ALTERED HYPOTHALAMIC-PITUITARY-ADRENAL AXIS RESPONSIVENESS IN MYOTONIC-DYSTROPHY - INVIVO EVIDENCE FOR ABNORMAL DIHYDROPYRIDINE-INSENSITIVECALCIUM-TRANSPORT

In persons with myotonic dystrophy (DM), the ACTH response to CRH is g reater than normal, while it is delayed in response to arginine vasopr essin. Since influx of extracellular Ca2+ ions is a common step in sig nal transduction by both of these secretagogues, an abnormality of cel lular Ca2+ transport may underlie the disturbances of hypothalamic-pit uitary-adrenal axis function in this condition. Seven myotonic patient s were given naloxone, which stimulates endogenous CRH release, and ni fedipine, which blocks L-type voltage-dependent Ca2+ channels. Each su bject underwent three tests, using different drug combinations, in a s ingle 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/nal oxone, respectively]. Additionally, nifedipine significantly reduced t he proportion of the mean integrated ACTH response that had occurred b y 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 o f the mean integrated cortisol response by 45 min after naloxone admin istration (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 response s to naloxone in DM. Since nifedipine has a different effect on normal controls (reduced response with unchanged timing), these findings imp ly an abnormality of dihydropyridine-insensitive Ca2+ transport (such as T-type Ca2+ channels) in the corticotrophs of DM patients.