Implications of changes in plasma asymmetric dimethylarginine during treatment of hypertension

Introduction: Nitric oxide (NO), an important vasoactive substance that exerts its effect through stimulation of cyclic guanosine monophosphate (cGMP), is produced in vascular endothelium by the action of endothelial NO synthase (eNOS). Inhibition of eNOS affects vascular tone, leading to endothelial dysfunction. Several studies have examined the effect of asymmetric dimethylarginine (ADMA) on NO synthesis. ADMA, an endogenous analogue of L-arginine that is normally degraded by dimethylarginine dimethylaminohydrolase 1,2 (DDAH1,2), inhibits the action of eNOS. Nebivolol, like other beta-adrenergic receptor (AR) blockers, has an antagonist effect at the β1-AR, but in addition it has an agonist effect at the β3-AR subtype. Stimulation of β3-AR has been shown to result in an increase in circulating NO. The authors cite evidence that nebivolol (presumably through β3 agonism) causes a decrease in ADMA production in cell culture, an effect not seen with traditional beta-blockers such as metoprolol, and thus imply that inhibition of ADMA may be the mechanism underlying the increase in NO. Aims: To compare the effects of nebivolol versus metoprolol succinate on plasma concentrations of ADMA in hypertensive subjects, and to compare their effects on other metabolic and hemodynamic parameters potentially associated with changes in ADMA and NO levels. Methods: This was a single-center, open-label randomized controlled trial in adult hypertensive patients with systolic blood pressure (BP)>140 mm Hg (> 130 mm Hg in type 2 diabetic subjects). After a placebo washout period of 1 to 2 weeks, 44 patients who met the criteria were randomly allocated to receive either nebivolol (5 mg) or metoprolol succinate extended-release (100 mg) daily. Subjects were observed at 2-week intervals for a total of 8 weeks; if the target BP (<140 mm Hg or <130 mm Hg in diabetics) was not met, the daily doses were uptitrated to 10 mg of nebivolol or 200 mg of metoprolol. BP and augmentation index (measured by applanation tonometry) were determined at each visit, and fasting samples were drawn for measurement of plasma ADMA and insulin-like growth factor-1 (IGF-1), both determined by ELISA methods, and for determination of the number of peripheral blood endothelial progenitor cells (EPCs). The primary end point was the change in plasma ADMA concentration and secondary end points were changes in BP, augmentation index, plasma IGF-1, and EPC number. Results: A total of 41 patients (22 in the nebivolol arm and 19 in the metoprolol arm) completed the study. Baseline BP was similar in both groups (approximately 156/86 mm Hg), falling to 135±26/75±13 (week 4) and 137±17/75±10 (week 8) in the nebivolol group and to 142±25/78±16 (week 4) and 149±28/83±17 (week 8) in the metoprolol group. These differences were not statistically significant. The augmentation index adjusted for heart rate (AI [75%]) was similar in the two groups at baseline (82.5± 12.3 for nebivolol and 85.5±12.0 for metoprolol), but at 8 weeks was statistically somewhat higher in the metoprolol group (91.7±17.1, vs 85.6±11.9 in the nebivolol group, P=0.017). Baseline plasma ADMA levels were somewhat higher in the nebivolol group (0.4035±0.1378 μmol/L) than in the metoprolol group (0.3248±0.1228 μmol/L), but the difference was said to be not statistically significant. Plasma ADMA did not change significantly in the nebivolol group (0.4363±0.9739 μmol/L at 4 weeks and 0.4353±0.640 μmol/ L at 8 weeks), but it tended to increase from baseline (to 0.3946±0.0633 μmol/L at 4 weeks and 0.4628± 0.1052 μmol/L at 8 weeks) in the metoprolol group (P< 0.05). The authors indicate that these changes represent increases of 44.78% and 71.72% respectively, which they attribute to the dosage of metoprolol (said to be 50 mg/day at week 4 and 100 mg/day at week 8). At baseline, 4 weeks, and 8 weeks, plasma IGF-1 was 127.2±46.4 μmol/L, 116.1±36.1 μmol/L, and 118.9± 40.1 μmol/L respectively for nebivolol and 136.0± 44.1 μmol/L, 109.8±36.7 μmol/L, and 114.2±29.8 μmol/ L for metoprolol. The measured EPC numbers were highly variable and did not change with treatment. No statistical analyses are presented for these data, other than comments that there were no correlations of either IGF-1 levels or EPC numbers with any of the other parameters measured. Discussion: The authors conclude that metoprolol succinate, but not nebivolol, increases plasma ADMA in hypertensive patients, confirming an earlier study in the Turkish cardiology literature [1]. They infer that this increase may result from a specific β1-AR antagonist effect, as preclinical data with nebivolol suggests that β3- AR agonism (due to the l-enantiomer of nebivolol) may counter this effect by decreasing ADMA levels, owing to stimulation of DDAH-mediated degradation [2]. They suggest that the dual, opposing actions of nebivolol on ADMA may explain why levels have been reported to decrease with nebivolol in some studies and have remained unchanged in others, such as the current study. Moreover, their study may provide further evidence for the importance of interplay amongst various adrenergic receptor subtypes in overall cardiovascular control. They conclude that pure β1-AR antagonists, such as metoprolol, may not produce optimal benefit for the treatment of hypertension because they increase ADMA in association with an increase in augmentation index, a change probably reflecting increased stiffness of large arteries [3]. population.