Loperamide inhibits corticotrophic cell function by a naloxone-insensitive mechanism in the rat in vitro.
The effect of the antidiarrheal drug loperamide, a mu-opiate agonist, on ACTH secretion and biosynthesis, cAMP generation and phosphoinositide turnover was studied in rat anterior pituitary cell cultures. The cAMP-dependent protein kinase A pathway was stimulated with both corticotropin-releasing hormone (CRH; 2-5 nM) and the membrane-permeable Bu(2)cAMP (0.5-2.5 mM). The protein kinase C pathway was stimulated with 1 microM arginine vasopressin (AVP) and 1-10 nM phorbol 12-myristate 13-acetate (PMA). After 3.5 h, loperamide (10 microM) had no effect on basal ACTH levels but significantly suppressed CRH-induced ACTH release, in a dose-dependent manner, to 60 +/- 4% of control (100%) (p < 0.0001). After 24 h, basal proopiomelanocortin mRNA was significantly decreased to 50% of control by loperamide (p < 0.05). The suppressive effect of loperamide on CRH-induced ACTH secretion was not reversible by naloxone (0.1-1,000 microM). Morphine (0.01-10 microM) had no effect on basal and CRH-induced ACTH secretion. Loperamide did not influence basal and CRH-induced adenylate cyclase activity in anterior pituitary cell membrane preparations, but it significantly blunted Bu(2)cAMP-induced ACTH secretion in cell culture from 100 +/- 4 to 77 +/- 4% (p < 0.05). In Ca(2+)-depleted medium (Ca2+ < 0.1 mM), loperamide had no suppressive effect on CRH-induced ACTH secretion. AVP-induced ACTH secretion was significantly suppressed by loperamide from 100 +/- 5 to 74 +/- 3% (p < 0.0001), while basal and AVP-induced inositol 1-phosphate generation and PMA-induced ACTH secretion were not affected by loperamide.(ABSTRACT TRUNCATED AT 250 WORDS)
Auernhammer
C J
CJ
Department of Medicine, University of Munich, FRG.
Renner
U
U
Müller
O A
OA
Stalla
J
J
Stalla
G K
GK
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000502:physiology; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D008139:Loperamide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems / Q000187:drug effects
D010716:Phosphatidylinositols; D012333:RNA, Messenger; D015124:8-Bromo Cyclic Adenosine Monophosphate; D009270:Naloxone; D011333:Pro-Opiomelanocortin; D008139:Loperamide; D009020:Morphine; D000324:Adrenocorticotropic Hormone; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D002118:Calcium