ISSN:
1432-1912
Keywords:
Key wordsα2-Adrenoceptor subtypes
;
α2-Autoreceptor
;
α2D-Adrenoceptor
;
Guinea-pig heart
;
Guinea-pig brain cortex
;
Sympathetic nerves
;
Noradrenaline release
;
UK 14
;
304
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract The study was devised to classify, by means of antagonist and agonist affinities, the presynaptic α2-autoreceptors in guinea-pig heart atria and brain cortex in terms of α2A, α2B, α2C and α2D. A set of antagonists and agonists was chosen that was able to discriminate between the four subtypes. Small pieces of the atria and slices of the brain cortex were preincubated with 3H-noradrenaline and then superfused and stimulated electrically. In one series of experiments (atria only), tissue pieces were stimulated by relatively long pulse trains (1 min) leading to marked α2-autoinhibition. All 10 antagonists increased the evoked overflow of tritium. pEC30% values (concentrations causing 30% increase) were interpolated from concentration-response curves. In a second series of experiments (atria and brain slices), tissue pieces were stimulated by brief pulse trains (0.4 s or 40 ms) that led to little (atria) or no (brain slices) α2-autoinhibition, and antagonist effects against the α2-selective agonist 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) were examined. All 10 (atria) or 8 (brain) antagonists shifted the concentration-inhibition curve of UK 14,304 to the right. pKd values of the antagonists were calculated from the shifts. In a third series of experiments (brain slices only), also with brief pulse trains (40 ms), pK a values (negative logarithms of dissociation constants of agonist-α2-adrenoceptor complexes) were determined by comparison of concentration-inhibition curves of UK 14,304, guanoxabenz and oxymetazoline in normal tissue and in tissue in which a fraction of the receptors had been blocked by phenoxybenzamine. pEC30% values in atria correlated with pKd values (r = 0.942). pKd values in atria correlated with pKd values in the brain cortex (r = 0.970). It is concluded that the α2-autoreceptors in atria and the brain cortex are the same. Comparison with antagonist affinities for prototypic native α2 binding sites, binding sites in cells transfected with α2 subtype genes, and previously classified presynaptic α2-adrenoceptors – all taken from the literature – indicates that both autoreceptors are α2D. In atria, this identification is reached with either of the two independent estimates of autoreceptor affinity, pEC30% and pKd, and in the brain cortex it is supported by the agonist pKa values. The results are compatible with the hypothesis that at least the majority of α2-autoreceptors belong to the α2A/D branch of the α2-adrenoceptor tree.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00169189
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