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Endothelial dysfunction develops with age and may precede cardiovascular disease. Animal data suggest that T‐type calcium channels play an important role in endothelial function, but data from humans are lacking. This study included 15 healthy, sedentary, elderly males for a double blinded, randomized controlled trial. For 8 weeks, they were given 40 mg/day of either efonidipine (L‐ and T‐type calcium channel blocker (CCB)) or nifedipine (L‐type CCB). Vascular function was evaluated by graded femoral arterial infusions of acetylcholine (ACh; endothelium‐dependent vasodilator) and sodium nitroprusside (endothelium‐independent vasodilator) both with and without co‐infusion of N‐acetylcysteine (NAC; antioxidant). We measured leg blood flow and mean arterial pressure and calculated leg vascular conductance to evaluate the leg vascular responses. Despite no significant change in blood pressure in either group, we observed higher leg blood flow responses (Δ 0.43 ± 0.45 l/min, P = 0.006) and leg vascular conductance (Δ 5.38 ± 5.67 ml/min/mmHg, P = 0.005) to intra‐arterial ACh after efonidipine, whereas there was no change in the nifedipine group, and no differences between groups. We found no upregulation of endothelial nitric oxide synthase in vastus lateralis muscle biopsies within or between groups. Smooth muscle cell responsiveness was unaltered by efonidipine or nifedipine. Intravenous co‐infusion of NAC did not affect endothelium‐dependent vasodilatation in either of the CCB groups. These results suggest that 8 weeks’ inhibition of T‐ and L‐type calcium channels augments endothelium‐dependent vasodilatory function in healthy elderly males. Further studies are required to elucidate if T‐type calcium channel inhibition can counteract endothelial dysfunction. What is the central question of this study? Does T‐type calcium channel inhibition prevent age‐related endothelium dysfunction in humans? What is the main finding and its importance? Eight weeks of L+T‐type calcium channel blockade (CCB) increased endothelium‐dependent vasodilatation in the leg of otherwise healthy elderly males, while 8 weeks of L‐type CCB only did not. Thus, T‐type calcium channels may be involved in endothelium dysfunction.

Skeletal muscle protein metabolism is resistant to the anabolic action of insulin in healthy, nondiabetic older adults. This defect is associated with impaired insulin-induced vasodilation and mTORC1 signaling. We hypothesized that, in older subjects, pharmacological restoration of insulin-induced capillary recruitment would improve the response of muscle protein synthesis and anabolism to insulin. Twelve healthy, nondiabetic older subjects (71 ± 2 years) were randomized to two groups. Subjects were studied at baseline and during local infusion in one leg of insulin alone (Control) or insulin plus sodium nitroprusside (SNP) at variable rate to double leg blood flow. We measured leg blood flow by dye dilution; muscle microvascular perfusion with contrast enhanced ultrasound; Akt/mTORC1 signaling by Western blotting; and muscle protein synthesis, amino acid, and glucose kinetics using stable isotope methodologies. There were no baseline differences between groups. Blood flow, muscle perfusion, phenylalanine delivery to the leg, and intracellular availability of phenylalanine increased significantly (P < 0.05) in SNP only. Akt phosphorylation increased in both groups but increased more in SNP (P < 0.05). Muscle protein synthesis and net balance (nmol · min(-1) · 100 ml · leg(-1)) increased significantly (P < 0.05) in SNP (synthesis, 43 ± 6 to 129 ± 25; net balance, -16 ± 3 to 26 ± 12) but not in Control (synthesis, 41 ± 10 to 53 ± 8; net balance, -17 ± 3 to -2 ± 3). Pharmacological enhancement of muscle perfusion and amino acid availability during hyperinsulinemia improves the muscle protein anabolic effect of insulin in older adults.

