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Proglycosyn, a phenylacyl imidazolium compound that lowers blood glucose levels, was demonstrated previously to promote hepatic glycogen synthesis, stabilize hepatic glycogen stores, activate glycogen synthase, inactivate glycogen phosphorylase, and inhibit glycolysis. In the present study proglycosyn was found to inhibit fatty acid synthesis, stimulate fatty acid oxidation, and lower fructose 2,6-bisphosphate levels, but to have no significant effects on cell swelling and the levels of cAMP in hepatocytes prepared from fed rats. Verapamil and atropine blocked the effects of proglycosyn on glycogen metabolism, but these compounds inhibit proglycosyn accumulation by hepatocytes. Proglycosyn stimulated phosphoprotein phosphatase activity in postmitochondrial extracts, as measured by dephosphorylation of phosphorylase a and glycogen synthase D, but this action required a very high concentration of the compound, making it unlikely to be the actual mechanism involved. It is proposed that a metabolite of proglycosyn is responsible for its metabolic effects.

Previously published results from studies of the in vivo effects of fluoride on cyclic AMP are contradictory. Because of the important physiological role of cyclic AMP as a "second messenger" in numerous metabolic processes, it was important to clarify the effect of fluoride on cyclic AMP. This study was designed to monitor cyclic AMP levels in the plasma, liver and kidney of rats at intervals of 0.5, 4 and 24 hours following acute intraperitoneal or intubated treatment with a single dose of 15 mg fluoride/kg and to relate cyclic AMP levels to plasma and tissue fluoride concentrations determined at the same time.

Correlation between the chemical structure and the ability to induce hepatic megamitochondria formation was studied by feeding mice and rats diets containing a wide spectrum of ammonia derivatives. Ammonia derivatives with electron-releasing groups, such as hydrazine, phenylhydrazine, hydroxylamine and aniline were effective in inducing megamitochondria. Ammonia derivatives with electron-withdrawing groups, such as formamide, sulfamic acid, acetamide were ineffective in inducing megamitochondria. Inducibility of ammonia derivatives with electron-releasing groups plus electron-withdrawing groups for the megamitochondria formation was dependent upon nucleophilicity of the chemical: 2,4-dinitrophenylhydrazine induced megamitochondria, while acetanilide did not induce megamitochondria. The megamitochondria formation induced by ammonia derivatives was a reversible process. Freeze-fracture studies on megamitochondria indicated that megamitochondria were formed by the fusion of adjacent mitochondria. Phosphorylating capacity of megamitochondria (hydrazine-induced megamitochondria, for example) were normal despite morphological changes. These data might suggest that the nucleophilicity of chemicals plays a key role in the induction of hepatic megamitochondria. These data might also suggest that the phenomenon is an adaptive process to changes of intracellular milieu.

Stimulation of amylase secretion from parotid glands by beta-adrenergic agonists is mediated by the activation of adenylate cyclase and the resultant increase in cellular cAMP. Since NaF is known to increase adenylate cyclase activity and cAMP accumulation in intact cells, we investigated whether it would stimulate amylase secretion from isolated rat parotid gland cells. The results provide evidence that the addition of NaF (0.01-10 mmol/L) increased cAMP concentration (1.5-2.8-fold) in, and amylase secretion (16-93%) from, isolated parotid gland acinar cells. NaF was found to increase cAMP-dependent protein kinase activity ratios (51-84%) in a concentration- and time-dependent manner. The data suggest that the stimulation of amylase secretion from parotid gland cells by NaF may be mediated by an increase in the cellular cAMP concentration, which exerts its effect, at least in part, by increasing the activity of cAMP-dependent protein kinase.

Male Wistar rats were fed a fluoride deficient diet (less than 0.5 parts/10(6) F), and either distilled water or fluoridated water (1.0 parts/10(6)). By week 3, the control group had urinary excretions of 106 +/- 5 nmol cAMP/day (mean +/- SEM) whereas the experimental group excreted 129 +/- 6 nmol cAMP/day. After 111 days, the control group excreted 270 +/- 26 nmol cAMP/day compared to 600 +/- 78 nmol cAMP/day for the experimental group. Body weight, food and water consumption, urine volume, and urinary creatinine and phosphate levels were not significantly different between the two groups. Tissue cAMP levels were determined after 4, 6 and 16 weeks. By week 4, the rats receiving the fluoridated water had significantly higher levels of cAMP in the liver (113 per cent) tibia (130 per cent), femur (89 per cent) and heart (35 per cent). At week 6, the liver (119 per cent), tibia (296 per cent), heart (168 per cent), kidney (73 per cent) and submandibular gland (27 per cent) had significantly higher levels of cAMP. By week 16, the liver, femur, kidney and submandibular gland continued to have elevated levels of cAMP. Liver glycolytic metabolites were determined after 6 weeks, and the results suggested a decrease in pyruvate kinase activity.

