Caitlin A. Dow

Chronic Nebivolol Treatment Suppresses Endothelin-1–Mediated Vasoconstrictor Tone in Adults With Elevated Blood Pressure

Abstract—Endothelin-1 (ET-1) plays a major role in the pathophysiology of hypertension and its associated cardiovascular risk. We tested the hypothesis that chronic nebivolol treatment reduces ET-1–mediated vasoconstrictor tone in adult humans with elevated blood pressure (BP). Furthermore, reducing ET-1 vasoconstrictor activity contributes to the improvement in endothelial vasodilator function associated with nebivolol treatment. Forty-two middle-aged adults with elevated BP (systolic BP ≥130 mm Hg or diastolic BP ≥85 mm Hg) completed a 3-month, double-blind, randomized, placebo controlled trial: 14 received nebivolol (8 men/6 women; 5 mg per day); 14 received metoprolol succinate (9 men/5 women; 100 mg per day); and 14 received placebo (9 men/5 women). Forearm blood flow (plethysmography) responses to selective (BQ-123: 100 nmol/min; 60 minutes) and nonselective (BQ-123+BQ-788 [50 nmol/min]; 60 minutes) ET-1 receptor blockade, as well as acetylcholine (4.0, 8.0, and 16.0 &mgr;g per 100 mL of tissue per minute) in the absence and presence of nonselective ET-1 receptor blockade were determined before and after each treatment intervention. Forearm blood flow responses to BQ-123 and BQ-123+BQ-788 were similarly and significantly elevated (≈30% and 60%, respectively) from baseline in all 3 groups. Nebivolol, but not metoprolol or placebo, therapy resulted in a marked (≈25% and 45%; P<0.05) reduction in forearm blood flow response to BQ-123 and BQ-123+BQ-788. Moreover, after nebivolol therapy only, vasodilator response to acetylcholine was not significantly increased by ET-1 receptor blockade. These results demonstrate that nebivolol, but not metoprolol, treatment reduces ET-1–mediated vasoconstrictor tone in adult humans with elevated BP. In addition, nebivolol-induced reduction in ET-1–mediated vasoconstrictor tone underlies the favorable effects of this &bgr;-blocker on endothelial vasodilation. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01395329.

Influence of habitual high dietary fat intake on endothelium-dependent vasodilation

High-fat diets are associated with an increased risk of cardiovascular disease. A potential underlying mechanism for the increased cardiovascular risk is endothelial dysfunction. Nitric oxide (NO)-mediated endothelium-dependent vasodilation is critical in the regulation of vascular tone and overall vascular health. The aim of this study was to determine the influence of dietary fat intake on endothelium-dependent vasodilation. Forty-four middle-aged and older sedentary, healthy adults were studied: 24 consumed a lower fat diet (LFD; 29% ± 1% calories from fat) and 20 consumed a high-fat diet (HFD; 41% ± 1% calories from fat). Four-day diet records were used to assess fat intake, and classifications were based on American Heart Association guidelines (<35% of total calories from fat). Forearm blood flow (FBF) responses to acetylcholine, in the absence and presence of the endothelial NO synthase inhibitor N(G)-monomethyl-l-arginine (L-NMMA), as well as responses to sodium nitroprusside were determined by plethysmography. The FBF response to acetylcholine was lower (∼15%; P < 0.05) in the HFD group (4.5 ± 0.2 to 12.1 ± 0.8 mL/100 mL tissue/min) than in the LFD group (4.6 ± 0.2 to 14.4 ± 0.6 mL/100 mL tissue/min). L-NMMA significantly reduced the FBF response to acetylcholine in the LFD group (∼25%) but not in the HFD group. There were no differences between groups in the vasodilator response to sodium nitroprusside. These data indicate that a high-fat diet is associated with endothelium-dependent vasodilator dysfunction due, in part, to diminished NO bioavailability. Impaired NO-mediated endothelium-dependent vasodilation may contribute to the increased cardiovascular risk with high dietary fat intake.

