Chronic propranolol treatment moderately attenuated development of N-methyl-N-nitrosourea-induced mammary carcinoma in female rats.

The sympathetic nervous system participates in the development and progression of several cancer types and this effect is mediated mainly via ß-adrenergic signaling. However, the potential of ß-adrenergic signaling blockade to prevent cancer development after exposure to carcinogens has not been investigated, yet. Therefore, in our study, we determined the effect of the ß-blocker propranolol on the development and progression of mammary cancer induced in female rats by administration of the chemical carcinogen N-methyl-N-nitrosourea (MNU). The propranolol treatment (20 mg/kg body weight) started 12 days after MNU administration and lasted 10 weeks. We found that both saline and propranolol treatment significantly increased gene expression of the catecholamine-synthesizing enzyme tyrosine hydroxylase, indicating that repeated injection of saline or propranolol-induced stress in these two groups. However, compared to the vehicle-treated group, propranolol slightly delayed the development and moderately reduced the incidence of mammary carcinoma in animals. To evaluate the mechanisms mediating the effect of propranolol on the development of MNU-induced cancer, we investigated several parameters of the tumor microenvironment and found that propranolol increased gene expression of Casp3. Our data indicate that propranolol treatment that starts after exposure to carcinogens might represent a new, useful approach for preventing the development of cancer, especially in stressed individuals. However, the potential efficiency of propranolol treatment for preventing cancer development and progression in individuals exposed to carcinogens needs further investigation.

Nicotine promotes cell proliferation via alpha7-nicotinic acetylcholine receptor and catecholamine-synthesizing enzymes-mediated pathway in human colon adenocarcinoma HT-29 cells.

Cigarette smoking has been implicated in colon cancer. Nicotine is a major alkaloid in cigarette smoke. In the present study, we showed that nicotine stimulated HT-29 cell proliferation and adrenaline production in a dose-dependent manner. The stimulatory action of nicotine was reversed by atenolol and ICI 118,551, a beta(1)- and beta(2)-selective antagonist, respectively, suggesting the role of beta-adrenoceptors in mediating the action. Nicotine also significantly upregulated the expression of the catecholamine-synthesizing enzymes [tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DbetaH) and phenylethanolamine N-methyltransferase]. Inhibitor of TH, a rate-limiting enzyme in the catecholamine-biosynthesis pathway, reduced the actions of nicotine on cell proliferation and adrenaline production. Expression of alpha7-nicotinic acetylcholine receptor (alpha7-nAChR) was demonstrated in HT-29 cells. Methyllycaconitine, an alpha7-nAChR antagonist, reversed the stimulatory actions of nicotine on cell proliferation, TH and DbetaH expression as well as adrenaline production. Taken together, through the action on alpha7-nAChR nicotine stimulates HT-29 cell proliferation via the upregulation of the catecholamine-synthesis pathway and ultimately adrenaline production and beta-adrenergic activation. These data reveal the contributory role alpha7-nAChR and beta-adrenoceptors in the tumorigenesis of colon cancer cells and partly elucidate the carcinogenic action of cigarette smoke on colon cancer.

Effect of a phenylethanolamine N-methyltransferase inhibitor, 2,3-dichloro-alpha-methylbenzylamine, on the alpha-2-adrenoceptor function in the hypothalamus in rats.

This study examines the in vivo effects of 2,3-dichloro-alpha-methylbenzylamine (DCMB), a centrally active phenylethanolamine-N-methyltransferase (PNMT) inhibitor, on alpha 2-adrenoceptors. Sixty-six rats received either DCMB, SKF29661, the peripheral PNMT inhibitor, at a dose of 50 mg/kg or saline intraperitoneally. To examine the functional responses of the alpha 2-adrenoceptors to these drugs, changes in spontaneous locomotor activity, concentration of 3-methoxy-4-hydroxyphenylglycol (MHPG) in dialysates from the hypothalamus, and the influence of clonidine on growth hormone (GH) secretion were investigated. (1) DCMB increased spontaneous motion of the rat. (2) DCMB increased extracellular MHPG concentration in the hypothalamus verified by micro-brain dialysis. (3) Clonidine failed to stimulate GH secretion in DCMB-treated rats. These results suggest that DCMB has an inhibitory action on the alpha 2-adrenoceptor function in vivo.

Phenylethanolamine-N-methyl transferase and catechol-O-methyl transferase activity in rat uterus. Cyclic and steroid-induced changes.

PURPOSE: The activity of phenylethanolamine-N-methyl-transferase (PNMT) and catechol-O-methyl-transferase (COMT) was studied in uterine homogenates from adult female Wistar rats with normal cycles and that had been ovariectomized, adrenalectomized, and steroid-treated. RESULTS: Activities of the two enzymes changed significantly during the normal estrus cycle. Both peaked during metestrus, with COMT showing a secondary peak of activity at proestrus. Progesterone treatment significantly increased and estradiol decreased PNMT activity in comparison to untreated controls. Hydrocortisone administration had no effect on uterine PNMT activity. COMT activity was not affected significantly by any of the steroid treatments. CONCLUSION: The data confirm that uterine tissues possess the enzymatic machinery to synthesize epinephrine from norepinephrine, and suggest the activity of this pathway may be mediated by variations in the sex hormone environment of the uterus.

Selective effect of chronic lead ingestion. II: Effect on phenylethanolamine N-methyltransferase activity in brain regions of rats.

Selectivity of lead effect to phenylethanolamine N-methyltransferase (PNMT) activity in regions of brain from rats postnatally exposed to lead was tested. Three groups of animals were prepared; (1) Rats exposed to lead at a low dose (0.05% PbAcetate: PbAc); (2) Rats exposed to lead at a high dose (0.2% PbAc); (3) Age-matched normal control rats. At 2, 4, 6 and 8 weeks of age weight of whole brain and body in each group were measured. At the same ages activities of PNMT and Na+/K(+)-ATPase were examined on 4 brain regions of each animal. Exposure of rats to lead generally decreased activity of Na+/K(+)-ATPase and showed alternative change of those of PNMT. Brain regions where changes of PNMT activity were detected without concomitant changes of Na+/K(+)-ATPase activity, were telencephalon and pons/medulla at 2 weeks of age and telencephalon at 4 weeks of age in rats exposed to lead at a low dose, and those in rats exposed to lead at a high dose were pons/medulla at 8 weeks of age. These data imply that adrenergic nervous system in the brain regions described above could selectively be affected by lead.