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Abstract
Nebivolol, unlike other selective β1-receptor blockers, induces vasodilation attributable to increased NO bioavailability. The relative contribution of this mechanism to the blood pressure (BP)–lowering effects of nebivolol is unclear because it is normally masked by baroreflex buffering. Autonomic failure provides a unique model of hypertension devoid of autonomic modulation but sensitive to the hypotensive effects of NO potentiation. We tested the hypothesis that nebivolol would decrease BP in these patients through a mechanism independent of β-blockade. We randomized 20 autonomic failure patients with supine hypertension (14 men; 69±2 years) to receive a single oral dose of placebo, nebivolol 5 mg, metoprolol 50 mg (negative control), and sildenafil 25 mg (positive control) on separate nights in a double-blind, crossover study. Supine BP was monitored every 2 hours from 8:00 pm to 8:00 am. Compared with placebo, sildenafil and nebivolol decreased systolic BP during the night (P<0.001 and P=0.036, by mixed-effects model, maximal systolic BP reduction 8-hour postdrug of −20±6 and −24±9 mm Hg, respectively), whereas metoprolol had no effect. In a subanalysis, we divided patients into sildenafil responders (BP fall >20 mm Hg at 4:00 am) and nonresponders. Nebivolol significantly lowered systolic BP in sildenafil responders (−44±13 mm Hg) but not in nonresponders (1±11 mm Hg). Despite lowering nighttime BP, nebivolol did not worsen morning orthostatic tolerance compared with placebo. In conclusion, nebivolol effectively lowered supine hypertension in autonomic failure, independent of β1-blockade. These results are consistent with the hypothesis that NO potentiation contributes significantly to the antihypertensive effect of nebivolol.
Introduction
See Editorial Commentary, pp 1194–1195
Nebivolol is a selective β1-adrenergic receptor blocker and is considered a third-generation β-blocker with unique vasodilatory actions.1 This characteristic makes it advantageous in the treatment of hypertension. It is proposed that augmentation of NO bioavailability underlie this vasodilatory effect.2–4 The magnitude and relative contribution of NO-dependent vasodilation to the blood pressure (BP)–lowering effect of nebivolol, however, is not known.
To address this question we studied patients with autonomic failure. The clinical hallmark of these patients is severe disabling orthostatic hypotension, but ≈50% of them also have severe supine hypertension.5 Autonomic failure patients have several characteristics that make them ideal to test the hypothesis that NO mechanisms contribute to the BP-lowering effects of nebivolol. First, these patients lack autonomically mediated baroreflex buffering and therefore have exaggerated responses to most pressor and depressor agents.6–9 Second, traditional β-blockers have no BP effect in these patients because of low β-adrenoreceptor tone.10,11 Finally, we have previously shown that these patients have an exaggerated response to NO-mediated vasodilation.12
Thus, autonomic failure provides a unique model of hypertension devoid of autonomic modulation, resistant to β-blockade, but sensitive to enhancement of NO-mediated vasodilation. This allowed us to compare the BP effect of placebo, nebivolol, metoprolol (negative control), and sildenafil (positive control). We hypothesized that if NO-mediated vasodilation contributes to the BP-lowering effect of nebivolol then BP will be lowered by nebivolol and sildenafil, but not by metoprolol in autonomic failure patients. Finally, to further assess the therapeutic potential of nebivolol for the management of supine hypertension in autonomic failure, we measured its effect on nocturnal natriuresis and morning orthostatic tolerance.
Methods
Subjects
We studied 20 patients with severe primary autonomic failure diagnosed with pure autonomic failure (n=10), Parkinson disease (n=4), or multiple system atrophy (n=6) using the diagnostic criteria of the American Autonomic Society.13 All patients had supine hypertension defined as systolic BP (SBP) ≥150 mm Hg or diastolic BP (DBP) ≥90 mm Hg.14 Patients were excluded if they had secondary causes of autonomic failure (eg, diabetes mellitus or amyloidosis) or renal failure. The Vanderbilt University Institutional Review Board approved this study, and written informed consent was obtained from each patient before initiating the study (http://clinicaltrials.gov identifier: NCT01044693).
