Endothelial Function In Hypertension Research Articles

Restoration of Mitochondrial Function Is Essential in the Endothelium-Dependent Vasodilation Induced by Acacetin in Hypertensive Rats.

Mitochondrial dysfunction in the endothelium contributes to the progression of hypertension and plays an obligatory role in modulating vascular tone. Acacetin is a natural flavonoid compound that has been shown to possess multiple beneficial effects, including vasodilatation. However, whether acacetin could improve endothelial function in hypertension by protecting against mitochondria-dependent apoptosis remains to be determined. The mean arterial pressure (MAP) in Wistar Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) administered with acacetin intraperitoneally for 2 h or intragastrically for six weeks were examined. The endothelial injury was evaluated by immunofluorescent staining and a transmission electron microscope (TEM). Vascular tension measurement was performed to assess the protective effect of acacetin on mesenteric arteries. Endothelial injury in the pathogenesis of SHR was modeled in HUVECs treated with Angiotensin II (Ang II). Mitochondria-dependent apoptosis, the opening of Mitochondrial Permeability Transition Pore (mPTP) and mitochondrial dynamics proteins were determined by fluorescence activated cell sorting (FACS), immunofluorescence staining and western blot. Acacetin administered intraperitoneally greatly reduced MAP in SHR by mediating a more pronounced endothelium-dependent dilatation in mesenteric arteries, and the vascular dilatation was reduced remarkably by NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis. While acacetin administered intragastrically for six weeks had no apparent effect on MAP, it improved the endothelium-dependent dilatation in SHR by activating the AKT/eNOS pathway and protecting against the abnormalities of endothelium and mitochondria. Furthermore, acacetin remarkably inhibited Ang II induced apoptosis by inhibiting the increased expression of Cyclophilin D (CypD), promoted the opening of mPTP, ROS generation, ATP loss and disturbance of dynamin-related protein 1 (DRP1)/optic atrophy1 (OPA1) dynamics in HUVECs. This study suggests that acacetin protected against endothelial dysfunction in hypertension by activating the AKT/eNOS pathway and modulating mitochondrial function by targeting mPTP and DRP1/OPA1-dependent dynamics.

CAROTID ELASTICITY IS IMPAIRED IN STAGE 1 HYPERTENSIVE PATIENTS EVEN IF BLOOD PRESSURE IS WELL CONTROLLED BY TREATMENT

Objective: Whether impaired arterial elasticity in stage 1 hypertension can be brought back to normal by antihypertensive treatment is unknown. Aim of this study was to evaluate the impact of long-term well-controlled blood pressure (BP) on carotid artery elasticity and endothelial function in stage 1 hypertensive patients at low cardiovascular risk. Design and method: We studied 40 middle-age hypertensives whose BP had been kept at target by pharmacological treatment and/or lifestyle modifications for a mean of 7.5 years. Carotid compliance coefficient (CC) and distensibility coefficient (DC) were measured by B-mode ultrasound system. Measurement of carotid intima-media thickness (IMT) was performed in each carotid artery segment, bilaterally. Endothelial function was evaluated by post-occlusion flow mediated dilation (FMD). hs-CRP and osteoprotegerin were measured as markers of inflammation. Forty normotensive subjects matched for age and sex served as controls. Results: In the hypertensive subjects, BP levels were well controlled throughout the study period (mean office BP 133.7 ± 9.0/81.2 ± 7.0 mmHg; mean 24 hours BP was 124.2 ± 10.4/78.2 ± 7.5 mmHg). However, compared to controls, significantly higher office BP levels and waist circumference were present. Compared to normotensives, carotid elasticity (DC 24.5 ± 9.0 vs 37.0 ± 8.5 10–3/kPa, and CC 0.92 ± 0.34 vs 1.28 ± 0.36 mm2/kPa, p < 0.0005 for both) as well as endothelial function (FMD 5.7 ± 2.4% vs 9.2 ± 2.9%, p < 0.0005) were significantly impaired in hypertensives. Moreover, hs-CRP and osteoprotegerin were higher in HT than in NT (1.41 ± 1.07 vs 0.97 ± 0.65 mg/L, p = 0.030; 1246 ± 560 vs 936 ± 148 pg/ml p = 0.001). In a logistic regression, hypertensive status was a significant predictor of local carotid vascular stiffness (DC < 30 10–3/kPa) with an odds ratio of 14.98 (95%CI, 2.60–18.55) p < 0.0005 for crude data; when data were adjusted for age, FMD, OPG, and BMI, the odds ratio only slightly decreased (13.04 (2.27–74.96), p = 0.004). Hypertensive status remained a significant predictor also after the adjustment for systolic, diastolic, mean BP. Conclusions: Despite the “pseudo-normalization’’ of BP levels, hypertensive patients with long term well-controlled BP according to current standards exhibited increased local arterial stiffness, endothelial dysfunction and increased markers of inflammation. Whether an earlier and more aggressive intervention could be useful to reduce arterial stiffening and improve endothelial function in hypertension should be explored.

