Investigating the effects of asymmetric dimethylarginine in the microcirculation

Thesis

Coronary resistance arteries develop spontaneous myogenic tone in response to intraluminal pressure, this autoregulation helps to couple blood flow to match metabolic demands of the myocardium. Endothelial dysfunction, involving the loss of nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH), is an early hallmark of cardiovascular disease. This compromises the autoregulation and is associated with reduced vasodilation and abnormal vasoconstriction (vasospasm). Endogenous methylarginines, such as asymmetric dimethylarginine (ADMA), reduce NO bioavailability by inhibiting endothelial NO synthase (NOS), and elevated plasma ADMA concentration is a strong predictor of cardiovascular disease and mortality. Despite the clinical importance, our understanding of the roles of ADMA and EDH in coronary microvascular dysfunction (CMD) is still rudimentary. This thesis aimed to investigate the effects of ADMA and EDH in the coronary and mesenteric microcirculation using wire and pressure myography, immunohistochemistry and Ca 2+ imaging. The significant findings of this thesis are: i) ADMA exerts greater inhibition on NOS in the coronary microcirculation compared to mesenteric arteries, abolishing NO-dependent vasodilation; ii) the expression of the ADMA-metabolising enzyme, dimethylarginine dimethylaminohydrolase 1 (DDAH1), is greater in the endothelium of mesenteric arteries compared to coronary arteries; iii) intermediate conductance Ca2+ -activated K + (IKCa ) channels alone underpins EDH vasodilation in coronary arteries; iv) L-arginine is effective in reversing endothelial dysfunction; and v) ADMA enhances vascular smooth muscle cell and endothelial cell Ca2+ events. In summary, this thesis demonstrates the ability of ADMA to cause endothelial dysfunction, which has previously been questioned. This results in the inhibition of NOdependent vasodilation and vasospasm. The expression of endothelial DDAH1 protects NOS activity and the lower expression in coronary arteries may predispose them to a greater susceptibility to endothelial dysfunction. Therefore, in addition to L-arginine, strategies to enhance DDAH1 expression and/or activity may be beneficial in CMD.

Authors: Ng, YYH

• DOI: 10.5287/ora-nonawvne7
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: vasospasm; coronary; microcirculation; EDH; nitric oxide; heart disease; DDAH; ADMA; microvascular dysfunction; asymmetric dimethylarginine
• Subjects: Coronary heart disease; Microcirculation disorders; ADMA; Nitric oxide; Microvascular dysfunction; Coronary vasospasm