Microcirculatory hemodynamics and endothelial dysfunction in systemic lupus erythematosus.

OBJECTIVE: Impaired flow-mediated dilation (FMD) occurs in disease states associated with atherosclerosis, including SLE. The primary hemodynamic determinant of FMD is wall shear stress, which is critically dependent on the forearm microcirculation. We explored the relationship between FMD, diastolic shear stress (DSS), and the forearm microcirculation in 32 patients with SLE and 19 controls. METHODS AND RESULTS: DSS was calculated using (mean diastolic velocity x 8 x blood viscosity)/baseline brachial artery diameter. Doppler velocity envelopes from the first 15 seconds of reactive hyperemia were analyzed for resistive index (RI), and interrogated in the frequency domain to assess forearm microvascular hemodynamics. FMD was significantly impaired in SLE patients (median, 2.4%; range, -2.1% to 10.7% versus median 5.8%; range, 1.9% to 14%; P<0.001). DSS (dyne/cm2) was significantly reduced in SLE patients (median, 18.5; range, 3.9 to 34.0 versus median 21.8; range, 14.1 to 58.7; P=0.037). A strong correlation between FMD and DSS, r(s)=0.65, P=0.01 was found. Postischemic RI was not significantly different between the 2 groups; however, there were significant differences in the power-frequency spectrums of the Doppler velocity envelopes (P<0.05). CONCLUSIONS: These data suggest that in SLE, altered structure and function of the forearm microcirculation contributes to impaired FMD through a reduction in shear stress stimulus.

Effects of dietary omega-3 fatty acid supplementation on endothelium-dependent vasodilation in patients with chronic heart failure.

We investigated the effects of omega-3 fatty acids administration on endothelium-dependent vasodilation in patients > or =65 years old who received treatment for chronic heart failure (CHF). Twenty patients (mean age 73 years; 15 men) with grade II and III CHF who were on maximal medical management were recruited. Patients were randomized in a double-blind, crossover fashion to 6 weeks of omega-3 fatty acid (1.8 g ecosapentaenoic acid and 1.2 g docosahexaenoic acid) or olive oil. Forearm blood flow (FBF) responses to incremental doses of intra-arterial sodium nitroprusside, acetycholine (ACH), angiotensin-II, and N(g)-nitro-L-arginine methyl ester were assessed by venous occlusion strain gauge plethysmography. The endothelium-dependent increase in FBF was greater in response in ACH infusion after omega-3 fatty acid administration (7.9, 95% confidence interval [CI] 4.81 to 11.08 to 11.3, 95% CI 7.31 to 15.23 arbitrary units (p <0.05) compared with baseline (7.95, 95% CI 4.8 to 11.08 arbitrary units) and olive oil administration (7.27, 95% CI 4.66 to 9.88 arbitrary units) (p = NS for both). Neither omega-3 fatty acid nor olive oil altered endothelium-independent vasodilation in response to infusion of sodium nitroprusside, nor did they influence vasoconstrictor responses to angiotensin-II or N(g)-nitro-L-arginine methyl ester. Dietary omega-3 fatty acid supplementation was accompanied by an increase in FBF response to ACH, which represents enhanced endothelium-dependent vasodilation in CHF. Further studies are warranted to assess the mechanism responsible for the beneficial actions of omega-3 fatty acids in CHF.

NAD(P)H-dependent superoxide production in platelets: the role of angiotensin II and protein kinase C.

OBJECTIVES: Vascular NAD(P)H oxidase represents a major source for excessive superoxide production in hypertension. Angiotensin II (AngII) can activate NAD(P)H oxidase via the angiotensin II type 1 (AT1) receptor and protein kinase C (PKC). Platelets possess AT1 receptors and all the components of the NAD(P)H oxidase system. We employed this tissue model to explore mechanisms involved in AngII-mediated superoxide production. DESIGN AND METHODS: Platelet suspensions from hypertensive patients' blood were activated with AngII or phorbol 12-myristate 13-acetate (PMA). Inhibitors of NAD(P)H oxidase, PKC, and the AT1 receptor were employed to study their effects on superoxide production. RESULTS: Superoxide production was stimulated by AngII and PMA and attenuated by AT1 receptor antagonists (mean percentage reduction 80.2%, P<0.01) and inhibitors of PKC (mean reduction 94.8%, P<0.001) and NAD(P)H oxidase (mean reduction 100%, P< 0.001). CONCLUSIONS: AngII stimulates platelet superoxide production through activation of vascular NAD(P)H oxidase via the AT1 receptor and PKC.

