Effects of cyclooxygenase inhibition on endothelial function in hypertensive patients treated with angiotensin-converting enzyme inhibitors

BACKGROUND: Cyclooxygenase inhibition restores endothelium-dependent vasodilatation in hypertension, but it is unknown whether it restores endothelial function in hypertensive patients treated with angiotensin-converting enzyme (ACE) inhibitors. HYPOTHESIS: The purpose of the present study was to evaluate the effects of cyclooxygenase inhibition on endothelial function in hypertensive patients treated with ACE inhibitors. METHODS: Endothelium-dependent flow-mediated dilatation (FMD) and endothelium-independent glyceryl trinitrate-induced dilatation were investigated in 10 patients treated with enalapril (ACE group), 11 patients treated with manidipine and metoprolol (non-ACE group), and 12 normotensive control subjects. After administration of 1000 mg of aspirin, FMD was investigated once again. Plasma cyclic guanosine monophosphate (cGMP) and eicosanoids were also measured during reactive hyperemia before and after aspirin administration. RESULTS: Flow-mediated dilatation was more impaired in the non-ACE group than in the ACE group (8.3 +/- 3.8%, 5.7 +/- 1.7%, respectively, p<0.04). Glyceryl trinitrate-induced dilatation was similar in the ACE group, the non-ACE group, and in the control subjects. In the ACE group, FMD was reduced after administration of aspirin (5.3 +/- 4.2%, p<0.05). The percent change in FMD after administration of aspirin correlated significantly with percent change in cGMP (r=0.77, p<0.03; y-intercept, -62.1%, p<0.01). After aspirin administration, levels of thromboxane B2 and 6-keto-prostaglandin(1alpha) were significantly decreased compared with those before aspirin administration in all groups. CONCLUSIONS: Cyclooxygenase inhibition may reduce the beneficial effect on endothelium-dependent vasodilatation induced by ACE inhibitors. The results suggested that prostacyclin in addition to nitric oxide plays a significant role in the restoration of endothelial function in hypertensive patients treated with ACE inhibitors.     

The evaluation of endothelial functions in patients with celiac disease

Aim: Celiac disease is characterized by malabsorption resulting from inflammatory injury to the mucosa of the small intestine after the ingestion of wheat gluten or related rye and barley proteins. This study aimed to identify individuals who are at risk of heart failure and increased risk for cardiovascular events by evaluating endothelial function in patients with celiac disease. Materials and Methods: The study included 36 patients with celiac disease and 35 healthy volunteers. After all routine laboratory examination, left ventricular functions were evaluated with standard two‐dimensional, M‐mode conventional Doppler methods. Then, flow‐mediated dilatation and nitroglycerin‐dependent dilatation tests on brachial artery were performed to all patients and controls. Results: A total of 36 celiac patients and 35 healthy volunteers were included in the study. The brachial artery diameter at baseline was similar between both groups. Measured brachial artery diameter after hyperemia was 30.19 ± 4.47 mm in celiac patients and 32.35 ± 3.77 mm in the control group. Differences between two groups were statistically significant (P = 0.031). Flow‐mediated vasodilatation was lower in celiac patients compared with in controls (10.61 ± 2.64% vs 13.09 ± 2.9%; P = 0.0003). Measured endothelium‐independent vasodilatation in the brachial artery before and after nitroglycerin was similar between both groups (P = 0.09 and P = 0.07, respectively). Conclusion: This research which aimed to evaluate endothelial dysfunction in patients with celiac disease is the first in the literature. As a result of this study, we found endothelial dysfunction at the macrovascular level in celiac patients. (Echocardiography 2012;29:471‐477)     