General Protocol
Patients were admitted to the Clinical Research Center at Vanderbilt University and were placed on a low-monoamine, methylxanthine-free diet containing 150-mEq sodium and 60- to 80-mEq potassium per day. Medications affecting BP, blood volume and the autonomic nervous system were withheld for ≥5 half-lives before testing, including fludrocortisone, β-blockers, or other antihypertensive medications. All other medications were held constant throughout the study. All patients were screened with a comprehensive medical history, physical examination, 12-lead ECG, laboratory assessments, and standardized autonomic function tests,15 including orthostatic stress test, Valsalva maneuver, hyperventilation, cold pressor test, isometric handgrip, and sinus arrhythmia.16 BP and heart rate (HR) were obtained intermittently using an automated oscillometric sphygmomanometer (Dinamap ProCare, GE Healthcare), and continuously with finger photoplethysmography (Nexfin, BMEYE). HR was measured by continuous ECG. During the orthostatic test, supine and upright blood samples were obtained for norepinephrine and renin measurements while patients were supine and upright, as previously described.17 Plasma norepinephrine was determined by high-performance liquid chromatography with electrochemical detection.18 Plasma renin activity was measured by conversion of angiotensinogen to Ang I using radioimmunoassay (IgG Corporation). For statistical analysis, values of renin activity that were below detection limits (<0.2 ng/mL per hour) were assigned a value of one-half the detection limit.
Overnight Medication Trials
We performed a randomized, double-blind, 4-period, 4-treatment, crossover study comparing the effects of a single oral dose of nebivolol 5 mg (Bystolic, Forest Laboratories, Inc), metoprolol tartrate 50 mg (Lopressor, Novartis Pharmaceuticals Corp.; negative control), sildenafil 25 mg (Viagra, Pfizer, Inc; positive control), and placebo on overnight BP in patients with primary autonomic failure. The primary outcome was the decrease in SBP after drug administration. Secondary outcomes included changes in HR, nocturnal natriuresis, and morning orthostatic tolerance. The doses of nebivolol and metoprolol were chosen based on comparative studies showing similar acute β1-blockade,19 which corresponds to the initial effective recommended dose in hypertensive patients.20,21 Medications were prepared by a compounding pharmacy, and patients and investigators were blinded to group assignment. The Vanderbilt Investigational Drug Pharmacy was responsible for randomization, independent of investigators. The order of the treatment sequences was randomized using computer-generated random numbers before study initiation. Consecutive subjects were randomly assigned to 1 of the 24 possible treatment sequences. Studies were conducted on consecutive nights in 12 patients. Medications were administered with 50 mL of tap water at 8:00 pm and ≥2.5 hours after the last meal. Patients were instructed to remain supine throughout the night. Fluid intake was restricted to avoid the pressor effect of water drinking.8 BP was measured twice in a row at 2-hour intervals from 8:00 pm to 8:00 am by an automated sphygmomanometer (Dinamap). Because supine hypertension increases nocturnal pressure natriuresis to promote volume depletion and worsening of morning orthostatic tolerance, we assessed the effect of the interventions on morning orthostatic tolerance.7 At 8:00 am, patients were asked to stand for ≤10 minutes. BP and HR were measured at 1, 3, 5, and 10 minutes of standing, or as long as tolerated, to assess morning orthostatic tolerance. Urine was collected for 12 hours after drug administration for determination of volume and sodium and creatinine levels. Nocturnal sodium excretion was defined as the ratio of urinary sodium to urinary creatinine to correct for the incomplete bladder emptying seen in these patients.13
Statistical Methods
