cyclic-gmp and Hypoglycemia

Topics: Acidosis; Animals; Biological Transport, Active; Brain Ischemia; Calcium; Cell Membrane; Cerebrovascular Disorders; Cyclic GMP; Electrophysiology; Energy Metabolism; Epilepsy; Fatty Acids, Nonesterified; Free Radicals; Glutathione; Hypoglycemia; Hypoxia, Brain; Ions; Lactates; Lactic Acid; Microscopy, Electron; Mitochondria; Neuroglia; Neurons; Phospholipids; Time Factors

Starting from a non-selective pyrazolo-pyrimidone lead, the sequential use of parallel medicinal chemistry and directed synthesis led to the discovery of potent, highly selective, and orally bioavailable PDE9 inhibitors. The availability of these tools allowed for a thorough evaluation of the therapeutic potential of PDE9 inhibition.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Administration, Oral; Catalytic Domain; Crystallography, X-Ray; Cyclic GMP; Diabetes Mellitus; Drug Design; Humans; Hypoglycemia; Hypoglycemic Agents; Inhibitory Concentration 50; Models, Chemical; Permeability; Phosphodiesterase Inhibitors; Structure-Activity Relationship

Taurine has been thought to be essential for the development and survival of neural cells and to protect them under cell-damaging conditions. In the brain stem taurine regulates many vital functions, including cardiovascular control and arterial blood pressure. We have recently characterized the release of taurine in the adult and developing brain stem under normal conditions. Now we studied the properties of preloaded [3H]taurine release under various cell-damaging conditions (hypoxia, hypoglycemia, ischemia, the presence of metabolic poisons and free radicals) in slices prepared from the mouse brain stem from developing (7-day-old) and young adult (3-month-old) mice, using a superfusion system. Taurine release was greatly enhanced under these cell-damaging conditions, the only exception being the presence of free radicals in both age groups. The ischemia-induced release was characterized to consist of both Ca2+-dependent and -independent components. Moreover, the release was mediated by Na+-, Cl--dependent transporters operating outwards, particularly in the immature brain stem. Cl- channel antagonists reduced the release at both ages, indicating that a part of the release occurs through ion channels, and protein kinase C appeared to be involved. The release was also modulated by cyclic GMP second messenger systems, since inhibitors of soluble guanylyl cyclase and phosphodiesterases suppressed ischemic taurine release. The inhibition of phospholipases also reduced taurine release at both ages. This ischemia-induced taurine release could constitute an important mechanism against excitotoxicity, protecting the brain stem under cell-damaging conditions.

Topics: 2,4-Dinitrophenol; Animals; Brain Ischemia; Brain Stem; Calcium Signaling; Cyclic GMP; Female; Guanylate Cyclase; Hydrogen Peroxide; Hypoglycemia; Ion Channels; Male; Mice; Microtomy; Neuroprotective Agents; Oxidants; Protein Kinase C; Sodium Chloride Symporters; Taurine; Uncoupling Agents

Responses to insulin-induced hypoglycemia in fasted sham-operated (SHAM), adrenodemedullated (ADM), and epinephrine-infused ADM (ADM + E) rats were studied to ascertain the specific role of epinephrine in increasing resting skeletal muscle content of adenosine 3',5'-cyclic monophosphate (cAMP) and fructose 2,6-bisphosphate (F-2,6-P2), which are involved in stimulation of muscle glycogenolysis and lactate production. Rats from each group were fasted for 24 h and then infused intravenously with insulin (30, 60, or 90 min) to produce plasma insulin values of approximately 92 microU/ml. One-half of the insulin-infused ADM rats were also infused with epinephrine (ADM + E). Muscle and blood lactate, muscle cAMP, and muscle F-2,6-P2 increased and muscle glycogen decreased in SHAM rats. Each of these changes was prevented or attenuated in ADM rats and restored in ADM + E rats. Liver cAMP, glycogen, and F-2,6-P2 responses to hypoglycemia were similar in SHAM, ADM, and ADM + E rats. Blood glucose decreased to 0.74 +/- 0.05 mM in ADM rats compared with 1.54 +/- 0.11 mM in SHAM and 1.34 +/- 0.15 mM in ADM + E rats after 90 min of insulin infusion. The increase in plasma epinephrine is therefore essential in the counterregulatory response to insulin-induced hypoglycemia in fasted rats. Resting skeletal muscle glycogenolysis and lactate production for hepatic gluconeogenic substrate appear to be important components of the counterregulatory response in fasted rats.