叶酸干预对老年高血压患者血管内皮功能的影响

目的探讨叶酸对老年高血压患者血管内皮功能的影响。方法42例轻、中度老年高血压患者,随机分为叶酸干预组22例,对照组20例。采用高分辨率超声检测治疗前及治疗12周后肱动脉血流介导的血管内皮依赖性舒张功能与硝酸甘油介导的非内皮依赖性舒张功能。结果治疗前后两组间及组内肱动脉基础内径差异无统计学意义,叶酸干预治疗12周后与治疗前和对照组比较肱动脉血流介导的血管内皮依赖性舒张功能(11.59%±4.79%比7.15%±3.20%和8.14%±3.01%)、肱动脉硝酸甘油介导的非内皮依赖性舒张功能(19.73%±5.80%比16.69%±4.75%和17.55%±6.05%)均有明显改善(P<0.05)。结论叶酸对老年高血压患者血管内皮功能损害有一定的改善作用。     

Short‐term improvement of endothelial function in rituximab‐treated rheumatoid arthritis patients refractory to tumor necrosis factor α blocker therapy

Objective

Cardiovascular disease is the major cause of excessive mortality in rheumatoid arthritis (RA) and endothelial dysfunction plays a key role in atherosclerosis. The aim of the present study was to assess whether rituximab therapy was able to improve endothelial function in RA patients refractory to tumor necrosis factor α (TNFα) blockers.

Methods

Six consecutive RA patients (5 women; age range 55–79 years) with active disease refractory to TNFα inhibitor therapy were studied. Patients received intravenous rituximab (1 course, consisting of 2 infusions of 1,000 mg each separated by 2 weeks). Flow‐mediated endothelium‐dependent vasodilatation (FMD%) and endothelium‐independent vasodilatation (postnitroglycerin) were measured at day 0 prior to the first rituximab infusion, at week 2 (before the second infusion), and at month 6.

Results

At week 2, a dramatic increase in FMD% values was observed in all patients (mean ± SD 7.02 ± 2.31%, median 7.29%, range 3.2–9.75%) compared with those observed before the first infusion (mean ± SD 3.35 ± 1.58%, median 3.04%, range 1.69–5.89%). In addition, at month 6, FMD% values in all patients (mean ± SD 7.66 ± 1.73%, median 7.64%, range 5.61–9.98%) were greater than those found before the first infusion (P = 0.03). The dramatic improvement of FMD% was associated with a significant decrease in C‐reactive protein level and Disease Activity Score in 28 joints.

Conclusion

Our study demonstrates an active effect of rituximab on endothelial function in RA patients refractory to TNFα blockers.     

Reactive Oxygen Species Are Necessary for High Flow (Shear Stress)‐induced Diameter Enlargement of Rat Resistance Arteries

Objectives: Chronic increases in blood flow induce remodeling associated with increases in diameter and endothelium‐mediated dilation. Remodeling requires cell growth and migration, which may involve reactive oxygen species (ROS). Nevertheless, the role of ROS in flow‐mediated remodeling in resistance arteries is not known. Materials and Methods: Rat mesenteric resistance arteries (MRAs) were exposed to high flow (HF) by sequentially ligating second‐order MRAs in vivo. After three weeks, arteries were collected for structural, pharmacological, and biochemical analysis. Results: In HF arteries, luminal diameter (431±12 to 553±14 μm; n=10), endothelium (acetylcholine)‐mediated vasodilatation (61±6 to 77±6% relaxation) and NAD(P)H subunit (gp91phox and p67phox) expression levels, and ROS (dihydroethydine microphotography) and peroxynitrite (3‐nitro‐tyrosine) production were higher than in normal flow arteries. Acute ROS scavenging with tempol improved acetylcholine‐dependent relaxation (92±4% relaxation), confirming that ROS are produced in HF arteries. Chronic treatment with tempol prevented the increase in diameter, reduced ROS and peroxynitrite production, and improved endothelium‐mediated relaxation in HF arteries. Thus, ROS and NO were involved in HF‐induced diameter enlargement, possibly through the formation of peroxynitrite, while ROS reduced the increase in endothelium‐dependent relaxation. Conclusions: ROS production is necessary for flow‐mediated diameter enlargement of resistance arteries. However, ROS counteract, in part, the associated improvement in endothelium‐mediated relaxation.     

