Role of Tetrahydrobiopterin in Adrenocorticotropic Hormone-Induced Hypertension in the Rat

Adrenocorticotropic hormone (ACTH)-induced hypertension in the rat is characterized by nitric oxide deficiency. Tetrahydrobiopterin (BH₄) is an essential cofactor for the enzyme nitric oxide synthase and glucocorticoids have been reported to reduce cytokine-induced BH₄ production. Accordingly we hypothesized that ACTH-induced hypertension would be reversed by BH₄ supplementation. Male Sprague-Dawley rats (n = 33) were treated with BH₄ in vehicle (10 mg/kg/day i.p.) or vehicle alone (5 mg/kg/day i.p. of ascorbic acid in 4 mM HCl) for 10 days. ACTH (0.2 mg/kg s.c.) or saline daily injection was started 2 days after BH₄ or vehicle treatment and continued for 8 days. Systolic blood pressure (SBP) was measured on alternate days using the tail cuff method. Treatment with HCl, ascorbic acid or BH₄ alone had no effect on SBP. In saline treated rats, neither BH₄ nor its vehicle modified SBP. In ACTH treated rats, SBP was increased in both BH₄ (from 128 ± 6 to 142 ± 4 mmHg, T0 to T10, P < 0.0005, one way ANOVA) and vehicle groups (from 127 ± 3 to 158 ± 7 mmHg, T0 to T10, P < 0.001, one way ANOVA). There was no significant difference in SBP between BH₄ + ACTH treated and vehicle + ACTH treated rats. Thus, daily injection of BH ₄ (10 mg/kg i.p.) failed to prevent the development of ACTH-induced hypertension in rat.