Therapeutic Advances in Cardiovascular Disease

This retrospective analysis examined the efficacy and tolerability of nebivolol, a ß₁-selective, vasodilatory β-blocker, in four different age groups of patients with hypertension.

Data were pooled from three 12-week, randomized, placebo-controlled trials (placebo, n = 205; nebivolol [1.25–30/40 mg/day], n = 1811) and stratified into age quartiles (Group 1: 22–46 years; Group 2: 47–53 years; Group 3: 54–62 years; Group 4: 63–84 years). Only patients treated with placebo and the three commonly used nebivolol dosages (5, 10, and 20 mg/day) are presented. Baseline-to-endpoint changes in trough sitting diastolic blood pressure (DBP), systolic blood pressure (SBP), and heart rate (HR) were analyzed for each age quartile using an analysis of covariance (ANCOVA) model. Tolerability was assessed by means of adverse event (AE) rates.

The analysis comprised 205 placebo-treated patients and 1380 patients treated with nebivolol dosages of 5, 10, or 20 mg/day. Older age was associated with higher SBP values at baseline. In all age groups, each of the three most frequently used nebivolol dosages significantly reduced DBP, compared with placebo (–9.1 to −11.8 mmHg versus −3.4 to −5.9 mmHg; p ≤ 0.008 overall). For SBP, a statistically significant effect versus placebo was observed for all dosages and age groups except for 5 and 10 mg/day in Group 4. Within each group, treatment with nebivolol (all three dosages) and placebo resulted in similar AE rates (nebivolol: 26.1–36.6%; placebo: 36.2–42.6%) and AE-related discontinuation rates (1.8–3.8% versus 0–4.3%). In each age group, there were no significant nebivolol-placebo differences in the rates of patients who experienced clinically significant changes or abnormal endpoint levels of metabolic parameters.

This retrospective analysis suggests that nebivolol monotherapy is efficacious and well tolerated across various age groups, with the efficacy in reducing SBP somewhat diminishing in patients over 62 years of age.

We have recently shown that the acute infusion of angiotensin-(1–7) [Ang-(1-7)] or chronic increase in plasma Ang-(1-7) produces important changes in regional blood flow in rats.

To further assess whether these changes are related to Mas, in this study hemodynamic measurements were performed in Ang-(1-7) receptor Mas knockout C57BL/6 (Mas-KO) mice and age-matched wild type (WT) control mice, using fluorescent microspheres.

Mean arterial pressure in urethane-anesthetized Mas-KO mice (12–16 weeks old) did not differ from that in WT mice (79 ± 2 and 80 ± 2 mmHg respectively). However, pronounced differences were observed in other hemodynamic measurements. Mas-KO mice exhibited a significant decrease in stroke volume (0.03 ± 0.01 versus 0.05 ± 0.01 ml/beat in WT) and decreased cardiac index (0.81 ± 0.08 versus 1.24 ± 0.24 ml/min/g in WT). Strikingly, Mas-KO mice exhibited a marked increase in vascular resistance and a decrease in blood flow in the kidney, lung, adrenal gland, mesentery, spleen and brown fat tissue. The decrease in blood flow ranged from 34% (spleen) to 55% (brown fat tissue).

These results suggest that the Ang-(1-7)/Mas axis plays an important role in regional and systemic hemodynamic adjustments in mice.