Significant Increase In Forearm Blood Flow Research Articles

Role of Mitochondrial Aldehyde Dehydrogenase in Nitroglycerin-Mediated Vasodilation: Observations Concerning the Dose-Response Relationship.

The mechanism of the bioactivation of nitroglycerin has long been controversial, with a number of suggested enzymatic pathways. More recently, aldehyde dehydrogenase-2 (ALDH-2) has been reported as the important enzyme involved in the bioactivation of nitroglycerin at therapeutically relevant concentrations. Other previously described enzyme systems can also bioactivate nitroglycerin, but only at concentrations, which are significantly higher than achieved in clinical practice. This study investigated the vascular response to nitroglycerin given over a wide range of concentrations in subjects with and without the ALDH-2 Glu504Lys polymorphism, a common genetic variant that greatly reduces the activity of ALDH-2 (n = 10 in both groups). Forearm blood flow (FBF) responses to a brachial artery infusion of nitroglycerin were assessed using venous occlusion plethysmography. Intra-arterial infusion of nitroglycerin caused a significant increase in FBF beginning at 0.464 µg/min with increasing responses seen in both groups at all infusion rates. However, there were no differences in the FBF responses to nitroglycerin in those with and without the ALDH-2 polymorphism, suggesting that ALDH-2 is not solely responsible for the bioactivation of nitroglycerin at either low (therapeutically relevant) or high concentrations of nitroglycerin.

ВЗАИМОСВЯЗЬ ПОЛИМОРФИЗМА ГЕНОВ ЭНДОТЕЛИАЛЬНОЙ NO-СИНТАЗЫ (G894T, T786C) И ГЕНА ЭНДОТЕЛИНА-1 (G5665T) С ЭФФЕКТИВНОСТЬЮ ТЕРАПИИ У ПАЦИЕНТОВ С АРТЕРИАЛЬНОЙ ГИПЕРТЕНЗИЕЙ ПОСЛЕ ПЕРЕНЕСЕННОГО ИШЕМИЧЕСКОГО ИНФАРКТА ГОЛОВНОГО МОЗГА

Background. Gene polymorphism of the endothelial NO-synthase (e-NOS) (G894T, T786C) and endothelin-1 (EDN-1) (G5665T) may be associated with a different response of patients with arterial hypertension (AH) to endotheliotropic therapy (ET).The aim of the study was to investigate the interrelation of the gene polymorphism of the e-NOS (G894T, T786C) and EDN-1 (G5665T) with the efficacy of therapy in patients with arterial hypertension after previous ischemic stroke.Material and methods: 65 people with arterial hypertension of II degree after previous ischemic stroke were examined. In all the patients, genotypes of e-NOS genes (G894T, T786C) and EDN-1 (G5665T) gene were determined.Endothelial function and vascular wall stiffness parameters were assessed in subgroups of homozygotes for dominant alleles (SGA) and in subgroups containing a recessive allele (SGB) before and after 12 weeks of ET.Results: Patients of SGB of e-NOS (G894T, T786C) and EDN-1 (G5665T) genes did not show a significant increase in forearm blood flow (FBF) and the percentage of target values of this parameter was lower compared to that in SGA.There was no significant decrease in the pulse wave velocity (PWV) in patients of EDN-1 (G5665T) gene SGB. The percentage of achievement of the target values of PWV in SGB was lower compared to that in SGA.Conclusions: Gene polymorphism of the e-NOS (G894T, T786C) and EDN-1 (G5665T) is not associated with the hypotensive effect of the drugs. The effect of the G894T e-NOS gene, T786C e-NOS gene and the G5665T EDN-1 gene correlated with the efficacy of endothelial dysfunction correction, which is manifested by the absence of a significant increase in FBF in carriers of genotypes with recessive alleles. The interrelation of the G5665T EDN-1 gene with the efficiency of correction of increased pulse wave velocity has been revealed, which is manifested by the absence of a significant lowering of this parameter in carriers of genotype with recessive alleles.

