Nitroglycerin-induced Vasodilation Research Articles

Biomechanics models predict increasing smooth muscle tone as a novel therapeutic target for central arterial dysfunction in hypertension.

Vasodilation can paradoxically increase arterial stiffness in older, hypertensive adults. This study modeled increasing smooth muscle tone as a therapeutic strategy to improve central arterial dysfunction in hypertension using participant-specific simulations. Participant-specific models of the carotid artery were parameterized from vascular ultrasound measures of nitroglycerin-induced vasodilation in 18 hypertensive veterans. The acute changes in carotid artery mechanics were simulated for changes of ±2, ±4, and ±6% in smooth muscle tone and ±5, ±10, and ±15 mmHg in mean arterial pressure (MAP). The chronic carotid artery adaptations were simulated based on the hypothesis that the carotid artery will remodel wall-cross sectional area to maintain mechanical homeostasis. A 6% increase in smooth muscle tone acutely decreased carotid pulse wave velocity from 6.89 ± 1.24 m/s to 5.83 ± 1.73 m/s, and a 15 mmHg decrease in MAP decreased carotid pulse wave velocity to 6.17 ± 1.23 m/s. A 6% increase in smooth muscle tone acutely decreased wall stress from 76.2 ± 12.3 to 64.2 ± 10.4 kPa, and a 15 mmHg decrease in MAP decreased wall stress to 60.6 ± 10.7 kPa. A 6% increase in smooth muscle tone chronically decreased wall cross-sectional area from 18.3 ± 5.4 to 15.2 ± 4.9 mm 2, and a 15 mmHg decrease in MAP decreased wall cross-sectional area to 14.3 ± 4.6 mm 2 . In participant-specific simulation, increasing smooth muscle tone can have a stronger or equivalent effect on carotid artery mechanics compared with decreasing blood pressure. Increasing central arterial smooth muscle tone may be a novel therapeutic target to improve central arterial dysfunction in older, hypertensive adults and should be a focus of future research.

Effects of nitroglycerin-induced vasodilation on elastic and muscular artery stiffness in older Veterans.

Vascular smooth muscle tone may play an important role in the physiology of increased arterial stiffness that occurs with aging. This study evaluated the impact of smooth muscle tone on arterial stiffness in older individuals following nitroglycerin-induced vasodilation in elastic and muscular arteries. Forty older Veterans (≥60 years old) without known cardiovascular disease were included in this study. Twenty Veterans were included as hypertensive participants (70.8 ± 6.6 years, 10 females), and 20 were included as normotensive controls (72.0 ± 9.3 years, 8 females). Nitroglycerin (NTG)-induced changes in arterial stiffness were measured locally with vascular ultrasound in the carotid and brachial arteries and regionally by carotid-femoral pulse wave velocity (cfPWV) with tonometry. With NTG treatment, both hypertensive participants and normotensive controls Veteransshowed increased carotid PWV (6.4 ± 1.3 m/s to 7.2 ± 1.4 m/s, Δ 0.8 ± 1.1 m/s, p = 0.007) and cfPWV (8.6 ± 1.9 m/s to 9.5 ± 2.4 m/s, Δ 0.9 ± 2.3 m/s, p = 0.020) but did not show changes in brachial PWV (11.2 ± 2.4 m/s to 11.1 ± 2.2 m/s, Δ -0.2 ± 2.5 m/s, p = 0.72). The carotid artery was dilated more in control participants than hypertensive Veterans (Δ 0.54 ± 0.19 mm vs. 0.42 ± 0.12 mm, p = 0.022). Brachial artery dilation was similar between the two groups (Δ 0.55 ± 0.26 mm vs. 0.51 ± 0.20 mm, p = 0.46). In older Veterans without known cardiovascular disease, NTG-induced vasodilation increased elastic artery stiffness but did not change muscular artery stiffness. Increased central arterial stiffness and a decrease in the arterial stiffness gradient could offset some of the benefits of lowering blood pressure in older patients who are prescribed vasodilators as an antihypertensive therapy. Elastic artery stiffening with vasodilation warrants further investigation, as it may be important for antihypertensive medication selection and influence CVD development.

Cerebral Oximetry-Monitored Nitroglycerin Infusion and Tissue Perfusion during Rewarming of Cardiopulmonary Bypass in Cardiac Surgery: A Prospective Randomized Trial.

