Alprazolam (a benzodiazepine activating GABA receptor) reduces the neuroendocrine responses to insulin-induced hypoglycaemia in humans.
OBJECTIVE
Alprazolam (ALP), a benzodiazepine-activating GABAergic receptor, possesses clear centrally mediated inhibitory effects on ACTH and cortisol secretion that could reflect an inhibitory influence on CRH- and/or AVP-secreting neurones. An inhibitory effect of ALP on catecholamine release has also been shown while its effect on GH secretion is unclear. To further clarify the neuroendocrine actions of ALP, we studied the ALP effects on the neurohormonal responses to hypoglycaemia in a group of normal subjects.


METHODS
In eight normal subjects [four women and four men, 22-34 years old, body mass index (BMI) 20-25 kg/m2] the ACTH, cortisol, GH, adrenaline (A) and noradrenaline (NA) responses to insulin-induced hypoglycaemia [ITT, 0.1 UI/kg regular insulin intravenously (i.v.) at 0 min] preceded by placebo or ALP (0.02 mg/kg orally at -90 min) were studied in two sessions at least 10 days apart.


METHODS
Blood samples were taken basely at -90 and 0 min and every 15 min up to +120 min. ACTH, cortisol, GH, A and NA level were assayed at each time point in both sessions.


RESULTS
All subjects experienced hypoglycaemia (plasma glucose levels below 2.2 mmol/l). After placebo ITT induced clear-cut increases in ACTH (peak vs. baseline, mean +/- SEM: 27.9 +/- 3.9 vs. 7.1 +/- 1.5 pmol/l), cortisol (438.1 +/- 32.0 vs. 237.7 +/- 19.3 nmol/l) and GH (38.1 +/- 9.7 vs. 5.7 +/- 2.0 micro g/l) levels (P < 0.05). Marked increase in A (6627.2 +/- 116.7 vs. 263.7 +/- 71.4 pmol/l) and NA (3.8 +/- 1.5 vs. 1.6 +/- 1.0 nmol/l) levels were also recorded (P < 0.05). Pretreatment with ALP significantly inhibited the ACTH peak response to ITT (17.8 +/- 5.0 pmol/l, P < 0.05), while the cortisol response showed a non significant reduction (342.1 +/- 38.7 nmol/l). ALP also significantly reduced the GH (21.7 +/- 4.7 micro g/l, P < 0.02) and A (3828.0 +/- 1400.7 pmol/l, P < 0.02) responses to ITT. On the contrary, ALP lowered basal NA levels (P < 0.05) but did not significantly affect its response to ITT (2.2 +/- 1.2 nmol/l). Glucose changes induced by ITT were not modified by ALP.


CONCLUSIONS
This study shows that GABAergic activation by alprazolam significantly inhibits the neuroendocrine and adrenomedullary responses to hypoglycaemia.
Giordano
Roberta
R
Divisions of Endocrinology and Nuclear Medicine, Department of Internal Medicine, University of Turin, Italy.
Grottoli
Silvia
S
Brossa
PierClaudio
P
Pellegrino
Micaela
M
Destefanis
Silvia
S
Lanfranco
Fabio
F
Gianotti
Laura
L
Ghigo
Ezio
E
Arvat
Emanuela
E
D000324:Adrenocorticotropic Hormone / Q000097:blood*; D000328:Adult; D000525:Alprazolam; D001786:Blood Glucose / Q000378:metabolism*; D003864:Depression, Chemical; D004837:Epinephrine / Q000097:blood; D005260:Female; D018757:GABA Modulators; D013006:Growth Hormone / Q000097:blood; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D007328:Insulin; D008297:Male; D009638:Norepinephrine / Q000097:blood
D001786:Blood Glucose; D018757:GABA Modulators; D007328:Insulin; D000324:Adrenocorticotropic Hormone; D013006:Growth Hormone; D006854:Hydrocortisone; D009638:Norepinephrine; D004837:Epinephrine; D000525:Alprazolam