Topics: Adrenal Medulla; Animals; Blood Glucose; Body Weight; Cyclic GMP; Epinephrine; Fasting; Glycogen; Hypoglycemia; Insulin; Lactates; Lactic Acid; Liver; Male; Muscle, Skeletal; Rats; Rats, Sprague-Dawley

Topics: Animals; Cyclic AMP; Cyclic GMP; Hypoglycemia; Lens, Crystalline; Nucleotides, Cyclic; Rats; Rats, Inbred Strains

Topics: Animals; Blood Glucose; Cerebellum; Cyclic AMP; Cyclic GMP; Electroencephalography; Energy Metabolism; Fatty Acids; Fatty Acids, Nonesterified; Hypoglycemia; Insulin; Male; Nucleotides, Cyclic; Phospholipids; Rats; Rats, Inbred Strains; Time Factors

In female rats aspirin-induced gastrin mucosal damage was increased and glycoprotein synthesis decreased by fasting and by insulin administration. Glucose added to the drinking water during the fasting period reduced mucosal damage and increased glycoprotein synthesis to control levels. Alloxan diabetes did not affect mucosal damage or glycoprotein synthesis. Alloxan diabetes plus insulin restored blood glucose levels to normal, and susceptibility to aspirin damage and glycoprotein synthesis were also normal. Alloxan diabetes plus fasting restored blood glucose levels to normal but increased aspirin-induced mucosal damage and reduced glycoprotein synthesis. In vitro incubation of gastric mucosal homogenates showed that diburyryl cyclic AMP and theophylline inhibited glycoprotein synthesis but dibutyryl cyclic GMP had no significant effects. The importance of an adequate supply of glucose to the gastric mucosa and the effects of cyclic nucleotides on glycoprotein synthesis are discussed.

Topics: Adrenal Cortex Hormones; Animals; Aspirin; Blood Glucose; Bucladesine; Cyclic AMP; Cyclic GMP; Diabetes Mellitus, Experimental; Dibutyryl Cyclic GMP; Fasting; Female; Gastric Mucosa; Glucosamine; Glycoproteins; Hypoglycemia; Insulin; Rats; Stomach Ulcer

The effects of insulin-induced hypoglycemic stupor and subsequent treatment with glucose on mouse cerebral cortical, cerebellar and brain stem levels of glucose, glycogen, ATP, phosphocreatine, glutamate, aspartate and GABA and on cerebral cortical and cerebellar levels of cyclic AMP and cyclic GMP have been measured. Hypoglycemia decreased glucose, glycogen and glutamate levels and had no effect on ATP levels in all three regions of brain. GABA levels were decreased only in cerebellum. Aspartate levels rose in cerebral cortex and brain stem, and creatine phosphate increased in cerebral cortex and cerebellum. In the hypoglycemic stuporous animals, cyclic GMP levels were elevated in cerebral cortex and depressed in cerebellum whereas cyclic AMP levels were unchanged from control values. Intravenous administration of 2.5-3.5 mmol/kg of glucose to the hypoglycemic stuporous animals produced recovery of near normal neurological function within 45 s. Only brain glucose and aspartate levels returned to normal prior to behavioral recovery. These results suggest that of the several substances examined in this study, only glucose and perhaps aspartate have important roles in the biochemical mechanisms producing neurological abnormalities in hypoglycemic animals.

Topics: Adenosine Monophosphate; Adenosine Triphosphate; Amino Acids; Animals; Aspartic Acid; Behavior, Animal; Central Nervous System; Coma; Cyclic AMP; Cyclic GMP; gamma-Aminobutyric Acid; Glucose; Glutamic Acid; Glycogen; Hypoglycemia; Insulin; Male; Mice; Phosphocreatine; Recovery of Function

Topics: Adrenergic alpha-Agonists; Adrenergic beta-Agonists; Amino Acids; Animals; Binding Sites; Blood Glucose; Calcium; Carbohydrate Metabolism; Cyclic AMP; Cyclic GMP; Diabetes Mellitus; Gastrointestinal Hormones; Gluconeogenesis; Growth Hormone; Hormones; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Lipid Metabolism; Obesity; Proteins; Receptors, Cell Surface; Sulfonylurea Compounds

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Anaphylaxis; Animals; Bordetella pertussis; Bucladesine; Corticosterone; Cyclic AMP; Cyclic GMP; Deoxyribonucleotides; Female; Histamine; Hypersensitivity, Immediate; Hypoglycemia; Inosine Nucleotides; Mice; Nucleotides; Prostaglandins; Spleen; Thymine Nucleotides; Thymus Gland; Time Factors