Prolonged fasting or clonidine can restore the defective growth hormone secretion in old dogs

Abstract

Age-related changes in GH secretion were studied in the dog. In preliminary experiments, administration of GH-relasing hormone (GHRH-40, 2 \g=m\g/kg,iv) or the \g=a\2-adrenoceptor agonist clonidine (4 \g=m\g/kg,iv) elicited significantly higher plasma GH rises in 3 to 4 years old than in 10 to 14 years old beagle dogs. The pulsatile patterns of GH secretion in both young and old dogs under baseline conditions and after prolonged fasting or clonidine administration were studied. Samples were taken every 10 min from 09.00 to 15.00 h from five young and five old dogs of both sexes. Under baseline conditions, GH peak frequency, total peak area, and integrated GH secretion were significantly lower in old than in young dogs. In old dogs, 5-day complete fasting or 14\ x=r eq-\ day clonidine administration (75 \g=m\g/dog,po, twice daily) increased the frequency and amplitude of spontaneous GH bursts, the total peak area, and the integrated GH secretion. After either stimulus, the GH secretory pattern was quantitatively and qualitatively indistinguishable from that of young dogs under baseline conditions. Similarly, the foregoing indices were significantly increased in young dogs by either stimulus, except for the inability of clonidine to affect peak frequency. These data demonstrate that the defective GH secretion in old dogs is not irreversible, since it is normalized when old dogs are exposed to central nervous system-directed stimuli.Among the several causes proposed for the geria¬ tric changes in structure and function, one is cessa¬ tion of endogenous growth hormone secretion, which occurs in about half of the elderly popula¬ tion (1). There are some similarities between the al¬ terations in ageing and those that occur in GHdeficient patients. In both, there are shrinkage of lean body mass, expansion of adipose mass, dim¬ inution of renal function, and decreased rates of cell division (1). In addition, both kinds of subjects have reduced bone mass and density, dental defi¬ cits, and a decrease in calcium absorption. Consist¬ ent with this proposition, one third of a large group of old subjects (55-80 years) had very low levels of somatomedin-C (2), the GH-related peptide that mediates most of the biological effects of GH (3).If defective GH secretion is one of the pacema¬ kers of ageing, it is of interest to study the mechan¬ isms underlying reduced GH secretion in aged hu¬ mans and animals (2,4-6), with the ultimate goal being to develop suitable pharmacological means for counteracting the age-related phenomena. The present studies were performed in the dog, a species with many aspects of GH regulation resem¬ bling those in humans (7,8).After an initial assessment of the ability of old and young dogs to respond to acute challenges with GH-releasing hormone (GHRH) or clonidine, an a-adrenergic agonist (9), dogs were fasted for a long period or given clonidine, two known stimuli for GH secretion in this species (10)(11)(12), and the ability of these stimuli to alter the secretory pat¬ tern of GH was evaluated over a...

Studies of Growth Hormone Secretion in Calorically Restricted Dogs: Effect of Cholinergic Agonists and Antagonists, Glucose and Thyrotropin-Releasing Hormone

“…This implied the occurrence of changes in hypotha lamic GHRH a n d /o r SS function [18,19], Interestingly, similar results were obtained by a 10-day treatment with clonidine [11]. an ct2-adrenoceptor agonist known to act via an enhanced GHRH [20,21] an d /o r a decreased SS [22] secretion.…”

“…Many factors, not mutually exclusive, can be advo cated to account for the increased GH secretion occurring dur ing fasting or CR. They include: (I) changes in the synthesis an d /o r release of hypothalamic GHRH a n d /o r SS, likely sec ondary to alterations in neurotransmitter function [11]; (2) a progressive reduction in circulating 1GF-I levels [14] with en suing decrease in the inhibitory feedback action of IGF-I on the hypothalamus an d /o r pituitary [15,16]; (3) a state of hypogly cemia triggering GH release via a direct action on hypophysiotropic neurons [ 17).…”

“…We have no readily explanation to ac count for this phenomenon, which would deny the alleged defi ciency of the SS tone in dogs during CR. It cannot be excluded, however, that this event in dogs under CR may be favored by a concomitant increase in GHRH release occurring during un dernutrition [10,11], A nonspecific effect of pyridostigmine due to stressful conditions is made unlikely by the presence of unal tered basal cortisol levels.…”

Effects of growth hormone secretagogues on the release of adenohypophyseal hormones in young and old healthy dogs

“…For identifying age-related differences in GH secretion, determination of the pulsatile secretion pattern of GH is much more sensitive. Indeed, the pulsatile secretion pattern of GH is significantly lower in old humans, rats, and dogs than in young individuals (Borst et al, 1994;Cella et al, 1989;Zadik et al, 1985). The higher basal plasma concentrations of ACTH and cortisol in the young dogs may indicate that the stress of handling caused a stronger activation of the pituitary-adrenocortical axis in these young dogs than in the old dogs.…”

“…Both basal and stimulated GH secretion and circulating insulin-like growth factor-I (IGF-1) concentrations decline with age in several mammalian species (Corpas et al, 1992;Finkelstein et al, 1972;Muller et al, 2002;Rudman, 1985;Wilshire et al, 1995;Zadik et al, 1985). In dogs too the GH responsiveness to GH stimuli, such as GHRH and hexarelin, decreases with ageing (Cella et al, 1989(Cella et al, , 1995. Until now, the effect of ageing on the GH responsiveness to ghrelin has not been studied in the dog.…”