Hypothyroidism is associated with signs of endothelial dysfunction despite 1-year replacement therapy with levothyroxine

Objective Hypothyroidism is associated with elevated cardiovascular risk, not fully explained by classical risk factors. Instead, endothelial dysfunction may link hypothyroidism to atherosclerosis. The effect of levothyroxine substitution on endothelial function has been sparsely studied and the results are unclear. This study tested endothelial function as estimated by concomitant measurements of endothelial dependent vascular dilatory capacity and plasma concentration of von Willebrand factor antigen in patients with hypothyroidism and further examined the impact of subsequent levothyroxine substitution. Design and patients Sixteen consecutive patients (13 women, 3 men, aged 46 ± 11 years) with hypothyroidism were included and compared to 16 matched healthy controls (13 women, 3 men, aged 49 ± 11 years). Patients with hypothyroidism were reexamined after 3, 6 and 12 months of levothyroxine substitution. Measurements Dilatory responses of the brachial artery to post‐ischaemic increased blood flow (endothelium‐dependent flow‐associated dilatation) and to nitroglycerin (endothelium‐independent nitroglycerin induced dilatation) were measured by ultrasound. Plasma concentrations of von Willebrand factor antigen were measured by ELISA. Results Flow‐associated dilatation was impaired in patients with hypothyroidism as compared to controls (102·7 ± 3·6 vs. 105·6 ± 3·8%, P = 0·04) whereas no differences in plasma concentration of von Willebrand factor antigen were found. One year levothyroxine substitution did not improve flow‐associated dilatation and was associated with an increase of the plasma von Willebrand factor antigen concentration. Conclusions Hypothyroid patients are characterized by endothelial dysfunction sustained despite long‐term levothyroxine substitution and potentially increasing the risk of atherosclerosis. Different estimates of endothelial dysfunction seem unequally influenced by hypothyroidism.     

The effect of non-steroidal anti-inflammatory drugs on the endothelial function of patients with osteoarthritis in short term

Objective: Our primary aim was to test whether non‐steroid anti‐inflammatory drug (NSAID) use may account for endothelial dysfunction (ED) in the acute period. Additionally, we also aimed to compare the effect of diclofenac and naproxen on endothelial function. Methods: Forty patients with osteoarthritis (OA) were included in the study. Subjects currently receiving NSAIDs were asked to discontinue their anti‐inflammatory medications (for at least 5 days) before the study. After the wash‐out period, all subjects underwent vascular ultrasound measurements. Following baseline vascular imaging, patients were randomly assigned in a 1 : 1 ratio to receive either diclofenac (75 mg twice daily, n = 20), or naproxen (500 mg twice daily, n = 20) for 7 days. Endothelial function was evaluated by using the flow‐mediated dilatation (FMD) method, at baseline, and after 1 week of NSAID treatment. Results: There were 40 OA patients (4 male, 36 female). The median age of the patients was 60 ± 14 years. There were equal numbers of subjects in each treatment group. Age, sex distribution, body mass index, serum lipids, erythrocyte sedimentation rate, C‐reactive protein and fasting glucose levels were similar between the diclofenac and naproxen groups (P > 0.05). The brachial artery diameter (BAD), endothelium‐dependent vasodilatation (FMD%) and nitroglycerin‐induced endothelium‐independent vasodilatation (NTG%) values were not different between pretreatment and on the seventh day in the NSAID treatment groups (P > 0.05). Subgroup analysis also showed similar values of BAD, FMD%, and NTG% between naproxen and diclofenac groups (P > 0.05). Conclusion: Our results suggest that nonselective cyclo‐oxygenase antagonists naproxen and diclofenac have no effect on endothelial function during short‐term use.     

