Dihydralazine Sulfate

In a randomized, double‐blind, placebo‐controlled trial, we investigated antihypertensive treatment effect of a quadruple single‐pill combination of reserpine 0.1 mg, dihydralazine 12.5 mg, hydrochlorothiazide 12.5 mg, and triamterene 12.5 mg, and changes in plasma levels of monoamine neurotransmitters (serotonin, norepinephrine, and dopamine) in patients with grade 1 hypertension. Eligible patients with a systolic/diastolic blood pressure (BP, average of six readings at two clinic visits during a 4‐week run‐in period) of 140‐159/90–99 mmHg were randomly assigned to the quadruple combination (n = 30) or placebo (n = 30). The randomized patients were instructed to take a pill of the combination or placebo once daily and followed up at 4, 8, and 12 weeks, respectively. Monoamine neurotransmitters were measured at baseline and 12 weeks of follow‐up. After 12‐week treatment, systolic/diastolic BP significantly (p ≤ .0001) decreased from 140.8 ± 7.9/89.5 ± 7.5 mmHg at baseline by 9.8 ± 1.8/6.4 ± 1.3 mmHg in the combination group. The corresponding values in the placebo group were 141.3 ± 7.9/90.3 ± 7.3 mmHg and 5.2 ± 1.8/0.4 ± 1.3 mmHg, respectively. The between‐group differences in systolic/diastolic BP changes were −4.6/−6.0 mmHg (95% CI, −9.7 to 0.6/−9.7 to −2.2 mmHg, p ≤ .08). The control rate of hypertension was higher in the combination than placebo group (63.3% vs. 16.7%, p = .0002). Plasma serotonin, but not norepinephrine or dopamine, changed in both treatment and placebo groups (p ≤ .01). Nonetheless, plasma norepinephrine tended to decrease in the treatment group (−34.4 pg/ml, p = .09). Adverse events occurred in 5 (16.7%) and 3 (10.0%) patients in the combination and placebo groups, respectively. Our study showed that the quadruple combination reduced BP and caused some changes in plasma neurotransmitters.

Hydralazine (HZ) and dihydralazine (DHZ) are phthalazine derivatives substituted at position 1 (HZ) or positions 1 and 4 (DHZ) by a hydrazinyl substituent. These compounds are widely used for treating hypertension and heart failure, essentially acting as vasodilators on the arteries and arterioles. In this study, the antioxidant activity of HZ and DHZ in the gas phase and in physiological environments was investigated by thermodynamic and kinetic calculations. It was found that the HOO^• radical scavenging activity of these compounds follows the formal hydrogen transfer (FHT) mechanism. The H abstraction of the N9-H bond plays a deciding role in the HOO^• radical scavenging of HZ-1 and DHZ-1, whereas the HOO^• radical scavenging activities of HZ-2 and DHZ-2 are defined by the dissociation of the N10-H and N11-H bonds, respectively. The rate constants for the HOO^• radical scavenging of the HZ and DHZ in the gas phase are in the range of 9.64 × 10⁶ to 4.52 × 10⁸ M^-1 s^-1, whereas in aqueous solutions and the lipid medium they are in the range of 2.62 × 10⁴ to 5.13 × 10⁷ M^-1 s^-1 and 5.75 × 10⁴ to 6.66 × 10⁶ M^-1 s^-1, respectively. The HOO^• radical scavenging of DHZ-1 and DHZ-2 is thus faster than that of the reference antioxidant compound Trolox in all the studied environments. Consistently, DHZs are not only vasodilators but also potent antioxidants.