Chronic nicotine effects on adrenergic function

Abstract

Smokers suggest that smoking relaxes them but after smoking, the two stress hormones epinephrine (EPI) and cortisol rapidly rise. Smoking is highly associated with cardiovascular pathology and morbidity, and EPI, a major vasopressor, may be an underlying factor. We propose that nicotine (NIC), the major addictive component in cigarettes, acts directly via nicotinic receptors and indirectly via the hypothalamic-pituitary-adrenal axis to elevate EPI biosynthesis by activating the EPI-synthesizing enzyme phenylethanolamine N-methyltransferase (PNMT). In PC12 cells transfected with a PNMT promoter-luciferase reporter gene construct, NIC (100 μM) stimulates luciferase activity in a dose- and time-dependent manner, with activity highest at 6 hr (2.5-fold), back to basal levels by 24 hr and increasing again with continued exposure. In combination with DEX (1 μM), synergistic activation is apparent at 24 hr. In addition, NIC and DEX induce endogenous PNMT mRNA and protein in untransfected PC12 cells. Whether the combination leads to cooperative stimulation remains to be determined. When NIC is administered chronically to rats (1.6 mg/kg i.p. twice daily for 7 days), PNMT mRNA and protein rise 2.0 to 2.5-fold in the adrenal medulla. Finally, in both NIC-treated PC12 cells (24 hr) or adrenal medulla of NIC-treated rats (7 days), mRNA for the immediate early gene transcription factor Egr-1 markedly rises. Together these results suggest that NIC and glucocorticoids, while independently activating the PNMT gene, may synergistically stimulate PNMT with chronic exposure, Egr-1 being one factor mediating induction.