Concomitant up-regulation of proopiomelanocortin and dopamine D2-receptor gene expression in the pituitary intermediate lobe of the spontaneously hypertensive rat.

Abstract

Alterations in central dopaminergic mechanisms in the Spontaneously Hypertensive Rat (SHR) have been previously implicated in the development of the hypertensive phenotype in this rat strain. We have examined the expression and regulation of the dopamine-responsive gene proopiomelanocortin (POMC) in the neurointermediate lobe (NIL) of the pituitary in both SHR and normotensive Wista Kyoto (WKY) rats. Solution hybridization/nuclease protection analysis showed that adult SHR express POMC mRNA in the NIL at approximately 2-4 times the level seen in normotensive WKY controls, associated with a concomitant 2-fold increase in dopamine D2-receptor (D2-R) mRNA expression. Despite the obvious difference in D2-R gene expression, NIL POMC mRNA in both rat strains was regulated in an identical manner following 4 d in vivo bromocriptine or haloperidol treatment. In contrast, though D2-R mRNA expression in the WKY NIL was significantly up-regulated by D2-R blockade with haloperidol, the elevated levels of D2-R mRNA in the NIL of the hypertensive strain were not altered by D2-R antagonism. Following isolation from all hypothalamic input by 5 d in vitro culture, SHR melanotrophs exhibited a 2-3 fold higher rate of beta EP secretion and POMC mRNA expression than melanotrophs derived from normotensive WKY rats, though beta EP secretion was inhibited in a similar fashion by the D2-R agonist quinpirole in both cultures. The current data demonstrate changes in expression of both POMC and D2-R mRNA in the SHR NIL which may be a consequence of altered dopaminergic input and/or alterations in D2-R regulation in this tissue, possibly enabling other factors in addition to dopamine to maintain the NIL of the SHR in a relatively hyperactive state. Whether or not POMC-derived peptides or other factors secreted from the melanotroph cell play any role in the development or maintenance of hypertension in this strain is yet to be established.