Background: Nitroglycerin facilitates microcirculation and oxygen delivery through vasodilation. The purpose of this study was to clarify the effects of nitroglycerin-induced vasodilation and potential hypotension on tissue perfusion under cerebral oximetry monitoring during rewarming in cardiopulmonary bypass. Methods: Elective cardiac surgical patients were randomly assigned to either a nitroglycerin group (n = 32) with an intravenous infusion of 1–5 mcg/kg/min or a control group (n = 31) with 0–0.1 mcg/kg/min infusion, since the initiation of rewarming. Perioperative arterial blood gas data were collected in addition to hemodynamic variables, cerebral oximetry values, urine output, and postoperative outcomes. Results: Nearly one-fifth (6/32) of patients in the nitroglycerin group experienced transient (≤5 min) profound hypotension (mean arterial blood pressure ≤40 mmHg) after the initiation of infusion. There were no significant differences between groups in terms of perioperative levels of cerebral oximetry, cardiac index, plasma glucose, lactate, bicarbonate, base excess, or post-bypass activated coagulation time. In the nitroglycerin group, urine output was nonsignificantly higher during cardiopulmonary bypass (p = 0.099) and within 8 h after surgery (p = 0.157). Perioperative transfused blood products, postoperative inotropic doses, extubation time, and intensive care unit stay were comparable for the two groups. Conclusions: Initiation of intravenous nitroglycerin infusion (at 1–5 mcg/kg/min) during rewarming in hypothermic cardiopulmonary bypass resulted in transient profound hypotension in one-fifth of patients and did not improve perioperative cerebral oxygenation, tissue perfusion, and coagulation in cardiac surgery.

Smooth muscle tone alters arterial stiffness: the importance of the extracellular matrix to vascular smooth muscle stiffness ratio.

Recent studies show that vascular smooth muscle (VSM) is more important to elastic artery mechanics than previously believed. It remains unclear whether increased VSM tone increases or decreases arterial stiffness. We developed a novel arterial mechanics model based on pressure-diameter relationships that incorporates the contributions of extracellular matrix (ECM) and VSM to arterial stiffness measures. This model is advantageous because it simple enough to use with limited clinical data but has biologically relevant parameters which include ECM stiffness, VSM stiffness, and VSM tone. The model was used to retrospectively analyze the effects of nitroglycerin-induced vasodilation in four clinical studies. Stiffness parameters were modeled for five arterial regions including both elastic and muscular arteries. The model describes complex experimental data with changing VSM tone and blood pressure. Our analysis found that when ECM is less stiff than VSM, increasing VSM tone increases arterial stiffness. The opposite is seen when ECM is stiffer than VSM, increasing VSM tone decreases stiffness. Our results also suggest that VSM tone is a compensatory mechanism for elevated ECM stiffness in hypertensive individuals. Based on retrospective analysis of four clinical studies, we propose a simple hypothesis for the role of VSM tone on arterial stiffness: increased VSM tone increases arterial stiffness when VSM is stiffer than ECM and decreases arterial stiffness when ECM is stiffer than VSM. This hypothesis and the methods used in this study could have important implications for understanding arterial physiology in both hypertension and cardiovascular disease and deserve further exploration.

Unifying the Estimation of Blood Volume Decompensation Status in a Porcine Model of Relative and Absolute Hypovolemia Via Wearable Sensing.

Hypovolemia remains the leading cause of preventable death in trauma cases. Recent research has demonstrated that using noninvasive continuous waveforms rather than traditional vital signs improves accuracy in early detection of hypovolemia to assist in triage and resuscitation. This work evaluates random forest models trained on different subsets of data from a pig model (n = 6) of absolute (bleeding) and relative (nitroglycerin-induced vasodilation) progressive hypovolemia (to 20% decrease in mean arterial pressure) and resuscitation. Features for the models were derived from a multi-modal set of wearable sensors, comprised of the electrocardiogram (ECG), seismocardiogram (SCG) and reflective photoplethysmogram (RPPG) and were normalized to each subject.s baseline. The median RMSE between predicted and actual percent progression towards cardiovascular decompensation for the best model was 30.5% during the relative period, 16.8% during absolute and 22.1% during resuscitation. The least squares best fit line over the mean aggregated predictions had a slope of 0.65 and intercept of 12.3, with an R2 value of 0.93. When transitioned to a binary classification problem to identify decompensation, this model achieved an AUROC of 0.80. This study: a) developed a global model incorporating ECG, SCG and RPPG features for estimating individual-specific decompensation from progressive relative and absolute hypovolemia and resuscitation; b) demonstrated SCG as the most important modality to predict decompensation; c) demonstrated efficacy of random forest models trained on different data subsets; and d) demonstrated adding training data from two discrete forms of hypovolemia increases prediction accuracy for the other form of hypovolemia and resuscitation.

