OBJECTIVE Endothelial dysfunction by the loss of nitric oxide (NO) is a critical event during reperfusion of ischemic myocardium. Reduced NO availability signals important pathophysiological changes leading to myocardial reperfusion injury. We have recently shown that NO biosynthesis can be disturbed by the endogenous NO synthase (NOS) inhibitor ADMA and that these changes are mediated by an im...

An efficient process for the discovery of inhibitors of DDAH enzymes, without the requirement for high throughput screening, is described. Physicochemical filtering of a 308,000-compound library according to drug likeness followed by reciprocal nearest neighbour selection produced a representative subset of 35,000 compounds. Virtual screening on a dual processor PC using FlexX, followed by biol...

Intracellular factors that regulate nitric oxide (NO) synthesis represent important targets in tumor progression. Overexpression of dimethylarginine dimethylaminohydrolase (DDAH), which metabolizes the endogenous inhibitors of NO synthesis asymmetric dimethylarginine and Nmonomethyl-L-arginine, results in C6 gliomas with enhanced growth rate compared with wild type. To investigate the effects o...

Intracellular factors that regulate nitric oxide (NO) synthesis represent important targets in tumor progression. Overexpression of dimethylarginine dimethylaminohydrolase (DDAH), which metabolizes the endogenous inhibitors of NO synthesis asymmetric dimethylarginine and N-monomethyl-L-arginine, results in C6 gliomas with enhanced growth rate compared with wild type. To investigate the effects ...

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS) and has been implicated in endothelial dysfunction. ADMA is metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), with DDAH2 representing the predominant endothelial DDAH isoform. Symmetric dimethylarginine (SDMA), also originating from arginine methylation by protein arginine methyl...

Hyperhomocysteinemia decreases vascular reactivity and is associated with cardiovascular morbidity and mortality. However, pathogenic mechanisms that increase oxidative stress by homocysteine (Hcy) are unsubstantiated. The aim of this study was to examine the molecular mechanism by which Hcy triggers oxidative stress and reduces bioavailability of nitric oxide (NO) in cardiac microvascular endo...

EFFECT OF DIMETHYLARGININE DIMETHYLAMINOHYDROLASE IN TEDEVELOPMENT OF SALT SENSITIVITYbySAMAR ABDULLA NASSERMay 2011Advisor: Dr. John FlackMajor: PhysiologyDegree: Doctor of PhilosophySalt sensitivity is associated with a rise in blood pressure (BP) occurring duringsodium loading and/or a fall in BP during sodium restriction that exceeds randomfluctua...

Insulin resistance syndrome (IRS) is a configuration of cardiovascular risk factors involved in the development of metabolic disorders including type 2 diabetes mellitus. In addition to diet, age, socioeconomic, and environmental factors, genetic factors that impair insulin signaling are centrally involved in the development and exacerbation of IRS. Genetic and pharmacological studies have demo...

BACKGROUND Asymmetric NG,NG-dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is regulated by the enzymatic participants of synthetic and metabolic processes, i.e., type I protein N-arginine methyltransferase (PRMT) and dimethylarginine dimethylaminohydrolase (DDAH). Previous reports have demonstrated that circulating ADMA levels can vary in patients with type 1 and typ...

Nitric oxide (NO) has been suggested to play a key role in the pathogenesis of pulmonary hypertension (PH). To determine which mechanism exists to affect NO production, we examined the concentration of endogenous nitric oxide synthase (NOS) inhibitors and their catabolizing enzyme dimethylarginine dimethylaminohydrolase (DDAH) activity and protein expression (DDAH1 and DDAH2) in pulmonary arter...