cp-154526 and Hyperglycemia

Hyperglycemia and insulin resistance after surgical stress are mediated by a complex neuroendocrine response. The present studies were undertaken to determine whether a corticotropin releasing factor (CRF)-receptor 1 (R1) antagonist, CP-154,526 (CP) could alter trauma-induced effects on blood glucose levels, insulin action on skeletal muscle, and dexamethasone-induced suppression of endogenous glucocorticoid secretion.. We used a standardized experimental model of small intestinal resection in the rat. Studies were performed 2 hours after surgery in four groups of rats (n = 24-48) given vehicle or 40 mg of CP i.p. 1 hour before surgical trauma or only anesthesia (controls). Measurements of (I) b-glucose and p-insulin, corticosterone, and ACTH; (II) glucose transport; (III) phosphatidylinositol 3-kinase (PI 3-K) activity in skeletal muscle; and (IV) the dexamethasone-suppression test were performed.. Surgery resulted in hyperglycemia, reduced insulin-stimulated glucose transport, and a pathological dexamethasone-suppression test. B-glucose levels were attenuated in traumatized rats given CP compared to vehicle (P < 0.05). After surgery, p-corticosterone levels were moderately reduced by CP (P < 0.05) and p-ACTH unchanged by the drug. Glucose transport and PI 3-kinase activity as well as the dexamethasone-suppression test were unaffected by administration of CP.. Hyperglycemia in response to small intestinal resection in the rat could be reduced but not inhibited by CRF-R1 blockade. We hypothesize that CRF action within the central nervous system can regulate the hyperglycemic response to surgical stress via mechanisms other than the pituitary-adrenal axis. Our results also indicate that the hypothalamic stress response after surgical stress is dependent on other factors apart from CRF.

Topics: Acute Disease; Adrenocorticotropic Hormone; Animals; Biological Transport; Blood Glucose; Corticosterone; Dexamethasone; Glucocorticoids; Glucose; Hyperglycemia; Insulin; Male; Muscle, Skeletal; Phosphatidylinositol 3-Kinases; Pyrimidines; Pyrroles; Rats; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone; Wounds and Injuries