Acute suppression of SRIH secretion with a beta-adrenergic antagonist can increase the GH response to GHRH. To determine whether chronic beta-blockade could enhance the growth-promoting effects of GHRH therapy, we conducted a double blind, placebo-controlled, randomized, cross-over trial of coadministration of the selective beta 1-antagonist atenolol together with GHRH in 11 GH-deficient children. In randomly chosen order, each patient received two 12-month treatment periods with a single daily injection of GHRH (20 micrograms/kg, sc, at bedtime), plus daily oral administration of either atenolol (1 mg/kg) or placebo. The growth velocity increased, rising from a mean +/- SD of 2.6 +/- 0.4 cm/yr before treatment to 5.4 +/- 1.0 cm/yr during the first year of treatment with GHRH plus placebo and to 6.8 +/- 1.2 cm/yr during the first year of treatment with GHRH plus atenolol. The mean growth velocity during treatment with GHRH plus atenolol was significantly greater than that observed during GHRH plus placebo (P < 0.05). After cross-over, however, during the second year of therapy, we did not observe any significant differences in growth velocity between the two groups (4.2 +/- 1.4 vs. 3.9 +/- 0.8 cm/yr during treatment with GHRH plus placebo and GHRH plus atenolol, respectively). The mean 24-h serum GH levels were 1.4 +/- 0.9 micrograms/L during the baseline period, 1.3 +/- 0.2 and 2.0 +/- 1.4 micrograms/L during the first year of GHRH plus placebo and GHRH plus atenolol, respectively (P = NS), and 2.7 +/- 1.4 and 1.4 +/- 0.4 micrograms/L during the second year of GHRH plus placebo and GHRH plus atenolol, respectively (P < 0.05). This is the first demonstration that alteration of neurotransmitter action can enhance the therapeutic response to a hypothalamic releasing factor.