The Determination of Presynaptic PA2 Values of Yohimbine and Phentolamine on the Perfused Rat Heart Under Conditions of Negligible Autoinhibition

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 1983 May 1

PMID 6307450

Citations 14

Authors

H Fuder

E Muscholl

R Spemann

Affiliations

Soon will be listed here.

Abstract

1 Rat isolated perfused hearts with the right sympathetic nerves attached were loaded with [3H]-(-)-noradrenaline. The nerves were stimulated with up to 40 trains of 10 pulses every min at 1 Hz, and the evoked increases of [3H-]noradrenaline overflow into the perfusate, of right atrial tension development and ventricular beating frequency were measured. 2 Oxymetazoline inhibited the evoked transmitter overflow (IC50: 10 nM) and decreased the postsynaptic responses in a concentration-dependent manner. It behaved as a full against in abolishing the evoked transmitter overflow. 3 Yohimbine up to 1 microM neither enhanced the evoked [3H]-noradrenaline overflow nor the postsynaptic parameters. Phentolamine (1 microM) caused a transient, minor (less than 30%) increase in [3H]-noradrenaline overflow. 4 Yohimbine (0.03-1.0 microM) and phentolamine (0.1-5.0 microM) shifted to the right the concentration-response curve of oxymetazoline for the inhibition of [3H]-noradrenaline overflow in response to nerve stimulation without depressing the maxima. The pA2 values were 7.82 and 7.52, respectively. 5 Yohimbine (0.1 microM) also antagonized the decrease induced by oxymetazoline in the postsynaptic responses to nerve stimulation. 6 The results confirm the existence of presynaptic inhibitory alpha 2-adrenoceptors at the adrenergic nerve fibres of the rat heart in vitro. Under the stimulation and perfusion conditions selected, the released endogenous transmitter apparently does not activate a negative feedback mechanism, thus permitting the determination of pA2 values.

Citing Articles

One hundred years of adrenaline: the discovery of autoreceptors.

Bennett M Clin Auton Res. 1999; 9(3):145-59.

PMID: 10454061 DOI: 10.1007/BF02281628.

Alpha 2C-adrenoceptor-modulated release of noradrenaline in human right atrium.

Rump L, Bohmann C, Schaible U, Schollhorn J, Limberger N Br J Pharmacol. 1995; 116(6):2617-24.

PMID: 8590979 PMC: 1909128. DOI: 10.1111/j.1476-5381.1995.tb17216.x.

Co-transmitter mediated facilitation by sympathetic nerve stimulation of evoked acetylcholine release from the rabbit perfused atria preparation.

Muscholl E Naunyn Schmiedebergs Arch Pharmacol. 1995; 351(2):164-72.

PMID: 7770098 DOI: 10.1007/BF00169330.

Subclassification of presynaptic alpha 2-adrenoceptors: alpha 2A-autoreceptors in rabbit atria and kidney.

Limberger N, Funk L, Trendelenburg A, Starke K Naunyn Schmiedebergs Arch Pharmacol. 1995; 352(1):31-42.

PMID: 7477423 DOI: 10.1007/BF00169187.

Further study of prerequisites for the enhancement by alpha-adrenoceptor antagonists of the release of noradrenaline.

Limberger N, Starke K Naunyn Schmiedebergs Arch Pharmacol. 1984; 325(3):240-6.

PMID: 6145100 DOI: 10.1007/BF00495950.

References

Starke K . Alpha sympathomimetic inhibition of adrenergic and cholinergic transmission in the rabbit heart. Naunyn Schmiedebergs Arch Pharmacol. 1972; 274(1):18-45. DOI: 10.1007/BF00501004. View

Graffe K, STEFANO F, Langer S . Preferential metabolism of (-) 3 H-norepinephrine through the deaminated glycol in the rat vas deferens. Biochem Pharmacol. 1973; 22(10):1147-60. DOI: 10.1016/0006-2952(73)90231-1. View

Starke K, Montel H, Gayk W, Merker R . Comparison of the effects of clonidine on pre- and postsynaptic adrenoceptors in the rabbit pulmonary artery. Alpha-sympathomimetic inhibition of Neurogenic vasoconstriction. Naunyn Schmiedebergs Arch Pharmacol. 1974; 285(2):133-50. DOI: 10.1007/BF00501149. View

Starke K . Regulation of noradrenaline release by presynaptic receptor systems. Rev Physiol Biochem Pharmacol. 1977; 77:1-124. DOI: 10.1007/BFb0050157. View