Preserved Vasodilator Response to Acetylcholine in Atherosclerotic Coronary Arteries Before and After PTCA

The vascular response to local administration of acetylcholine is used, clinically, to assess endothelial function in vivo. However, whether this response predominantly reflects the functional state of the vascular endothelium, or rather results from smooth muscle reactivity per se is not clear. In 15 patients with chronic stable angina and angiographically significant coronary disease, we studied the effects of increasing doses of intracoronary acetylcholine (5, 10, 30, 50, and 80 μg) and nitroglycerin (200 μg) on coronary vascular tone. In three patients the protocol was perfrnned at the time of diagnostic coronary angiographv and 7 and 24 hours after angioplasty. The remaining five underwent acetylcholine administration before and after percutaneous transluminl coronary angioplasty (PTCA). We quantitatively assessed the diameter of 54 coronary arterial segments; 12 stenotic segments, 13 post-PICA segments with residual irregularities, 18 reference segments of the ranee arteries taken proximal to the stenosis or to the dilatation site, and II remote segments ofnonstenotic vessels. They all showed a bimodal response to acetylcholine. At the lowest concentration (5 μg) the agent invariably caused dilatation (9.22 ± 6.55%), which was not significantly different in the various segments and was always less than that induced by nitroglycerin (24.56 ± 12.82%, P < 0.0001). At the highest doses (50 or 80 μg) acetylcholine always induced vasoconstriction, which was significantly more pronounced in the post-PTCA (-31.54 ± 10.65%) and stenotic segments (-23.08 ± 11.88%) than in the reference and remote segments (respectively, -14.88 + 7.63% and - 18.67 + 8.37%, P < 0.05). We conclude that: (l) some degree of endothelial dependent vasodilatation is preserved even in the presence of atheroma and intimal injury induced by angioplasty; (2) atheroma and especially acute intimal injury augment the vasoconstrictor response to high dose acetylcholine, the effect being most probably mediated by primary smooth muscle supersensivity: (3) since acetylcholine has direct and endothelium-mediated vasoactive effects, this agent may not be the ideal one for testing endothelial integrity. (J Interven Cardiol 1994; 7:57–64)     

青年高血压病患者血管内皮依赖性舒张功能的无创伤性评价

为了评价无其它动脉粥样硬化因素及粥样斑块的青年高血压病患者的血管内皮依赖性舒张功能 ,用B型超声对 45例 35岁以下的青年高血压病患者和 2 0例健康对照者在反应性充血和舌下含服硝酸甘油后肱动脉内径进行了检测。结果发现 ,青年高血压病患者前臂加压后肱动脉内径增加的比例明显小于对照组 (前者为 12 .32 %± 4.94% ,后者为 16 .6 3%± 5 .87% ,P <0 .0 1) ,而在舌下含服硝酸甘油后肱动脉内径的变化两组间无显著性差异(前者为 18.94%± 6 .5 0 % ,后者为 2 1.0 2 %± 6 .6 5 % ,P >0 .0 5 )。提示青年高血压病患者虽然没有明显的动脉粥样硬化的证据和其它易患因素 ,但已经存在显著的血管内皮依赖性舒张功能障碍。     

Determinants of coronary arterial flow‐mediated dilatation following percutaneous coronary intervention

Objective : It has previously been observed that coronary diameter may increase following relief of flow‐limiting obstruction. Flow mediated dilatation (FMD) is a fundamental adaptive mechanism for arteries, which is dependent on intact endothelial function. We thus aimed to characterize whether the degree of this flow‐mediated dilatation was related to risk factors, which may impair endothelial function. Design : We measured coronary diameter with quantitative angiography before and after relief of chronic total or subtotal (≥99%) occlusion in 171 patients, in which TIMI‐0 or TIMI‐1 flow was rapidly restored to TIMI‐3 (with attendant increase in flow hypothesized to result in FMD). Patients : Of the 171 patients, 73% were male, 62% were current or ex‐smokers, 47% were diabetic, 53% had hypertension, 64% had dyslipidemia (documented hypercholesterolemia or total cholesterol >5.0 mg/dL) and 65% were taking statin therapy. Results : Mean vessel diameter was 2.8 ± 0.7 mm and flow‐mediated dilatation measured 15.1% ± 20.1% in target vessel, compared with 1.6 ± 3.1 in control vessels (P < 0.05). FMD was strongly and inversely related to baseline vessel diameter (r = ?0.48, P < 0.001). The degree of vessel dilation correlated negatively with the presence of diabetes (r = ?0.33, P < 0.001), smoking (r = ?0.30, P < 0.001) and extent of coronary artery disease (CAD, r = ?0.17, P = 0.01) and positively with the use of statins (r = 0.27, P = 0.001). These factors, apart from extent of CAD, remained significant predictors of FMD on multivariate analysis. Conclusions : FMD occurs in human coronary arteries following restoration of flow. The magnitude of FMD appears related to vascular risk factors and their treatment. © 2008 Wiley‐Liss, Inc.     