Hematocrit, hemoglobin and red blood cells are associated with vascular function and vascular structure in men

High and low hematocrit (Hct) and hemoglobin (Hb) levels are associated with the risk of cardiovascular disease. The purpose of this study was to determine the relationships of Hct, Hb and red blood cells (RBCs) with vascular function and structure. We measured flow-mediated vasodilation (FMD), nitroglycerin-induced vasodilation (NID), brachial intima media thickness (IMT), and brachial-ankle pulse wave velocity (baPWV) in 807 men. The subjects were divided into six groups according to the levels of Hct, Hb and RBCs. NID was highest in the 46.0–48.9% Hct group among the six groups according to Hct levels. Brachial IMT was lowest in the 46.0–48.9% Hct group among the six groups. There were no significant differences in FMD and baPWV among the six groups. We used 46.0–48.9% Hct as a reference to define the lower tertile. The adjusted odds ratio of being in the low tertile of NID was significantly higher in the < 42.9% and ≥ 49.0% Hct groups. Adjusted odds ratio of being in the low tertile of brachial IMT was significantly lower in the < 39.9% Hct groups. Similar results were obtained for Hb and RBCs. Low and high levels of Hct, Hb and RBCs were associated with vascular smooth muscle dysfunction, and low Hct levels were associated with abnormal vascular structure. Increases in the levels of Hct, Hb and RBCs within normal ranges may have beneficial effects on the vasculature.

Diagnostic Criteria of Flow‐Mediated Vasodilation for Normal Endothelial Function and Nitroglycerin‐Induced Vasodilation for Normal Vascular Smooth Muscle Function of the Brachial Artery

BackgroundDiagnostic criteria of flow‐mediated vasodilation (FMD), an index of endothelial function, and nitroglycerin‐induced vasodilation (NID), an index of vascular smooth muscle function, of the brachial artery have not been established. The purpose of this study was to propose diagnostic criteria of FMD and NID for normal endothelial function and normal vascular smooth muscle function.Methods and ResultsWe investigated the cutoff values of FMD and NID in subjects with (risk group) and those without cardiovascular risk factors or cardiovascular diseases (no‐risk group) in 7277 Japanese subjects (mean age 51.4±10.8 years) from the Flow‐Mediated Dilation Japan study and the Flow‐Mediated Dilatation Japan Registry study for analysis of the cutoff value of FMD and in 1764 Japanese subjects (62.2±16.1 years) from the registry of Hiroshima University Hospital for analysis of the cutoff value of NID. Receiver‐operator characteristic curve analysis of FMD to discriminate subjects in the no‐risk group from patients in the risk group showed that the optimal cutoff value of FMD to diagnose subjects in the no‐risk group was 7.1%. Receiver‐operator characteristic curve analysis of NID to discriminate subjects in the no‐risk group from patients in the risk group showed that the optimal cutoff value of NID to diagnose subjects in the no‐risk group was 15.6%.ConclusionsWe propose that the cutoff value for normal endothelial function assessed by FMD of the brachial artery is 7.1% and that the cutoff value for normal vascular smooth muscle function assessed by NID of the brachial artery is 15.6% in Japanese subjects.Clinical Trial Registration http://www.umin.ac.jp Unique identifiers: UMIN000012950, UMIN000012951, UMIN000012952, and UMIN000003409

Abstract 12610: Vascular Function and Vascular Structure are impaired in Patients With Heart Failure With Preserved Ejection Fraction

