ALPHA(2)-ADRENERGIC RECEPTORS OF THE ALPHA(2C)-SUBTYPE MEDIATE INHIBITION OF NOREPINEPHRINE RELEASE IN HUMAN KIDNEY CORTEX

The pharmacological properties of the an-adrenergic receptors regulati ng the release of norepinephrine were investigated in human kidney cor tex. Slices were preincubated with [H-3]norepinephrine, superfused in the presence of desipramine, and stimulated electrically. Two procedur es were used to estimate the affinity of alpha-adrenergic antagonists at the autoreceptors. First, pEC(30) values (negative logarithms of an tagonist concentrations that increased the electrically evoked overflo w of tritium by 30%) were determined. Second, antagonist pK(d) values were determined against the overflow-inhibiting effect of the alpha(2) receptor-selective agonist UK 14,304. Antagonist pEC(3O) values corre lated well with the respective pK(d) values (r = 0.96, p < 0.01). The site of action of the phenylethylamine norepinephrine, as well as of t he imidazoline derivative UK 14,304, is an alpha(2)-adrenergic recepto r. Neither the cyclooxygenase inhibitor indomethacin nor the adenosine receptor antagonist 8-sulfophenyltheophylline changed the concentrati on-inhibition curve of UK 14,304. When compared with binding data from the literature, the pEC(30) values correlated best with the antagonis t affinities at alpha(2C) binding sites in an opossum kidney cell line and rat brain cortex (r greater than or equal to 0.95, p < 0.001) and at the affinities of alpha(2C) sites obtained in COS cells transfecte d with either the human alpha(2)-C4 or rat RG10-alpha(2) gene (r great er than or equal to 0.95, p < 0.01). In contrast, the correlations wit h alpha(2A), alpha(2B), and alpha(2D) sites were not as good. Moreover , the alpha(2C)-autoreceptors in human kidney cortex were very similar to the alpha(2C)-adrenergic receptors mediating prostaglandin synthes is in rabbit aorta but differed from alpha(2A)- and alpha(2D)-autorece ptors in rabbit and rat tissues. It is concluded that in human kidney cortex prejunctional autoreceptors are alpha(2C).