Phloroglucinol and dieckol isolated from Ecklonia cava suppress impaired diabetic angiogenesis; A study of in-vitro and in-vivo

Abnormalities in angiogenesis that are associated with diabetes may contribute to vascular complications and result in disabilities and death. Furthermore, an imbalance in angiogenesis in different tissues, including the retina and kidney, can play a role in the pathogenesis of diabetic microvascular complications. Phlorotannins, such as phloroglucinol (PG) and dieckol (DK), which are found in Ecklonia cava exhibit antioxidant and anti-inflammatory activities that improve endothelial function in hypertension. However, reports on the effects of these compounds on diabetes-induced angiogenesis in vivo and in vitro are scarce. In this study, we assessed the antiangiogenic effects of PG and DK on endothelial cells treated with a high concentration of glucose to mimic angiogenesis. In addition, we sought to determine the effects of these compounds on cell proliferation, cell migration, and capillary formation. In silico docking of PG and DK into VEGFR-2 revealed their potential as therapeutic agents against angiogenesis. Further, both compounds were identified to inhibit the formation of the retinal vessel in transgenic zebrafish (flk:EGFP) embryos under high glucose conditions. These findings suggested that PG and DK derived from E. cava are potential inhibitors of angiogenesis in diabetic vascular complications and could, therefore, be used to develop angiogenic agents.

Chronic remote ischemic preconditioning-induced increase of circulating hSDF-1α level and its relation with reduction of blood pressure and protection endothelial function in hypertension.

Although previous data showed that remote ischemic preconditioning (RIPC) has beneficial effect on blood pressure (BP) reduction, the efficacy of RIPC-induced decline in BP and the favorable humoral factors in hypertension is elusive. This present study is performed to evaluate whether RIPC reduces BP, improves microvascular endothelial function and increases circulating hSDF-1α generation in hypertension. Fifteen hypertensive patients received 3 periods of 5-min inflation/deflation of the forearm with a cuff on the upper arm daily for 30 days. Clinic and 24-h ambulatory blood pressure monitoring (ABPM) were examined before and after the end of this procedure. Microvascular endothelial function was measured by finger reactive hyperemia index (RHI) using the Endo-PAT 2000 device. The circulating hSDF-1α level was tested by ELISA. RIPC significantly decreased systolic BP (139.13 ± 6.68 versus 131.45 ± 7.45 mmHg) and diastolic BP (89.67 ± 4.98 versus 83.83 ± 6.65 mmHg), meanwhile 24-h ambulatory systolic and diastolic BP dropped from 136.33 ± 9.10 mmHg to 131.33 ± 7.12 mmHg and 87.60 ± 6.22 mmHg to 82.47 ± 4.47 mmHg respectively. RHI was improved (1.95 ± 0.34 versus 2.47 ± 0.44). Plasma hSDF-1α level was markedly increased after RIPC (1585.86 ± 167.17 versus 1719.54 ± 211.17 pg/ml). The increase in hSDF-1α level was associated with the fall in clinic and 24-h ABPM and rise in RHI. The present data suggests that RIPC may be a novel alternative or complementary intervention means to treat hypertension and protect endothelial function.

PPAR-α agonists acutely inhibit Ca2+-independent PLA2 to reduce H2O2-induced contractions in aortae of spontaneously hypertensive rats.