Background: Endothelial dysfunction and abnormal vascular structure may be involved in the pathogenesis of chronic heart failure. The purpose of this study was to evaluate simultaneously the vascular dysfunction and structure in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results: We measured flow-mediated vasodilatation (FMD) and nitroglycerine-induced vasodilation as indices of vascular function and intima-media thickness (IMT) as an index of vascular structure of brachial artery in 116 patients with HFpEF (66 men and 50 women; mean age, 61±14 yr) and 64 patients without HF (48 men and 16 women; mean age, 50±17 yr). There were significant differences in age, sex, blood pressure, N-terminal pro-brain natriuretic peptide, estimated glomerular filtration and prevalence of diabetes mellitus between the 2 groups. FMD was significantly smaller in patients with HFpEF than in patients without HF (3.6±2.5% versus 5.2±3.1%, P&lt;0.001). Nitroglycerin-induced vasodilation was significantly smaller in the patients with HFpEF than in patients without HF (11.3±5.0% versus 13.3±4.9%, P=0.015). Brachial artery IMT were significantly larger in the patients with HFpEF than in patients without HF (0.34±0.07 mm versus 0.29±0.08 mm, P&lt;0.001). After adjustment for age and sex, hypertension, diabetes mellitus, the associations remained significant between HFpEF and FMD (hazard ratio, 1.18; 95% confidence interval, 1.02-1.37: P=0.025) and brachial artery IMT (hazard ratio, 0.93; 95% confidence interval, 0.88-0.99: P=0.031) but not nitroglycerine-induced vasodilation (hazard ratio, 1.05; 95% confidence interval, 0.98-1.13: P=0.17). Conclusions: These findings suggest that both endothelial dysfunction and abnormal vascular structure contribute to the pathogenesis of HFpEF. Endothelial function and vascular structure may be potential therapeutic targets for HFpEF.

Controlled exposure to particulate matter from urban street air is associated with decreased vasodilation and heart rate variability in overweight and older adults.

BackgroundExposure to particulate matter (PM) is generally associated with elevated risk of cardiovascular morbidity and mortality. Elderly and obese subjects may be particularly susceptible, although short-term effects are poorly described.MethodsSixty healthy subjects (25 males, 35 females, age 55 to 83 years, body mass index > 25 kg/m2) were included in a cross-over study with 5 hours of exposure to particle- or sham-filtered air from a busy street using an exposure-chamber. The sham- versus particle-filtered air had average particle number concentrations of ~23.000 versus ~1800/cm3 and PM2.5 levels of 24 versus 3μg/m3, respectively. The PM contained similar fractions of elemental and black carbon (~20-25%) in both exposure scenarios. Reactive hyperemia and nitroglycerin-induced vasodilation in finger arteries and heart rate variability (HRV) measured within 1 h after exposure were primary outcomes. Potential explanatory mechanistic variables included markers of oxidative stress (ascorbate/dehydroascorbate, nitric oxide-production cofactor tetrahydrobiopterin and its oxidation product dihydrobiopterin) and inflammation markers (C-reactive protein and leukocyte differential counts).ResultsNitroglycerin-induced vasodilation was reduced by 12% [95% confidence interval: −22%; −1.0%] following PM exposure, whereas hyperemia-induced vasodilation was reduced by 5% [95% confidence interval: −11.6%; 1.6%]. Moreover, HRV measurements showed that the high and low frequency domains were significantly decreased and increased, respectively. Redox and inflammatory status did not change significantly based on the above measures.ConclusionsThis study indicates that exposure to real-life levels of PM from urban street air impairs the vasomotor function and HRV in overweight middle-aged and elderly adults, although this could not be explained by changes in inflammation, oxidative stress or nitric oxide-cofactors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-015-0081-9) contains supplementary material, which is available to authorized users.

Abstract 12591: Impact of Aldosterone Producing Adenoma on Endothelial Function and Rho-Associated Kinase Activity in Patients With Primary Aldosteronism

