Blood pressure lowering and anti-fibrotic effect of zinc specific chelator-tetraethylthiuram disulfide in rat model of L-NAME-induced hypertension

Background: (TTD) is a zinc-specific popularly used to treat chronic alcoholism by targeting zinc-dependent alcohol enzyme. Interestingly, enzyme (ACE), neutral (NEP) and N (APN) implicated in hypertension are zinc-dependent enzymes. Objective: This study aimed to evaluate the inhibitory potential of TTD against ACE, NEP, and APN in vitro. Further, the anti-hypertensive and efficacy of TTD in were evaluated using N (ω)-nitro-L-arginine-methyl ester (L-NAME)-induced hypertensive rat model. Method: Dose-dependent inhibition of ACE, NEP, and APN by TTD was evaluated in vitro. Further, five groups consisting of 6 rats in each group were used for animal studies. Group one served as control, and the second group received L-NAME alone (40mg/kg/day). The third group was TTD control. Fourth and fifth group received L-NAME and simultaneously treated with TTD (10mg/kg/day) and (10mg/kg/day) respectively. Systolic blood pressure, heart and kidney weight; angiotensin, atrial natriuretic peptide urea, creatinine, aspartate transaminase, alanine transaminase, and nitrite levels were measured in serum of all group of rats. Fibrosis in heart and kidney tissues were evaluated by staining collagen with red. Results: TTD effectively inhibited the activities of ACE, NEP, and APN in a dose-dependent manner with IC50 of 10.15 µM, 22.35 µM and 3.032 µM respectively. Further, administration of the TTD effectively decreased systolic blood pressure (140±8 mmHg) when compared to L-NAME group (190±10 mmHg), improved hypertension markers (Ang II and ANP), kidney and liver markers. TTD ameliorated heart and kidney hypertrophy and partially prevented fibrosis. Conclusion: These findings provide evidence that TTD affords efficient anti-hypertensive effect with moderate end-organ protection possibly by cumulative inhibition of the aforementioned enzymes.