HETEROGENEITY OF GROWTH-HORMONE (GH)-PRODUCING CELLS IN AGING MALE-RATS - IN-VITRO GH RELEASING ACTIVITY OF SOMATOTROPE SUBPOPULATIONS

Studies on the age-related decline of growth hormone (GH) release have ignored that the population of GH-producing cells (somatotropes) is h eterogeneous. In aging male rats, centrifugation of dispersed pituitar y cells in a density gradient yields two somatotrope subpopulations, i .e. low- (LD) and high-density (HD) cells. A previous analysis of ultr astructure and GH mRNA levels has shown that storage and biosynthetic features were inversely related in both subsets. Furthermore, ultrastr uctural and molecular differences between LD- and HD-cells were retain ed throughout the rat lifespan, suggesting that the heterogeneity of s omatotropes may have a biological meaning. Accordingly, the main objec tive of the present study was to analyze the functional heterogeneity of the somatotrope population during the aging process in male rats. F or this purpose, the response of LD- and HD-somatotropes from 5-, 19-, and 26-month-old male rats was analyzed with an optimized cell immuno blot assay both under basal conditions, and after GH-releasing factor (GRF) and/or somatostatin (SS) treatments. Simultaneous measurements o f hormonal release, intracellular GH content, and cell size were perfo rmed at the single-somatotrope level. Average values for those paramet ers were significantly higher in HD- than in corresponding LD-cells, s uch differences being irrespective of age or treatment. Releasing acti vity and GH content were significantly reduced with age in both subpop ulations. GRF stimulated GH release from LD- and HD-somatotropes, and the GRF responsiveness was similar in both subpopulations and in all a ges. On the other hand, SS prevented GRF-stimulated GH release in most cases. At the level of single cells, both releasing activity and cell size showed a significant, linear dependence on intracellular GH cont ent, correlations being irrespective of age, subpopulation, or treatme nt. Taken together, our results demonstrate that LD- and HD-somatotrop e subpopulations display quantitative differences in releasing activit y that are essentially retained through aging. This functional heterog eneity is more dependent on the basal GH release of these somatotrope subsets than in their responsiveness to GRF and SS. The present findin gs suggest that the reduction in secretory activity at the single soma totrope level observed in both subpopulations underlies the age-relate d decline of pituitary GH release. Finally, a theoretical model of sec retory cycle is proposed which might contribute to the understanding o f the biological meaning of the somatotrope subpopulations in aging ma le rats.