Comment on ‘Cardiac effects of 6 months' dietary nitrate and spironolactone in patients with hypertension and with/at risk of type 2 diabetes, in the factorial design, double‐blind, randomised controlled VaSera trial’ by Faconti et al.

Hypertension and diabetes are leading risk factors for cardiovascular complications and frequently occur together 1. Faconti et al. 2 evaluated if the administration of beetroot juice, as a source of dietary nitrate, in patients with hypertension and with/at risk of type 2 diabetes mellitus would improve the effects of the antihypertensive drugs spironolactone and doxazosin. They showed that, whereas spironolactone and doxazosin both equally reduced the systolic blood pressure (SBP), supplementation with nitrate does not improve the antihypertensive effects of these drugs. However, nitrate improved cardiac remodelling complications suggesting that the beneficial effects of nitrate are independent on blood pressure lowering effects 2. This study provides clinical evidence that supports the idea that dietary nitrate may be a useful therapeutic approach to treat cardiomyopathies given that it seems to provide additional beneficial effects to antihypertensive drugs. It is well known that endothelial nitric oxide (NO) generation by the canonical L‐arginine‐nitric oxide synthase pathway is compromised in hypertensive patients 3. Nitrate and nitrite once considered as physiological inert are currently recognized as a store of NO capable of eliciting physiological functions. Circulating nitrite is converted to NO by several nitrite reductase enzymes and promotes arterial and venous dilatation 4. Preclinical studies from our group have indicated that oral sodium nitrite treatment reduces the SBP in 2‐kidney 1clip or L‐NAME hypertensive rats 5, 6. However, the mechanisms causing this effect are not fully understood. Our group has compelling data demonstrating that sustained blood pressure lowering effect of nitrate and nitrite are dependent on NO and S‐nitrosothiol formation in the stomach 5. While Faconti et al. 2 showed interesting effects of nitrate, we would like to point out that we have recently shown that treatment with oral nitrite protected against hypertension‐induced cardiomyocyte hypertrophy by mechanisms that are independent of blood pressure lowering effects of nitrite 7. In our study, a low dose of nitrite induced antioxidant effects in the heart of hypertensive animals which negatively modulated the mTOR signalling, a common promoter of cardiac hypertrophy that stimulates protein synthesis. Reactive oxygen species (ROS) are implicated in the pathophysiology of hypertension, and increased ROS production in the heart modulates mTORC2 which phosphorylates Akt at S437 and upregulates mTORC1 pathway to contribute to cardiac remodelling 7. In multiple systems, NO is known to exert its function in association with mTOR activation 8, 9. Previous data demonstrated that nitrite treatment exerts antioxidant effects in hypertension possibly mediated by downregulation of NADPH oxidase expression 10 or increasing activity of antioxidant enzymes 11, and the low dose of nitrite decreased the ROS generation in the heart. Thus, based on these preclinical data, a reasonable explanation for the beneficial effects of nitrate supplementation on cardiac remodelling in hypertensive patients studied by Faconti et al. 2 could be associated with a nitrate‐mediated downregulation of ROS‐mTOR signalling pathway.

Competing Interests

There are no competing interests to declare.

This study was funded by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP‐Brazil).

Guimaraes, D. A. , and Tanus‐Santos, J. E. (2019) Comment on ‘Cardiac effects of 6 months' dietary nitrate and spironolactone in patients with hypertension and with/at risk of type 2 diabetes, in the factorial design, double‐blind, randomised controlled VaSera trial’ by Faconti et al . Br J Clin Pharmacol, 85: 1035–1036. 10.1111/bcp.13835.