Mast Cell Degranulation, Hepatic Glycogen Depletion, and Hyperglycemia in Compound 48/80 or Pilocarpine-Treated Rats

Abstract

Blood glucose, hepatic glycogen, and mean carotid blood pressure were determined in anesthetized Sprague-Dawley rats receiving an i.v. infusion of Compound 48/80, pilocarpine, or Ringer's solution as a control. Histochemical determinations of the integrity and number of hepatic mast cells and hepatic glycogen content also were performed at the light microscopic level, and the results compared to those from rats whose livers were treated topically with each of these compounds. Compound 48/80 produced a marked decrease in mean carotid blood pressure, while pilocarpine produced a slight increase in this parameter. Injection of either Compound 48/80 or pilocarpine provoked an increase in blood glucose and a decrease in hepatic glycogen as well as in the number of hepatic mast cells. Infusion produced no change in glycogen within cardiac or skeletal muscle. The application of Compound 48/80 or pilocarpine to the surface of the liver evoked no alteration in the histochemical appearance of hepatic glycogen. However, the topical application of these substances elicited a significant decrease in the number of Falck-Hillarp-positive hepatic mast cells. Blood glucose was higher in rats that survived 30 min or more after injection of either compound. However, glucose levels were significantly higher in rats that survived 30 min or longer following Compound 48/80 infusion than in those surviving pilocarpine treatment. These results provide evidence that the i.v. injection of Compound 48/80 or pilocarpine causes: (a) hyperglycemia; (b) depletion of hepatic glycogen, and (c) a concomitant decrease in the number of Falck-Hillarppositive mast cells. The degree of hyperglycemia appeared to correlate with the length of survival of the rats and to be independent of the hyper-or hypotensive effects elicited by either chemical.A recent study of mast cells, and their role in hepatic microvascular regulatory mechanisms, revealed that i.v. and topical administration of Compound 48/80 or pilocarpine evokes mast cell degranulation and a decrease in blood flow through the liver of the rat (1-3). Compound 48/80 also was found histochemically to provoke a decrease in hepatic glycogen content following i.v. administration. Rat mast cells contain histamine, serotonin, and heparin (4-8). Of these constituents, serotonin has been reported to produce glycogenolysis and hyperglycemia when infused into rat liver (9). The present study was designed as part of investigations to test the hypothesis that Compound 48/80 or pilocarpine-induced degranulation of hepatic mast cells causes hyperglycemia and depletion of hepatic glycogen. Blood glucose was Received March 16, 1981; accepted February 3,1982. However, since the glycolytic response elicited by Compound 48/80 and pilocarpine-induced degranulation mimicked that evoked by serotonin (9), it is hypothesized that the hyperglycemia and glycogenolysis are mediated by neuroendocrine mechanisms which are related to the degranulation of extrahepatic mast cells. MATERIALS AND METHODS ANIMALS A N D PHARMAC...

Hepatic Microvascular Regulatory Mechanisms. II. Cholinergic Mechanisms

“…These data suggested an involvement of mast cell constituents in hepatic cholinergic mechanisms, and they were consistent with data from other studies in the liver (9,10,13) bethanechol (lo-' gm per ml)-treated rats as determined by three histochemical methods. There was a significant decrease in the number of mast cells in the pilocarpine or bethanechol-treated rats when compared to Ringer's-treated (control) rats.…”

“…Several studies suggest that there is considerable interaction among topically applied or infused cholinergic substances and nerves and/or these substances and mast cells or hepatocytes. Cholinergic stimulation has been reported to affect hepatocellular metabolism (5)(6)(7)(8)(9), or to cause the release of neurotransmitters and the constituents of mast cells which modify and/or mask vascular responses and influence glucose metabolism (9)(10)(11)(12).…”

“…Accordingly, due to the limited number of studies and information on hepatic cholinergic mechanisms, an in vivo microscopic study of these mechanisms concomitant with physiological, pharmacological, histochemical, biochemical, and electron microscopic procedures was initiated as part of investigations of intrahepatic mechanisms that regulate blood flow through the hepatic mi-crovascular system of the rat (9)(10)(11)(12)(13)(14)(15). This paper reports the effect of cholinergic agonists and their antagonists on various segments of the hepatic microvasculature.…”

Compound 48/80, a mast cell degranulator, causes oxidative damage by enhancing vitamin C synthesis via reduced glutathione depletion and lipid peroxidation through neutrophil infiltration in rat livers

“…(8,12) In the present study, fasted rats treated once with C48/80 had decreased hepatic glycogen content at 0.5 h after treatment and further decreased hepatic glycogen content at 3 and 6 h, although the decreased hepatic glycogen content was almost equal at 3 and 6 h. It is known that a single C48/80 treatment enhances glycogenolysis in the liver of rats, resulting in glycogen depletion in the tissue. (9) It is also known that enhanced glycogenolysis in the liver of rats treated once with C48/80 is independent of the content of glycogen stored in the tissue. (10) Therefore, these findings and the above-described results allow us to suggest that, in the liver of rats with a single C48/80 treatment, H 2 O 2 generation and lipid peroxidation are enhanced following VC synthesis via GSH depletion-dependent glycogenolysis, resulting in the occurrence of oxidative damage.…”

“…(8) It has been shown in rats treated once with C48/80 that hepatic glycogen is depleted by enhanced glycogenolysis, resulting in an increase in blood glucose level. (9) It has also been shown in rats treated once with C48/80 that C48/80-induced glycogenolysis in the liver is independent of the content of glycogen stored in the tissue. (10) Furthermore, it has been shown that degranulation of mast cells existing in the liver tissue of rats treated once with C48/80 is not associated with glycogen depletion in the tissue.…”