Substances which stimulate alpha-adrenergic receptors and/or degranulate mast cells have been shown to elicit hemodynamic and early glucotropic responses in the liver which resemble those reported during endotoxicosis. Catecholamines (norepinephrine-epinephrine), compound 48/80 (a mast cell degranulator), or endotoxin, each trigger low flow, hepatic glycogenolysis, and elevate circulating levels of blood glucose within 30 min. in rats. The relationship of the glycemic response to the generation of low flow or to the activation of alpha-adrenergic receptors is unclear. However, it is hypothesized that mast cell mediators and catecholamines are the effecters of the responses induced within 30 min following adrenergic stimulation of mast cell degranulation.
The specific aims of the current proposal include extension and expansion of these preliminary studies (a) to characterize the alpha-receptor subtype (1 or 2) mediating initial glycemic responses to catecholamines, compound 48/80, or endotoxin, (b) to evaluate the potential inhibitory effect of alpha-adrenergic antagonists, depletion of catecholamine from adrenergic nerves with reserpine, and/or adrenalectomy, on the early hemodynamic and glucoregulatory responses to selected doses of compound 48/80 or endotoxin, and (c) to determine how glucose/glycogen levels differ between conditions of optimal circulation and of low-flow states provoked by catecholamines as well as the other two agents during this 30 min. period of experimentation. Optimal circulation will be maintained in the latter case by blocking vascular (constrictor) alpha receptors, depleting mast cell mediators with subacute doses of compound 48/80 for five days, and/or inhibiting mast cell degranulation with lodoxamide prior to infusion or topical application of these chemicals. The results of these studies should provide an improved understanding of the mechanisms that regulate blood flow and carbohydrate metabolism in the liver. This should be helpful in the development of more effective therapy for disturbances of hepatic circulation and glucoregulation that occur during conditions of low flow.
