ALPHA(2C)-ADRENOCEPTOR-MODULATED RELEASE OF NORADRENALINE IN HUMAN RIGHT ATRIUM

1 The aim of the present study was to characterize the presynaptic alp ha(2)-autoreceptors in human right atrium in terms of the alpha(2A-D) system. Segments of atrial appendages were preincubated with [H-3]-nor adrenaline and then superfused in the presence of cocaine and stimulat ed electrically. pEC(30%) values of eight alpha-adrenoceptor antagonis ts with discriminatory power were determined. pEC(30%) is the negative logarithm of the antagonist concentration that increased the stimulat ion-induced overflow of tritium by 30%. For four antagonists, the diss ociation constant K-D was determined, in addition to pEC(30%), against the overflow-inhibiting effect of 5-bromo-6-(2-imidazolin-2-ylamino)- quinoxaline (UK 14,304) under autoinhibition-free conditions. 2 pEC(30 %) and K-D values yielded identical rank orders of antagonist affinity (rauwolscine>WB 4101 >phentolamine>prazosin) suggesting that both rel eased noradrenaline and the exogenous agonist UK 14,304 activated the same receptor to inhibit release. 3 The eight antagonist pEC(30%) valu es obtained in right atrium correlated significantly with their pEC(30 %) values, reported in the literature, at the presynaptic alpha(2C)-au toreceptors in human kidney (r=0.817; slope of the regression line 1.0 3). No significant correlation was obtained between pEC(30%) values at atrial autoreceptors and pK(D) values at previously characterized alp ha(2A)-autoreceptors in rabbit and alpha(2D)-autoreceptors in rat, mou se and guinea-pig tissues. 4 Comparison of antagonist pEC(30%) values with their pK(D) values at native alpha(2) binding sites in cells or t issues that express a single subtype only, and with pK(D) values at al pha(2) binding sites in membranes of COS cells transfected with human alpha(2) subtype genes confirms the alpha(2C) character of the atrial autoreceptors: significant correlations were obtained exclusively with the alpha(2C) binding sites. 5 Ratios of K-D values were computed for alpha(2)-autoreceptors in human right atrium and for binding sites in COS cells transfected with human alpha(2) subtype genes. The autorece ptor ratios corresponded well with the respective ratios for the alpha (2C) binding sites (maximal three fold deviation) but were, in part, m arkedly different from ratios calculated for alpha(2A) and alpha(2B) b inding sites (up to 166 fold deviation). This outcome supports the alp ha(2C) designation of the autoreceptors. 6 In conclusion, the presynap tic alpha(2)-autoreceptors in human right atrium are alpha(2C). In thi s they agree with the previously characterized alpha(2)-autoreceptors in human kidney. The alpha(2C) classification possibly separates, in g eneral, human alpha(2)-autoreceptors from those in lagomorph (rabbit) and rodent (rat, mouse, guinea pig) species that have been proposed to be predominantly alpha(2A) or alpha(2D).