Hypertension is associated with endothelial dysfunction, which favors the release of endothelium-derived contracting factors, including vasoconstrictor prostanoids and reactive oxygen species. Peroxisome proliferator-activated receptor-α (PPAR-α) agonists, clinically used as lipid-lowering drugs, possess antioxidant properties and exert beneficial effects in the vascular system. The present study aimed to identify the mechanism(s) underlying the acute effects of the PPAR-α agonists Wy14643 and fenofibate on endothelium-dependent contractions, in particular those related to oxidative stress, in the aorta of the spontaneously hypertensive rat (SHR). Aortic rings with and without endothelium of male SHRs and normotensive Wistar-Kyoto rats were suspended in organ chambers for isometric tension measurements and homogenized for enzyme activity assays. Contractions to acetylcholine in quiescent SHR aortae with endothelium were reduced by tiron (superoxide anion scavenger), diethyldithiocarbamic acid (superoxide dismutase inhibitor), and acute treatment with either Wy14643 or fenofibrate. Similarly to contractions evoked by acetylcholine, H2O2-induced increases in tension in SHR aortae involved, in succession, phospholipase A2 (PLA2), cyclooxygenase, and thromboxane-prostanoid receptors. Wy14643 or fenofibrate, by decreasing the activity of endothelial Ca2+-independent PLA2, attenuated the contractions to H2O2. In conclusion, the increased oxidative stress in the SHR aorta (mainly increased production of H2O2 and its partially reduced product, hydroxyl radical) contributed to acetylcholine-induced, endothelium-dependent contractions; PPAR-α agonists likely inhibit the H2O2-mediated contractions by inhibiting endothelial Ca2+-independent PLA2. The present study highlights the prospective therapeutic effects of PPAR-α agonists in improving endothelial function in hypertension and other vascular implications due to oxidative stress. NEW & NOTEWORTHY Peroxisome proliferator-activated receptor-α agonists, which are used clinically as lipid-lowering drugs, acutely reduce H2O2-induced contractions in aortae of hypertensive rats by inhibiting the activity of endothelial Ca2+-independent phospholipase A2. These vascular effects of peroxisome proliferator-activated receptor-α agonists suggest that they may help to prevent vascular complications under pathological conditions associated with oxidative stress.

Abstract P161: Inspiratory Muscle Training and Aerobic Training in the Treatment of Hypertension: Baroreflex Sensitivity, Sympathetic Activity and Endothelial Function Responses

Arterial hypertension is associated to sympathetic hyperactivity and endothelial dysfunction. Aerobic training (AT) is highly recommended to improve vascular function minimizing complications and Inspiratory muscle training (IMT) has demonstrated beneficial effects in this population, especially improving cardiovascular autonomic control. We sought to observe the effects of both training modalities on baroreflex sensitivity, sympathetic activity and endothelial function, in patients with controlled arterial hypertension. 10 patients (55±4 years old, both genders) were included and allocated into two groups: IMT (n=5, 7days/week, 30min/day, load=30%PImax) and AT (n=5, 2days/week, 1hour/day, load=70%HRmax). Both training protocols were performed during 12 weeks. Blood pressure (BP) and heart rate (HR) signals were recorded before and after protocols, as well as the other evaluations, by pulse telemetry (Finometer®PRO) and ECG (PowerLab®). Arterial baroreflex sensitivity was analysed by sequence method. Sympathetic activity was evaluated by microneurography (PowerLab®) and the endothelial function was evaluated by flow mediated dilation (EnVisor CHD, Philips, Bothell, WA, USA). After 12 weeks treatment IMT improved baroreflex sensitvity to both tachycardic and bradycardic responses respectively (BRR Down Gain (mean): IMT=26.51(±1.7)vs15.57(±6.7), AT=13.94(±5.5)vs17.92(±1.6); BRR Up Gain (mean): IMT=17.16(±1.2)vs16.28(±1.1), AT=12.39(±5)vs12.69(±3.3)). Additionally, we observed reduction of sympathetic activity in both groups (IMT:33.23±11.79vs25.07±13.28; AT:29.88±7.07vs24.09±6.37) and improvement of endothelial function independent of the treatment (IMT:6.4±2.18vs7.22±2.08; AT:5.49±7.43vs7.06±3.12). Regarding the responses to inspiratory muscle training and aerobic training on autonomic cardiovascular control and endothelial function in Hypertension, we demonstrated for the first time that IMT and AT present quite similar effects in patients with controlled blood pressure.

Demethoxycurcumin Preserves Renovascular Function by Downregulating COX-2 Expression in Hypertension.

