CHRONIC DEXAMETHASONE TREATMENT SUPPRESSES HYPERTENSION DEVELOPMENT IN THE TRANSGENIC RAT TGR(MREN2)27

Introduction: The transgenic rat TCR(mREN2)27 is a monogenetic rat mod el in hypertension research. Integration of mouse Ren-2 gene into the rat genome led to fulminant hypertension despite suppressed plasma and kidney renin concentrations. Renin is highly expressed in extrarenal tissues, especially throughout the adrenal cortex. Aims and methods: B ecause plasma and urinary corticosteroid concentrations are elevated d uring the development of hypertension in these rats, we investigated t he effect of dexamethasone on blood pressure, adrenal renin and steroi d metabolism. Results: A daily injection of 100 mu g/kg dexamethasone for 8 weeks was capable of suppressing the development of hypertension in the transgenic rats. The same regimen did not alter blood pressure in Sprague-Dawley control rats. Plasma concentrations of adrenocortic otrophic hormone (ACTH)-dependent steroids (corticosterone and 18-hydr oxydeoxycorticosterone) decreased markedly in both strains treated wit h dexamethasone, but more pronouncedly in transgenic rats. Surprisingl y, plasma aldosterone concentrations increased exclusively in the tran sgenic rats, and not in control rats, treated with dexamethasone. The decrease in corticosterone and 18-hydroxydeoxycorticosterone productio n was accompanied by a decrease in the abundance of the messenger RNA (mRNA) encoding the rate-limiting enzyme in steroidogenesis (P450scc c holesterol side-chain cleavage) and a decrease in the mRNA encoding P4 50c11 beta (11 beta-hydroxylase). The increase in aldosterone was acco mpanied by a massive increase in the abundance of the mRNA encoding zo na glomerulosa-specific P450c11AS (aldosterone synthase), which was no t increased in control rats. Conclusion: We conclude that ACTH-depende nt steroids other than the mineralocorticoid aldosterone are responsib le for the development of hypertension in the transgenic rat.