Insulin/hypoglycemia-induced adrenocorticotropin and beta-endorphin release: involvement of hypothalamic histaminergic neurons.
We have previously found that histamine (HA) is involved in the mediation of restraint- and ether stress-induced release of the POMC-derived peptides ACTH and beta-endorphin (beta-END). In the present study we investigated the possible involvement of hypothalamic histaminergic neurons in the mediation of insulin/hypoglycemia-induced release of ACTH and beta-END in conscious male rats. To do so, hypoglycemia stress was performed during 1) inhibition of HA synthesis, 2) activation of inhibitory presynaptic HA H3-auto-receptors, or 3) blockade of postsynaptic HA H1- or H2-receptors. Hypoglycemia (plasma glucose, 2.2 +/- 0.3 nmol) induced by insulin (3 IU/kg, ip) caused a 3- to 5-fold increase in the plasma concentrations of ACTH and beta-END. A negative exponential correlation was found between the plasma glucose concentration and the ACTH and beta-END levels. Pretreatment of the animals with the HA synthesis inhibitor alpha-fluoromethylhistidine (1.0 mumol) intracerebroventricularly (icv) in a lateral ventricle, inhibited the ACTH and beta-END responses to insulin/hypoglycemia by 60%. When administered ip (100 mumol/kg), the synthesis inhibitor decreased the beta-END response 50%, but did not affect ACTH secretion significantly. Pretreatment of the rats with the H3-receptor agonist R(alpha)methylhistamine (50 mumol/kg, ip, twice) inhibited the secretory responses of ACTH and beta-END to insulin/hypoglycemia by 60-80%. This inhibitory effect of R(alpha)methylhistamine was reversed by prior administration of the specific H3-receptor antagonist thioperamide. Administration of the H1-antagonists mepyramine and cetirizine dose-dependently inhibited the ACTH and beta-END responses to insulin/hypoglycemia, with the highest dose (mepyramine, 350 nmol, icv; cetirizine, 40 mumol/kg, ip) inhibiting the response by 80-100%. The H1-antagonist SKF-93944 (226 nmol, icv) inhibited the ACTH response, but had no effect on the beta-END response. Administration of the H2-antagonists cimetidine (400 nmol, icv) and ranitidine (400 nmol, icv) inhibited the ACTH and beta-END responses to insulin/hypoglycemia by 50-80%. We conclude that histaminergic neurons are involved in the mediation of the insulin/hypoglycemia-induced release of ACTH and beta-END and that the effect is mediated via activation of primarily postsynaptic H1-receptors and, to a lesser extent, H2-receptors.
Kjaer
A
A
Department of Medical Physiology, Panum Institute, University of Copenhagen, Denmark.
Knigge
U
U
Madsen
E L
EL
Søe-Jensen
P
P
Bach
F W
FW
Warberg
J
J
D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D017332:Cetirizine / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology; D006632:Histamine / Q000502:physiology*; D017442:Histamine Agonists / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology; D007003:Hypoglycemia / Q000139:chemically induced / Q000503:physiopathology*; D007031:Hypothalamus / Q000503:physiopathology*; D007328:Insulin; D008297:Male; D008761:Methylhistamines / Q000494:pharmacology; D009474:Neurons / Q000502:physiology; D011738:Pyrilamine / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D001615:beta-Endorphin / Q000378:metabolism*
D017442:Histamine Agonists; D006633:Histamine Antagonists; D007328:Insulin; D008761:Methylhistamines; D011744:Pyrimidinones; D001615:beta-Endorphin; C069357:alpha-methylhistamine; D002927:Cimetidine; D006632:Histamine; D000324:Adrenocorticotropic Hormone; C049054:temelastine; D011738:Pyrilamine; D017332:Cetirizine