非侵入法对高血压早期血管内皮功能障碍的评价

为了评估高血压 1 2级无心血管危险因素病人是否存在内皮依赖性血管内皮功能的损害 ,并探讨高血压对内皮功能的影响 ,我们应用非侵入方法研究了高血压病人和正常人各 2 5例。用高分辨二维超声方法检测反应性充血前后肱动脉直径和血流 ,比较两组的肱动脉直径变化率、血流以及它们与血压之间的关系。结果发现 ,高血压病人血流介导的肱动脉舒张明显低于对照组 (9.8%± 6 .7%比 14 .7%± 6 .8% ,P <0 .0 1) ;血流介导的肱动脉血流亦较对照组明显减少 (5 2 9± 114mL min比 6 4 2± 16 0mL min ,P <0 .0 1) ;相关分析发现 ,血流介导的肱动脉舒张分别与收缩压 (r=- 0 .4 73,P <0 .0 1)、舒张压 (r=- 0 .30 8,P <0 .0 5 )呈负相关 ;血流介导的肱动脉血流与收缩压呈负相关 (r=- 0 .35 5 ,P <0 .0 1) ,而与舒张压无关。此结果提示 ,高血压病早期虽无明显动脉硬化 ,但已存在血管内皮功能的损伤。     

Contribution of High Flux Membranes to the Therapy of Uremia‐Associated Dyslipidemia

Cardiovascular diseases are the leading causes of mortality in hemodialysis patients. Uremia induced hypertriglyceridemia; increased levels of lipoprotein remnants and low high‐density lipoprotein are the main features of cardiovascular risk factors. Also, elevated oxidative stress and inflammation are the main contributors of endothelial dysfunction. Even statin based interventional trials failed to improve mortality in dialysis patients, and different treatment options have been proved to be useful. We aimed to evaluate the effect of dialyzer type on uremia‐associated dyslipidemia and endothelial dysfunction. In total 312 patients were enrolled. The initial and 6^th month blood samples were obtained from the non‐arteriovenous fistula arm on the day before the first hemodialysis session of the week. Flow mediated dilatation of the patients was measured from the same arm before obtaining the blood samples. Patients were on hemodialysis therapy for 76.43 ± 52.7 months. According to their dialyzer type, there has been a statistically significant improvement noted in terms of total cholesterol, low‐density lipoprotein‐cholesterol, high‐density lipoprotein‐cholesterol and triglyceride levels. The flow mediated dilatation of the patients are measured as 4.3 ± 0.5 and 4.4 ± 0.4 in baseline measurements of the low flux and high flux groups, respectively. Sixth month values of the patients were measured as 4.34 ± 0.4 and 4.62 ± 0.6. The improvement in low flux groups was not statistically significant but in the high flux group the endothelial dysfunction was significantly improved. Our results show that high‐flux dialyzers improved dyslipidemia and endothelial dysfunction in hemodialysis patients. These findings provide a new insight on the selection of high efflux in hemodialysis.     

