Altered hypothalamic-pituitary-adrenal axis responsiveness in myotonic dystrophy: in vivo evidence for abnormal dihydropyridine-insensitive calcium transport.
In persons with myotonic dystrophy (DM), the ACTH response to CRH is greater than normal, while it is delayed in response to arginine vasopressin. Since influx of extracellular Ca2+ ions is a common step in signal transduction by both of these secretagogues, an abnormality of cellular Ca2+ transport may underlie the disturbances of hypothalamic-pituitary-adrenal axis function in this condition. Seven myotonic patients were given naloxone, which stimulates endogenous CRH release, and nifedipine, which blocks L-type voltage-dependent Ca2+ channels. Each subject underwent three tests, using different drug combinations, in a single blind, placebo-controlled protocol. Pretreatment with nifedipine delayed the time of the peak plasma hormone responses after naloxone [ACTH, 32.1 +/- 2.1 vs. 51.4 +/- 4.5 min (P < 0.05); cortisol, 42.9 +/- 2.1 vs. 70.7 +/- 4.3 min (P < 0.02); for naloxone and nifedipine/naloxone, respectively]. Additionally, nifedipine significantly reduced the proportion of the mean integrated ACTH response that had occurred by 30 min after naloxone administration (32.0 +/- 4.0% for naloxone vs. 17.6 +/- 2.4% for nifedipine/naloxone; P < 0.02) and the proportion of the mean integrated cortisol response by 45 min after naloxone administration (34.7 +/- 3.5% for naloxone vs. 25.0 +/- 2.6% for nifedipine/naloxone; P < 0.02). However, the total integrated responses did not change [ACTH, 1182.6 +/- 548.9 vs. 905.5 +/- 157.0 pmol/min.L (P = NS); cortisol 17,353 +/- 2,984 vs. 18,469 +/- 3,561 nmol/min.L (P = NS); for naloxone and nifedipine/naloxone, respectively]. We conclude that nifedipine delays, but does not reduce, the ACTH and cortisol responses to naloxone in DM. Since nifedipine has a different effect on normal controls (reduced response with unchanged timing), these findings imply an abnormality of dihydropyridine-insensitive Ca2+ transport (such as T-type Ca2+ channels) in the corticotrophs of DM patients.
University of Queensland, Department of Medicine, Greenslopes Hospital, Brisbane, Australia.
G I
GI
Hockings
J E
JE
Grice
G V
GV
Crosbie
M M
MM
Walters
R V
RV
Jackson
D000293:Adolescent; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002648:Child; D004095:Dihydropyridines / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System; D008297:Male; D008875:Middle Aged; D009223:Myotonic Dystrophy / Q000503:physiopathology*; D009270:Naloxone / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology*; D010913:Pituitary-Adrenal System; D012016:Reference Values
D004095:Dihydropyridines; D009270:Naloxone; D000324:Adrenocorticotropic Hormone; D009543:Nifedipine; D002118:Calcium; D006854:Hydrocortisone