minimal (Kalsner, 1979;Kuriyama & Makita, 1983).…”

Section: Analysis Of Discrete Eventsmentioning

confidence: 93%

Interactions between the effects of yohimbine, clonidine and [Ca]_o on the electrical response of the mouse vas deferens

Blakeley

Mathie

Petersen

1986

Excitatory junction potentials (e.j.ps) were recorded from mouse vas deferens and resolved into families of ‘discrete events’ (d.es) reflecting intermittent release of packets of transmitter from one or a few sites. Within families d.es vary in amplitude between a few preferred values unaffected by any treatments used in these experiments. As [Ca]o is raised from 1.1 to 4.0 mm there is a rise in d.e. amplitude due to an increase in the frequency of large events and a decrease in that of small. At all [Ca]o clonidine reduces d.e. amplitude by increasing failures and small events and decreasing large events. Yohimbine has opposite effects. Both drug effects are concentration‐dependent in the range 5 × 10−9‐10−6 m. As [Ca]o is raised from 1.1 to 4.0 mm, and therefore more natural agonist is released, clonidine becomes more effective at altering d.e. amplitude whereas yohimbine becomes less so. With very low frequency stimulation yohimbine elevates e.j.p. amplitude only if [Ca]o is below 1.6 mm. These results are not easily compatible with the notion that yohimbine breaks a ‘negative feedback’ control of transmitter release.

“…Results Guinea-pig left atria which had been cut into 2 equivalent portions (Furchgott et al, 1971) responded to field stimulation with 100 pulses at 2Hz with effluxes of 3H-transmitter well above background levels, as described previously (Kalsner et al, 1980;Kalsner, 1983).…”

Section: Ismentioning

confidence: 99%

Clonidine and presynaptic adrenoceptor theory

Kalsner

1985

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1The effects of clonidine, a presumed selective presynaptic x2-adrenoceptor agonist or partial agonist, were examined in guinea-pig atria. 2 Split left atrial preparations were stimulated transmurally at 2Hz with 100 pulses of 0.5 ms duration and the efflux of 3H-transmitter determined. 3 Clonidine inhibited efflux at 3 x 10-8M to 3 x 10 7M by about 30%. Yohimbine, at a concentration (10-6M) which caused a 3 fold increase in the release of 3H-transmitter during field stimulation, did not alter the ability of clonidine to inhibit transmitter efflux. 4 At 10-6M clonidine alone had no significant effect on the stimulation-induced efflux of 3H-transmitter, but in the presence of yohimbine (10-'M), inhibited efflux by over 50%.5 The inhibitory effect of noradrenaline (10-6M) on 3H-transmitter efflux was antagonized by clonidine at 10-6M but not at 10-8M, although neither concentration of clonidine alone inhibited transmitter efflux. 6 The present findings indicate that the effects of clonidine on the efflux of noradrenaline from sympathetic nerves cannot be accommodated within the currently held view that the compound is an agonist or partial agonist on presynaptic M2-adrenoceptors. It appears that clonidine has multiple sites of action few of which are antagonized by a concentration of the prototypical presynaptic antagonist yohimbine, which enhances efflux 3 fold.