Effects of improved glycaemic control on endothelial function in patients with type 2 diabetes

Background: Patients with type 2 diabetes have abnormal endothelial function but it is not certain whether improvements in glycaemic control will improve endothelial function. Aims: To examine the effects of short‐term improved glycaemic control on endothelial function in patients with inadequately regulated type 2 diabetes mellitus. Methods: Forty‐three patients with type 2 diabetes and glycosylated haemoglobin (HbA_1c) > 8.9% were randomized to either improved glycaemic control (IC) n = 21 or usual glycaemic control (UC) n = 22 for 20 weeks. Using high‐resolution B‐mode ultrasound, brachial artery flow‐mediated dilatation (FMD) and glyceryl trinitrate‐mediated dilatation (GTN‐D) were measured at baseline and 20 weeks later. Results: After 20 weeks, HbA_1c was significantly lower in IC versus UC (IC 8.02 ± 0.25% versus UC 10.23 ± 0.23%, P < 0.0001) but changes in FMD and GTN‐D were not different between the groups (FMD at baseline and week 20 IC 5.1 ± 0.56% versus 4.9 ± 0.56% and UC 4.2 ± 0.51% versus 3.1 ± 0.51%; P = 0.23: GTN‐D IC 12.8 ± 1.34% versus 10.4 ± 1.32% and UC 13.7 ± 1.2% versus 12.7 ± 1.23%; P = 0.39). In the IC group weight increased by 3.2 ± 0.8 kg after 20 weeks compared to 0.02 ± 0.70 kg in UC (P = 0.003). Blood pressure and serum lipid concentrations did not change in either group. Conclusions: Short‐term reduction of HbA_1c levels did not appear to affect endothelial function in patients with type 2 diabetes and previously poorly regulated glycaemic control. (Intern Med J 2001; 31: 322–328)     

血脂康对高脂血症患者血管内皮功能的影响

为探讨血脂康对高脂血症患者血管内皮功能的改善作用 ,5 8例高脂血症患者随机分为两组 ,分别给予血脂康或安慰剂治疗 8周 ,利用高分辨率超声测定血流介导的肱动脉舒张及其对硝酸甘油的反应 ,并观察血脂变化。结果显示 ,两组治疗前血脂水平相似 ,血脂康治疗后血清总胆固醇、低密度脂蛋白胆固醇和甘油三酯分别下降2 1 5 %、2 8 2 %和 16 2 % ,血流介导的血管舒张显著增加 (P <0 0 1) ,而安慰剂治疗组无显著差异。两组硝酸甘油介导的舒张相似 ,治疗前后均无显著差异。以上表明 ,血脂康可降低高脂血症患者血清总胆固醇、低密度脂蛋白胆固醇和甘油三酯水平 ,改善高脂血症患者的血管内皮功能     

Acute administration of sildenafil enhances hepatic cyclic guanosine monophosphate production and reduces hepatic sinusoid resistance in cirrhotic patients

Aim: In liver cirrhosis, the increased production of nitric oxide (NO) contributes to increased systemic and splanchnic vasodilatation. The inhibition of phosphodiesterase-5 (PDE-5), an enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP), is widely used in the treatment of erectile dysfunction. The aim of our study is to evaluate the overall effects of PDE-5 inhibitor administration on splanchnic, pulmonary and systemic hemodynamics in cirrhotic patients. Methods: Sildenafil, a specific PDE-5 inhibitor, was administrated orally to cirrhotic patients (n = 7) to see the hemodynamic changes. A control group receiving a placebo was used as a point of comparison (n = 6). Results: Compared to the control group, the hepatic vein NO and cGMP levels were significantly increased after sildenafil administration in the sildenafil group (NO from 112.3 ± 43.5 to 325.3 ± 117.5 nM, P = 0.018; cGMP from 7.3 ± 0.4 to 19.2 ± 4.2 pmol, P = 0.018). The hepatic venous pressure gradient in the sildenafil group did not differ from that of the control group. However, a significantly decreased hepatic sinusoidal resistance in the sildenafil group (1999 ± 1243 vs. 1563 ± 1014 dyne/s/cm⁻⁵, P < 0.05) was noted. The study also found that the right arterial pressure, mean pulmonary arterial pressure and pulmonary capillary wedge pressure were reduced at 60 min after administration, compared with the basal parameters in cirrhotic patients receiving sildenafil (RAP1.3 ± 2.0 vs −0.6 ± 1.3 mmHg, MPAP 14.1 ± 11.3 vs 11.7 ± 9.5 mmHg, PCWP 4.6 ± 1.7 vs 2.9 ± 1.6 mmHg, P < 0.05 respectively). Conclusions: An oral administration of 50 mg of sildenafil significantly decreased the mean pulmonary arterial pressure and hepatic sinusoid resistance with a significant increase in hepatic NO and cGMP production, and did not worsen portal hypertension in cirrhotic patients.     

