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Differential Control of Adrenal and Sympathetic Catecholamine Release by ₂-Adrenoceptor Subtypes

Institut für Pharmakologie und Toxikologie (M.B., M.P., M.J.L., L.H.), Universität Würzburg, 97078 Würzburg, Germany; and Max-Planck-Institut für Biophysikalische Chemie (G.N., J.B.S.), 37077 Göttingen, Germany

Address all correspondence and requests for reprints to: Lutz Hein, Institut für Pharmakologie und Toxikologie, Universität Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany. E-mail: hein{at}toxi.uni-wuerzburg.de.

In the adrenergic system, release of the neurotransmitter norepinephrine from sympathetic nerves is regulated by presynaptic inhibitory ₂-adrenoceptors, but it is unknown whether release of epinephrine from the adrenal gland is controlled by a similar short feedback loop. Using gene-targeted mice we demonstrate that two distinct subtypes of ₂-adrenoceptors control release of catecholamines from sympathetic nerves (_2A) and from the adrenal medulla (_2C). In isolated mouse chromaffin cells, ₂-receptor activation inhibited the electrically stimulated increase in cell capacitance (a correlate of exocytosis), voltage-activated Ca²⁺ current, as well as secretion of epinephrine and norepinephrine. The inhibitory effects of ₂-agonists on cell capacitance, voltage-activated Ca²⁺ currents, and on catecholamine secretion were completely abolished in chromaffin cells isolated from _2C-receptor-deficient mice. In vivo, deletion of sympathetic or adrenal feedback control led to increased plasma and urine norepinephrine (_2A-knockout) and epinephrine levels (_2C-knockout), respectively. Loss of feedback inhibition was compensated by increased tyrosine hydroxylase activity, as detected by elevated tissue dihydroxyphenylalanine levels. Thus, receptor subtype diversity in the adrenergic system has emerged to selectively control sympathetic and adrenal catecholamine secretion via distinct ₂-adrenoceptor subtypes. Short-loop feedback inhibition of epinephrine release from the adrenal gland may represent a novel therapeutic target for diseases that arise from enhanced adrenergic stimulation.

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