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 o f growth hormone (GH)-releasing hormone (GHRH) alone or co-administere d with clonidine (CLO), an alpha2-adrenergic agonist, on the GH secret ory pattern (cluster analysis), and GH responsiveness to an acute GHRH or GHRH + CLO challenge and plasma somatomedin C (SMC) levels. Dogs w ere given either GHRH alone twice daily for 10 days (treatment 1) or c ombined 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 t he end of the 6-hour sampling period, dogs were challenged with simult aneous administration of GHRH and CLO, while they were tested with GHR H alone on the morning of the following day. In dogs undergoing treatm ent 1, acute administration of GHRH or GHRH + CLO elicited mean GH pea k responses higher than before treatment, but none of the GH secretory indices were modified during the 6-hour sampling period, except for t he 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 induc ed a mean GH peak response not different from that elicited by GHRH CLO before treatment or by GHRH alone after treatment. However, this t reatment significantly augmented the frequency of spontaneous bursts o f GH secretion, the mean GH peak amplitude and the total peak area. In dogs undergoing treatment 3, acute administration of GHRH alone or GH RH + CLO elicited a mean GH peak response higher than that elicited by the same drugs before treatment. Moreover, there was an increase of G H peak frequency, mean GH peak amplitude and total peak area, even hig her 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 b e restored by pharmacological means acting at both the pituitary and t he hypothalamic level, and (3) CLO given only once daily was more effe ctive than CLO given twice daily, perhaps due to the property of this drug to down-regulate at high doses hypothalamic alpha2-adrenoceptors.