5-Hydroxytryptamine mediates endothelium dependent coronary vasodilatation in the isolated rat heart by the release of nitric oxide

STUDY OBJECTIVE--The aim was to investigate further the endothelium dependent vasodilator action of 5-hydroxytryptamine (5-HT) on the rat coronary circulation. DESIGN--Using saponin to damage the endothelium and L-NMMA (NG-monomethyl-L-arginine), the selective inhibitor of nitric oxide formation, we examined the role of endothelium and nitric oxide in causing 5-HT induced vasodilatation in the isolated rat heart. EXPERIMENTAL MATERIAL--56 rat hearts were excised and perfused on a Langendorff preparation. MEASUREMENTS AND MAIN RESULTS--5-HT at (10(-9) to 10(-5) M) and glyceryl trinitrate at (10(-5) to 10(-3) M) (n = 24) induced a dose dependent increase in coronary flow. Chemical removal of the endothelium by exposure to saponin (30 micrograms.ml-1) (n = 8) abolished the 5-HT induced vasodilatation but had no effect on the response to glyceryl trinitrate. Pretreatment of rats (n = 8) with L-NMMA (100 mg.kg-1) unmasked a strong vasoconstrictor effect of 5-HT but did not affect the glyceryl trinitrate induced vasodilatation. Perfusion of L-NMMA pretreated hearts with L-arginine at 10(-4) M (n = 8) restored the vasodilatation induced by 5-HT but L-arginine perfusion had no effect on the extent of 5-HT or glyceryl trinitrate induced vasodilatation in normal hearts (n = 8). CONCLUSIONS--In the coronary circulation of the isolated rat heart, 5-HT mediates its vasodilator effect via endothelium dependent release of nitric oxide.     

Effect of Atrial Natriuretic Factor [ANF (arg 101–Tyr 126)] on Kallikrein and Cyclic GMP in the Renovascular Hypertensive Rat

The intravenous injection of an ED₅₀ natriuretic dose (1 μg) of synthetic ANF decreases blood pressure by 61 ± 6 mmHg in 2-K, 1-C, and of 45 ± 6 mmHg in 1-K, 1-C hypertensive rats, which was positively correlated with its initial level only in the 2-K, 1-C group. The hypotensive response lasted longer in the latter (> 40 min) than in normotensive sham-operated rats. No difference in duration was seen between 1-K, 1-C hypertensive and its uninephrectomized normotensive controls. The diuretic response to ANF was higher in 2-K, 1-C rats. No hematocrit changes were observed in any group. ANF induced a rise in urinary kallikrein in all groups but the 1-K, 1-C. Urinary kallikrein excretion was positively correlated with natriuresis in normotensive but not in hypertensive groups. ANF induced an increase in urinary cGMP excretion in all groups but the 1-K, 1-C, and an increase in plasma cGMP in the normotensive sham-operated animals.

Our results suggest that the fall in blood pressure induced by synthetic ANF could be due to vasodilatation, a drop in cardiac output cannot, however, be eliminated. Whether the hypotensive effect of ANF is mediated by cGMP remains to be demonstrated.     