Hypertension-associated endothelial dysfunction is largely due to the exaggerated vasoconstrictor generation by cyclooxygenase-2 (COX-2). COX-2 is induced under inflammatory condition. Demethoxycurcumin (DMC) is a major component of Curcuma longa L, which possesses anti-inflammatory action. This study aimed to examine whether DMC protects endothelial function in hypertension by modulating COX-2. Changes in isometric tension showed that in vivo and ex vivo treatment with DMC rescued the attenuated endothelium-dependent relaxations (EDRs) and elevated endothelium-dependent contractions (EDCs) in the renal arteries of SHR, which were also corrected by acute usage of the COX-2 inhibitor celecoxib. The restoration of renovascular activity by DMC was accompanied by the normalization of COX-2 expression. The enhanced COX-2 expression observed in the renal arteries of hypertensive patients was suppressed by incubation of excised arteries with DMC for 12 hrs. In the renal arteries of Wistar-Kyoto rats (WKY), DMC prevented the endothelial dysfunction caused by angiotensin II. The reduction in the generation of nitric oxide (NO) and expression of eNOS phosphorylation (Ser1177) in human umbilical vein endothelial cells caused by angiotensin II (Ang II) were restored by DMC or celecoxib. Our findings suggest that DMC may decrease COX-2 expression and improve endothelial function in hypertension.

Endothelial Mineralocorticoid Receptors Differentially Contribute to Coronary and Mesenteric Vascular Function Without Modulating Blood Pressure.

Arteriolar vasoreactivity tightly regulates tissue-specific blood flow and contributes to systemic blood pressure (BP) but becomes dysfunctional in the setting of cardiovascular disease. The mineralocorticoid receptor (MR) is known to regulate BP via the kidney and by vasoconstriction in smooth muscle cells. Although endothelial cells (EC) express MR, the contribution of EC-MR to BP and resistance vessel function remains unclear. To address this, we created a mouse with MR specifically deleted from EC (EC-MR knockout [EC-MR-KO]) but with intact leukocyte MR expression and normal renal MR function. Telemetric BP studies reveal no difference between male EC-MR-KO mice and MR-intact littermates in systolic, diastolic, circadian, or salt-sensitive BP or in the hypertensive responses to aldosterone±salt or angiotensin II±l-nitroarginine methyl ester. Vessel myography demonstrated normal vasorelaxation in mesenteric and coronary arterioles from EC-MR-KO mice. After exposure to angiotensin II-induced hypertension, impaired endothelial-dependent relaxation was prevented in EC-MR-KO mice in mesenteric vessels but not in coronary vessels. Mesenteric vessels from angiotensin II-exposed EC-MR-KO mice showed increased maximum responsiveness to acetylcholine when compared with MR-intact vessels, a difference that is lost with indomethacin+l-nitroarginine methyl ester pretreatment. These data support that EC-MR plays a role in regulating endothelial function in hypertension. Although there was no effect of EC-MR deletion on mesenteric vasoconstriction, coronary arterioles from EC-MR-KO mice showed decreased constriction to endothelin-1 and thromboxane agonist at baseline and also after exposure to hypertension. These data support that EC-MR participates in regulation of vasomotor function in a vascular bed-specific manner that is also modulated by risk factors, such as hypertension.

Protective Effects of Glucagon-like Peptide 1 on Endothelial Function in Hypertension.

Vascular endothelial cells play a major role in maintaining cardiovascular homeostasis. Endothelial dysfunction, characterized by reduced endothelium-dependent relaxations or accompanied by enhanced endothelium-dependent contractions, is a hallmark of and plays a pivotal role in the pathogenesis of hypertension. Endothelial dysfunction in hypertension has been linked to decreases in nitric oxide (NO) bioavailability, reflecting the impaired generation of NO and/or the enhanced inactivation of NO by reactive oxygen species. Many of these conditions can be improved by glucagon-like peptide 1 (GLP-1), a proglucagon-derived hormone secreted by intestinal endocrine L-type cells, which is rapidly inactivated by an enzyme dipeptidyl peptidase 4 in circulation. On one hand, GLP-1 analogues or dipeptidyl peptidase 4 inhibitors upregulate endothelial nitric oxide synthase expression and increase endothelial nitric oxide synthase phosphorylation, resulting in improved production of NO and thus endothelium-dependent relaxations. On the other hand, GLP-1 and related agents attenuate endothelium-dependent contractions by reducing reactive oxygen species generation and cyclooxygenase-2 expression. GLP-1 elevating agents and GLP-1 receptor agonists improve endothelial function in hypertension, suggesting that GLP-1 signaling could be a therapeutic target in hypertension-related vascular events.

