Examining the vasoactive properties of nitrite in normoxia and hypoxia

Gollop, Nicholas (2020) Examining the vasoactive properties of nitrite in normoxia and hypoxia. Doctoral thesis, University of East Anglia.

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Introduction: Inorganic nitrite is a nitric oxide-soluble guanylyl cyclase-cyclic guanosine monophosphate-protein kinase G (NO-sGC-cGMP-PKG)-dependent vasodilator, the effects of which are augmented in hypoxia. In normoxia (murine, ex vivo), the underlying vasoactive mechanisms may be NO-independent and mediated by multiple intermediates. In humans, this may also apply. It is unknown if the coronary arteries are subject to hypoxia-augmentation of nitrite-mediated vasodilation. Harnessing the vasoactive properties of nitrite could provide novel therapeutic approaches to managing multiple cardiovascular diseases.

Aims: To examine the effect of nitrite on the nitrite-PKG pathway in normoxia (murine, ex vivo), on NO-attenuated resistance arteries (humans, in vivo), and on epicardial coronary haemodynamics (humans, in vivo) in normoxia and hypoxia.

Methods and Results:
Chapter 3: Using tension wire-myography, NO scavenging and sGC inhibition in normoxia, we showed that nitrite caused NO-dependent conduit artery vasodilation and NO-independent resistance vasodilation. We identified that NO-independent processes included a novel NO-sGC-independent, PKG1α oxidation pathway, utilising hydrogen peroxide and cysteine/glutathione persulfides.
Chapter 4: In the Haem and Nitrite Study, we showed that intra-brachial nitrite led to dose-dependent increases in forearm blood flow ratio (FBFR). We showed that 30-35-day stored autologous whole blood transfusion led to non-significant increases in subject circulating cell-free haem and NO consumption, but did not change FBFR in normoxia or hypoxia.
Chapter 5: In the Nitrite and Coronary Artery Study, we showed that systemic nitrite administration led to an increase in epicardial coronary artery CSA and a reduction in velocity (hypoxia>normoxia) and flow, associated (probably causally) with a reduction in MAP in normoxia.

Conclusions: In vitro nitrite utilises hydrogen peroxide and persulfides to induce tissue-specific vasodilation via PKGIα oxidation in normoxia. In vivo, nitrite-mediated FBF is not modified by transfusion of ~500mls of 30-35-day old autologous blood in normoxia or hypoxia, and, nitrite significantly increases epicardial coronary CSA but decreases blood velocity and flow (hypoxia>normoxia).

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Chris White
Date Deposited: 03 Jun 2021 12:52
Last Modified: 31 Dec 2022 01:38
URI: https://ueaeprints.uea.ac.uk/id/eprint/80094


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