Background: Hypertension is associated with endothelial dysfunction and activated Rho-associated kinases (ROCKs) activity. Primary aldosteronism (PA) is a most common cause of secondary hypertension. Recent studies have shown that risk of cardiovascular events is higher in patients with PA than in patients with essential hypertension (EH). However, there is little information on the relationship between subtype of PA and the grade of atherosclerosis. The purpose of this study was to evaluate the vascular function and ROCK activity in patients with PA. Methods: Vascular function, including flow-mediated vasodilation (FMD) and nitroglycerin-induced vasodilation, and ROCK activity in peripheral leukocytes were evaluated in 21 patients with aldosterone producing adenoma (APA) group (50.7±14.3 years, 9 males), 23 patients with idiopathic hyperaldosteronism (IHA) group (55.8±9.9 years, 12 males), and 33 age-, gender-, and blood pressure-matched EH group (54.9 ± 10.7 years, 18 males). Results: FMD was significantly lower in the APA group than in the IHA group and EH group (3.2±2.0% vs. 4.6±2.3% and 4.4±2.2%, P&lt;0.05, respectively), whereas there was no significant difference in FMD between the IHA group and EH group. There was no significant difference in the response of nitroglycerine in three groups. ROCK activity was significantly higher in the APA group than in the IHA group and EH group (1.29±0.57 vs. 1.00±0.46 and 0.81±0.36, P&lt;0.05 and P&lt;0.001, respectively), whereas there was no significant difference in ROCK activity between the IHA group and EH group. FMD correlated with age (r=-0.31, P&lt;0.01), brachial arterial diameter (r=-0.44, P&lt;0.01), plasma aldosterone concentration (PAC) (r=-0.35, P&lt;0.01) and plasma renin activity ratio (ARR) (r=-0.34, P&lt;0.01). ROCK activity correlated with age (r=-0.24, P=0.04), PAC (r=0.33, P&lt;0.01) and ARR (r=0.46, P&lt;0.01). Conclusions: APA was associated with both endothelial dysfunction and increased ROCK activity compared with those in IHA and EH. These findings suggest that APA may have a higher risk of future cardiovascular events.

Vascular Reactivity is Impaired and Associated With Walking Ability in Patients With Intermittent Claudication.

We verified whether vascular reactivity is impaired and whether there is any association between vascular reactivity, walking ability, and peripheral artery disease (PAD) severity in patients with intermittent claudication (IC). We studied 63 patients and 17 age- and sex-matched volunteers without PAD. Vascular reactivity was evaluated in the brachial artery during reactive hyperemia (flow-mediated dilation [FMD]) and after a sublingual single dose of nitroglycerin (nitroglycerin-induced vasodilation [NID]). Walking ability was verified by a 6-minute walk test. Vascular reactivity and walking ability were significantly worse in patients with IC compared with control participants. The ankle-brachial index correlated with FMD, NID, as well as total and pain-free distances. The NID and walking ability progressively decreased as PAD severity increased. Walking ability correlated with NID but not with FMD. In patients with IC, vascular reactivity is impaired and is related to the severity of PAD and to walking ability.

Borderline Ankle-Brachial Index Value of 0.91–0.99 Is Associated With Endothelial Dysfunction

An ankle-brachial index (ABI) value of 0.91-0.99 is considered borderline and associated with an increased risk of cardiovascular events. However, there is no information on the relationship between borderline ABI and endothelial function. We measured ABI and assessed vascular function by flow-mediated vasodilation (FMD) and nitroglycerin-induced vasodilation in 389 subjects who underwent health examinations. Subjects were divided into 3 groups according to ABI (normal group: 1.00-1.40, borderline group: 0.91-0.99, abnormal group: ≤0.90 or >1.40). FMD was significantly smaller in both the borderline and the abnormal group than in the normal group. There was no significant difference in the vascular responses to nitroglycerin between the normal and borderline groups. Vascular response to nitroglycerin was significantly higher in the normal group than in the abnormal group. Borderline and abnormal ABI values were significantly associated with an increased odds ratio of low tertile of FMD levels, using the normal ABI group as the reference. Multiple logistic regression analysis for FMD revealed that age, sex, hypertension, diabetes mellitus, and borderline ABI independently remained associated with FMD. ABI of 0.91-0.99 is associated with endothelial dysfunction. ABI examination is a simple and cost-effective method for obtaining the additional information on the initial step of atherosclerosis beyond the assessment of peripheral artery disease.

