Central suppressive effect of octreotide on the hyperglycemic response to 2-deoxy-D-glucose injection or cold-swim stress in awake rats: possible mediation role of hypothalamic noradrenergic drive.
Somatostatin (SRIH) and its analog have been reported to act within the central nervous system to suppress the hyperglycemic response to a variety of neural stimuli. On the other hand, the hyperglycemic response to 2-deoxy-D-glucose (2-DG) injection or cold-swim stress is well demonstrated to be closely associated with an increase in hypothalamic noradrenergic neuronal activity (NNA). To evaluate whether the suppression of the hypothalamic NNA response could be involved in the central mechanism whereby a SRIH analog inhibits the hyperglycemic response, octreotide, a clinically used long-acting octapeptide SRIH analog, was administered into the third cerebral ventricle of awake rats prior to the intraperitoneal injection of 2-DG or cold-swim stress. Hypothalamic noradrenaline (NA) and its neuronal metabolite, 3,4-dihydroxyphenylethyleneglycol (DHPG), were analyzed, and the ratio of DHPG to NA was used as an index of NNA. Intracerebroventricular (i.c.v.) pretreatment with octreotide suppressed the 2-DG-induced increase in hypothalamic NNA, accompanied by the inhibition of the serum glucose, NA and adrenaline responses. This suppressive effect of octreotide was dose-dependent. Similarly, i.c.v. pretreatment with octreotide prevented the hypothalamic NNA response to cold-swim stress, accompanied by a blockade of the increases in serum glucose, NA and adrenaline. A close relationship between hypothalamic NNA and serum glucose emerged from these studies. Intraperitoneal pretreatment with octreotide had no significant effect on the hyperglycemic or hypothalamic NNA response to 2-DG injection. These findings suggest that the inhibitory effect of octreotide on the hypothalamic NNA response to 2-DG injection or cold-swim stress is associated with the simultaneous suppression of the hyperglycemic response. Supporting the concept that hypothalamic NNA contributes to the modulation of blood glucose in stressful conditions, it is suggested that the suppression of the hypothalamic NNA response is, at least in part, involved in the central mechanism by which octreotide inhibits the hyperglycemic response to 2-DG injection or cold-swim stress.
Gotoh
M
M
Department of Laboratory Medicine, Aichi Medical University School of Medicine, 21-Karimata, Nagakute, Aichi 480-1195, Japan. mgotoh@amugw.aichi-med-u.ac.jp
Iguchi
A
A
Kakumu
S
S
Hirooka
Y
Y
Smythe
G A
GA
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003080:Cold Temperature / Q000009:adverse effects; D003847:Deoxyglucose / Q000494:pharmacology; D006728:Hormones / Q000494:pharmacology; D006943:Hyperglycemia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives* / Q000378:metabolism; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D015282:Octreotide / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000378:metabolism; D013312:Stress, Physiological / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013550:Swimming
D001786:Blood Glucose; D006728:Hormones; D013004:Somatostatin; D008734:Methoxyhydroxyphenylglycol; D003847:Deoxyglucose; D015282:Octreotide; C010117:3,4-dihydroxyphenylglycol; D009638:Norepinephrine