Abstract 139: Vascular Endothelin-1 Activity Increases with Age in Hypertensive Patients

Background: Vascular endothelin-1 (ET-1) dependent vasoconstriction is elevated in patients with hypertension. The effect of increasing age on ET-1 activity is unknown. This study investigated the hypothesis that age is directly associated with ET-1 activity in hypertensive patients. Methods: Retrospective analysis of data collected in a prospective clinical study that investigated vascular ET-1 activity in patients with essential hypertension (BP>140/90mmHg). Endothelin-1 activity was expressed as forearm blood flow (FBF) responses as measured by strain-gauge plethysmography during the intra-arterial infusion of the selective endothelin type-A receptor antagonist BQ-123 (100 nmol/min) for 60 minutes. Changes in FBF from baseline in response to BQ-123 were assessed by one-way ANOVA for repeated measures. Association analyses were performed with use of the Pearson correlation coefficient. Results: Data from 40 patients were included in the current analyses. The baseline characteristics of the study population are reported in the table. Infusion of BQ-123 induced a significant increase in FBF from baseline (p<0.001). The percent increase in FBF from baseline at 60 minutes of BQ-123 infusion was significantly directly associated with age (r=0.435; p=0.006), but not with blood pressure, parameters of glucose and lipid metabolism, markers of endothelial activation, and adipocytokine levels (p=NS for all). Conclusions: In patients with essential hypertension, ET-1 activity is directly associated with age. Our findings suggest that, in this population, aging may contribute to vascular damage and cardiovascular disease risk through an enhanced activation of the ET-1 system. Further study is needed to elucidate the mechanisms underlying the association between age and vascular ET-1 activity.

Abstract 474: Effects of Race on Endothelial Function in Type 2 Diabetes

Background: Patients with type 2 diabetes mellitus (DM2) have abnormal endothelial function. Healthy African Americans (AA) appear to have impaired nitric oxide-mediated vascular responses compared to Caucasians Americans (CA). Whether race-specific differences in endothelial function exist in patients with DM2 has not been investigated. We tested the hypothesis that in patients with DM2 endothelium-dependent dilation is lower in AA compared to CA. Methods: Retrospective analysis of data collected in a study that investigated vascular function in patients with DM2. Forearm blood flow (FBF) responses were measured by strain-gauge plethysmography during the intra-arterial infusion of acetylcholine (ACh), sodium nitroprusside (SNP), and the endothelin type A receptor blocker BQ-123 in AA and CA patients with DM2. Results: 34 patients took part in the study. One patient was excluded from the analyses because of incomplete data set. Their baseline characteristics are reported in the table. Infusion of ACh, SNP, and BQ-123 induced a significant increase in FBF from baseline (p<0.01 for all) in both AA and CA. When compared between groups, the response to ACh was significantly lower in AA (p = 0.022 by 2-way ANOVA). However, no differences were noted in the responses to SNP and BQ-123 between AA and CA (p=0.699 and p=0.118, respectively, by 2-way ANOVA). Conclusions: African American patients with DM2 have lower endothelial reactivity to ACh compared with CA. Our findings suggest that the detrimental vascular effects of type 2 diabetes on vascular reactivity are additive to the already impaired endothelium-dependent vasodilation observed in healthy AA.

Increased blood flow induces oxidative stress through an endothelium- and nitric oxide-independent mechanism

Bradykinin, a potent vasodilator, stimulates the formation of reactive oxygen species and F2-isoprostanes in vitro. The effect of bradykinin on oxidative stress in humans is not known. This study tested the hypothesis that bradykinin induces oxidative stress through a nitric oxide (NO)-dependent mechanism in the human vasculature. We measured forearm blood flow (FBF) and net F2-isoprostane release in response to intraarterial bradykinin (50–200ng/min), nitroprusside (1.6–6.4µg/min), or diltiazem (3.6–14.4µg/min) in the absence and presence of the NO synthase inhibitor Nω-monomethyl-L-arginine (L-NMMA) in normotensive and hypertensive subjects pretreated with aspirin. L-NMMA significantly decreased basal FBF and basal net F2-isoprostane release (from 28.7±5.2 to 13.4±3.5pg/min/100ml, P=0.01) in all subjects. Bradykinin caused a significant increase in FBF and net F2-isoprostane release in both normotensive and hypertensive subjects. During NO synthase inhibition, bradykinin significantly increased net F2-isoprostane release in both groups (P=0.001) and there was no effect of L-NMMA on bradykinin-stimulated F2-isoprostane release (P=0.46). Nitroprusside also significantly increased net F2-isoprostane release in hypertensive subjects (P=0.01) and this response was not affected by L-NMMA (P=0.50). Diltiazem increased FBF as well as net F2-isoprostane release (from 44.5±12.5 to 61.2±14.7pg/min/100ml at the highest dose, P=0.05). Increasing blood flow induces oxidative stress through a NO- and endothelium-independent mechanism.

