Proof for histaminergic but not for adrenergic involvement in the growth hormone-releasing effect of an enkephalin analog in the dog.
A series of studies was performed in unanesthetized dogs to ascertain whether, in addition to cholinergic pathways, other neurotransmitter systems were involved in the GH-releasing effect of the potent enkephalin analog [D-Ala2, MePhe4, Met(o)5-ol]enkephalin (DAMME). DAMME at a dose of 8 microgram/kg iv elicited a striking rise in plasma canine GH (cGH), with peak levels at 30 min. Blockade of histaminergic H1 receptors by diphenhydramine (30 mg,iv, 15 min before) or clemastine (1 mg orally three times for 2 days and 2 mg orally 60 min before) completely suppressed the cGH release induced by DAMME without significantly altering baseline cGH levels. A slight reduction of the effect of DAMME was also induced by the histamine H2 receptor antagonist cimetidine (300 mg, iv, 15 min before). Pretreatment with the alpha-adrenergic inhibitor phentolamine (0.4 mg/min for 45 min) did not alter the neuroendocrine effect of DAMME, despite the occurrence of a rise in blood glucose (peak levels, 185 +/- 47 mg/dl). The administration of propranolol, a blocker of beta-receptors, did not potentiate the cGH release induced by a threshold dose of DAMME (4 microgram/kg, iv). An iv bolus injection of glucose (1 g/kg), which induced peak glucose levels of 296 +/- 29 mg/dl, completely suppressed the cGH release induced by DAMME or propranolol plus DAMME. These results indicate that histaminergic H1 receptors play an important role in the cGH release induced by DAMME, whereas this action occurs independently from adrenergic mediation. Based on these and previous findings, a neuromodulator role in GH-releasing mechanisms is suggested for opioid peptides.
D000818:Animals; D002927:Cimetidine / Q000494:pharmacology; D002974:Clemastine / Q000494:pharmacology; D005405:D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; D004155:Diphenhydramine / Q000494:pharmacology; D004285:Dogs; D004723:Endorphins / Q000494:pharmacology*; D004745:Enkephalins / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000494:pharmacology; D013006:Growth Hormone / Q000378:metabolism*; D006632:Histamine / Q000502:physiology*; D008297:Male; D010646:Phentolamine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000502:physiology*
D004723:Endorphins; D004745:Enkephalins; D005405:D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; D002927:Cimetidine; D006632:Histamine; D004155:Diphenhydramine; D013006:Growth Hormone; D002974:Clemastine; D011433:Propranolol; D005947:Glucose; D010646:Phentolamine