Sebastian Oehmer

Impaired Endothelial Function of the Retinal Vasculature in Hypertensive Patients

Background and Purpose— Arterial hypertension constitutes a central factor in the pathogenesis of stroke. We examined endothelial function of the retinal vasculature as a model of the cerebral circulation. Methods— Thirty-eight young subjects (19 hypertensive and 19 normotensive) were treated with the AT1-receptor blocker candesartan cilexetil and placebo, each over 7 days. Retinal capillary flow and blood flow velocity in the central retinal artery were assessed with scanning laser Doppler flowmetry and pulsed Doppler ultrasound, respectively. NG-mono-methyl-L-arginine (L-NMMA) was infused to inhibit nitric oxide (NO) synthesis. Diffuse luminance flicker was applied to stimulate NO release. Results— In normotensive subjects, L-NMMA decreased retinal capillary flow by 8.2%±13% (P < 0.05) and flickering light increased mean blood flow velocity in the central retinal artery by 19%±29% (P < 0.01). In contrast, no significant change to these provocative tests was seen in hypertensive subjects. Treatment with candesartan cilexetil restored a normal pattern of reactivity in retinal capillaries (L-NMMA: decrease in perfusion by 10%±17%, P < 0.05) and the central retinal artery (flicker: increase in mean blood flow velocity by 42%±31%, P < 0.001) in hypertensive patients. Conclusions— Endothelial function of the retinal vasculature is impaired in early essential hypertension but can be improved by AT1-receptor blockade.

Rapid Nongenomic Effects of Aldosterone on Human Forearm Vasculature

Abstract—The impact of aldosterone in cardiovascular disease and hypertension has recently gained new interest. Aldosterone is now suggested to be a more common cause of hypertension than previously believed and has been linked to myocardial fibrosis, independent of its hypertensive effects. Finally, rapid nongenomic aldosterone effects have been proposed to be important in hypertension, in addition to its genomic effects. Forty-eight healthy male volunteers were examined in a randomized, placebo-controlled, double-blind crossover trial to elucidate the rapid nongenomic, vascular effects of aldosterone in humans. Forearm blood flow was measured by venous occlusion plethysmography. First, aldosterone (500 ng/min) and placebo were infused into the brachial artery for 8 minutes. The volunteers then received ascending doses of acetylcholine, NG-monomethyl-l-arginine (L-NMMA), sodium nitroprusside, or phenylephrine. Aldosterone increased forearm blood flow (P <0.001, ANOVA). The maximum effect was an increase in forearm blood flow with aldosterone of 7.9±2.6% compared with 0.1±1.9% with placebo treatment after 8 minutes. With aldosterone, L-NMMA induced a greater vasoconstriction (P <0.05, ANOVA), sodium nitroprusside induced an attenuated vasoconstriction (P <0.01, ANOVA), and phenylephrine induced an exaggerated vasoconstriction (P <0.01, ANOVA) within minutes as compared with placebo. These data suggest that aldosterone acts through rapid nongenomic effects at the endothelium by increasing NO release and at the vascular smooth muscle cells by promoting vasoconstriction. This is consistent with in vitro data showing an increase in intracellular calcium in both cell types. Disturbances of these aldosterone effects on both levels might be important in promoting hypertension.

The C242T p22phox polymorphism and endothelium-dependent vasodilation in subjects with hypercholesterolaemia

Oxidative stress plays a major pathogenetic role in cardiovascular disease. The C242T variant of the CYBA gene encoding the p22phox subunit of the NAD(P)H oxidase, a major source of superoxide production, has been shown to be associated with coronary artery disease and with vascular superoxide production in human veins ex vivo. Since superoxide degrades nitric oxide (NO), we hypothesized that the C242T variant influences endothelium-dependent vasodilation of the human forearm vasculature in vivo. In the present study, 90 subjects with elevated cholesterol levels were stratified for the C242T polymorphism of the CYBA p22phox gene. Endothelium-dependent and -independent vasodilation were assessed by plethysmographic monitoring of forearm blood flow responses to intra-arterial infusion of acetylcholine and sodium nitroprusside respectively. N(G)-Monomethyl-L-arginine (L-NMMA) was infused to analyse NO-mediated basal vascular tone. Baseline parameters (age, gender, blood pressure, body mass index, cholesterol level) were similar across the genotypes. No differences in forearm blood flow responses to the intra-arterial infusion of acetylcholine, sodium nitroprusside or L-NMMA were found across the CYBA p22phox genotypes. Our sample size of n =90 had a power of >80% (beta=0.20) with a P value of <0.05 (alpha=0.05) to detect a difference greater than 156% in the forearm blood flow response to acetylcholine across genotypes (S.D. 336%; average increase in forearm blood flow=514%). In conclusion, at a power of 80%, our study excludes a major effect of the C242T CYBA p22phox polymorphism on acetylcholine-mediated endothelium-dependent vasodilation and basal NO-mediated vascular tone of the human forearm circulation in subjects with hypercholesterolaemia.

