CRF-receptor 1 blockade attenuates acute posttraumatic hyperglycemia in rats.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Hager
Peter
P
Department of Surgery, Center for Surgical Sciences at Karolinska Institutet, Karolinska University Hospital at Huddinge, Stockholm, Sweden.
Hagman
Beth
B
Wikström
Ann-Charlotte
AC
Strömmer
Lisa
L
D000208:Acute Disease; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose / Q000032:analysis; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000517:prevention & control*; D007328:Insulin / Q000097:blood; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D014947:Wounds and Injuries / Q000097:blood / Q000188:drug therapy*; D000099052:CRF Receptor, Type 1
D001786:Blood Glucose; C101628:CP 154526; D005938:Glucocorticoids; D007328:Insulin; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose; D003345:Corticosterone