It has been postulated in the context of hypertension that when fumarate accumulates in the cell, which may occur when HIF-1α is expressed, there is a reduced availability of l-arginine necessary for NOS action, which is formed during the breakdown of argininosuccinate into fumarate and l-arginine, leading to a reduction in NO production (378, 379). This evidence concerns the gene HIF1A and hypertensive disorder.