The determination of presynaptic pA<sub>2</sub> values of yohimbine and phentolamine on the perfused rat heart under conditions of negligible autoinhibition

Fuder, H.; Muscholl, E.; Spemann, Romeo

doi:10.1111/j.1476-5381.1983.tb10502.x

Cited by 23 publications

(8 citation statements)

References 28 publications

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“…It is well established that the release of NE from cardiac sympathetic neurons is regulated through a receptor with properties of an « 2 -adrenergic receptor (Yamaguchi et al, 1977;van Meel et al, 1981;Rand et al, 1982;Fuder et al, 1983). We confirmed this in our preparation by comparing the effects of yohimbine and prazosin on 3 H overflow from atria prelabeled with [ (Fig.…”

Section: Resultssupporting

confidence: 77%

Acetylcholine release from rat atria can be regulated through an alpha 1-adrenergic receptor.

Wetzel¹,

Goldstein²,

Brown³

1985

Circulation Research

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]Norepinephrine overflow from isolated rat atria is also inhibited by norepinephrine, but this effect is antagonized by yohimbine and not by prazosin. We suggest that the release of acetylcholine from cardiac parasympathetic neurons can be regulated through an «i -adrenergic receptor, and that this mechanism may underly, at least in part, the relative lack of effects of prazosin on heart rate. (Circ Res 56: 763-766, 1985) ACETYLCHOLINE (ACh) is the neurotransmitter of the cardiac vagus and is the chemical signal by which parasympathetic activity modulates heart rate, impulse conduction, and contractility. The activity of the vagus nerve is known to be controlled centrally, but the possibility that there is local modulation of ACh release from cardiac parasympathetic neurons has not been adequately explored. We recently found that ACh overflow from parasympathetic neurons in isolated rat atria was inhibited by the sympathetic neurotransmitter norepinephrine and by the sympathetic hormone epinephrine (Wetzel and Brown, 1985). Further studies with selective agonists and antagonists are reported here. These studies demonstrate that the adrenergic receptor regulating ACh release does not have the a 2 -adrenergic characteristics typical of presynaptic receptors but, instead, has the pharmacological properties of an «,-adrenergic receptor (Starke et al., 1975;Wikberg, 1978;Hoffman and Lefkowitz, 1980;Langer, 1981 (Wetzel and Brown, 1985).Eight individual atria were superfused in each experiment. The release of [ Results and DiscussionThe naturally occurring catecholamines epinephrine (EPI) and norepinephrine (NE) inhibit the K + -stimulated overflow of 3 H by as much as 60%, decreasing the S 2 :S, ratio to -0 . 3 (Table 1). The catecholamine concentrations that give half-maximal inhibition are 2 HM and 6 //M for EPI and NE, respectively. In contrast, isoproterenol does not inhibit K + -stimulated 3 H overflow (Table 1). These data indicate that NE inhibits ACh overflow through activation of an a-rather than a /3-adrenergic receptor. This is supported by our previous observation that the effect of NE is blocked by yohimbine, an «-adrenergic receptor antagonist, but not by the /?-adrenergic receptor antagonist propranolol (Wetzel and Brown, 1985).

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Section: Resultssupporting

confidence: 77%

Acetylcholine release from rat atria can be regulated through an alpha 1-adrenergic receptor.

Wetzel¹,

Goldstein²,

Brown³

1985

Circulation Research

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“…This was achieved by stimulating the tissue with short (91 ms) trains of electric pulses, too short to allow autoinhibition to develop (Singer, 1988). Autoinhibition-free conditions are required for valid determination of dissociation constants (Fuder et al, 1983;Limberger et al, 1989;see Starke et al, 1989).…”