Loss of nitroglycerin-induced blood pressure lowering in redox-dead Cys42Ser PKG1α knock-in mouse

Nitroglycerin has remained in clinical use since 1879 however the mechanism by which it relaxes blood vessels to lower blood pressure remains incompletely understood. Metabolism of nitroglycerin generates several reaction products, including oxidants, and this ‘bioactivation’ process is essential for vasodilation. Protein kinase G (PKG) mediates classical nitric oxide-dependent vasorelaxation, but the 1α isoform is also independently activated by oxidation involving interprotein disulfide formation within this homodimeric protein complex. We hypothesised that nitroglycerin-induced vasodilation is mediated by disulfide activation of PKG1α. Treating smooth muscle cells or isolated blood vessels with nitroglycerin caused PKG1α disulfide dimerization. PKG1α disulfide formation was increased in wild-type mouse aortae by in vivo nitroglycerin treatment, but this oxidation was lost as tolerance developed. To establish whether kinase oxidation underlies nitroglycerin-induced vasodilation in vivo we employed a Cys42Ser PKG1α knock-in mouse that cannot transduce oxidant signals as it does not contain the vital redox-sensing thiol. This ‘redox-dead’ knock-in mouse was substantively deficient in hypotensive response to nitroglycerin compared to wild-type littermates as measured in vivo using radiotelemetry. Resistance blood vessels from knock-ins were markedly less sensitive to nitroglycerin-induced vasodilation (EC50 = 39.2 ± 10.7 μM) than wild-types (EC50 = 12.1 ± 2.9 μM). Furthermore, after 24 h of treatment wild-type controls stopped vasodilating to nitroglycerin and the vascular sensitivity to nitroglycerin was decreased, whereas this ‘tolerance’ phenomenon that routinely hampers the management of hypertensive patients was absent in knock-ins. We conclude that PKG1α disulfide formation is a significant mediator of nitroglycerin-induced vasodilation and tolerance to nitroglycerin is associated with loss of kinase oxidation.

Nitroglycerin Fails to Lower Blood Pressure in Redox-Dead Cys42Ser PKG1α Knock-In Mouse

Although nitroglycerin has remained in clinical use since 1879, the mechanism by which it relaxes blood vessels to lower blood pressure remains incompletely understood. Nitroglycerin undergoes metabolism that generates several reaction products, including oxidants, and this bioactivation process is essential for vasodilation. Protein kinase G (PKG) mediates classic nitric oxide-dependent vasorelaxation, but the 1α isoform is also independently activated by oxidation that involves interprotein disulfide formation within this homodimeric protein complex. We hypothesized that nitroglycerin-induced vasodilation is mediated by disulfide activation of PKG1α. Treating smooth muscle cells or isolated blood vessels with nitroglycerin caused PKG1α disulfide dimerization. PKG1α disulfide formation was increased in wild-type mouse aortas by in vivo nitroglycerin treatment, but this oxidation was lost as tolerance developed. To establish whether kinase oxidation underlies nitroglycerin-induced vasodilation in vivo, we used a Cys42Ser PKG1α knock-in mouse that cannot transduce oxidant signals because it does not contain the vital redox-sensing thiol. This redox-dead knock-in mouse was substantively deficient in hypotensive response to nitroglycerin compared with wild-type littermates as measured in vivo by radiotelemetry. Resistance blood vessels from knock-ins were markedly less sensitive to nitroglycerin-induced vasodilation (EC(50)=39.2 ± 10.7 μmol/L) than wild-types (EC(50)=12.1 ± 2.9 μmol/L). Furthermore, after ≈24 hours of treatment, wild-type controls stopped vasodilating to nitroglycerin, and the vascular sensitivity to nitroglycerin was decreased, whereas this tolerance phenomenon, which routinely hampers the management of hypertensive patients, was absent in knock-ins. PKG1α disulfide formation is a significant mediator of nitroglycerin-induced vasodilation, and tolerance to nitroglycerin is associated with loss of kinase oxidation.

Paclitaxel-Induced Endothelial Dysfunction in Living Rats Is Prevented by Nicorandil via Reduction of Oxidative Stress

