Sympathetic activation and endothelial dysfunction as therapeutic targets in obesity-related hypertension

The interest in obesity, hypertension and the metabolic syndrome has escalated together with the burgeoning obesity epidemic over the past 30 years. Obesity, especially in association with abdominal fat pattern, is linked not only with elevated blood pressure but also with abnormalities of insulin action, glucose and lipid metabolism, proinflammatory factors and oxidative stress, the fibrinolytic system, the autonomic nervous system and endothelial dysfunction as well as other structural and functional vascular abnormalities [1,2]. As a result, interest in therapies that simultaneously address multiple abnormalities has also erupted. In this regard, renin–angiotensin system blockade has generated considerable interest as a single pharmacological intervention, which favourably alters multiple components of the cardiometabolic syndrome [3–5]. The study by Dorresteijn et al. [6] examines the effects of various classes of antihypertensive agents on several risk factors and risk markers in obese hypertensive patients. The investigators employ a rigorously designed, four-way, double-blind, crossover study in obese adults with blood pressures of at least 130 mmHg systolic and/or at least 85 mmHg diastolic on no antihypertensive treatment. The authors show that blockade of the renin–angiotensin system with aliskiren 300 mg daily is more effective than either moxonodine 0.4 mg daily or hydrocholorothiazide 25 mg daily for lowering blood pressure over an 8-week treatment period. Moreover, only aliskiren improved flow-mediated dilation, a clinical marker of endothelial function, relative to the placebo control. Although only hydrochlorothiazide reduced the urinary markers of oxidative stress, none of the therapies altered serum markers of adipocyte function or oxidative stress. Moreover, none of the three treatments reduced pulse-wave velocity, an index of vascular stiffness, although aliskiren and hydrochlorothiazide equally improved estimates of central blood pressure and the augmentation index. The findings in the current report will be compared with a sample of previous studies on the effects of various blockers of the renin–angiotensin system on blood pressure and other variables that cluster with high-risk obesity. PREVIOUS STUDIES WITH RENIN–ANGIOTENSIN SYSTEM BLOCKADE IN OBESITY-ASSOCIATED HYPERTENSION In the Treatment in Obese Patients with Hypertension (TROPHY) study, 232 obese patients were randomized to lisinopril (10, 20, 40 mg/day), hydrochlorothiazide (12.5, 25, 50 mg/day) or placebo [7]. Doses were escalated during the trial as needed to control elevated blood pressure values. After 12 weeks, lisinopril lowered SBP/DBP by 9.2/8.3 mmHg, hydrochlorothiazide by 10.0/7.7 mmHg and placebo by 4.5/3.3 mmHg. Similar to the current report, TROPHY investigators included 24-h ambulatory blood pressure monitoring. Lisinopril reduced 24-h SBP/DBP by 10.5/7.2 mmHg and hydrochlorothaizide by 12.4/ 6.7 mmHg. TROPHY, while lacking the crossover design of the current report, addressed one of its limitations, which is a comparison of single doses of the various compounds. Although lisinopril controlled office DBP better than the thiazide diuretic, no significant differences were observed between the two therapies in the magnitude of the blood pressure-lowering effects in the office environment or over a 24-h period. Of note, nearly half of obese hypertensive patients in the TROPHY trial required the highest doses of hydrochlorothiazide, that is, 50 mg/day, which exceeds the more typically prescribed upper limit of 25 mg daily that was the focus of the current report. Moxonidine did not significantly lower elevated blood pressure values among obese hypertensive patients in the present report [6]. However, other evidence indicates that the sympathetic nervous system plays an important role in obesity-related hypertension in dogs and in humans [8,9]. The potential reasons for apparent discrepancies between the blood pressure-lowering effects of different ‘sympatholytic’ therapies go beyond the scope of this commentary. RENIN–ANGIOTENSIN BLOCKADE, ENDOTHELIUM-DEPENDENT VASODILATION AND VASCULAR FUNCTION: COMPARISON WITH OTHER ANTIHYPERTENSIVE THERAPIES Several, but not all, studies have shown that renin–angiotensin blockade with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers improves endothelium-dependent vasodilation and vascular distensibility [10–12]. Evidence suggests that treatment with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers improves endothelium-dependent vasodilation by increasing superoxide dismutase activity in endothelial cells [10]. The current report indicates that renin–angiotensin blockade via a direct renin inhibitor also improves flow-mediated dilation, a nitric oxide-dependent phenomenon [6]. Of note, aliskiren did not alter leptin, which is implicated in neurogenic hypertension in obesity [6,13]. Although hydrochlorothiazide does not typically improve endothelial function as a monotherapy, thiazide-based regimens improved endothelial function similar to renin–angiotensin system based strategies in hypertensive diabetic patients [14,15]. This is an important consideration, given that most hypertensive patients, and especially most obese hypertensive patients, require multiple medications often including a diuretic to control hypertension. RENIN–ANGIOTENSIN BLOCKADE AND OXIDATIVE STRESS Although not confirmed in the current report, several studies documented that renin–angiotensin blockers, including angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, reduce oxidative stress [16]. Antihypertensive treatment with dihydropyridine calcium channel blockers can also reduce oxidative stress [17]. The observations that renin–angiotensin system blockers reduce oxidative stress were not confirmed with the direct renin inhibitor aliskiren when given to obese hypertensive patients in the present study [6]. In summary, the report by Dorresteijn et al. [6] shows that blockade of the renin–angiotensin system with aliskiren, similar to previous studies with angiotensin-converting enzyme inhibitors and angiotensin II receptor blocker therapy, significantly reduces 24-h blood pressure, while significantly enhancing flow-mediated dilation, an established marker of endothelial function. Obese and insulin-resistant patients frequently require combination antihypertensive therapy including a diuretic to achieve blood pressure control. Although comparisons of monotherapies are instructive, evidence that vascular benefits can be maintained in an antihypertensive regimen including other agents, for example a diuretic and calcium channel blocker, is also noteworthy. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.