Ginsenoside Rb3 attenuates oxidative stress and preserves endothelial function in renal arteries from hypertensive rats

Panax ginseng is commonly used to treat cardiovascular conditions in Oriental countries. This study investigated the mechanisms underlying the vascular benefits of ginsenoside Rb3 (Rb3) in hypertension. Rings of renal arteries were prepared from spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats and were cultured ex vivo for 8 h. Contractile responses of the rings were assessed with myograph techniques. Expression of NADPH oxidases was assessed by Western blotting and immunohistochemistry. Reactive oxygen species (ROS) were measured using dihydroethidium fluorescence imaging and production of NO was determined using the fluorescent NO indicator DAF-FM diacetate in human umbilical vein endothelial cells. Ex vivo treatment with Rb3 concentration-dependently augmented endothelium-dependent relaxations, suppressed endothelium-dependent contractions and reduced ROS production and expressions of NOX-2, NOX-4 and p67(phox) in arterial rings from SHR. Rb3 treatment also normalized angiotensin II (Ang II)-stimulated elevation in ROS and expression of NOX-2 and NOX-4 in arterial rings from WKY rats. Rb3 inhibited Ang II-induced reduction of NO production and phosphorylation of endothelial NOS in cultures of human umbilical vein endothelial cells. Rb3 also inhibited oxidative stress in renal arterial rings from hypertensive patients or in Ang II-treated arterial rings from normotensive subjects. Ex vivo Rb3 treatment restored impaired endothelial function in arterial rings from hypertensives by reversing over-expression of NADPH oxidases and over-production of ROS, and improved NO bioavailability. Our findings suggest that medicinal plants containing Rb3 could decrease oxidative stress and protect endothelial function in hypertension.

CD144 + EMPs/CD62E + EMPs: A couple of new biomarkers to monitor endothelial function in hypertension with hyperlipidemia involved

CD144 + EMPs/CD62E + EMPs: A couple of new biomarkers to monitor endothelial function in hypertension with hyperlipidemia involved

Uncoupling Protein-2 Mediates DPP-4 Inhibitor-Induced Restoration of Endothelial Function in Hypertension Through Reducing Oxidative Stress

Although uncoupling protein 2 (UCP2) negatively regulates intracellular reactive oxygen species (ROS) production and protects vascular function, its participation in vascular benefits of drugs used to treat cardiometabolic diseases is largely unknown. This study investigated whether UCP2 and associated oxidative stress reduction contribute to the improvement of endothelial function by a dipeptidyl peptidase-4 inhibitor, sitagliptin, in hypertension. Pharmacological inhibition of cyclooxygenase-2 (COX-2) but not COX-1 prevented endothelial dysfunction, and ROS scavengers reduced COX-2 mRNA and protein expression in spontaneously hypertensive rats (SHR) renal arteries. Angiotensin II (Ang II) evoked endothelium-dependent contractions (EDCs) in C57BL/6 and UCP2 knockout (UCP2KO) mouse aortae. Chronic sitagliptin administration attenuated EDCs in SHR arteries and Ang II-infused C57BL/6 mouse aortae and eliminated ROS overproduction in SHR arteries, which were reversed by glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin 9-39, AMP-activated protein kinase (AMPK)α inhibitor compound C, and UCP2 inhibitor genipin. By contrast, sitagliptin unaffected EDCs in Ang II-infused UCP2KO mice. Sitagliptin increased AMPKα phosphorylation, upregulated UCP2, and downregulated COX-2 expression in arteries from SHR and Ang II-infused C57BL/6 mice. Importantly, exendin 9-39, compound C, and genipin reversed the inhibitory effect of GLP-1R agonist exendin-4 on Ang II-stimulated mitochondrial ROS rises in SHR endothelial cells. Moreover, exendin-4 improved the endothelial function of renal arteries from SHR and hypertensive patients. We elucidate for the first time that UCP2 serves as an important signal molecule in endothelial protection conferred by GLP-1-related agents. UCP2 could be a useful target in treating hypertension-related vascular events. UCP2 inhibits oxidative stress and downregulates COX-2 expression through GLP-1/GLP-1R/AMPKα cascade.

Usefulness of Brachial Artery Flow-Mediated Dilation to Predict Long-Term Cardiovascular Events in Subjects Without Heart Disease

