Objective Characterize effects of the novel beta-adrenergic antagonist nebivolol on central aortic blood pressures, arterial properties, and nitroxidergic activity in individuals with prehypertension. Background Preypertension is emerging as a major risk factor for several adverse cardiovascular consequences. Increased pulse wave velocity, aortic augmentation index, and aortic blood pressures have been linked with augmented risk of cardiovascular disease and mortality. While the effects of antihypertensive drugs on these parameters in hypertensive patients have been studied, there are limited data so far in prehypertension. Methods 50 individuals with prehypertension were randomized to either nebivolol (5 mg daily) or placebo in a double-blind clinical trial. Subjects underwent measurement of pulse wave velocity as well as aortic blood pressure and aortic augmentation index via pulse wave analysis at baseline and 8 weeks. Subjects also had blood and urine biochemistries done at each visit. Results Nebivolol achieved significant reductions in central aortic systolic (p=0.011), diastolic (p=0.009), and mean arterial blood pressure (p=0.002). Pulse wave velocity trended toward improvement, but did not achieve significance (p=0.088). Nitric oxide production, measured as urinary nitrite/nitrite excretion, also rose substantially in the nebivolol group (by ~60%, p=0.030). Conclusions Central blood pressures can be effectively lowered by beta-blockade while subjects are still in the prehypertension phase, and the effects may be coupled to improved nitric oxide release by the drug.

BackgroundElevated sympathetic activity is associated with kidney dysfunction. Here we used twin pairs to probe heritability of GFR and its genetic covariance with other traits.MethodsWe evaluated renal and adrenergic phenotypes in twins. GFR was estimated by CKD-EPI algorithm. Heritability and genetic covariance of eGFR and associated risk traits were estimated by variance-components. Meta-analysis probed reproducibility of DBH genetic effects. Effect of DBH genetic variation on renal disease was tested in the NIDDK-AASK cohort.ResultsNorepinephrine secretion rose across eGFR tertiles while eGFR fell (p<0.0001). eGFR was heritable, at h2 = 67.3±4.7% (p = 3.0E-18), as were secretion of norepinephrine (h2 = 66.5±5.0%, p = 3.2E-16) and dopamine (h2 = 56.5±5.6%, p = 1.8E-13), and eGFR displayed genetic co-determination (covariance) with norepinephrine (ρG = −0.557±0.088, p = 1.11E-08) as well as dopamine (ρG = −0.223±0.101, p = 2.3E-02). Since dopamine β-hydroxylase (DBH) catalyzes conversion of dopamine to norepinephrine, we studied functional variation at DBH; DBH promoter haplotypes predicted transcriptional activity (p<0.001), plasma DBH (p<0.0001) and norepinephrine (p = 0.0297) secretion; transcriptional activity was inversely (p<0.0001) associated with basal eGFR. Meta-analysis validated DBH haplotype effects on eGFR across 3 samples. In NIDDK-AASK, we established a role for DBH promoter variation in long-term renal decline rate (GFR slope, p = 0.003).ConclusionsThe heritable GFR trait shares genetic determination with catecholamines, suggesting new pathophysiologic, diagnostic and therapeutic approaches towards disorders of GFR as well as CKD. Adrenergic activity may play a role in progressive renal decline, and genetic variation at DBH may assist in profiling subjects for rational preventive treatment.

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