[OP.2D.07] THE EFFECTS OF ALPHA 1-ADRENOCEPTOR-BLOCKADE BY DOXAZOSIN OR ACE-INHIBITION BY RAMIPRIL ON ENDOTHELIAL FUNCTION IN PRIMARY HYPERTENSION: THE DORA STUDY

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Abstract

Objective:

To study whether reducing noradrenergic sympathetic vascular tone by doxazosin or blocking the renin-angiotensin-aldosterone system by ramipril will alter endothelial function in patients with uncomplicated hypertension.

Design and method:

Mild-to-moderate hypertensive patients (age 54 ± 12 years, 34% women, blood pressure (BP) 148 ± 11/88 ± 9 mmHg) were randomized double-blind to ramipril (10 mg od, n = 33) or doxazosin (8 mg od, n = 28) for 12 weeks. Endothelium dependent and independent vasodilatation was studied by forearm post-ischemic flow mediated vasodilatation (FMD) and sublingual glyceryl trinitrate (GTN), respectively; by the forearm skin microcirculation responses to acetylcholine (Ach) and sodium nitroprusside (SNP) applied by iontophoresis, respectively; and by endothelium dependent vasodilatation following beta 2-adrenoceptor-agonist stimulation (sc terbutaline) assessed by the reflection index from pulse wave analysis.

Results:

Drug treatment reduced aortic and brachial BP, and reduced indices of aortic stiffness. The effects (mean ± SD or medians and interquartiles; and mean ± SEM; for delta week 0–12), by ramipril and doxazosin on FMD (5.3 ± 4.2 to 4.5 ± 4.3%, delta −1.1 ± 1.0, and 6.3 ± 4.4 to 5.5 ± 3.1%, delta −0.3 ± 1.0); GTN (14.4 ± 7.0 to 14.4 ± 6.9%, delta 0.3 ± 1.3, and 15.5 ± 6.8 to 14.4 ± 7.0, delta −0,5 ± 1.3); endothelial function index (ie FMD/GTN, 0.49 ± 0.56 to 0.44 ± 0.64, delta 0.07 ± 0.12, and 0.47 ± 0.38 to 0.51 ± 0.41, delta 0.07 ± 0.12); and reflection index (−6.8 ± 3.2 to −7.7 ± 3.8, delta −0.8 ± 1.0, and −7.3 ± 2.8 to −6.6 ± 3.1, delta 0.3 ± 0.9) were small. Also the effects by ramipril and doxazosin on skin microcirculation (peak flux, arbitrary units) were small: 33 [18–62] to 28 [19–53], delta −2 ± 5, and 36 [21–62] to 41 [20–67], delta 1 ± 9 by Ach; and 46 [34–84] to 43 [26–87], delta −9 ± 8, and 58 [33–78] to 60 [44–82], delta −0.3 ± 10 by SNP; and 0.5 [0.4–1.0] to 0.8 [0.4–1.3], delta 0.2 ± 0.2, and 0.6 [0.4–1.0] to 0.8 [0.3–1.4], delta 0.3 ± 10 by the peak flux ratio (Ach/SNP), respectively. Also skin microcirculatory responses to heat induced hyperemia remained unchanged.

Conclusions:

ACE-inhibition and alpha 1-adrenoceptor-blockade for 12 weeks reduce BP and improve indices of aortic stiffness but appear to have no effects on endothelial function assessed in multiple ways in mild-to moderate uncomplicated hypertension. Evidence of endothelial dysfunction and the potential benefit of treatment might require more advanced stages of hypertensive disease.

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