Langer S, Adler-Graschinsky E, Giorgi O . Physiological significance of alpha-adrenoceptor-mediated negative feedback mechanism regulating noradrenaline release during nerve stimulation. Nature. 1977; 265(5595):648-50. DOI: 10.1038/265648a0. View

Langer S . Sixth gaddum memorial lecture, National Institute for Medical Research, Mill Hill, January 1977. Presynaptic receptors and their role in the regulation of transmitter release. Br J Pharmacol. 1977; 60(4):481-97. PMC: 1667392. DOI: 10.1111/j.1476-5381.1977.tb07526.x. View

Drew G . Pharmacological characterization of the presynaptic alpha-adrenoceptors regulating cholinergic activity in the guinea-pig ileum. Br J Pharmacol. 1978; 64(2):293-300. PMC: 1668329. DOI: 10.1111/j.1476-5381.1978.tb17303.x. View

Wemer J, van der Lugt J, DE LANGEN C, Mulder A . On the capacity of presynaptic alpha receptors to modulate norepinephrine release from slices of rat neocortex and the affinity of some agonists and antagonists for these receptors. J Pharmacol Exp Ther. 1979; 211(3):445-51. View

Wikberg J . The pharmacological classification of adrenergic alpha 1 and alpha 2 receptors and their mechanisms of action. Acta Physiol Scand Suppl. 1979; 468:1-99. View

10.

Kalsner S . Limitations of presynaptic adrenoceptor theory: the characteristics of the effects of noradrenaline and phenoxybenzamine on stimulation-induced efflux of [3H]noradrenaline in vas deferens. J Pharmacol Exp Ther. 1980; 212(2):232-9. View

11.

Pelayo F, Dubocovich M, Langer S . Inhibition of neuronal uptake reduces the presynaptic effects of clonidine but not of alpha-methylnoradrenaline on the stimulation-evoked release of 3H-noradrenaline from rat occipital cortex slices. Eur J Pharmacol. 1980; 64(2-3):143-55. DOI: 10.1016/0014-2999(80)90037-0. View

12.

Drew G . Presynaptic modulation of heart rate responses to cardiac nerve stimulation in pithed rats. J Cardiovasc Pharmacol. 1980; 2(6):843-56. DOI: 10.1097/00005344-198011000-00013. View

13.

Langer S, Dubocovich M . Cocaine and amphetamine antagonize the decrease of noradrenergic neurotransmission elicited by oxymetazoline but potentiate the inhibition by alpha-methylnorepinephrine in the perfused cat spleen. J Pharmacol Exp Ther. 1981; 216(1):162-71. View

14.

Starke K . Alpha-adrenoceptor subclassification. Rev Physiol Biochem Pharmacol. 1981; 88:199-236. View

15.

Carr S, Fozard J . Lack of modulation by presynaptic alpha 2-adrenoceptors of adrenergic transmitters release evoked by activation of 5-hydroxytryptamine and nicotine receptors. Eur J Pharmacol. 1981; 72(1):27-34. DOI: 10.1016/0014-2999(81)90293-4. View

16.

Grundstrom N, Andersson R, Wikberg J . Prejunctional alpha 2 adrenoceptors inhibit contraction of tracheal smooth muscle by inhibiting cholinergic neurotransmission. Life Sci. 1981; 28(26):2981-6. DOI: 10.1016/0024-3205(81)90275-7. View

17.

Story D, McCulloch M, Rand M . Conditions required for the inhibitory feedback loop in noradrenergic transmission. Nature. 1981; 293(5827):62-5. DOI: 10.1038/293062a0. View

18.

Wakade A, Wakade T . Release of noradrenaline by one pulse: modulation of such release by alpha-adrenoceptor antagonists and uptake blockers. Naunyn Schmiedebergs Arch Pharmacol. 1981; 317(4):302-9. DOI: 10.1007/BF00501310. View

19.

Fuder H, Rink D, Muscholl E . Sympathetic Nerve Stimulation on the perfused rat heart. Affinities of N-methylatropine and pirenzepine at pre- and postsynaptic muscarine receptors. Naunyn Schmiedebergs Arch Pharmacol. 1982; 318(3):210-9. DOI: 10.1007/BF00500482. View

20.

Doxey J, Roach A . Presynaptic alpha-adrenoreceptors; in vitro methods and preparations utilised in the evaluation of agonists and antagonists. J Auton Pharmacol. 1980; 1(1):73-99. DOI: 10.1111/j.1474-8673.1980.tb00444.x. View