Effects of the vasodilating beta-blocker nebivolol on smoking-induced endothelial dysfunction in young healthy volunteers

ORIGINAL RESEARCH Effects of the vasodilating beta-blocker nebivolol on smoking-induced endothelial dysfunction in young healthy volunteers André C Schmidt 1 Burkhard Flick 1 Elke Jahn 2 Peter Bramlage 3 1 Charité – Universitätsmedizin Berlin, Institute for Clinical Pharmacology and Toxikology, Berlin, Germany; 2 Berlin-Chemie AG, Clinical Research and Medical Information, Berlin, Germany; 3 Institute for Clinical Pharmacology, Medical Faculty Carl Gustav Carus, TU Dresden, Germany Objective: To assess the effect of nebivolol, a highly selective third generation β1-adrenoceptor antagonist with an endothelium-dependent vasodilatory action, on smoking-induced endothelial dysfunction. Research design and methods: This open-label study examined the effect of 14 daily doses of 5 mg nebivolol on forearm blood flow in 21 healthy, young, male, light smokers (ⱕ5 cigarettes/day), measured by plethysmography on Days 1, 7, and 14. The primary endpoint was the difference in forearm blood flow after smoking one standard cigarette from baseline (Day 1) until treatment end on Day 14. Secondary outcomes included the difference in forearm blood flow between Day 1 and Day 7 compared with Day 14 before and after smoking, the effect of nebivolol on blood coagulation parameters, high-sensitive-C-reactive protein (hs-CRP), and the safety and tolerability of nebivolol. Results: Nebivolol for 14 days did not significantly affect forearm blood flow after smoking. On Day 7 of nebivolol treatment, forearm blood flow after smoking was significantly greater than blood flow before smoking (increase of 0.44 mL/min; p = 0.00656). Serum level of hs-CRP showed a marked decrease from Day 1 to Day 14. No changes in coagulation parameters were observed over the course of nebivolol treatment. Nebivolol was well tolerated throughout the study. Conclusions: The increase in forearm blood flow and the marked decrease in hs-CRP over 14 days of treatment suggest that nebivolol has a positive effect on endothelial function in light smokers, but larger studies are required to confirm these observations. Keywords: C-reactive protein, endothelial dysfunction, nebivolol, nitric oxide (NO), smoking Introduction Correspondence: André C Schmidt Charité Universitätsmedizin Berlin, Institute for Clinical Pharmacology and Toxikology, Hindenburgdamm 30, 12200 Berlin, Germany Tel +49 163 3106434 Fax +49 33708 928069 Email The endothelium is responsible for the synthesis of the potent vasodilator nitric oxide (NO). NO is involved in a large number of cardiovascular processes, and NO deficiency represents an important determinant of cardiovascular risk (Moncada and Higgs 2006). Endothelial dysfunction and the associated reduced synthesis or action of NO may lead to vasoconstriction, elevated blood pressure and thrombus formation, and can ultimately result in atherosclerosis (Brunner et al 2005; Moncada and Higgs 2006). Cigarette smoking is a major modifiable risk factor for atherosclerosis and peripheral artery disease (Lu and Creager 2004). The pathophysiology of these potentially fatal diseases has been linked, at least in part, to cigarette-induced increases in oxidative stress. By enhancing the production of superoxide and other reactive oxygen species, cigarette smoke inactivates NO within the vasculature, thereby disrupting endothelial function (Cai and Harrison 2000). Indeed, long-term smokers show markedly impaired endothelium-dependent vasodilation, demonstrated in, for example, the brachial artery, Vascular Health and Risk Management 2008:4(4) 909–915 909 © 2008 Schmidt et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Schmidt et al which is consistent with endothelial dysfunction (Celermajer et al 1993). Smoking cessation has been shown to drastically improve endothelial function by limiting vascular endothelial damage as well as improving lipid profile and decreasing thrombotic tendency (Eagles and Martin 1998). Smoking is also associated with increased levels of C-reactive protein (CRP) (Kao et al 2006). Recent research has confirmed a role for CRP in cardiovascular risk prediction (Willerson and Ridker 2004), and CRP has also been directly been involved in endothelial dysfunction in experimental models (Wilson et al 2006). Serum CRP level, as well as representing a marker of inflammation, is also, therefore, a valid means of quantifying endothelial dysfunction. Nebivolol is the newest third-generation cardioselective beta-blocker with vasodilator activity. In addition to its conventional antihypertensive effect, nebivolol also has an endothelium-dependent vasodilatory action that may slow or prevent some of the vascular complications associated with hypertension, and may be of particular benefit in patients with impaired endothelial function (eg, diabetes, hypercholesterolemia, or ischemic heart disease) (Cockcroft 2004). A recent study showed that the treatment of hypertensive patients, concomitantly suffering from type-2 diabetes, with nebivolol not only reduced systolic and diastolic blood pressure, but also improved metabolic parameters (eg, HbA1c) and physical capability of those patients (Schmidt et al 2007). The vasodilatory effect of nebivolol is thought to derive from its ability to stimulate NO production by endothelial cells (Broeders et al 2000). Infusion of nebivolol into the brachial artery has been shown to increase forearm blood flow in normotensive individuals, and this effect, which is antagonized by the NO synthase inhibitor NG-monomethylL-arginine (L-NMMA), implicates the L-arginine–NO pathway in nebivolol-induced vasodilation (Cockcroft et al 1995). By preserving endothelial function, nebivolol may help to reduce peripheral resistance and arterial stiffness, and may ultimately protect against cardiovascular disease (Luscher et al 2001). This open-label pilot study examined the effects of a therapeutic dose of nebivolol on forearm blood flow, measured by plethysmography, and level of inflammatory marker, in light smokers over a 14-day period. Methods Study design This was an open-label, single-center study that examined the efficacy and safety of oral nebivolol 5 mg given once daily (Figure 1). It was conducted according to the Declaration of 910 Helsinki, taking into account the recent version of the German Drug Law (AMG), and in accordance with the German legal requirements as well as the principles of Good Clinical Practice (GCP). Blood and urine samples were taken on Day 1, in overnight-fasted healthy voluteers. Subjects then received a standard breakfast and forearm plethysmography was performed 2 hours after breakfast. Vital signs and 12-lead ECG measurements were taken after plethysmography. Each subject then received nebivolol 5 mg (about 3 hours after breakfast). Further visits to the study center were scheduled on Days 7 and 14 for plethysmography and other efficacy (...truncated)