Effect of 10 days of bedrest on metabolic and vascular insulin action: a study in individuals at risk for type 2 diabetes

Physical inactivity is a known risk factor for type 2 diabetes. We studied whole body and forearm insulin sensitivity in subjects at increased risk for type 2 diabetes [persons with low birth weight (LBW group; n = 20) and first-degree relatives to type 2 diabetic patients (FDR group; n = 13)] as well as a control (CON) group (n = 20) matched for body mass index, age, and physical activity levels before and after 10 days of bedrest. Subjects were studied by hyperinsulinemic isoglycemic clamp combined with arterial and deep venous catheterization of the forearm. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. All groups responded with a decrease in whole body insulin sensitivity in response to bedrest [CON group: 6.8 +/- 0.5 to 4.3 +/- 0.3 mg x min(-1) x kg(-1) (P < 0.0001), LBW group: 6.2 +/- 0.5 to 4.3 +/- 0.3 mg x min(-1) x kg(-1) (P < 0.0001), and FDR group: 4.3 +/- 0.7 to 3.1 +/- 0.3 mg x min(-1) x kg(-1) (P = 0.068)]. The percent decrease was significantly greater in the CON group compared with the FDR group (CON group: 34 +/- 4%, LBW group: 27 +/- 4%, and FDR group: 10 +/- 13%). Forearm insulin-stimulated glucose clearance decreased significantly in the CON and LBW groups in response to bedrest; in the FDR group, clearance was very low before bedrest and no change was observed. Before bedrest, the CON and LBW groups demonstrated a significant increase in FBF during hyperinsulinemia; after bedrest, an increase in FBF was observed only in the CON group. In conclusion, bedrest induced a pronounced reduction in whole body, skeletal muscle, and vascular insulin sensitivity in the CON and LBW groups. The changes were most pronounced in the CON group. In the FDR group, insulin resistance was already present before bedrest, but even this group displayed a high sensitivity to changes in daily physical activity.

Enhanced vascular activity of endogenous endothelin-1 in obese hypertensive patients.

Hypertensive patients have increased endothelin-1-dependent vasoconstrictor tone. This abnormality, however, might not be uniformly present in all forms of hypertension, as suggested by experimental studies showing that endothelin-1 activity is enhanced predominantly in low-renin, high-volume models and in insulin-resistant states. Because hypertension in obesity is commonly associated with both expanded plasma volume and insulin resistance, this study sought to determine whether increased body mass index (BMI) in hypertensive patients relates to activation of the endothelin-1 system. Forearm blood flow (FBF) responses (plethysmography) to intra-arterial infusion of an ETA receptor blocker (BQ-123) were analyzed in hypertensive patients and normotensive control subjects according to BMI. The vasodilator response to BQ-123 was significantly higher in hypertensive patients than in control subjects (P<0.001). During BQ-123, a significant increase in FBF from baseline was observed in obese (BMI > or =30 kg/m2; P<0.001) and overweight (BMI, 27 to 29.9 kg/m2; P=0.04) but not in lean (BMI <27 kg/m2; P=0.83) hypertensive patients. In contrast, no significant change in FBF was observed during BQ-123 either in obese (P=0.53), overweight (P=0.76), or lean (P=0.93) normotensive subjects. Moreover, a significant correlation between BMI and the vasodilator response to ETA blockade was observed in hypertensive subjects (R=0.53; P=0.005) but not in control subjects (R=0.11; P=0.58). In human hypertension, increased BMI is associated with enhanced ETA-dependent vasoconstrictor activity, suggesting that this abnormality may play a role in the pathophysiology of obesity-related hypertension and that targeting the endothelin-1 system may be useful in the treatment of these patients.

Combined endothelin receptor blockade evokes enhanced vasodilatation in patients with atherosclerosis.

