Alpha 2-adrenergic receptors of the alpha 2c subtype mediate inhibition of norepinephrine release in human kidney cortex.

The pharmacological properties of the alpha 2-adrenergic receptors regulating the release of norepinephrine were investigated in human kidney cortex. Slices were preincubated with [3H]norepinephrine, superfused in the presence of desipramine, and stimulated electrically. Two procedures were used to estimate the affinity of alpha-adrenergic antagonists at the autoreceptors. First, pEC30 values (negative logarithms of antagonist concentrations that increased the electrically evoked overflow of tritium by 30%) were determined. Second, antagonist pKd values were determined against the overflow-inhibiting effect of the alpha 2 receptor-selective agonist UK 14,304. Antagonist pEC30 values correlated well with the respective pKd values (r = 0.96, p < 0.01). The site of action of the phenylethylamine norepinephrine, as well as of the imidazoline derivative UK 14,304, is an alpha 2-adrenergic receptor. Neither the cyclooxygenase inhibitor indomethacin nor the adenosine receptor antagonist 8-sulfophenyltheophylline changed the concentration-inhibition curve of UK 14,304. When compared with binding data from the literature, the pEC30 values correlated best with the antagonist affinities at alpha 2c binding sites in an opossum kidney cell line and rat brain cortex (r > or = 0.95, p < 0.001) and at the affinities of alpha 2c sites obtained in COS cells transfected with either the human alpha 2-C4 or rat RG10-alpha 2 gene (r > or = 0.95, p < 0.01). In contrast, the correlations with alpha 2A, alpha 2B, and alpha 2D sites were not as good. Moreover, the alpha 2-autoreceptors in human kidney cortex were very similar to the alpha 2C-adrenergic receptors mediating prostaglandin synthesis in rabbit aorta but differed from alpha 2A- and alpha 2D-autoreceptors in rabbit and rat tissues. It is concluded that in human kidney cortex prejunctional autoreceptors are alpha 2C.