Metopirone-induced hypertension in the rat

Uninephrectomized rats were administered 10 mg of Metopirone (Su-4885; metyrapone), an adrenal 11 β -hydroxylase inhibitor, ip either once or twice daily for 6 weeks. All were given 1% sodium chloride as drinking solution. Both Metopirone-treated groups showed a significant elevation in systolic blood pressure. All rats were sacrificed 24 hr after the last injection of Metopirone. Adrenals were collected and corticosteroidogenesis from progesterone, measured in adrenal homogenates, was not impaired by Metopirone treatment. However, in short-term studies when rats were sacrificed either 1 or 4 hr after the final administration of Metopirone, inhibition of 11 Î -hydroxylation was demonstrable in vitro. The hypertensive groups did show a substantial increase in plasma 11-deoxycorticosterone (DOC) levels, thus indicating some inhibition of 11 β - hydroxylase in vivo. Adrenal hypertrophy in those rats treated twice daily with Metopirone further substantiated the effectiveness of the dose of Metopirone employed in that group. These rats also were found to be hypernatremic and hypokalemic. Organ weights recorded at the time of sacrifice showed that the heart and kidney sizes of these rats were significantly greater than those of the controls. Only the heart weights were significantly elevated in those rats treated once a day with Metopirone. In addition, these organs showed macroscopic and microscopic lesions characteristically found with DOC hypertension. These findings tend to solidify the hypothesis that the inhibition of 11 β -hydroxylation in the rat with the resulting increase in DOC production is a valid mechanism for the development of hypertension.