This investigation demonstrates that intraperitoneal injections of NaF (15 mg F/kg) results in hyperglycemia, inhibition of glycolysis, and an increase in tissue cAMP concentrations. Sodium fluoride significantly increases the cAMP concentration in liver, submaxillary gland, lung, heart, and kidney within 60 minutes following the injection.

The ingestion of fluoride from dentifrices or mouthrinses can contribute substantially to the total daily intake of the ion, even in communities that provide optimally fluoridated drinking water. It is concluded that the frequent and unsupervised use of these products by children six years of age or younger, especially those living in areas with water fluoridation, places them at risk of dental fluorosis. Recommendations to reduce the risk are presented. The use of 1.23% (12,300 ppm) APF gels, particularly in the absence of suctioning during the application and expectoration after the application, is associated with the swallowing of relatively large quantities of fluoride. The resulting increases in plasma fluoride levels may be sufficient to cause dental fluorosis, as judged by studies with laboratory animals, and a reduction in the kidney's ability to concentrate the urine, as judged by studies with both laboratory animals and humans. The epigastric distress experienced by some patients during or after APF gel applications appears to be due, at least in part, to a direct toxic effect of fluoride on the gastric mucosa. Data from studies with humans and laboratory animals indicate that there may also be associated changes in plasma and tissue cAMP levels, glucose metabolism, and salivary amylase secretion. There is an immediate need for the dissemination to the dental profession of standardized methods for gel application that will minimize the quantities of fluoride available for ingestion and systemic absorption.

Evidence is presented that accumulation of cAMP in isolated rat thoracic aorta and diaphragm is stimulated by several fluorine containing compounds (NaF, Na2PO3F (MFP) and SnF2). Time course experiments with NaF showed that maximal stimulation of cAMP accumulation was observed within 2.5 min. NaF and MFP produced significant increases in cAMP accumulation at concentrations of 0.1 microM and SnF2 produced a significant increase at 0.01 microM. The sensitivity of these tissues to the fluorine compounds is similar to that previously reported (Curro and Mickunas, 1981) for the inhibition of norepinephrine induced contractions by fluorine compounds in isolated thoracic aorta.

The effect of NaF on cAMP production was studied in hepatocytes isolated from fed and fasted rats. A four-six fold increase in hepatocyte cAMP production was observed in the presence of 10-20 mM NaF in cells isolated from either fed or fasted rats. The maximal stimulation of cAMP production was observed after a 10 min incubation in the presence of 1 mM theophylline. However, as little as 0.05-0.15 mM NaF induced a significant increase in cAMP production. It was also found that NaF would alter the production of glucose in isolated rat hepatocytes. When hepatocytes from fed rats were incubated with 0.05-5 mM NaF there was an increase in amount of glucose released from endogenous sources. Also NaF resulted in a decrease in lactate and pyruvate production. Similarly NaF stimulated glucose production in hepatocytes from fasted rats. The maximal stimulation was observed with about 0.15-0.25 mM NaF. At NaF concentrations greater than 1.5 mM a decrease in glucose production was observed. It is concluded that NaF increases the level of cAMP and alters glucose metabolism in intact hepatocytes.

The effect of NaF on cAMP accumulation, cAMP-dependent protein kinase activity (cAMP-dPK) ratios and [14C]-glucosamine-labelled mucin release from these isolated cells was investigated. NaF (0.01-5 mM) increased significantly the cellular cAMP concentration and cAMP-dPK activity ratios in a dose- and time-dependent manner. NaF (5.0 mM) increased [14C]-glucosamine-labelled mucin release in a time-dependent manner. Thus the stimulation of prelabelled mucin secretion by NaF is mediated by an increase in the cAMP concentration, which exerts its effect, at least partly, via the activation of cAMP-dPK activity.