ANTERIOR-PITUITARY PROOPIOMELANOCORTIN EXPRESSION IS DECREASED IN HYPERTENSIVE RAT STRAINS

Studies comparing neuroendocrine differences between the spontaneously hypertensive rat (SHR) and the normotensive Wistar-Kyoto (WKY) strains have suggested altered anterior pituitary corticotrope expression of POMC associated with the development of hypertension in SHR animals. One major difficulty in comparing the SHR and WKY strains is that the two strains exhibit genetic differences unrelated to blood pressure status, because inbred in the SHR genome is a profile of behavioral characteristics different from those in the WKY, including hyperactivity in a novel environment and hyperreactivity in responding to stress. The present studies examine two new inbred rat strains, the WKHT and WKHA, which independently express the hypertension and behavioral traits, respectively. Together with the SHR and WKY, these genetically related, homozygous strains permit a more definitive means of examining the neuroendocrine correlates of either hypertension or behavior. The adult (5-month-old) male anterior pituitary gland content of the POMC peptides beta-endorphin and ACTH was decreased approximately 50% in the SHR and WKHT strains compared to that in the WKY strain, whereas hormone levels in the WKHA strain were not significantly different from those in the WKY strain. Reduced POMC peptide levels were, therefore, specifically associated with the hypertensive trait. Hormone content in prehypertensive weanling (5- to 7-week-old) SHR and WKHT animals was also reduced approximately 35% compared to that in WKY animals. Northern blot analysis identified a 45% decrease in POMC mRNA expression in the hypertensive SHR and WKHT strains, which paralleled the changes in tissue hormone content. Using both immunocytochemistry and in situ hybridization histochemistry, the number of labeled cells per unit area of tissue section was reduced approximately 45% in anterior pituitary tissues from SHR and WKHT rats compared to that in WKY tissues. The levels of POMC mRNA per cell, determined by quantitative densitometry, were not statistically different in the anterior pituitaries of WKHT, SHR, and WKY rats. The decrease in hormone content and POMC mRNA levels may, thus, reflect decreased anterior pituitary gland corticotrope populations. Although POMC peptide levels in the anterior pituitaries of adult WKHA animals were not significantly different from those in WKY animals, the morphological studies demonstrated a 30% increase in the corticotrope population in the WKHA strain. In contrast, POMC mRNA levels in WKHA animals were decreased 30%, and the amount of POMC mRNA per corticotrope was decreased approximately 35% compared to that in WKY, SHR, and WKHT tissues. Using four related rat strains, SHR, WKY, WKHA, and WKHT, changes in anterior pituitary gland corticotrope POMC expression associated with the hypertensive phenotype in both adult hypertensive and weanling prehypertensive rats suggest a possible involvement of the hypothalamic-pituitary-adrenal axis in both the development and maintenance of the hypertensive state. The distinct profile of POMC expression in WKHA rats suggests altered corticotrope function associated with the hyperactive/hyperreactive to stress responses.