Endothelial dysfunction is considered an important prognostic factor in atherosclerosis. To determine the long-term association of brachial artery flow-mediated dilation (FMD) and adverse cardiovascular (CV) events in healthy subjects, we prospectively assessed brachial FMD in 618 consecutive healthy subjects with no apparent heart disease, 387 men (63%), and mean age 54 ± 11 years. After overnight fasting and discontinuation of all medications for ≥12 hours, FMD was assessed using high-resolution linear array ultrasound. Subjects were divided into 2 groups: FMD ≤11.3% (n = 309) and >11.3% (n = 309), where 11.3% is the median FMD, and were comparable regarding CV risk factors, lipoproteins, fasting glucose, C-reactive protein, concomitant medications, and Framingham 10-year risk score. In a mean clinical follow-up of 4.6 ± 1.8 years, the composite CV events (all-cause mortality, nonfatal myocardial infarction, hospitalization for heart failure or angina pectoris, stroke, coronary artery bypass grafting, and percutaneous coronary interventions) were significantly more common in subjects with FMD ≤11.3% rather than >11.3% (15.2% vs 1.2%, p = 0.0001, respectively). Univariate analysis demonstrated that the median FMD significantly predicted CV events (odds ratio 2.78, 95% CI 1.35 to 5.71, p <0.001). Multivariate analysis, controlling for traditional CV risk factors, demonstrated that median FMD was the best independent predictor of long-term CV adverse events (odds ratio 2.93, 95% CI 1.28 to 6.68, p <0.001). In conclusion, brachial artery median FMD independently predicts long-term adverse CV events in healthy subjects with no apparent heart disease in addition to those derived from traditional risk factor assessment.

Dipeptidyl Peptidase 4 Inhibitor Sitagliptin Protects Endothelial Function in Hypertension Through a Glucagon–Like Peptide 1–Dependent Mechanism

Sitagliptin, a selective dipeptidyl peptidase 4 inhibitor, inhibits the inactivation and degradation of glucagon like peptide 1 (GLP-1), which is used for the treatment of type 2 diabetes mellitus. However, little is known about the role of GLP-1 in hypertension. This study investigated whether the activation of GLP-1 signaling protects endothelial function in hypertension. Two-week sitagliptin treatment (10 mg/kg per day, oral gavage) improved endothelium-dependent relaxation in renal arteries, restored renal blood flow, and reduced systolic blood pressure in spontaneously hypertensive rats. In vivo sitagliptin treatment elevated GLP-1 and GLP-1 receptor expressions, increased cAMP level, and subsequently activated protein kinase A, liver kinase B1, AMP-activated protein kinase-α and endothelial NO synthase in spontaneously hypertensive rat renal arteries. Inhibition of GLP-1 receptor, adenylyl cyclase, protein kinase A, AMP-activated protein kinase-α, or NO synthase reversed the protective effects of sitagliptin. We also demonstrate that GLP-1 receptor agonist exendin 4 in vitro treatment had similar vasoprotective effects in spontaneously hypertensive rat renal arteries and increased NO production in spontaneously hypertensive rat aortic endothelial cells. Studies using transient expressions of wild-type and dominant-negative AMP-activated protein kinase-α2 support the critical role of AMP-activated protein kinase-α in mediating the effect of GLP-1 in endothelial cells. Ex vivo exendin 4 treatment also improved endothelial function of renal arteries from hypertensive patients. Our results elucidate that upregulation of GLP-1 and related agents improve endothelial function in hypertension by restoring NO bioavailability, suggesting that GLP-1 signaling could be a therapeutic target in hypertension-related vascular events.

Noninvasive pressure pulse waveform analysis of flow-mediated vasodilation evoked by post-occlusive reactive hyperemia maneuver

Post-occlusive reactive hyperemia (PORH) assesses flow-mediated vasodilation at microvascular level due to bioactivity of endothelial-derived factors. Ordinary augmentation index that quantifies endothelial response is based on an ensemble-averaged waveform that limits its short-time application. This study proposes a mathematical model and two corresponding indices to evaluate arterial pressure response after blood flow restoration. Radial pressure pulse waveforms were acquired by a 12bits acquisition board at a sampling rate of 1.0kHz using a piezoelectric transducer. Signals were stored during 30s at baseline condition and 60s after 5-min occlusion using an arm-cuff placed over the brachial artery. In both conditions, the pressure pulse waveform presents systolic and diastolic phases with progressive and regressive pulse waveforms, respectively. Changes in pulse wave morphology were also observed and comprised attenuation of the pulse pressure amplitude (markedly first and second systolic peaks). This characteristic of the pulse pressure was described by the time-domain summation of two pairs of Gaussian-like waveforms (representing independent progressive and regressive components) with parameters related to amplitude, time lag, and duration for each component. A steepest descent optimization routine was used to fit the model parameters to experimental data of normotensive and subjects with hypertension. The optimized parameters were used to calculate two indices, RIx1,2 (second-to-first systolic peak ratio) and RIx1,3 (first diastolic-to-first systolic ratio). The observed responses between groups suggest that RIx1,2 is related to an endothelial response to the ischemic process and could be used as a clinical tool to assess endothelial function in hypertension.

