Adrenocorticotrophin-induced hypertension: effects of mineralocorticoid and glucocorticoid receptor antagonism.

OBJECTIVE: To examine whether the increase of blood pressure in adrenocorticotrophin-treated rats is mediated through mineralocorticoid or glucocorticoid receptors or corticosterone 6 beta-hydroxylation inhibition.

DESIGN: Rats were randomly allocated to 14 treatment groups for 10 days. The treatments included sham injection (n = 35), adrenocorticotrophin (5, 100, 500 micrograms/kg per day, subcutaneously, n = 5, 15 and 15, respectively), spironolactone (100 mg/kg per day, subcutaneously, n = 15), standard-dose or high-dose RU 486 (70 mg/kg every 3 days or 70 mg/kg per day, subcutaneously, n = 5 and 10, respectively), spironolactone + adrenocorticotrophin (100 micrograms/kg per day, n = 5, or 500 micrograms/kg per day, n = 10), standard-dose RU 486 + adrenocorticotrophin (500 micrograms/kg per day, n = 5), high-dose RU 486 + adrenocorticotrophin (100 micrograms/kg per day, n = 10), troleandomycin (40 mg/kg per day, subcutaneously, n = 5) and troleandomycin + adrenocorticotrophin (5 micrograms/kg per day, n = 5). Systolic blood pressure and metabolic parameters were measured every second day.

RESULTS: Adrenocorticotrophin treatment increased systolic blood pressure dose-dependently (5 micrograms/kg per day: +14 +/- 2 mmHg; 100 micrograms/kg per day: +20 +/- 2 mmHg; 500 micrograms/kg per day: +28 +/- 2 mmHg, all P < 0.001). Adrenocorticotrophin at 100 and 500 micrograms/kg per day increased plasma sodium and decreased plasma potassium concentrations. Spironolactone did not block adrenocorticotrophin-induced systolic blood pressure changes but did block changes in plasma sodium and potassium levels. Standard-dose RU 486 did not modify the adrenocorticotrophin-induced (500 micrograms/kg per day) systolic blood pressure rise but blocked the effect of adrenocorticotrophin on body weight. High-dose RU 486 partially blocked the adrenocorticotrophin-induced (100 micrograms/kg per day) systolic blood pressure increase (adrenocorticotrophin at 100 micrograms/kg per day: 143 +/- 3 mmHg; high-dose RU 486 + adrenocorticotrophin at 100 micrograms/kg per day: 128 +/- 5 mmHg, P < 0.001) and body-weight loss. Troleandomycin did not alter the development of adrenocorticotrophin-induced hypertension.

CONCLUSIONS: Spironolactone and standard-dose RU 486 did not modify adrenocorticotrophin-induced hypertension despite demonstrable antimineralocorticoid and antiglucocorticoid actions. High-dose RU 486 partially blocked adrenocorticotrophin-induced (100 micrograms/kg per day) hypertension, suggesting either a permissive effect of glucocorticoid on blood pressure or other antihypertensive actions of RU 486. Inhibition of glucocorticoid 6 beta-hydroxylation by troleandomycin did not modify adrenocorticotrophin-induced hypertension, suggesting that effects of corticosterone 6 beta-hydroxylation in adrenocorticotrophin-induced hypertension are negligible.