Bolus injection of the synthetic hexapeptide GH-releasing peptide-6 (GHRP-6) reliably promotes GH secretion. However, desensitization to the GH-releasing effects of GHRP has been shown to occur during short term iv infusion. To determine whether humans would remain responsive to prolonged exposure to GHRP and to study the mechanism of action of GHRP, we compared the effects of a 34-h iv infusion of either GHRP or normal saline on parameters of pulsatile GH concentration in nine healthy young men. Each infusion was administered from 0800 h on day 1 to 1800 h on day 2. GHRP was given as a 1 microgram/kg loading bolus, then at the rate of 1 microgram/kg.h. A 50-microgram iv bolus of TRH was given at 0800 h on day 2, followed by iv boluses of GH-releasing hormone (GHRH; 1 microgram/kg, iv, at 1000, 1200, and 1400 h) and then a bolus of GHRP (1 microgram/kg at 1600 h). The integrated GH concentration (IGHC) and parameters of pulsatile GH concentration were calculated for the period between 1400 h on day 1 to 0800 h on day 2, and IGHC was calculated for 2 h after each bolus of GHRP or GHRH. During GHRP infusion, there was a significant increase in IGHC (2908 +/- 450 vs. 1374 +/- 160 micrograms x min/L), maximum pulse amplitude (15.2 +/- 2.8 vs. 8.4 +/- 1.7 micrograms/L), and mean pulse amplitude (7.0 +/- 1.1 vs. 3.8 +/- 1.5 micrograms/L). Plasma insulin-like growth factor-I increased from 252 +/- 23 to 312 +/- 23 micrograms/L. There was no change in either GH pulse frequency or interpulse GH concentration. During GHRP infusion, the GH responses to the GHRH boluses were augmented; however, baseline TSH was lower, and the GH and TSH/PRL responses to GHRP and TRH, respectively, were smaller. We conclude that the pituitary remains sensitive to GHRP during a prolonged GHRP infusion. The mechanisms of the GHRP effect on GH secretion are uncertain, and the possibility that GHRP acts as a functional somatostatin antagonist is discussed. The contrasting effects of GHRP on GH and TSH/PRL secretion could be due to differential effects of GHRP on the pituitary and hypothalamus.