Impaired endothelium-dependent and -independent vasodilation in elderly patients with chronic heart failure.

BACKGROUND: Impaired endothelium-dependent and independent vasodilator responses in chronic heart failure (CHF) have been well described. Previous studies involved younger patients and omitted medications prior to study. AIMS: We explored if new therapeutic interventions would restore vasodilator responses in typical patients with chronic heart failure. METHODS AND RESULTS: 24 patients and 15 controls were recruited, patients were maintained on their usual medications. Forearm blood flow responses were measured by venous occlusion plethysmography in response to incremental doses of sodium nitroprusside (SNP) (6, 9 and 12 nmol/min), acetylcholine (ACH) (120, 180 and 240 nmol/min), angiotensin II (AII) (1, 10 and 100 nmol/min) and N(g)-Nitro-L-arginine methyl ester (L-NAME) (1, 2 and 4 nmol/min) infused into the non-dominant brachial artery. FBF responses to SNP were impaired in patients compared with controls (13.7(9.9,17.4) vs. 24.8(18.6,30.9)) arbitrary units, P<0.001). Similarly FBF responses to ACH were reduced in patients compared with controls (7.5(4.2,10.9) vs. 24.8(16.4,33.2)) arbitrary units, P<0.001. Decreased FBF was noted in response to AII and L-NAME but was significant only for AII and did not differ between groups. CONCLUSIONS: In elderly patients with CHF, endothelium-dependent and independent vasodilator responses were blunted compared with controls. Defects in nitric oxide bioavailability and smooth muscle responsiveness are not reversed by modern medical management of the heart failure syndrome.

Platelet nitric oxide and superoxide release during the development of nitrate tolerance: effect of supplemental ascorbate.

BACKGROUND: The therapeutic benefits that accompany the continuous administration of organic nitrates are attenuated by the development of tolerance to the compounds. Altered superoxide production and NO bioavailability have been implicated in contributing to the development of tolerance, an effect that may be ameliorated by the administration of antioxidants. METHODS AND RESULTS: We studied the effect of 3 days of continuous transdermal administration of nitroglycerin (NTG) (10 mg/24 hours) on platelet free radical (NO and superoxide anion [O2*-] activity) with and without coadministration of supplemental ascorbate (2.4 g/24 hours). NAD(P)H oxidase activity, nitric oxide synthase (NOS) activity, and cyclic guanosine monophosphate (cGMP) content were also assessed. Radial artery pressure pulse waveforms were used to track the hemodynamic actions of NTG. Three days of NTG/placebo was associated with a significant increase in platelet NO and O2*- production from 1.0+/-1.17 to 2.52+/-0.88 pmol/10(8) platelets and 13.2+/-4.8 to 72.5+/-34.4 pmol/10(8) platelets, respectively (P<0.01 for both). These changes were accompanied by increased platelet NADH oxidase activity from 47.9+/-11.0 to 65.3+/-13.6 pmol O2*- min/mg protein and cGMP content from 0.60+/-0.10 to 0.89+/-0.16 pmol/10(9) platelets (P<0.05 for both). Administration of NTG/ascorbate attenuated both NO and O2*- release in platelets. CONCLUSIONS: Three days of continuous transdermal administration of NTG was accompanied by increased platelet NO and O2*- production and NADH oxidase activity that was suppressed by coadministration of oral ascorbate. Although a significant degree of tolerance would be expected during continuous nitrate administration, a residual hemodynamic action could be identified by arterial pulse contour analysis.