The primary outcome was the decrease in SBP after drug administration defined as the change in the supine SBP (ΔSBP) values after drug (9:00 pm to 8:00 am) from baseline (8:00 pm). The main comparisons were between the active treatment groups versus placebo. A mixed-effects model was used to examine whether the ΔSBP differed among treatment groups. The model included the intercept and the time slope as random effects. To model a time trend, linear and quadratic functions of time as well as their interaction with treatment group were included in the model. Age, body mass index, period, and the baseline measurements were included as fixed effects to adjust for their potential confounding effects. Differences in the changes in mean arterial pressure and DBP between treatment groups were analyzed using the same approach. Secondary outcomes included changes in HR, morning orthostatic tolerance and nocturnal natriuresis. Orthostatic tolerance was defined as the area under the curve of standing SBP calculated by the trapezoidal rule (upright SBP multiplied by standing time).22 Comparisons were made only for patients who could stand after all treatment groups, as previously reported.22 Overall differences in secondary outcomes among treatment groups in the secondary outcomes were analyzed using repeated-measures ANOVA. If a significant overall treatment difference was found, paired comparisons between treatment groups were performed using paired t tests with Bonferroni correction as post hoc test. Power calculation was based on preliminary data from 3 patients. The difference in SBP mean values between nebivolol and placebo 8 hours after drug administration was of 28 mm Hg, with SD of difference of 33 mm Hg. A sample size of 20 patients would have 95% power to detect a difference in mean values between treatments with an α level of 0.05 using paired t test analysis (PS Dupont, Version 3.0.34). Data are presented as mean±SEM. All of the tests were 2-tailed, and a P value of <0.05 was considered significant. Analyses were performed with STATA 11.0 (StataCorp) and SPSS 22.0 (IBM Corp).
Results
Patient Characteristics and Autonomic Testing
We studied 20 severe primary autonomic failure patients with supine hypertension (14 men; 69±2 years; Table 1). A history of hypertension was present before the diagnosis of autonomic failure in only 4 patients (20%). In the remainder, hypertension followed the diagnosis of autonomic failure. The presence of severe autonomic failure was evidenced by profound orthostatic hypotension (fall in SBP from 169±6 supine to 83±6 mm Hg standing) without an adequate compensatory HR increase (from 68±2 supine to 83±3 bpm standing), and by impaired autonomic reflexes (Table 2). Sinus arrhythmia was blunted, the decrease in BP during the strain phase (phase II early) of the Valsalva maneuver was exaggerated, and the expected BP increase before the release (phase II late) and recovery phase (phase IV) was absent.
Patient Characteristics
Autonomic Function and Orthostatic Stress Tests
Antihypertensive Effects of Nebivolol Versus Metoprolol
The effect of placebo, metoprolol, nebivolol, and sildenafil on nighttime supine SBP is shown in Figure 1A and on HR in Figure 1B. Average baseline supine SBP was similar among treatment groups (placebo 154±7 mm Hg, metoprolol 157±5 mm Hg, nebivolol 162±5 mm Hg, and sildenafil 158±6 mm Hg; P=0.635). Both sildenafil and nebivolol decreased SBP significantly compared with placebo (P<0.001 and P=0.036 by mixed-effects model, respectively), whereas metoprolol produced no significant effect. DBP and mean arterial BP followed a similar trend. Compared with placebo, sildenafil and nebivolol decreased DBP (P<0.001 for both drugs) and mean arterial BP (P<0.001 for sildenafil and P=0.002 for nebivolol), whereas metoprolol had no significant effect. The maximal reduction in SBP was seen at 8 hours after drug (4:00 am) for all active medications (metoprolol, −7±6 mm Hg; sildenafil, −20±6 mm Hg; and nebivolol, −24±9 mm Hg). At this time point, nebivolol produced a significantly greater decrease in SBP and DBP compared with metoprolol (SBP, −24±9 versus −7±7 mm Hg, respectively; P=0.006 [Figure 2A] and DBP, −12±4 versus −2±3 mm Hg, respectively; P=0.010).
Effect of a single oral dose of placebo, metoprolol (50 mg), nebivolol (5 mg), and sildenafil (25 mg) on nighttime blood pressure (A) and heart rate (B) in autonomic failure patients with supine hypertension. Medications were administered at 8:00 pm. Changes from baseline (8:00 pm) in supine systolic blood pressure (ΔSBP) and heart rate (ΔHR) are expressed as mean±SEM. Sildenafil and nebivolol decreased blood pressure significantly compared with placebo (P<0.001 and P=0.036 by mixed-effects model, respectively), and the maximal effect was seen at 4 am (8 hours) for both drugs. Nebivolol and metoprolol produced a similarly small decrease in heart rate compared with placebo and sildenafil.
