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Effect of Synthetic Ovine Corticotropin-Releasing Factor: Prolonged Duration of Action and Biphasic Response of Plasma Adrenocorticotropin and Cortisol^*

C. ROWAN DEBOLD, G. STEPHEN DECHERNEY, RICHARD V. JACKSON, WILLIAM R. SHELDON^||, A. NANCYE ALEXANDER, DONALD P. ISLAND, JEAN RIVIER, WYLIE VALE^** and DAVID N. ORTH

Department of Medicine, Vanderbilt University School of Medicine (C.R.D., G.S.D., R.V.J., W.R.S., A.N.A., D.P.I., D.N.O.) Nashville, Tennessee 37232
Peptide Biology Laboratory, The Salk Institute (J.R., W. V.) San Diego, California 92138

Address all correspondence and requests for reprints to: Dr. C. Rowan DeBold, Department of Medicine, A4215 Vanderbilt Medical Center North, Nashville, Tennessee 37232.

The duration of the response to synthetic ovine corticotropin-releasing factor (CRF) was studied in 13 healthy male volunteer subjects. Placebo or CRF (0.3, 3, or 30 µg/kg BW) was administered as an iv bolus or, in the case of the largest dose, a 30-sec infusion in single blind fashion in the late afternoon. Basal plasma immunoreactive ACTH (IR-ACTH) and IR-cortisol were 10.8 ± 7.7 pg/ml and 5.0 ± 1.8 µg/dl (mean ± SD), respectively. IR-ACTH rose rapidly after CRF, reached an initial peak at 15 min, fell rapidly until 1.5 h after CRF, and then either fell more slowly (after the lowest dose) or rose to a second major peak at 2–3 h before falling back to baseline. After 0.3, 3, and 30 µg/kg CRF, IR-ACTH remained elevated for 4, 7, and 8 h, respectively. The effect on plasma IR-cortisol was similar, but more prolonged. The magnitude of both peaks of IR-ACTH, the duration of the response, and the area under the curve all appeared dose dependent. The same was true for IR-cortisol, except that the first peak height was similar after all three doses. The duration of CRF's action is probably due to its long circulating half-life. The biphasic response curve may reflect initial secretion of a readily releasable pool of ACTH, followed by later secretion of a second pool of newly synthesized and/or matured peptide. The next morning's normal circadian rise in both IR-ACTH and IR-cortisol was delayed and diminished after 3 µg/kg CRF; there was no increase in IR-ACTH after 30 µg/kg CRF, and the IR-cortisol level was diminished. Inhibition of the normal circadian rise may reflect inhibition of ACTH secretion by the sustained high plasma cortisol levels.

^* This work was supported in part by USPHS Research Grants 5-R01-CA-11685 and 5-R25-CA-19429 from the NCI, 5-M01-RR00095 from the General Research Center Branch of the NIH, and 5-R01-AM-26741 from the NIADDKD. Research at The Peptide Biology Laboratory was conducted in part by the Clayton Foundation for Research, California Division.

Recipient of National Research Fellowship Award 1-F32-CA-06939 from the NCI.

Recipient of National Research Fellowship Award 1-F32-AM-06758 from the NIADDKD.

Applied Health Sciences Fellow, National Health and Medical Research Council of Australia.

^|| Recipient of a Fellowship Award from Research Training in Diabetes and Endocrinology Grant 5-T32-AM-07061.

^** Clayton Foundation Investigator.

Received November 29, 1982.

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