Functional Relevance of Aldosterone for the Determination of Left Ventricular Mass

In experimental studies, the importance of aldosterone for the development of left ventricular (LV) hypertrophy has been demonstrated. In 120 healthy Caucasian men (aged 25 +/- 3 years; blood pressure, 134 +/- 15/86 +/- 12 mm Hg), we determined LV mass (2-dimensionally guided M-mode echocardiography), urinary aldosterone concentration, and the response of aldosterone to angiotensin II infusion (3.0 ng/kg/min). Seventy-six volunteers took part in a follow-up visit after 2 years when urinary aldosterone concentration and LV mass were determined again. At follow-up, LV mass increased in 42 subjects (by 33 +/- 26 g), whereas in 34 subjects LV mass decreased (by 27 +/- 22 g). Between the 2 groups, only the change in urinary aldosterone concentration over time was significantly different (group with increased LV mass had an increase in urinary aldosterone concentration by 2.5 +/- 5.4 microg/day; group with decreased LV mass had a decrease in urinary aldosterone concentration by 0.7 +/- 4.6; p <0.01 between groups). In accordance, we found significant correlations between changes in LV mass and changes in urinary aldosterone concentration (r = 0.29, p <0.05) and between changes in LV mass and the response of aldosterone to angiotensin II at baseline (r = 0.25, p <0.05). Both changes in aldosterone concentration over time and the response of aldosterone to angiotensin II were related to changes in LV mass over time. These data underscore the importance of aldosterone for the development of LV hypertrophy. This process is already evident in young subjects with apparently small changes in LV mass over a mean follow-up period of 2 years.

Effect of NOS inhibition on retinal arterial and capillary circulation in early arterial hypertension

Background: Arterial hypertension is involved in the pathogenesis of end organ damage by influencing the ability of the vascular endothelium to produce nitric oxide (NO). This study analyzes changes of retinal and systemic NO-dependent circulation parameters by inhibiting nitric oxide synthase (NOS) in both hypertensive and normotensive individuals. Methods: In a double-blind crossover trial, 19 hypertensive patients (H, age 28.2 ± 0.9 years) and 19 normotensive controls (N, age 26.9 ± 0.9 years) were randomized treated either with candesartan or placebo. Both retinal capillary flow (RCF) and mean blood flow velocity of the central retinal artery (VCRA) were registered before and after NOS inhibition with NG-monomethyl-L-arginine (L-NMMA, 3 mg/kg). In a subpopulation mean arterial pressure (MAP), cardiac output (CO), and the total peripheral resistance (TPR) were determined simultaneously. Results: Changes from baseline: In normotensive and hypertensive subjects infusion of L-NMMA led to an increase of MAP (N, +13.3 ± 1.8%, P < 0.01; H, +14.3 ± 2.4%, P < 0.01) and TPR (N, +36.9 ± 3.8%, P < 0.01; H, +45.0 ± 4.5%, P < 0.01), and to a decrease of CO (N, -21.1 ± 1.5%, P < 0.01; H, -24.6 ± 2.3%, P < 0.01). The L-NMMA effect on VCRA and RCF differed between controls and hypertensives. VCRA changed by + 17.3 ± 6.2% (P < 0.05) and RCF by -7.3 ± 3.0% (P < 0.05) in controls. In hypertensive subjects corresponding results were + 9.5 ± 5.2% (P = NS) and + 2.7 ± 3.8% (P = NS), respectively. The decrease of RCF due to L-NMMA was reduced in hypertension as compared to controls (P < 0.05). The calculated cross-sectional area of CRA was reduced by -58.7% in controls and increased by + 31.1% in hypertensive subjects. There was no significant correlation between the flow in the systemic and retinal circulation. Conclusion: Only normotensives L-NMMA induces an acceleration of VCRA due to a probable vasoconstriction of the central retinal artery and despite of a reduced RCF. Already in early hypertension the NOS-dependent vascular tone in retinal arteries and capillaries is impaired. The regulation of the retinal capillary flow appeared to be independent from systemic circulation.

Valsartan and retinal endothelial function in elderly hypertensive patients

Background. The aim of this study was to investigate the impact of short‐term treatment with the angiotensin II receptor blocker (ARB) valsartan on retinal endothelial function in elderly patients with mild to moderate essential hypertension. Methods. In an open‐labeled study, 20 elderly, male patients with arterial hypertension (WHO I–II) were treated with the ARB valsartan (80–160 mg once daily) over 8 days. Central retinal artery perfusion at rest and during flicker light stimulation was measured before and after treatment using pulsed wave Doppler sonography. Retinal capillary flow was assessed with scanning laser Doppler flowmetry at rest and following systemic infusion of the nitric oxide synthase (NOS) inhibitor NG‐monomethyl‐l‐arginine (L‐NMMA). Results. While valsartan significantly lowered blood pressure, central retinal artery perfusion at rest as well as after flicker light stimulation was similar before and after treatment. Similarly, retinal capillary flow at rest and after infusion of L‐NMMA did not change with valsartan after 7 days of treatment. Subgroup analysis revealed that changes in retinal capillary flow in response to L‐NMMA might be dependent on serum low‐density lipoprotein (LDL) cholesterol levels of study participants. After treatment with valsartan, retinal capillary flow in response to L‐NMMA decreased more in patients with low (<3.54 mmol/l) than with high LDL‐cholesterol levels (−12.6±20.2% vs 12.3±19.5%, p<0.05). Conclusion. Short‐term treatment with valsartan did not improve retinal endothelial function in elderly hypertensive patients.