Paclitaxel-eluting stents dramatically reduce rates of in-stent restenosis; however, paclitaxel is known to lead to endothelial dysfunction. Protective effects of nicorandil on paclitaxel-induced endothelial dysfunction by examining flow-mediated dilation (FMD) were investigated in anesthetized rats. After 7-day osmotic infusion of paclitaxel (5 mg/kg per day), FMD was measured by high-resolution ultrasound in the femoral artery of living rats. Paclitaxel significantly reduced FMD (21.6% ± 3.2% to 7.1% ± 1.7%); this reduction was prevented by co-treatment with nicorandil (15 mg/kg per day), while paclitaxel did not affect nitroglycerin-induced vasodilation. Diazoxide and tempol, but not isosorbide dinitrate, had an effect similar to nicorandil in preventing paclitaxel-induced decrease in FMD. Nicorandil significantly prevented paclitaxel-induced reduction in acetylcholine-induced vasodilation. On the underling mechanisms, paclitaxel increased reactive oxygen species (ROS) production (dihydrorhodamine 123, DCF fluorescence intensity) and NADPH oxidase (p47phox, gp91phox mRNA) in arteries and human coronary artery endothelial cells (HCAECs), while paclitaxel reduced nitric oxide (NO) release (DAF-2 fluorescence intensity), but not endothelial NO synthase (eNOS) phosphorylation in HCAECs. Nicorandil prevented the increased ROS production in arteries and HCAECs, which was 5-hydroxydecanoate (5-HD)-sensitive but 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)-resistant, without significant effect on the reduced NO release. In conclusion, nicorandil prevents paclitaxel-induced endothelial dysfunction, which may be brought by improved NO bioavailability due to the reduction of oxidative stress via KATP channel activation.

Mineralocorticoid Receptor Blocker Eplerenone Improves Endothelial Function and Inhibits Rho-Associated Kinase Activity in Patients With Hypertension

Hypertension is associated with endothelial dysfunction and activated Rho-associated kinases (ROCKs). The purpose of this study was to evaluate the effects of the selective mineralocorticoid receptor blocker, eplerenone, on endothelial function and ROCK activity in patients with hypertension. The study was carried out over 48 weeks in 60 untreated patients with hypertension who were randomly assigned to eplerenone, nifedipine, and losartan groups. We evaluated the effects of each treatment on flow-mediated vasodilation (FMD) and ROCK activity in peripheral leukocytes. Eplerenone increased FMD and decreased leukocyte ROCK activity. Nifedipine decreased ROCK activity but did not alter FMD. Losartan increased FMD but did not alter ROCK activity. Hypotensive effects were similar in the three groups, as was nitroglycerin-induced vasodilation during the follow-up period. There were no significant differences between the groups with respect to other parameters. The study results show that eplerenone improves endothelial function and inhibits ROCK activity in patients with essential hypertension.

Flow-mediated vasodilation is augmented in a corkscrew collateral artery compared with that in a native artery in patients with thromboangiitis obliterans (Buerger disease)

A healthy endothelium maintains vascular tone and structure. The purpose of this study was to evaluate endothelial function in corkscrew collateral arteries in Buerger disease. We measured flow-mediated vasodilation (FMD) in corkscrew arteries in 26 patients with Buerger disease, in control arteries in 26 healthy subjects, and in native arteries in 16 patients with Buerger disease. Hyperemic flow was lower in corkscrew arteries than in native arteries in patients with Buerger disease and in control arteries in healthy subjects. There was no significant difference between hyperemic flow in patients with Buerger disease in whom measurements were performed in native arteries and that in healthy subjects. FMD was lower in corkscrew arteries and native arteries in patients with Buerger disease than in control arteries in healthy subjects. There was no significant difference between FMD in corkscrew arteries in patients with Buerger disease and in that in native arteries. The ratio of FMD to hyperemic flow was significantly smaller in native arteries in patients with Buerger disease than in corkscrew arteries and in control arteries in healthy subjects (5.5 ± 6.2 vs 8.8 ± 8.9 and 9.6 ± 7.6 mL/min, P < .001, respectively). There was no significant difference in the ratio of FMD to hyperemic flow between corkscrew arteries in Buerger disease and control arteries in healthy subjects. Nitroglycerin-induced vasodilation was similar in all leg arteries. Endothelial function of a corkscrew collateral artery in patients with Buerger disease is maintained, while endothelial function is impaired in a native artery in Buerger disease.

Effect of High Intensity Exercise on Peak Oxygen Uptake and Endothelial Function in Long-Term Heart Transplant Recipients

