Abstract
BackgroundNitric oxide (NO) is a key signalling molecule in the human cardiovascular system. Relatively recently, it has been recognised that, in addition to NO synthesis from L-arginine by NO synthase enzymes, a second major pathway of NO production exists in humans i.e. the inorganic nitrate-nitrite-NO pathway. In the nitrate-nitrite-NO pathway, orally-ingested inorganic nitrate (e.g. as beetroot juice) is sequentially reduced, via nitrite, to NO.
Methods and Results
This thesis comprises a series of mechanistic experimental medicine studies in humans along two key themes. Firstly, I explored the in vivo effects of inorganic nitrite on left ventricular and coronary artery function. An additional experiment sought to identify the mechanism of action of nitrite-induced conduit artery dilatation. The key findings of these studies are that: nitrite enhances LV diastolic function through a combination of direct myocardial and indirect effects; nitrite dilates epicardial coronary arteries without a significant effect on flow or coronary resistance; and Na+/K--ATPase is not the channel responsible for nitrite-induced conduit artery dilatation.
Secondly, I performed two experimental studies to identify the mechanisms of altering the oral reduction of inorganic nitrate to nitrite, through co-administration of oral inorganic nitrate with grapefruit juice (as a CYP3A4 inhibitor) and through altering oral pH. These studies found that grapefruit juice enhanced the clinical effect of inorganic nitrate, although not via the hypothesised mechanism. Lowering oral pH also increased the clinical effect of inorganic nitrate.
Conclusions
This study has identified a number of important mechanistic findings relating to the nitrate-nitrite-NO pathway.
Firstly, inorganic nitrite has beneficial cardiac and vascular effects whose profile suggest therapeutic potential in heart failure states e.g. hypertensive heart disease, heart failure with preserved ejection fraction (HFpEF). Secondly, the clinical effects of dietary nitrate can be enhanced by altering conditions in the oral cavity and therefore manipulating the nitrate-nitrite-NO pathway. In addition to the clinical relevance of the findings, the studies within this thesis have also generated hypotheses for further work.
| Date of Award | 1 Oct 2021 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Andrew Webb (Supervisor) & Ajay Shah (Supervisor) |