Section: Resultsmentioning

confidence: 99%

α_2c‐Adrenoceptor‐modulated release of noradrenaline in human right atrium

Rump

Böhmann

Schaible

et al. 1995

British J Pharmacology

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1 The aim of the present study was to characterize the presynaptic a2-autoreceptors in human right atrium in terms of the a2AD system. Segments of atrial appendages were preincubated with [3H]-noradrenaline and then superfused in the presence of cocaine and stimulated electrically. pEC30% values of eight a-adrenoceptor antagonists with discriminatory power were determined. pEC30% is the negative logarithm of the antagonist concentration that increased the stimulation-induced overflow of tritium by 30%. For four antagonists, the dissociation constant KD was determined, in addition to pEC30%, against the overflow-inhibiting effect of 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) under autoinhibition-free conditions. 2 pEC30% and KD values yielded identical rank orders of antagonist affinity (rauwolscine > WB 4101> phentolamine > prazosin) suggesting that both released noradrenaline and the exogenous agonist UK 14,304 activated the same receptor to inhibit release. In conclusion, the presynaptic a2-autoreceptors in human right atrium are X2C. In this they agree with the previously characterized a2-autoreceptors in human kidney. The a2C classification possibly separates, in general, human a2-autoreceptors from those in lagomorph (rabbit) and rodent (rat, mouse, guinea pig) species that have been proposed to be predominantly a2A or a2D.

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“…The stimulation-evoked increase in [3H]-noradrenaline overflow under control conditions (no exposure to irreversible antagonists) in the stimulation period S2 before addition of agonists (24 ± 4 fmol per 10 pulses, n = 25) accounted for most of the evoked increase in total tritium overflow (25 ± 4 fmol per 10 pulses, n = 25). In addition, [3H]-noradrenaline represents the more sensitive parameter (Fuder et al, 1983) of evoked release in the rat heart. We therefore used the modulation of evoked [3H]-noradrenaline release for the determination of presynaptic agonist affinity constants.…”

Section: Methodsmentioning

confidence: 99%

“…[3H]-noradrenaline was determined in the remaining perfusate after separation of 3H-metabolites from [3H]-noradrenaline by column chromatography according to Graefe et al (1973) and with the modification described by Fuder et al (1983). The overflow of 3H and of [3H]-noradrenaline was expressed as fmol 2.5 min-' referring to the specific activity of [3H]-noradrenaline infused.…”

Section: Methodsmentioning

confidence: 99%

Affinity and efficacy of racemic, (+)‐, and (−)‐methacholine in muscarinic inhibition of [³H]‐noradrenaline release

Fuder

Jung

1985

British J Pharmacology

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Mackay (1966). KA of( + )-, (± )-, and (-)-methacholine were 2.5, 4 and 440 ZlM, resulting in an isomeric affinity ratio KA (+ )/KA (-) of 180.The discrepancy between the isomeric IC50 ratio and the isomeric KA ratio is explained by a higher intrinsic efficacy of the (+ )-enantiomer compared to the (-)-enantiomer. Thus, (+ )-methacholine has to occupy fewer receptors to induce a given inhibition of release than its antipode as revealed by a plot of fractional receptor occupancy vs response. 4 The results show that, in the effector system of presynaptic muscarinic inhibition, methacholine enantiomers differ greatly not only in affinity for the receptor, but also to some extent in the efficiency of signal transmission, and both parameters contribute to the high isomeric potency ratio. The activity of the racemate is fully accounted for by the activity of the (+)-enantiomer.

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The determination of presynaptic pA₂ values of yohimbine and phentolamine on the perfused rat heart under conditions of negligible autoinhibition

Cited by 23 publications

References 28 publications

Acetylcholine release from rat atria can be regulated through an alpha 1-adrenergic receptor.

Acetylcholine release from rat atria can be regulated through an alpha 1-adrenergic receptor.

α_2c‐Adrenoceptor‐modulated release of noradrenaline in human right atrium

Affinity and efficacy of racemic, (+)‐, and (−)‐methacholine in muscarinic inhibition of [³H]‐noradrenaline release

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The determination of presynaptic pA2 values of yohimbine and phentolamine on the perfused rat heart under conditions of negligible autoinhibition

Cited by 23 publications

References 28 publications

Acetylcholine release from rat atria can be regulated through an alpha 1-adrenergic receptor.

Acetylcholine release from rat atria can be regulated through an alpha 1-adrenergic receptor.

α2c‐Adrenoceptor‐modulated release of noradrenaline in human right atrium

Affinity and efficacy of racemic, (+)‐, and (−)‐methacholine in muscarinic inhibition of [3H]‐noradrenaline release

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Product

Resources

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The determination of presynaptic pA₂ values of yohimbine and phentolamine on the perfused rat heart under conditions of negligible autoinhibition

α_2c‐Adrenoceptor‐modulated release of noradrenaline in human right atrium

Affinity and efficacy of racemic, (+)‐, and (−)‐methacholine in muscarinic inhibition of [³H]‐noradrenaline release