Comparison of the changes in supine systolic blood pressure (ΔSBP; A) and heart rate (ΔHR; B) from baseline (8:00 pm) to the time of the maximal blood pressure effect (4:00 am, 8 hours after drug). Nebivolol produced a significantly greater decrease SBP compared with metoprolol. Heart rate was similarly decreased in both groups. Values are expressed as mean±SEM. The P values were generated by Wilcoxon signed-rank test.
Both nebivolol and metoprolol produced a small but significant decrease in HR during the night compared with placebo (P=0.01 by 2-way ANOVA; Figure 1B), resulting in a similar maximal decrease of −8±2 bpm at 6:00 am with nebivolol and −8±1 bpm at 8:00 am with metoprolol. At a time when the BP-lowering effects were maximal (4:00 am), the negative chronotropic effect of both medications was similar (−6±2 nebivolol versus -6±2 metoprolol bpm; P=0.996; Figure 2B).
We found no evidence of a carry-over effect between study days. There was no difference in baseline BP between groups, and our statistical analysis included baseline BP as a cofounder.
Effects of Treatment on Urinary Sodium Excretion and Morning Orthostatic Tolerance
None of the medications had an effect on nocturnal urinary sodium excretion compared with placebo (P=0.607 by 1-way ANOVA; Figure 3A). Orthostatic tolerance, estimated as the area under the curve of standing SBP during a 10-minute standing test, was similar among treatment groups (P=0.597 by 1-way ANOVA; Figure 3B).
Effect of medications on nocturnal urinary sodium excretion (UNa+/Cr; A) and morning upright blood pressure (calculated as the area under the curve of upright systolic blood pressure [AUCSBP] during a 10-minute standing test; B). There were no significant differences either outcome between groups. Values are expressed as mean±SEM. Comparisons between groups were performed using 1-way ANOVA.
BP Effect of Nebivolol in Responders and Nonresponders to Sildenafil
To determine whether the SBP reduction with sildenafil was associated with that of nebivolol, patients were divided into responders (n=11) and nonresponders (n=9) to sildenafil. A sildenafil response was arbitrarily defined as a decrease in SBP of >20 mm Hg from baseline to 4:00 am (maximal response). Sildenafil responders also had a significant decrease in SBP with nebivolol (−44±13 mm Hg). In nonresponders to sildenafil, nebivolol had no effect (1±11 mm Hg). The difference in the BP effects produced by nebivolol between responders and nonresponders to sildenafil was statistically significant (P=0.016; Figure 4).
Comparison of the effect of nebivolol on systolic blood pressure (ΔSBP) between responders (n=11) and nonresponders (n=9) to sildenafil. Response to sildenafil was defined as a drop from baseline in SBP >20 mm Hg measured at 4 am (maximal response). Responders to sildenafil had a significant decrease in SBP with nebivolol compared with nonresponders, in whom nebivolol had no effect. Values are expressed as mean±SEM. The P values were generated by Wilcoxon signed-rank test.
Discussion
The main finding of this study is that nebivolol, but not metoprolol, lowered BP in patients with autonomic failure and supine hypertension, and the magnitude of this effect was similar to that of the phosphodiesterase-5 inhibitor sildenafil. Furthermore, nebivolol only lowered BP in those patients who were sensitive to sildenafil. Taken together, our findings suggest that NO-mediated vasodilation contributes to the BP-lowering effect of nebivolol in human hypertension.