Regular aerobic exercise reduces endothelin‐1‐mediated vasoconstrictor tone in overweight and obese adults

What is the central question of this study? Does aerobic exercise training reduce endothelin‐1 (ET‐1)‐mediated vasoconstrictor tone in overweight/obese adults? And, if so, does lower ET‐1 vasoconstriction underlie the exercise‐related enhancement in endothelium‐dependent vasodilatation in overweight/obese adults? What is the main finding and its importance? Regular aerobic exercise reduces ET‐1‐mediated vasoconstrictor tone in previously sedentary overweight/obese adults, independent of weight loss. Decreased ET‐1 vasoconstriction is an important mechanism underlying the aerobic exercise‐induced improvement in endothelium‐dependent vasodilator function in overweight/obese adults.

Elevations in C-reactive protein and endothelin-1 system activity in humans.

AIMS C-reactive protein (CRP) is an inflammatory cytokine that has been shown to be an independent predictor of future atherothrombotic events. Hyperactivity of endothelin-1 (ET-1), a potent vasoconstrictor peptide produced by the endothelium, is linked with cardiovascular disease development and progression. ET-1 is sensitive to inflammatory stimuli, though the influence of CRP on ET-1 system activity is unknown. We tested the hypothesis that ET-1-mediated vasoconstrictor tone is enhanced in adults with elevated plasma CRP concentrations. MATERIALS AND METHODS Sixty non-obese adults (43-70years) were studied: 20 with hsCRP<1.0mg/L (low CRP; 0.5±0.1mg/L); 20 with hsCRP 1.0-3.0mg/L (moderate CRP; 2.0±0.1mg/L); and 20 with hsCRP>3.0mg/L (high CRP; 6.3±0.5mg/L). Forearm blood flow (FBF; plethysmography) was determined in response to intra-arterial infusions of ET-1 (5pmol/min for 20min) and selective ETA receptor blockade (BQ-123, 100nmol/min for 60min). KEY FINDINGS In response to ET-1, FBF decreased ~10% in the low (-10.0±2.3%), moderate (-10.7±4.0%), and high (-6.6±5.2%) CRP groups, with no significant differences between groups. Additionally, all groups demonstrated a marginal, though significant (~10%), vasodilator response to BQ-123; however, there were no differences in the FBF response to BQ-123 across CRP groups. There were no significant correlations between plasma CRP concentrations and peak FBF response to either ET-1 or BQ-123. SIGNIFICANCE These results indicate that ET-1 system activity is not influenced by elevations in CRP. Enhanced ET-1 system activity may not be involved in the increased cardiovascular disease risk associated with elevations in plasma CRP concentrations.

Nebivolol, But Not Metoprolol, Treatment Improves Endothelial Fibrinolytic Capacity in Adults With Elevated Blood Pressure

Background Vascular endothelial fibrinolytic function is impaired in adults with prehypertension and hypertension and plays a mechanistic role in the development of atherothrombotic events. The influence of β‐blockers on endothelial fibrinolysis is unknown. This study compared the effects of chronic nebivolol and metoprolol treatment on endothelial tissue‐type plasminogen activator (t‐PA) release in adults with elevated blood pressure (BP). Methods and Results Forty‐four middle‐aged adults (36% women) with elevated BP completed a 3‐month, double‐blind, randomized, placebo‐controlled trial comparing nebivolol (5 mg/d), metoprolol succinate (100 mg/d), and placebo. Net endothelial t‐PA release was determined in vivo in response to intrabrachial infusions of bradykinin and sodium nitroprusside before and after each intervention. In a subset, the dose‐response curves to bradykinin and sodium nitroprusside were repeated with a coinfusion of the antioxidant vitamin C. At baseline, resting BP and endothelial t‐PA release were comparable between the 3 groups. BP decreased to a similar extent (≈10 mm Hg) in the nebivolol‐ and metoprolol‐treated groups. There was a substantial increase (≈30%; P<0.05) in the capacity of the endothelium to release t‐PA following chronic treatment with nebivolol but not metoprolol or placebo. Mitigating oxidant stress with vitamin C coinfusion potentiated t‐PA release (90%; P<0.05) at baseline in all groups. However, after the intervention, t‐PA release was unchanged by vitamin C coinfusion in the nebivolol group only. Conclusions Nebivolol but not metoprolol improves endothelial t‐PA release in adults with elevated BP. This may be an important vascular benefit of nebivolol. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01595516.