Vol. 286, Issue 2, 848-854, August 1998

Regulation of Tyrosine Hydroxylase Activity by Muscarinic Agonists in Rat Adrenal Medulla¹

A. William Tank, Cheryl A. Osterhout and Carol R. Sterling

Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York

Regulation of tyrosine hydroxylase (TH) enzymatic activity in vivo by muscarinic receptor agonists in rat adrenal medulla was characterized in this study. Bethanechol and carbachol produce dose-dependent increases in rat adrenal TH activity. These increases are maximal (~3-fold) using 10 mg/kg bethanechol or 0.5 mg/kg carbachol and are totally inhibited by prior administration of 2 mg/kg atropine but not by 15 mg/kg hexamethonium. Transection of the splanchnic nerve innervating the adrenal gland leads to a loss in the activation of TH elicited by bethanechol, suggesting that transsynaptic influences are necessary for enzyme activation. When bethanechol is administered repeatedly once every hour for 3 hr (four injections), TH activity is not increased 20 min after the last injection, suggesting that the muscarinic receptor-mediated response desensitizes. In contrast, when nicotine is administered repeatedly once every hour for 3 hr, TH remains activated 20 min after the last injection. Cross-tolerance between the nicotine- and bethanechol-mediated effects on TH enzyme activity are not observed, when rats are injected repeatedly with nicotine and then administered bethanechol or vice versa. Coadministration of atropine and hexamethonium does not inhibit the nicotine-mediated activation of TH, suggesting that noncholinergic receptors participate in the transsynaptic activation of adrenal TH elicited by nicotine. Our results demonstrate that agonist occupation of muscarinic cholinergic receptors is associated with activation of TH enzyme in rat adrenal medulla. However, stimulation of the adrenal muscarinic receptor is not essential for the transsynaptic regulation of the enzyme.