Should We Target the Sympathetic Nervous System in the Treatment of Obesity-Associated Hypertension?

Abstract

A n estimated 60% to 70% of hypertension may be attributed to obesity. 1 As our population increases in weight and girth, obesity-associated hypertension will be an increasing medical problem, contributing to greater health care costs and reversing the gains that we have achieved in the treatment of hypertension. Considering that 30% of hypertensive subjects are undiagnosed, 40% remain untreated, and, of those being treated, 65% do not meet treatment goals, 2 the opening of the spigot of obesityassociated hypertension will result in an ever-growing number of patients with uncontrolled hypertension, particularly because obesity is a predictor of poor blood pressure control. 3 It is important, therefore, to understand the pathophysiology of obesity-associated hypertension. This commentary focuses on the role that the sympathetic nervous system plays in this condition and its relevance to treatment. Sympathetic Activity and Obesity-Associated HypertensionLandsberg 4 postulated that obesity induces sympathetic activation as a compensatory mechanism to increase resting energy expenditure and restore energy balance; sympathetically mediated hypertension is the price to pay for this beneficial metabolic effect. A competing MONA LISA (Most Obesities kNown Are Low In Sympathetic Activity) hypothesis postulates that lower sympathetic activity is an initiating event leading to decreased energy expenditure and obesity. 5 In white populations, in whom most of the studies have been done, the preponderance of evidence supports the concept that sympathetic activation accompanies obesity-associated hypertension. There is less agreement about the cause of sympathetic activation; potential culprits include the increase in insulin, leptin, and angiotensin II; the decrease of adiponectin; and the sleep apnea 6,7 associated with obesity. Despite the disparity of these mechanisms, it is interesting that all of them act in the central nervous system to increase sympathetic outflow. This central sympathetic activation is not generalized; rather, it is selectively increased in organs relevant to blood pressure regulation, including the kidney, heart, and skeletal muscle vasculature. 6,8 To determine whether sympathetic activation indeed contributed to obesity-associated hypertension, Wofford et al 9 used combined ␣-and ␤-blockade with doxazosin and atenolol and showed a greater decrease in blood pressure in obese compare with lean hypertensive subjects. We recently used a similar approach, inducing complete but transient autonomic withdrawal with the ganglionic blocker trimethaphan, and showed that most of the increase in blood pressure observed in obese subjects was mediated by the autonomic nervous system. 10 As expected, resting energy expenditure was higher in obese subjects but, in contrast to blood pressure, it remained significantly elevated after autonomic blockade. We found that the increase in energy expenditure was likely because of the increase in muscle mass that usually companies obesity 10 ; in our patients, a 30-kg increa...

Metalloproteinases: key and common mediators of multiple GPCRs and candidate therapeutic targets in models of hypertensive cardiac disease

“…The prevalence of chronic, noncommunicable diseases is increasing dramatically worldwide with close to 20 million people dying every year from cardiovascular disease associated with hypertension, diabetes, or obesity [1][2][3]. The association of metabolic disorders such as diabetes type I, insulin resistance (diabetes type II) and obesity with hypertension and cardiac problems is higher than would be the case by chance.…”

“…Over 60% of hypertensive individuals are obese, which has been explained through the chronic activation of the sympathetic nervous system by adipocyte-derived hormones such as leptin, which promotes energy expenditure but also systemic vasoconstriction and pathological cardiovascular remodeling [3].…”

“…Despite advances in the identification of triggers of disease, the treatment of cardiovascular disorders remains empirical and ineffective due to the complex and often unknown etiology of hypertensive cardiac disease in the general population [2,3].…”

“…Among the primary causative factors of hypertensive cardiac disease are life style, stress, environmental factors and genetic predisposition as well as metabolic morbidities such as diabetes and obesity [1][2][3].…”

Molecular Signals Elicited by GPCR Agonists in Hypertension, Cardiovascular Remodeling: Are MMPs and ADAMs Elusive Therapeutic Targets?

“…In the 21 st century physicians still treat hypertension empirically by choosing a drug or drug combination until adequate blood pressure reduction and regression of cardiac remodeling are achieved. Over half of patients receiving treatment do not meet current treatment goals (of <140/90 mmHg for adults with hypertension and <130/80 mmHg for hypertensives with diabetes or chronic renal disease) (1,21). There is a need for alternative treatment strategies targeting common downstream mediators of multiple agonists.…”