Uric Acid Restores Endothelial Function in Patients With Type 1 Diabetes and Regular Smokers W. Stephen Waring 1 , John A. McKnight 2 , David J. Webb 1 and Simon R.J. Maxwell 1 1 Clinical Pharmacology Unit, The Queen’s Medical Research Institute, The University of Edinburgh, Scotland, U.K 2 Department of Diabetes, Western General Hospital, Edinburgh, U.K Address correspondence and reprint requests to W.S. Waring, Clinical Pharmacology Unit, University of Edinburgh, The Queen’s Medical Research Institute, 3rd Floor East, Room E3.22, 47 Little France Crescent, Edinburgh, EH16 4TJ, U.K. E-mail: s.waring{at}ed.ac.uk Abstract Endothelial dysfunction is a characteristic finding in both patients with type 1 diabetes and in regular smokers and is an important precursor to atherosclerosis. The urate molecule has antioxidant properties, which could influence endothelial function. The impact of acutely raising uric acid concentrations on endothelial function was studied in eight men with type 1 diabetes, eight healthy regular smokers, and eight age-matched healthy control subjects in a randomized, four-way, double-blind, placebo-controlled study. Subjects received 1,000 mg uric acid i.v. in vehicle, 1,000 mg vitamin C as a control antioxidant, vehicle alone, or 0.9% saline on separate occasions over 1 h. Forearm blood flow responses to intrabrachial acetylcholine and sodium nitroprusside were assessed using venous occlusion plethysmography. Responses to acetylcholine, but not sodium nitroprusside, were impaired in patients with diabetes ( P < 0.001) and in smokers ( P < 0.005) compared with control subjects. Administration of uric acid and vitamin C selectively improved acetylcholine responses in patients with type 1 diabetes ( P < 0.01) and in regular smokers ( P < 0.05). Uric acid administration improved endothelial function in the forearm vascular bed of patients with type 1 diabetes and smokers, suggesting that high uric acid concentrations in vivo might serve a protective role in these and other conditions associated with increased cardiovascular risk. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted August 16, 2006. Received February 28, 2006. DIABETES

Patients with the metabolic syndrome (MetS) have impaired insulin-induced enhancement of vasodilator responses. The incretin hormone glucagon-like peptide 1 (GLP-1), beyond its effects on blood glucose, has beneficial actions on vascular function. This study, therefore, aimed to assess whether GLP-1 affects insulin-stimulated vasodilator reactivity in patients with the MetS. Forearm blood flow responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed in MetS patients before and after the addition of GLP-1 to an intra-arterial infusion of saline (n = 5) or insulin (n = 5). The possible involvement of oxidative stress in the vascular effects of GLP-1 in this setting was investigated by infusion of vitamin C (n = 5). The receptor specificity of GLP-1 effect during hyperinsulinemia was assessed by infusing its metabolite GLP-1(9-36) (n = 5). The metabolic actions of GLP-1 were also tested by analyzing forearm glucose disposal during hyperinsulinemia (n = 5). In MetS patients, GLP-1 enhanced endothelium-dependent and -independent responses to ACh and SNP, respectively, during hyperinsulinemia (P < 0.001 for both), but not during saline (P > 0.05 for both). No changes in vasodilator reactivity to ACh and SNP were seen after GLP-1 was added to insulin and vitamin C (P > 0.05 for both) and after GLP-1(9-36) was given during hyperinsulinemia (P > 0.05 for both). Also, GLP-1 did not affect forearm glucose extraction and uptake during hyperinsulinemia (P > 0.05 for both). In patients with the MetS, GLP-1 improves insulin-mediated enhancement of endothelium-dependent and -independent vascular reactivity. This effect may be influenced by vascular oxidative stress and is possibly exerted through a receptor-mediated mechanism.

