1. Riboflavin analogues were tested in three hypertensive rat models: the DOCA-salt hypertensive rat, spontaneously hypertensive rats (SHR) and Dahl S rats.
2. When 1.6 mg of 7,8-dimethyl-10-formyl-methylisoalloxazine (FMI) or 7,8-dimethyl-10-(2′-hydroxyethyl)isoalloxazine (HEI) was administered with 3.0 mg of DOCA twice weekly for 9 weeks, the systolic blood pressure (SBP) of the unanaesthetized rats rose to only 136 ± 5 mmHg compared with 165 ± 5 mmHg during DOCA treatment alone. The analogues blunted the retention of iliopsoas muscle Na+ and water due to DOCA.
3. In subsequent studies, the more potent riboflavin analogue 7,8-dimethyl-10-(3-chlorobenzyl)isoalloxazine (CBI) was employed. Administration of 0.5 mg of CBI/100 g body wt. twice weekly for 7 weeks lowered the SBP of the unanaesthetized SHR from 188 ± 7 mmHg to 148 ± 2 mmHg. The rats tolerated the medication well. CBI was more effective than hydrochlorothiazide, which at 2.2 mg/100 g body wt. daily only lowered the SBP to 167 ± 5 mmHg. The combined administration of CBI and hydrochlorothiazide produced an additive effect in that the SBP was reduced to 126 ± 4 mmHg.
4. CBI treatment resulted in a 36% and 11% decrease in the iliopsoas muscle Na+ concentration and water content respectively, suggesting that the untreated SHR is retaining Na+. The hydrochlorothiazide-treated SHR exhibited elevated levels of serum aldosterone. There was a profound suppressive effect of CBI on the secondary hyperaldosteronism generated by hydrochlorothiazide which was also reflected in the iliopsoas muscle K+ concentration.
5. In contrast to the SHR, the administration to the Dahl S rats of CBI for 8 weeks at 0.5 mg/100 g body wt. twice weekly reduced neither their SBP nor their iliopsoas muscle Na+ and water contents.
6. These results are consistent with our hypothesis that the antihypertensive actions of the riboflavin analogues are closely associated with their ability to modify the effects of mineralocorticoids on Na+ balance. These data suggest that riboflavin analogues also decrease aldosterone production and may function as dual-mechanism diuretic agents with K+ sparing properties and thus act as a novel class of antihypertensive drugs.