Selective antagonists of β1-adrenergic receptors, such as the second-generation β-blocker metoprolol, are effective in preventing cardiovascular events in patients with coronary artery disease and heart failure,23,24 primarily via chronotropic and inotropic inhibitory mechanisms resulting in decreased cardiac output.25 Through this mechanism, these agents effectively lower BP in essential hypertensive patients in a magnitude comparable with other hypertensive drugs. Nonetheless, selective β1-adrenoreceptor antagonists are not recommended as first-line therapy,20 because previous studies have shown that they are less efficacious in reducing cardiovascular events in uncomplicated hypertensive patients.26,27 Such inferiority has been proposed to be the result of failure of selective β1-adrenoreceptor antagonists to reduce central BP compared with other antihypertensive drugs with vasodilatory properties.28–30
The third-generation β-blocker nebivolol is a highly selective β1-adrenoreceptor antagonist that has vasodilatory properties. Studies in vitro, animal models, and humans have shown that nebivolol produced endothelial-derived NO-dependent vasodilation of conductance and resistance arteries and veins by increasing NO bioavailability.2–4,31,32 Intrabrachial infusion of nebivolol increased forearm blood flow in healthy subjects and essential hypertensive patients,31,32 whereas selective β1-blockade with atenolol had no effect.31 Furthermore, the NO synthase inhibitor NG-monomethyl-L-arginine could inhibit this vasodilation.31 The precise mechanisms by which nebivolol increases endothelial-derived NO bioavailability is not completely understood but may involve activation of endothelial NO synthase through stimulation of β3-adrenoreceptors expressed in endothelial cells, reduction of asymmetrical dimethylarginine levels, and reduction of reactive oxygen species.1,33 The well-established changes induced by nebivolol in forearm blood flow and individual vessels, however, may not necessarily translate into reduced peripheral resistance as indicated by the absence of effect on systemic vascular resistance in some studies in hypertensive patients.34,35 It is difficult, therefore, to assess the contribution of NO-mediated vasodilation to the BP-lowering effect of nebivolol in essential hypertension because of the buffering effect of the autonomic baroreflex.
Patients with primary autonomic failure have severe baroreflex impairment characterized by disabling orthostatic hypotension, hypersensitivity to pressor and depressor stimuli, and in approximately half of them, supine hypertension.5–9 The hypertension in autonomic failure patients with impairment of central autonomic pathways (multiple system atrophy) is driven by unregulated residual sympathetic tone.36 The cause of hypertension in patients with peripheral autonomic neuropathy (pure autonomic failure, Parkinson’s disease) is not known but it is characterized by increased vascular resistance despite having low plasma norepinephrine and renin activity.5,37 NO function is increased in both forms of autonomic failure, as evidenced by a significant increase in BP when endothelial NO synthase was inhibited by NG-monomethyl-L-arginine and a significant BP reduction with the phosphodiesterase-5 inhibitor sildenafil.12 Therefore, these patients provide a unique opportunity to examine the contribution of NO-mediated vasodilatory mechanisms to the BP-lowering effect of nebivolol. Indeed, we found that nebivolol and sildenafil significantly reduced nighttime BP compared with placebo, whereas metoprolol had no effect. In our study, nebivolol decreased nighttime BP by −44±13 mm Hg in patients who responded to sildenafil, whereas having no effect in nonresponders (1±11 mm Hg). Sildenafil potentiates endogenous cyclic GMP signaling, which in humans is mostly triggered by NO mechanisms and by atrial natriuretic peptides. Patients with autonomic failure have increased responses to NO mechanisms and, conversely, smokers, known to have deficient NO mechanisms, have less improvement of endothelium-dependent vascular responses to sildenafil.38 Taken together, these observations are consistent with the postulate that the decrease in BP by nebivolol in autonomic failure is related to NO mechanisms. We cannot rule out, however, that natriuretic peptides or other mechanisms such as impairment of cyclic GMP signaling can contribute to our observations.
Both metoprolol and nebivolol produced a similar small but significant decrease in HR. Given that the loss of efferent sympathetic function may be incomplete in some patients with severe autonomic failure, this finding may not be unexpected because these patients may have some residual sympathetic tone.6 These data suggest that the BP-lowering effect of nebivolol was independent of β1-adrenoreceptor blockade, given that both nebivolol and metoprolol were equipotent with respect to the β1-blocking effect of residual cardiac sympathetic tone but only nebivolol had a significant BP-lowering effect compared with placebo.
