Growth Hormone Releasing Hormone Induced Release of Growth Hormone in Aging Male Rats: Dependence on Pharmacological Manipulation and Endogenous Somatostatin Release

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Abstract
These studies were designed to assess whether a decline in pituitary response to growth hormone-releasing factor (GRF) contributes to the decline in amplitude of growth hormone (GH) pulses with age. Atrial cannulated young (3–4 months), middle-aged (12–14 months) and old (20–22 months) Fischer 344 male rats were anesthetized with pentobar-bital to suppress pulsatile release of GH. One hour later, animals were injected with hpGRF(l-44) (10 µg/kg) and blood samples were removed at 0, 5, 10, 20, 40 and 80 min. Animals were then passively immunized with somatostatin antiserum and hpGRF(l-44) was reinjected. Samples were removed at the time intervals previously described. In response to 10 µg/kg GRF, plasma GH in young and middle-aged animals increased to 921 ± 105 and 866 ± 126 ng/ml, respectively, at 10 min and declined. In old animals, GH concentrations only increased to 654 + 80 ng/ml (p < 0.05 compared to young rats). This represents a 28% reduction in the peak GH response to GRF. Despite passive immunization with somatostatin anti-serum, the peak GH response to a second injection of GRF was diminished in all age-groups. However, integration of the area under the response curve indicated that GH secretion was similar in young and old animals during the 80-min sampling period after somatostatin antiserum. In another study, diethyldithiocarbamate (DDC; 250 mg/kg, i.v.), a dopamine-β-hydroxylase inhibitor, was used to inhibit pulsatile GH release. One hour later, animals were injected with hpGRF(l-44) (50 µg/kg, i.v.) and blood samples were removed as previously described. At the end of this sampling period, animals were passively immunized with somatostatin antiserum and the GH response to 0.5 and 5 µg/kg GRF was studied. In response to 50 µg/kg GRF, plasma GH increased to approximately 130 ng/ml in all age-groups at 10 min and declined. No age-related differences in the GH response to GRF were observed in the three age-groups. In the presence of somatostatin antiserum, a dose-related increase in plasma GH was found in all age-groups and the rise in GH was greater in old as compared to young rats (p < 0.05 at 10 and 20 min after injection). Studies of the time course and dose-response characteristics of GH release from in vitro pituitary slices of young, middle-aged and old rats were similar in response to 109–107M hpGRF( 1 -44) although basal GH release was reduced by 44–53% in old as compared to young rats (p < 0.05). These results demonstrate that (1) the diminished response of aging rats to GRF in vivo is dependent on the pharmacological treatments used to inhibit pulsatile release of GH, (2) after passive immunization with somatostatin antiserum, pituitary GH response to GRF is equal to or greater in old as compared to young rats and (3) the temporal and dose-response characteristics of freshly prepared pituitary tissue are similar in animals of all age-groups. Our results suggest that diminished GH release with age is not associated with decreased pituitary response to GRF.