Vasodilator function is reported to be reduced in rheumatoid arthritis (RA), and is considered an early sign of vascular dysfunction, which is normalised by TNF inhibitors (TNFi). To optimise cost-effectiveness, tapering or interruption of TNFi therapy in established RA patients is advocated. We explored whether cessation of TNFi results in impaired vasodilator function and whether this relates to the development of a Disease Activity Score (DAS28)-based flare. Forty-one patients were assessed for eligibility as RA with at least 12 months of low disease activity (based on 28 joint counts); 35 enrolled into the randomised study: 8 were randomised to continue, 27 to stopping TNFi. Forearm vasodilation to acetylcholine (ACh) and sodium nitroprusside (SNP) was assessed before cessation of TNFi therapy (visit 1) and 6 months after (dis)continuation of TNFi or at flare (based on DAS28) whichever came first (visit 2). None of the patients who continued their TNFi therapy flared. Eight out of 22 patients who stopped TNFi therapy flared. The vasodilator response to ACh and SNP was reduced significantly in patients who experienced a flare of RA: In patients who did not experience a flare, the vasodilator response to ACh or SNP was not significantly affected. Vasodilator function is reduced after cessation of TNFi, but only when RA reactivates, indicating that early vasodilator dysfunction is a consequence rather than a cause of systemic inflammation in RA and not specifically related to inhibition of TNFα signalling. Without close monitoring, microvascular damage can occur after TNFi interruption with potential devastating implications for cardiovascular health. Trial registration: NCT02130076

Danshen is the dried root extract of the plant Salvia Miltiorrhiza and it is used as traditional Chinese medicinal herbal product to prevent and treat atherosclerosis. However, its efficacy has not been thoroughly investigated. This study evaluates the effect of Danshen on hyperlipidemia and hypertension, two well known risk factors for the development of atherosclerosis. This was a randomized, placebo-controlled, double-blind crossover study performed at a tertiary referral center. Participants were recruited by newspaper advertisement and randomized to treatment with Danshen (water-extract of the Salvia Miltiorrhiza root) or placebo for 4 consecutive weeks. There was a wash out period of 4 weeks. Of the 20 analysed participants, 11 received placebo first. Inclusion criteria were: age 40-70 years, hyperlipidemia and hypertension. At the end of each treatment period, plasma lipids were determined (primary outcome), 24 hours ambulant blood pressure measurement (ABPM) was performed, and vasodilator endothelial function was assessed in the forearm. LDL cholesterol levels were 3.82±0.14 mmol/l after Danshen and 3.52±0.16 mmol/l after placebo treatment (mean±SE; p<0.05 for treatment effect corrected for baseline). Danshen treatment had no effect on blood pressure (ABPM 138/84 after Danshen and 136/87 after placebo treatment). These results were further substantiated by the observation that Danshen had neither an effect on endothelial function nor on markers of inflammation, oxidative stress, glucose metabolism, hemostasis and blood viscosity. Four weeks of treatment with Danshen (water-extract) slightly increased LDL-cholesterol without affecting a wide variety of other risk markers. These observations do not support the use of Danshen to prevent or treat atherosclerosis. ClinicalTrials.gov NCT01563770.

