guanylyl-imidodiphosphate and Body-Weight

Insulin caused an 8- or a 3-fold increase in lipogenesis in control rats (C) or diabetic rats (DM), respectively. Following insulin treatment for DM, insulin resistance was clearly reversed. Phospholipase C (PLC) caused a 4-fold increase in lipogenesis in C, but not in DM. Insulin treatment partially restored PLC-induced lipogenesis. Insulin or PLC increased protein kinase C (PKC) activity in the membrane fraction in C, but not in DM. Insulin treatment partially restored insulin- or PLC-stimulated PKC activity. 5'-Guanylylimidodiphosphate (Gpp(NH)p) exerted a stimulatory effect on diacylglycerol (DAG) generation in permeabilized adipocytes from C, but not in DM. Insulin treatment partially restored the stimulatory effect of Gpp(NH)p. These findings suggest that a particular G protein(s) is involved in the regulation of DAG generation in adipocytes, and that diabetes leads to a functional or quantitative abnormality in G protein and G protein-PLC. Insulin therapy partially restored G protein-PLC dependent glucose uptake.

Topics: Adipocytes; Animals; Blood Glucose; Body Weight; Cell Membrane Permeability; Diabetes Mellitus, Experimental; Diglycerides; GTP-Binding Proteins; Guanylyl Imidodiphosphate; Insulin; Male; Protein Kinase C; Rats; Rats, Wistar; Type C Phospholipases

Cardiac ventricular muscarinic cholinergic receptors and agonist binding properties were determined in Fischer 344 rats at 3, 12, and 24 months of age. Muscarinic receptors were determined by specific (-)-[3H]quinuclidinyl benzilate (QNB) binding, and the agonist binding properties were determined by competition assays. There were no differences in the concentration of the receptor or the dissociation constant of [3H]QNB binding among the three age groups. In cardiac membranes from 3- and 12-month-old animals, 5'-guanylyl-imidodiphosphate (Gpp(NH)p) increased by 16- to 18-fold (p less than .01) the concentration of carbachol required to inhibit [3H]QNB binding by 50% (IC50). At 24 months, however, Gpp(NH)p induced only a 2.7-fold shift in the carbachol IC50 value (p less than .01). The reduced shift was due to an increase in the carbachol IC50 value determined in the absence of Gpp(NH)p (p less than .01). There was no significant differences among the 3-, 12-, and 24-month-old animals in the half-maximal concentration of Gpp(NH)p required to produce the carbachol IC50 shift. The data indicated that with age there is a reduced ability of the muscarinic receptor to form a high affinity agonist binding state.

Topics: Aging; Animals; Body Weight; Carbachol; Guanylyl Imidodiphosphate; Heart; Male; Myocardium; Organ Size; Quinuclidinyl Benzilate; Rats; Rats, Inbred F344; Receptors, Cholinergic; Receptors, Muscarinic

Prolonged stimulation of cells by beta-adrenergic receptor agonists may lead to diminished responsiveness of the cells to subsequent activation by catecholamines. This phenomenon has been termed desensitization; the mechanism(s) for desensitization may involve an apparent loss in the number of beta-adrenergic receptors or an alteration in receptor-effector coupling. We have examined the consequences of prolonged stimulation of beta-adrenergic receptors in an interesting rat model harboring pheochromocytoma. New England Deaconess Hospital rats with transplanted pheochromocytomas developed systolic hypertension and plasma norepinephrine concentrations approximately 40-fold greater than controls. beta-Adrenergic receptors were quantitated in several tissues from controls and rats with transplanted pheochromocytoma using the beta-adrenergic receptor antagonist [125I]iodocyanopindolol. Down-regulation of beta 1-receptors was found in heart tissue (22.8 vs. 13.6 fmol/mg protein; P less than 0.001) and adipocytes (29,400 vs. 2,800 sites/cell; P less than 0.001). Also, maximal isoproterenol-stimulated cAMP accumulation in isolated adipocytes was diminished in pheochromocytomic animals (13.1 vs. 4.9 pmol cAMP/10(5) cells/min; P less than 0.05). Interestingly, there was no change in beta-receptors in lung and mesenteric artery, which predominantly contain beta 2-receptors. Furthermore, the competition curves of isoproterenol in the heart membranes from control and pheochromocytomic rats in the absence and presence of guanylylimidodiphosphate indicated uncoupling of the beta-adrenergic receptors in pheochromocytomic animals. Rats with pheochromocytoma secreting large amounts of norepinephrine provide a valuable model system for studying the in vivo development of desensitization.

Topics: Adipose Tissue; Adrenal Gland Neoplasms; Animals; Body Weight; Cell Membrane; Cyclic AMP; Energy Intake; Guanylyl Imidodiphosphate; Heart Ventricles; Iodocyanopindolol; Isoproterenol; Kinetics; Lung; Mesenteric Arteries; Myocardium; Pheochromocytoma; Pindolol; Rats; Receptors, Adrenergic, beta