The supine hypertension of autonomic failure is associated with hypertensive heart disease and impaired renal function.39–41 Furthermore, nighttime pressure natriuresis and the resulting volume depletion can exacerbate orthostatic hypotension in the morning.2,7 Treatment of supine hypertension in autonomic failure is therefore aimed at not only preventing long-term consequences of hypertension but also reducing pressure diuresis to improve early morning orthostatic tolerance. Because nebivolol was effective in treating nighttime hypertension and did not worsen morning orthostatic tolerance, it may be useful in the treatment of nighttime supine hypertension. The fact that it was not effective in all patients, however, underscores the need to individualize treatment in these patients.
In conclusion, nebivolol effectively improved supine hypertension in autonomic failure, to a similar degree as sildenafil. The mechanism seems to be independent of β-blockade and is likely because of potentiation of NO. The decrease in nighttime BP was not associated with worsening of morning orthostatic tolerance and, therefore, nebivolol might be a useful alternative as a treatment of supine hypertension in patients with autonomic failure. As with other drugs used in this patient population, treatment should be individualized, and further studies are needed to assess the efficacy and safety of chronic administration.
Perspectives
Traditional β-blockers are effective BP-lowering agents but are not recommended as first-line therapy for uncomplicated essential hypertension because they are less efficacious in reducing cardiac events. This is thought to be associated with failure to reduce central BP compared with other antihypertensive drugs with vasodilatory properties. Newer generation β-blockers, however, have ancillary vasodilating properties but the contribution of this mechanism to their antihypertensive effects is unknown. In particular, nebivolol is a highly selective β1-adrenoreceptor antagonist with NO-mediated vasodilatory properties. Our findings in autonomic failure patients with supine hypertension showed that nebivolol effectively lowered BP by a β1-blockade–independent mechanism, presumably associated with NO potentiation. These patients offer a unique model to explore human cardiovascular pharmacology in the absence of the confounding effects of autonomic buffering. Given that they have extreme sensitivity to any pressor or depressor stimuli, nonautonomic mechanisms of action of drugs can be unmasked in these patients. Our findings also have important implications for the management of these patients but the long-term safety and efficacy of this approach will need to be addressed in future studies.
Acknowledgments
We acknowledge the patients who volunteered for these studies and the Clinical Research Center nurses who made this study possible.
Sources of Funding
This work was supported by the National Institutes of Health (NIH) grants RO1 NS055670, PO1 HL56693, Autonomic Rare Diseases Clinical Research Consortium Grant U54 NS065736, and UL1 RR024975-01 (Clinical and Translational Science Award, now at the National Center for Advancing Translational Sciences, Grant 2 UL1 TR000445-06), the Paden Dysautonomia Center, and by the Forest Research Institute (BYS-MD 34). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Disclosures
This study was funded by an Investigator-Initiated Research grant from Forest Research Institute (PI: Italo Biaggioni, MD). There are no other financial disclosures related to this study.
- Received June 23, 2014.
- Revision received July 4, 2014.
- Accepted August 14, 2014.
- © 2014 American Heart Association, Inc.
References
Novelty and Significance
What Is New?
Nebivolol effectively lowers blood pressure in autonomic failure patients with supine hypertension without worsening morning orthostatic tolerance.
β1-blockade–independent mechanisms, presumably nitric oxide potentiation, contribute to the blood pressure–lowering effect of nebivolol in these patients.
What Is Relevant?
Our findings provide evidence of the contribution of β1-blockade–independent mechanisms, namely nitric oxide potentiation, to the blood pressure–lowering effects of nebivolol in human hypertension.
Nebivolol might be an alternative for the treatment of supine hypertension in autonomic failure patients. Safety and long-term efficacy studies, however, are required to address the clinical usefulness of this approach.
Summary
Nebivolol, a third-generation β1-adrenoreceptor blocker, effectively reduces blood pressure in patients with autonomic failure and supine hypertension through a mechanism independent of β1-blockade. Nitric oxide potentiation may contribute to this effect because nebivolol had a similar blood pressure drop to that of patients who were sensitive to sildenafil.
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