Coronary allograft vasculopathy is a well-known long-term complication after cardiac transplantation. Endothelial dysfunction is involved and may be prevented by aerobic exercise. The purpose of this study was to examine whether high intensity aerobic exercise improves peak oxygen uptake (VO(2 peak) ) and endothelial function in heart transplant (HT) recipients. Twenty-seven long-term HT recipients were randomized to either 8-weeks high intensity aerobic exercise or no training. Flow mediated dilation of the brachial artery (FMD) was measured by ultrasound and VO(2 peak) by the analysis of expired air. Blood pressure and biomarkers were measured before and after 8 weeks. VO(2 peak) increased significantly in the exercise group (VO(2 peak) 23.9 ± 1.79 to 28.3 ± 1.63 mL/kg/min compared to controls (VO(2 peak) 24.6 ± 1.38 to 23.4 ± 1.58, p < 0.001 exercise vs. control).FMD increased in the exercise group compared to controls (8.3 ± 1.1% to 11.4 ± 1.2% vs. 5.6 ± 1.0% to 5.3 ± 1.7%, p = 0.024). No increase in nitroglycerin-induced vasodilation was observed. Systolic blood pressure fell in the exercise group (142 ±4.2 mmHg to127 ± 3.4 mmHg, p = 0.01) and was unchanged in controls (141 ± 4.2 mmHg to 142 ±6.4 mmHg, NS). High intensity aerobic exercise reduces systolic blood pressure and improves endothelial function in HT recipients.

Vascular Dysfunction in Obstructive Sleep Apnea and Type 2 Diabetes Mellitus

Despite the high prevalence of obstructive sleep apnea (OSA) in type 2 diabetes mellitus (DM), the attributable vascular risk from each condition is unknown. We hypothesize that OSA may have a similar effect on vascular function as type 2 diabetes does. Healthy normal-weight subjects, healthy obese subjects, subjects with type 2 diabetes, and obese subjects with OSA were enrolled. Vascular function was assessed with brachial artery ultrasound for flow-mediated dilatation (FMD) and in skin microcirculation by laser Doppler flowmetry. One hundred fifty-three subjects were studied: healthy normal-weight controls (NCs) (n = 14), healthy obese controls (OCs) (n = 33), subjects with DM (n = 68), and obese subjects with OSA (n = 38). The DM group did not undergo sleep study and thus may have had subclinical OSA. The OSA and type 2 diabetes groups had impaired FMD as compared to both the normal-weight and OC groups (5.8 ± 3.8%, 5.4 ± 1.6% vs. 9.1 ± 2.5%, 8.3 ± 5.1%, respectively, P < 0.001, post hoc Fischer test). When referenced to the NC group, a multiple linear regression model adjusting for covariates found that baseline brachial artery diameter (β = -3.75, P < 0.001), OSA (β = -2.45, P = 0.02) and type 2 diabetes status (β = -2.31, P = 0.02), negatively predicted % FMD. OSA status did not seem to affect nitroglycerin-induced vasodilation (endothelium-independent) of the brachial artery or vascular function in the skin microcirculation. OSA impairs endothelial function in the brachial artery to a similar degree as type 2 diabetes does. OSA, however, does not appear to affect brachial endothelium-independent vasodilation or skin microcirculatory function. Treatment of OSA in patients with concomitant type 2 diabetes, therefore, may be a potential therapeutic option to improve macro-, but not microvascular outcomes.

Association Between Chronic Caregiving Stress and Impaired Endothelial Function in the Elderly

We examined the relationship between chronic caregiving stress and endothelial function. Evidence suggests that caregiving stress is associated with pathophysiologic processes related to atherosclerosis. Endothelial dysfunction is a possible underlying mechanism explaining the relationship between caregiving stress and cardiovascular morbidity. We investigated the relationship between chronic caregiving stress and endothelial dysfunction assessed by reactive hyperemia-induced flow-mediated dilation (FMD). Seventy-eight elderly individuals participated in the study. Fifty-five were providing in-home care to a spouse with Alzheimer's disease, and 23 were married and living with a healthy, nondemented spouse. Analysis of covariance was used to examine the relationships between advancing dementia severity (Clinical Dementia Rating scores) and FMD and nitroglycerin-induced vasodilation of the brachial artery. Multiple linear regression was used to examine the relationship between years of caregiving and FMD. Clinical Dementia Rating scale scores were significantly related to FMD (p = 0.033), with participants caring for a spouse with moderate to severe dementia showing significantly worse FMD than those caring for a spouse with mild dementia (p = 0.028) and noncaregivers (p = 0.032). Within the caregiver sample, the number of years of caregiving was significantly related to FMD (r = -0.465, p < 0.001). These results suggest that the chronic stress of caregiving is associated with impaired endothelial function, which may be a potential mechanistic link to the observed increased risk of cardiovascular disease in elderly caregivers.