Vascular Effects of Improving Metabolic Control With Metformin or Rosiglitazone in Type 2 Diabetes Andrea Natali , MD 1 , Stephanie Baldeweg , MD 2 , Elena Toschi , MD 1 , Brunella Capaldo , MD 3 , Daniele Barbaro , MD 4 , Amalia Gastaldelli , PHD 1 , John S. Yudkin , MD 2 and Ele Ferrannini , MD 1 1 Department of Internal Medicine and C.N.R. Institute of Clinical Physiology, University of Pisa, Pisa, Italy 2 Department of Medicine, University College, London, U.K. 3 Department of Internal Medicine, “Federico II” University, Naples, Italy 4 Livorno General Hospital, Livorno, Italy Address correspondence and reprint requests to Dr. Andrea Natali, Department of Internal Medicine, Via Roma, 67, 56100 Pisa, Italy. E-mail: anatali{at}ifc.cnr.it Abstract OBJECTIVE —The aim of this study was to test whether vascular reactivity is modified by improving metabolic control and peripheral insulin resistance in type 2 diabetes. RESEARCH DESIGN AND METHODS —In a randomized, double-blind design, we assigned 74 type 2 diabetic patients to rosiglitazone (8 mg/day), metformin (1,500 mg/day), or placebo treatment for 16 weeks and measured insulin sensitivity (euglycemic insulin clamp), ambulatory blood pressure, and forearm blood flow response to 1 ) intra-arterial acetylcholine (ACh), 2 ) intra-arterial nitroprusside, 3 ) the clamp, and 4 ) blockade of nitric oxide (NO) synthase. RESULTS —Compared with 25 nondiabetic subjects, patients had reduced insulin sensitivity (30 ± 1 vs. 41 ± 3 μmol · min −1 · kg fat-free mass −1 ; P < 0.001) and reduced maximal response to ACh (586 ± 42 vs. 883 ± 81%; P < 0.001). Relative to placebo, 16 weeks of rosiglitazone and metformin similarly reduced fasting glucose (−2.3 ± 0.5 and −2.3 ± 0.5 mmol/l) and HbA 1c (−1.2 ± 0.3 and −1.6 ± 0.3%). Insulin sensitivity increased with rosiglitazone (+6 ± 3 μmol · min −1 · kg fat-free mass −1 ; P < 0.01) but not with metformin or placebo. Ambulatory diastolic blood pressure fell consistently (−2 ± 1 mmHg; P < 0.05) only in the rosiglitazone group. Nitroprusside dose response, clamp-induced vasodilatation, and NO blockade were not affected by either treatment. In contrast, the slope of the ACh dose response improved with rosiglitazone (+40% versus baseline, P < 0.05, +70% versus placebo, P < 0.005) but did not change with either metformin or placebo. This improvement in endothelium-dependent vasodilatation was accompanied by decrements in circulating levels of free fatty acids and tumor necrosis factor-α. CONCLUSIONS —At equivalent glycemic control, rosiglitazone, but not metformin, improves endothelium dependent vasodilatation and insulin sensitivity in type 2 diabetes. ABPM, ambulatory blood pressure monitoring ACh, acetylcholine eNOS, endothelial nitric oxide synthase EGP, endogenous glucose production FBF, forearm blood flow l-NMMA, NG-monomethyl-l-arginine NEFA, nonesterified fatty acid SNP, sodium nitroprusside TNF-α, tumor necrosis factor-α Footnotes A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Accepted March 1, 2004. Received November 7, 2003. DIABETES CARE

Abstract Rationale: High-altitude pulmonary edema (HAPE) is characterized by excessive pulmonary vasoconstriction and is associated with decreased concentrations of nitric oxide (NO) in the lung. Objectives: We hypothesized that individuals susceptible to HAPE (HAPE-S) would also have dysfunction of the vascular NO vasodilator pathway during hypoxia in the systemic vasculature. Methods: During normoxia (FIO2 = 0.21) and 4 hours of normobaric hypoxia (FIO2 = 0.12, corresponding to an altitude of 4,500 m above sea level) endothelium-dependent and endothelium-independent vasodilator responses to intraarterial infusion of acetylcholine (ACh) and sodium nitroprusside, respectively, were measured by forearm venous occlusion plethysmography in nine HAPE-S subjects and in nine HAPE-resistant control subjects. Main Results: Pulmonary artery systolic pressure increased from 22 ± 3 to 33 ± 6 mm Hg (p < 0.001) during hypoxia in control subjects, and from 25 ± 4 to 50 ± 9 mm Hg in HAPE-S subjects (p < 0.001). Despite similar responses during normoxia in both groups, ACh-induced changes in forearm blood flow markedly decreased during hypoxia in HAPE-S subjects (p = 0.01) but not in control subjects. The attenuated vascular response to ACh infusion during hypoxia inversely correlated with increased pulmonary artery systolic pressure (p = 0.04) and decreased plasma nitrite correlated with attenuated ACh-induced vasodilation in HAPE-S subjects (p = 0.02). Conclusions: Hypoxia markedly impairs vascular endothelial function in the systemic circulation in HAPE-S subjects due to a decreased bioavailability of NO. Impairment of the NO pathway could contribute to the enhanced hypoxic pulmonary vasoconstriction that is central to the pathogenesis of HAPE.