Effect of dairy foods on cell adhesion molecules (CAMs)

CAMs mediate atherosclerosis and thus are considered biomarkers of endothelial dysfunction. Elevated levels of CAMs predict heart disease risk and research has focused on strategies to lower them. Yet, studies of how diet affects CAMs are lacking. This study examined the effect of dairy foods on CAMs serum levels. Adults with untreated hypertension (n=23) were fed 3 experimental diets (5 wk each) in a randomized crossover study design. Diets included a dairy‐rich, high fruits and vegetables diet (D‐F&amp;V; 30% fat, 7% saturated fat [SFA], 3.4 servings [svg]/d dairy, 9.6 svg/d F&amp;V), a high fruits and vegetables diet (F&amp;V; 30% fat, 7% SFA, 0.4 svg/d dairy, 9.6 svg/d F&amp;V), and an average Western diet (AWD; 36% fat, 15% SFA, 0.4 svg/d dairy, 3.6 svg/d F&amp;V). The D‐F&amp;V diet reduced VCAM‐1 (547 ± 33 ng/mL) by about 16% compared with the F&amp;V diet (649 ± 33 ng/mL, p &lt; 0.05) and the AWD diet (650 ± 34 ng/mL, p &lt; 0.05). Compared with the AWD diet, ICAM‐1 (242 ± 14 ng/mL) was significantly reduced by both the D‐F&amp;V (225 ± 14 ng/mL, p &lt; 0.05) and F&amp;V diets (226 ± 14 ng/mL, p &lt; 0.05). E‐selectin and P‐selectin followed a similar pattern, with the D‐F&amp;V diet eliciting the lowest levels (D‐F&amp;V vs. AWD, p &lt; 0.02; D‐F&amp;V vs. F&amp;V, p &lt; 0.1; F&amp;V vs. AWD, p=ns). Collectively, these results suggest that dairy foods may have beneficial effects on endothelial function in hypertension.Funding: National Dairy Council, GCRC Penn State University NIH M01 RR10732

Calcitriol protects renovascular function in hypertension by down-regulating angiotensin II type 1 receptors and reducing oxidative stress

The present study investigated whether or not calcitriol, an active form of vitamin D, protects against renovascular dysfunction in hypertension and, if so, whether or not such protection alters the expression of key proteins involved in that dysfunction. Changes in isometric tension showed that the impaired endothelium-dependent relaxations in renal arteries of hypertensive patients were enhanced by 12 h in vitro treatment with calcitriol. Dihydroethidium fluorescence revealed an elevated level of reactive oxygen species (ROS) in these arteries which was reduced by calcitriol. Immunofluorescence showed that calcitriol treatment reduced the expression of AT(1)R, NOX-2, NOX-4, and p67(phox) and increased that of superoxide dismutase (SOD)-1. Twelve-hour exposure to calcitriol prevented angiotensin (Ang) II-induced increases in ROS and the over-expression of NOX-2, NOX-4, and p67(phox) in renal arteries from normotensive patients. A specific antagonist of the human vitamin D receptor (VDR), TEI-9647, abolished these effects of calcitriol. Both in vitro exposure to and chronic in vivo administration of calcitriol enhanced relaxations to acetylcholine and abolished exaggerated endothelium-dependent contractions in renal arteries of normotensive rats pre-exposed to Ang II or harvested from spontaneously hypertensive rats (SHR). Reactive oxygen species levels and expressions of AT(1)R, NAD(P)H oxidase subunits, SOD-1, and SOD-2 in SHR arteries were normalized by the chronic treatment with calcitriol. In vivo and in vitro activation of VDR with calcitriol improves endothelial function by normalizing the expressions of AT(1)R and radical generating and scavenging enzymes and thus preventing ROS over-production. The present findings suggest that calcitriol is effective in preserving endothelial function in hypertension.