Reconstituted HDL in Acute Coronary Syndromes

Objectives: The strong inverse relationship between plasma high‐density lipoprotein (HDL)‐cholesterol and atherosclerotic cardiovascular disease provides the epidemiological basis that HDL is atheroprotective. Since HDL enhances cholesterol efflux and exhibits potent antiinflammatory properties, the aim of the present study was to investigate whether infusion of reconstituted HDL (rHDL) impacts on vascular function, a well‐established surrogate of atherosclerotic vascular disease, as well as markers of inflammation and oxidative stress in patients with acute coronary syndromes (ACS). Methods: Twenty‐nine patients with ACS were randomized to double‐blind treatment with rHDL or albumin. Endothelium‐dependent and independent vasodilatation to intraarterial acetylcholine and sodium nitroprusside were measured by forearm venous occlusion plethysmography. In addition, oxidized LDL and high‐sensitivity C‐reactive protein were determined as markers of oxidative stress and vascular inflammation. Results: rHDL infusion increased plasma HDL (P < 0.0001) and decreased LDL (P < 0.0001). Oxidized LDL (P= 0.11), high‐sensitivity C‐reactive protein (P= 0.12) and the response to endothelium‐dependent and ‐independent vasodilatators remained unchanged after rHDL compared to albumin infusion (14.9 ± 9.2 versus 14.5 ± 12.4, P= 0.93 and 12.8 ± 7.1 versus 13.2 ± 9.6, P= 0.27, respectively). Conclusions: An increase of HDL and a reduction of LDL notwithstanding, human rHDL did not improve vascular function in patients with ACS thus further challenging the clinical benefit of interventions, which rapidly raise HDL in ACS, particularly with the infusion of reconstituted HDL.     

Effect of Add‐on Aliskiren to Type 1 Angiotensin Receptor Blocker Therapy on Endothelial Function and Autonomic Nervous System in Hypertensive Patients With Ischemic Heart Disease

The aim of this study was to evaluate the add‐on effect of aliskiren to valsartan on endothelial‐dependent vasodilation in hypertensive patients with ischemic heart disease (IHD). After 4 weeks of treatment with 80 mg of valsartan, 28 patients were allocated to either continued treatment with valsartan or an add‐on treatment with valsartan plus 150 mg of aliskiren. Aliskiren significantly decreased plasma renin activity, whereas endothelium‐dependent vasodilation measured by flow‐mediated dilation (FMD) did not change. In contrast, heart rate significantly decreased (73.1 ± 9.8 to 66.3 ± 7.0 beats per minute at baseline and 24 weeks, respectively [P = .009]) and the standard deviation of the R‐R intervals (SDNN) significantly increased in the aliskiren group. The add‐on aliskiren to valsartan therapy may not improve endothelial functions, although it significantly reduced resting heart rate via regulation of the autonomic nervous system in hypertensive patients with IHD.     

Acute and Subacute Effect of Rheopheresis on Microvascular Endothelial Function in Patients Suffering From Age‐related Macular Degeneration

This study was performed on seven patients affected by the atrophic form of age‐related macular degeneration (AF‐ARMD). The patients under investigation belonged to a larger study aimed at evaluating the efficacy of rheopheresis treatment (RT) on the visual function of AF‐ARMD patients. Following the protocol of the larger study, patients received RT twice a week, every two weeks, for a total of ten treatments, as well as high‐dose supplementation with zinc and vitamins A, E and beta‐carotene. Recruited patients underwent skin laser Doppler flowmetry coupled with skin iontophoresis of the endothelium‐dependent vasodilator acetylcholine (ACh) and a test of skin post‐ischemic reactive hyperemia, before and after the first RT (time 1: all seven patients) and the fifth RT (time 2: six patients). A significantly higher absolute (anova for repeated measures) and relative (percentage change from the baseline) skin blood flux response (SBFR) to ACh iontophoresis was observed after RT, compared to before RT at time 1 (679 ± 43% and 436 ± 78%, respectively; P < 0.05), as well as before RT at time 2 compared to before RT at time 1 (683 ± 74% and 436 ± 78%, respectively; P < 0.05). Absolute and relative SBFR to ischemia did not differ either after RT compared to before RT at time 1, or before RT at time 2 compared to before RT at time 1. These findings are consistent with an acute and subacute beneficial effect of RT on skin microvascular endothelial function in the studied AF‐ARMD patients.