It has been suggested that mineralocorticoid receptor antagonists have direct cardioprotective properties, because these drugs reduce mortality in patients with heart failure. In murine models of myocardial infarction, mineralocorticoid receptor antagonists reduce infarct size. Using gene deletion and pharmacological approaches, it has been shown that extracellular formation of the endogenous nucleoside adenosine is crucial for this protective effect. We now aim to translate this finding to humans, by investigating the effects of the selective mineralocorticoid receptor antagonist eplerenone on the vasodilator effect of the adenosine uptake inhibitor dipyridamole, which is a well-validated surrogate marker for extracellular adenosine formation. In a randomised, double-blinded, placebo-controlled, cross-over study we measured the forearm blood flow response to the intrabrachial administration of dipyridamole in 14 healthy male subjects before and after treatment with placebo or eplerenone (50 mg bid for 8 days). The forearm blood flow during administration of dipyridamole (10, 30 and 100 µg·min(-1)·dl(-1)) was 1.63 (0.60), 2.13 (1.51) and 2.71 (1.32) ml·dl(-1)·min(-1) during placebo use, versus 2.00 (1.45), 2.68 (1.87) and 3.22 (1.94) ml·dl(-1)·min(-1) during eplerenone treatment (median (interquartile range); P = 0.51). Concomitant administration of the adenosine receptor antagonist caffeine attenuated dipyridamole-induced vasodilation to a similar extent in both groups. The forearm blood flow response to forearm ischemia, as a stimulus for increased formation of adenosine, was similar during both conditions. In a dosage of 50 mg bid, eplerenone does not augment extracellular adenosine formation in healthy human subjects. Therefore, it is unlikely that an increased extracellular adenosine formation contributes to the cardioprotective effect of mineralocorticoid receptor antagonists. ClinicalTrials.gov, NCT01837108.

Experimental evidence suggests a lipid-independent effect of statins on endothelial function and nitric oxide (NO) availability in humans. We investigated whether improvement in NO availability in hypercholesterolemia can be achieved rapidly with statins before lipid-lowering therapy is complete. We studied 41 patients (52 ± 11 years) with low-density lipoprotein (LDL) cholesterol ≥ 130 mg/dL (179 ± 45 mg/dL) randomly assigned to treatment either with atorvastatin (20 mg/day) or cerivastatin (0.4 mg/day). Endothelium-dependent vasodilation of the forearm vasculature was measured by plethysmography and intra-arterial infusion of acetylcholine (ACh) after 3 days (n = 18) and 14 days (n = 39) of treatment. NO availability and oxidative stress were assessed by coinfusion of l-NMMA and vitamin C. After 3 days of treatment, LDL-cholesterol decreased by 11.9% with a further decrease to 29.6% after 14 days ( P < .001). Endothelium-dependent vasodilation improved by +46.7% after 3 days of statin therapy compared with before therapy (ACh 48 μg/min: +15.7 ± 10.6 vs +10.7 ± 10.8 mL/min per 100 mL, P < .05). No further improvement in endothelium-dependent vasodilation (+42.7% compared with before therapy) could be demonstrated after 14 days of treatment (ACh 48 μg/min: +17.7 ± 10.3 vs +12.4 ± 9.3 mL/min per 100 mL before therapy, P < .001). Coinfusion of ACh plus vitamin C was able to improve endothelium-dependent vasodilation before but not after 3 or 14 days of statin therapy either. The improvement in endothelium-dependent vasodilation after therapy was no longer observed when the NO-synthase inhibitor l-NMMA was coinfused together with ACh. Short-term lipid-lowering therapy with statins is able to improve endothelial function and NO availability almost completely after 3 days in hypercholesterolemic patients probably by decreasing oxidative stress. This improvement seems to be more rapid than the accompanying decline in LDL-cholesterol and not related to these lipid changes. This finding can support the concept of lipid-independent effects of statins in humans.