Blood Pressure Variability and Vascular Dysfunction in Essential Hypertension

❙ABSTRACT❙ There are several aspects of blood pressure. Clinically, how to best assess blood pressure average and variability is still a matter of the ongoing debate. Besides office blood pressure, we must pay more careful attention focused on hypertension with blood pressure fluctuation. Impaired endothelial function is intimately associated with the development of hypertension and atherosclerosis. In this review, we describe the relation between endothelial dysfunction and hypertension, the effect of gene polymorphism on endothelial dysfunction, the effects of antihypertensive agents and dietary supplementation on impaired endothelial function in hypertension. In order to predict the future atherosclerosis and cardiovascular events in subjects with hypertension, the adequate assessment of endothelial function is one of the most reliable markers. Furthermore, we discuss the close relationship between blood pressure variability and endothelial function. Blood pressure variability during a day or a week is an important, new risk factor for cardiovascular disease and restoring impaired endothelial function might be a target to prevent blood pressure variation and future cardiovascular events. (J Korean Soc Hypertens 2012;18(3):75-87)

De-risking the clinical development of cholesteryl ester transfer protein inhibitors: how much is good enough?

This editorial refers to ‘Torcetrapib impairs endothelial function in hypertension’†, by B. Simic et al. , on page 1615 Modification of HDL cholesterol (HDL-C) metabolism is the next frontier in cardiovascular drug development, and modulation of cholesteryl ester transfer protein (CETP) is an important addition to our armentarium in this field. Clinical trials have shown that CETP inhibitors substantially improve blood lipid profiles by raising plasma levels of HDL-C while simultaneously lowering LDL-C over and above what can be achieved with statin therapy.1–3 The Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial was the first phase III trial testing the efficacy of the CETP inhibitor torcetrapib (Pfizer, New York, NY, USA) in reducing the risk of cardiovascular events. ILLUMINATE had to be halted in late 2006 after an interim analysis by the Data Safety and Monitoring Board had indicated a statistically significant increase in total mortality in the torcetrapib arm.4 Almost simultaneously, the entire clinical development programme of torcetrapib was stopped. This unexpected finding has called into question the validity of CETP as a potential therapeutic target, but it has also challenged the concept of raising HDL-C levels to reduce cardiovascular disease risk. Despite suffering from this unprecedented set back, CETP is still considered by many to be a viable therapeutic target, and other CETP inhibitors are being developed by a robust number of pharmaceutical companies. Following the publication of ILLUMINATE, analyses of the imaging trials with torcetrapib, in vitro and in vivo experiments, genetic epidemiology studies, and phase II studies with other CETP inhibitors have been used to clarify whether torcetrapib's unexpected detrimental effects were an off-target side effect of the compound itself, or a phenomenon …

Interleukin-10 Released by CD4 + CD25 + Natural Regulatory T Cells Improves Microvascular Endothelial Function Through Inhibition of NADPH Oxidase Activity in Hypertensive Mice

We previously demonstrated that a reduced number of CD(4+)CD(25+)-regulatory T cells (Tregs) was associated with microvascular dysfunction in hypertension. However, the underlying mechanism by which Tregs regulate vascular endothelial function remains unknown. Control and interleukin (IL)-10(-/-) knockout mice were infused with angiotensin II (400 ng/kg/min) for 2 weeks (hypertensive [HT] and HT-IL-10(-/-)). Endothelium-dependent relaxation (EDR) in response to acetylcholine was significantly reduced in mesenteric resistance artery (MRA) from HT and HT-IL-10(-/-) compared with control and IL-10(-/-) mice. Importantly, the incubation of MRA from HT mice with the conditioned media of cultured Tregs, isolated from control mice, reduced NADPH oxidase activity and improved EDR, whereas no effect was observed in MRA from control mice incubated with the same media. These effects were reversed when MRAs were preincubated with IL-10 antibody or IL-10 receptor antagonist, whereas incubation with transforming growth factor-β receptor antagonist had no effect. The transfer of cultured Tregs, isolated from control mice, into HT-IL-10(-/-) mice reduced systolic blood pressure (SBP) and NADPH oxidase activity and improved EDR in MRA compared with untreated HT-IL-10(-/-) mice. In vivo treatment of HT mice with IL-10 (1000 ng/mouse) significantly reduced SBP and NADPH oxidase activity and improved EDR in MRA compared with untreated HT mice. The transfer of cultured Tregs, isolated from IL-10(-/-) mice, into HT mice did not reduce SBP or NADPH oxidase activity or improve EDR. The incubation of MRA from HT mice with apocynin improved EDR, whereas NADPH oxidase substrate attenuated EDR in MRA from control mice, which was reversed with exogenous IL-10. These data demonstrate that IL-10 released from Tregs attenuates NADPH oxidase activity, which is a critical process in the improvement of microvascular endothelial function in hypertension, suggesting that Tregs/IL-10 could be a therapeutic target for treatment of vasculopathy in hypertension.