Endothelin (ET)-1 causes vasoconstriction via ET(A) and ET(B) receptors located on vascular smooth muscle cells and vasodilatation via ET(B) receptors on endothelial cells. Studies in vitro indicate an upregulation of ET(B) receptors in atherosclerosis. The present study investigated the vascular effects evoked by endogenous ET-1 in atherosclerotic patients. Forearm blood flow (FBF) was measured with venous occlusion plethysmography in 10 patients with atherosclerosis and in 10 healthy control subjects during intra-arterial infusion of selective ET receptor antagonists. The ET(B) receptor antagonist BQ788 evoked a significant increase in FBF (31+/-13%) in the patients, whereas a 20+/-9% reduction was observed in the control subjects. The ET(A) receptor antagonist BQ123 combined with BQ788 evoked a marked increase in FBF (102+/-25%) in the patients compared with no effect in the control subjects (-3+/-9%, P<0.001 versus patients). The ET(A) receptor antagonist BQ123 increased FBF to a similar degree in patients (39+/-11%) as in control subjects (41+/-11%). The increase in FBF evoked by selective ET(A) receptor blockade was significantly (P<0.05) less than that evoked by combined ET(A)/ET(B) receptor blockade in the atherosclerotic patients. These observations suggest an enhanced ET-1-mediated vascular tone in atherosclerotic patients, which is at least partly due to increased ET(B)-mediated vasoconstriction.

Cardiovascular side effects of inhaled salbutamol in hypoxic asthmatic patients

BACKGROUNDBeta-2 adrenoceptor agonists have been associated with sudden death in asthma patients but the cause and underlying mechanism are unclear. Animal experiments indicate that the combination of hypoxia and β2 agonists may result in detrimental cardiovascular effects. A study was undertaken to investigate the effect of hypoxia on the systemic vascular effects of salbutamol in patients with asthma who are hypoxic by assessing forearm blood flow (FBF) as a measure of peripheral vasodilatation.METHODSEight men with mild asthma underwent the following treatments: normoxia + placebo (NP), normoxia + salbutamol (NS), hypoxia + placebo (HP), and hypoxia + salbutamol (HS). The period of mask breathing started at t=0 minutes, lasted for 60 minutes, and at 30 minutes 800 μg salbutamol was inhaled. The experiment was completed 30 minutes after the inhalation (t=60 minutes). For the hypoxia treatment the Spo2 level was 82%. Differences between treatments were sought using factorial ANOVA on percentage change from the pretreatment value.RESULTSThere were no significant differences in blood pressure and potassium levels between the treatments. After 60 minutes the increase in FBF was 13% (95% CI –12 to 39) more for HP treatment than for NP, 21% (95% CI –5 to 46) more for NS than for NP, and 32% (95% CI 7 to 58) more for HS than for HP (p=0.016). The inhalation of salbutamol during hypoxia resulted in a significant increase in FBF of 45% (95% CI 20 to 71) compared with NP (p=0.001).CONCLUSIONPatients with asthma who are hypoxic and inhale β2 agonists have serious systemic vascular side effects which may be an additional explanation for the association between asthma treatment and sudden death.

HEART RATE VARIABILITY DURING AND FOLLOWING FOREARM OCCLUSION IN HEALTHY INDIVIDUALS

1202 Non-invasive techniques to examine changes in flow-mediated dilation to forearm occlusion are increasingly used to describe vascular modifications following clinical trials. Yet, few trials have considered the effect of forearm occlusion on other possible confounding factors (i.e. central hemodynamics or sympathovagal balance (SVB)). The purpose of this study was to determine if forearm occlusion resulted in changes in heart rate variability (HRV). In twelve subjects (Age:20±2.8yrs, range;18-28), forearm blood flow (FBF) was evaluated at rest and following 5 min of forearm occlusion, using plethysmography. In addition, blood pressure responses were recorded and means and standard deviations (SDNN) of the RR intervals calculated during: Rest, Forearm occlusion (min1 and min4), and Release (min1 and min4). A repeated measures ANOVA with Tukey post hoc analysis was used to determine statistical differences across conditions. Alpha level was set a priori at p < 0.05. Results indicated a significant increase in FBF from rest (10.9±4.14 ml/min/100ml) to immediately post forearm occlusion (22.3±4.28 ml/min/100ml, p=0.0001). Although there were no significant fluctuations in HR, MAP and SDNN across conditions, the association between HRV measures during and the change in blood flow immediately after forearm occlusion approached significance (min1: r=−0.529, p=0.17; min4; r=−0.677, p=0.06). The stability of the central hemodynamics and HRV measures suggests that SVB remains unaltered during 5 min of forearm occlusion. However, the apparent inverse relationship between measures of SVB during and subsequent blood flow responses after forearm occlusion warrants further research as it may have important implications when evaluating vasodilatory responsiveness following treatment interventions.