Say NO to Obesity-Related Hypertension

Obesity and its complications represent one of the major emerging challenges for the developed world.1,2 Hypertension is a common sequelae of obesity,3,4 and the obesity pandemic is estimated to contribute to 75% of cases of hypertension in men and 65% in women.1 Frequently, subjects with obesity are resistant to standard antihypertensive medication,4 and poor understanding of the precise mechanisms underlying the link between obesity and hypertension has presented roadblocks for the development of new and effective therapy.4 In this context, we recently found that obesity is associated with reduced nitric oxide (NO) bioavailability caused by impaired transport of its substrate l-arginine and that augmentation of endothelial l-arginine transport prevents experimental obesity-induced hypertension.5 Findings by others also provide clear evidence that endothelial dysfunction plays an important role in the pathogenesis of hypertension6,7 including that associated with obesity.8 In the current review, we will discuss the role of the l-arginine–NO pathway in the long-term regulation of blood pressure, its complex inter-relationship with other key neurohormonal and biochemical determinants of arterial pressure, and the way in which this system becomes deranged in obesity-related hypertension. NO is well recognized as a pivotal endogenous modulator of vascular tone and endothelial function.9 l-Arginine is the sole substrate for NO formation and transport of extracellular l-arginine via cationic amino acid transporter-1 (CAT1) is a rate limiting factor for endothelial NO synthase (eNOS)–dependent NO formation (Figure 1).9–11 This occurs despite the fact that intracellular concentration of l-arginine far exceeds the Michaelis constant Km of eNOS for l-arginine, and this phenomenon is commonly referred to as the l-arginine paradox.9 The precise factors underlying this paradox remain to be determined, but …