Combined administration of growth hormone-releasing hormone and clonidine restores defective growth hormone secretion in old dogs

We have studied in old dogs the effects of short-term administration of growth hormone (GH)-releasing hormone (GHRH) alone or co-administered with clonidine (CLO), an alpha2-adrenergic agonist, on the GH secretory pattern (cluster analysis), and GH responsiveness to an acute GHRH or GHRH + CLO challenge and plasma somatomedin C (SMC) levels. Dogs were given either GHRH alone twice daily for 10 days (treatment 1) or combined GHRH + CLO both given twice daily (treatment 2) or GHRH + CLO given once daily (treatment 3). Animals were sampled from 09.00 to 15.00 h, at 10-min intervals, both before and 14 h after treatments. At the end of the 6-hour sampling period, dogs were challenged with simultaneous administration of GHRH and CLO, while they were tested with GHRH alone on the morning of the following day. In dogs undergoing treatment 1, acute administration of GHRH or GHRH + CLO elicited mean GH peak responses higher than before treatment, but none of the GH secretory indices were modified during the 6-hour sampling period, except for the increase in mean GH peak amplitude. In dogs undergoing treatment 2, acute administration of GHRH elicited a mean GH peak response higher than that before treatment, whereas administration of GHRH + CLO induced a mean GH peak response not different from that elicited by GHRH + CLO before treatment or by GHRH alone after treatment. However, this treatment significantly augmented the frequency of spontaneous bursts of GH secretion, the mean GH peak amplitude and the total peak area. In dogs undergoing treatment 3, acute administration of GHRH alone or GHRH + CLO elicited a mean GH peak response higher than that elicited by the same drugs before treatment. Moreover, there was an increase of GH peak frequency, mean GH peak amplitude and total peak area, even higher than after treatment 2. Plasma SMC levels rose significantly after all treatments, treatment 3 being the most effective in this instance. These data demonstrate that: (1) both a hypothalamic and a pituitary component play a role in the defective GH secretion in old dogs; (2) GH hypofunction is not an irreversible event, since GH secretion may be restored by pharmacological means acting at both the pituitary and the hypothalamic level, and (3) CLO given only once daily was more effective than CLO given twice daily, perhaps due to the property of this drug to down-regulate at high doses hypothalamic alpha2-adrenoceptors.