Lesions of the ventromedial-arcuate (VMH-ARC) region of the hypothalamus result in impaired growth accompanied by a marked suppression in spontaneous GH secretory bursts. We studied the effects of an analog of the recently characterized human pancreas GH-releasing factor hpGRF(l-40) on GH secretory dynamics in freelymoving chronically cannulated rats bearing electrolytic lesions of the VMH-ARC. Intravenous administration of the hpGRF analog (hpGRFa) caused a dramatic surge of GH within 5 min; plasma GH levels rose to values as high as 2900 ng/ml and remained significantly elevated for 15-30 min post treatment. The simultaneous iv administration of somatostatin-14 and hpGRFa resulted in a significant inhibition of the hpGRF a -induced GH release at 5 min but not at 15 min. These results clearly demonstrate that impaired GH secretion resulting from VMH-ARC lesions can be restored by hpGRF. The findings are promising in that hpGRF and its analogs may provide valuable agents for the diagnosis and treatment of disorders of growth secondary to CNS dysfunction.The most common form of GH deficiency in childhood is thought to be due to hypothalamic dysfunction (1). It is now well recognized that GH secretion is regulated by at least two hypothalamic neurohormones -a GH releasing factor, GRF, which has not been fully characterized, and a GH-release inhibiting factor, somatostatin (2). The ventromedial-arcuate (VMH-ARC) region of the hypothalamus has been implicated as an important neural locus for GH regulation, since electrical stimulation of this brain region causes a rise in plasma GH (3,4) whereas lesions result in growth retardation (5,6) accompanied by a marked suppression in spontaneous GH surges (7,8). We have demonstrated that the latter is not due to increased release of somatostatin (8) and have suggested that the GH suppression is a consequence of damage to putative GRF neurons localized in the VMH-ARC. The recent isolation and characterization of peptides, from human pancreas (hp) tumors (9,10), which exhibit high GH-releasing activity and appear to be identical in biological activity to the still unidentified hypothalamic GRF (9-12) provides a useful tool to evaluate this hypothesis. We report here that an analog of hpGRF(l-40), [Ala34, S e r 3 8 , Arg40]hpGRF(l-40)-0H, successfully restores high-amplitude GH secretory pulses in GH-deficient rats bearing lesions of VMH-ARC.
MATERIAL AND METHODSAdult male Sprague-Dawley rats (320-360 g) were implanted with chronic intracardiac venous cannulae and received bilateral electrolytic lesions of the VMH-ARC by methods previously described (8). Shamoperated control rats were treated identically to lesioned animals but the lesionmaker was not turned on. After surgery the animals were placed directly in isolation test chambers (lights on between 0600-1800 h) with Purina rat chow and tap water available ad libitum. Following recovery of preoperative body weight, a 6-h basal hormonal profile was obtained from both groups of rats. Subsequently, VMH-ARClesioned r...