Ach Iontophoresis Research Articles

The deleterious effects of acute hypoxia on microvascular and large vessel endothelial function.

What is the central question of this study? The aim was primarily to determine the effect of hypoxia on microvascular function and secondarily whether superior cardiorespiratory fitness is protective against hypoxia-induced impairment in vascular function. What is the main finding and its importance? Hypoxia reduced endothelium-dependent but not endothelium-independent microvascular function. The extent of impairment was twofold higher in the microcirculation compared with the large blood vessels. This study suggests that individuals with superior cardiorespiratory fitness might preserve microvascular function in hypoxia. These findings highlight the sensitivity of the microvascular circulation to hypoxia. Hypoxia is associated with diminished bioavailability of the endothelium-derived vasodilator, nitric oxide (NO). Diminished NO bioavailability can have deleterious effects on endothelial function. The endothelium is a heterogeneous tissue; therefore, a comprehensive assessment of endothelial function is crucial to understand the significance of hypoxia-induced endothelial dysfunction. We hypothesized that acute hypoxia would have a deleterious effect on microvascular and large vessel endothelial function. Twenty-nine healthy adults [24(SD = 4 )years of age] completed normoxic and hypoxic [inspired O2 fraction=0.209] trials in this double-blinded, counterbalanced crossover study. After 30min, we assessed the laser Doppler imaging-determined perfusion response to iontophoresis of ACh as a measure of endothelium-dependent microvascular function and iontophoresis of sodium nitroprusside as a measure of endothelium-independent microvascular function. After 60min, we assessed brachial flow-mediated dilatation as a measure of large vessel endothelial function. Thirty minutes of hypoxia reduced endothelium-dependent microvascular function determined by the perfusion response to ACh (median difference (x̃∆)=-109% {interquartile range: 542.7}, P<0.05), but not endothelium-independent microvascular function determined by the perfusion response to sodium nitroprusside (x̃∆ = 69% {interquartile range: 453.7}, P=0.6). In addition, 60min of hypoxia reduced allometrically scaled flow-mediated dilatation compared with normoxia ( [95% CI = -1.80, -0.58 (Confidence Intervals)]%, P<0.001). The decrease in microvascular endothelial function was associated with cardiorespiratory fitness (r =0.45, P=0.02). In conclusion, acute exposure to normobaric hypoxia significantly reduced endothelium-dependent vasodilatory capacity in small and large vessels. Collectively, these findings highlight the sensitivity of the microvascular circulation to hypoxic insult, particularly in those with poor cardiorespiratory fitness.

Comparative evaluation of instrumental methods for studying the state of endothelium in type II diabetes mellitus

Introduction . The method for assessing the flow-dependent vasodilation (FDV) and vasodilation induced by local iontophoresis of acetylcholine (Ach) is widely used, but has not yet been introduced into everyday clinical practice. Aim . Comparison of 2 ultrasound methods for assessing endothelial function in patients with diabetes mellitus (DM). Materials and methods . Effectiveness of reactive hyperemia tests of the brachial artery was compared using Vivid7pro ultrasound device, GE, with transducer 7.5 MHz. and the endothelium-dependent vasodilation and Ach iontophoresis in the microvasculature of the forearm were evaluated using a Minimax-Doppler-K ultrasound device with a 25 MHz transducer. After iontophoresis Ach, the linear blood flow velocity (%) was measured in comparison with the initial velocity. FDV is expressed as a % increase in arterial diameter in response to the test performed. Results . % of increase in blood flow velocity in the DM group was less than that in the control group for 2–6 minutes after the test and varied from 105.35 to 119.11 % in the DM group and from 130.0 to 270.0 % in healthy control subjects (p<0.05 for 2–6 min). After occlusion of the artery in reactive hyperemia test, as well as after 20, 40, and 180 sec, patients with DM had a lower % of increase in the diameter of the vessel, compared with healthy control subjects. When performing Celermaer test in 7 patients (43.75 %), in a number of measurements, an increase in the diameter of the vessel of more than 10 % was observed (which is characteristic of healthy control subjects). Conclusion . We associated the poor reproducibility of reactive hyperemia of the brachial artery with the difficulty in interpreting the results, which is probably due to the real-time resolution of the ultrasound method, and the Doppler method for assessing the linear blood flow velocity in the microvasculature turned to be less operator-dependent and more reproducible.

Is metabolically healthy obesity indeed healthy at the microvascular level?

Abstract Background In the current “obesity epidemic”, obese individuals without insulin resistance, lipid disorders, or hypertension, have been called “metabolically healthy” (MHO) and considered to have intermediate cardiovascular risk, between that of healthy nonobese (HNO) individuals and of metabolically unhealthy obese (MUO). Nonetheless, this is controversial, as MHO may have subclinical abnormalities, and indeed may be a transitory state in the way to the unhealthy phenotype. Purpose To evaluate systemic microvascular reactivity in MHO, MUO and HNO. Methods Ten MHO, 10 MUO and 20 HNO individuals were studied. Obesity was considered as a BMI ≥30 kg/m2. The NCEP/ATPIII criteria, excluding waist circumference, were used to define the metabolically healthy phenotype (absence of all criteria) or unhealthy phenotype (presence of any of the criteria). Laser speckle contrast imaging coupled with skin acetylcholine (Ach) iontophoresis was employed to study cutaneous microvascular reactivity (endothelial-dependent vasodilatation), as a surrogate for systemic microvascular function, and cutaneous vascular conductance [CVC in arbitrary perfusion units of microvascular flow (APU)/mean arterial pressure (mmHg)] was measured. Results Mean age was 34.8, 36.7 and 32.3 years (P=0.17, ANOVA) and BMI was 20.7, 32.2 and 33.3 kg/m2 (P&amp;lt;0.0001) for HNO, MHO and MUO, respectively. Both MHO and MUO had significantly decreased microvascular vasodilation in comparison to HNO (Figure 1). Of note, there was no significant difference between MHO and MUO regarding CVC (both similarly decreased when compared to the healthy controls). Conclusions This study underscores that MHO is not a “benign” condition, as it has adverse effects on microvascular function, similarly to those found in MUO. The study of cutaneous microvascular function may be useful to identify subclinical abnormalities in obese individuals who might deserve more intensive management. Figure 1 Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): FAPERJ - Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro - Brazil

Systemic microvascular endothelial dysfunction is associated with reduction of left ventricular ejection fraction in chronic Chagas disease patients

Abstract Introduction Chagas disease (CD) affects millions of patients around the world, many of whom may develop cardiovascular complications, including heart failure and stroke. Notwithstanding, little is known about the effects of CD in the reactivity of the systemic microcirculation. Purpose The present study aims to compare the microvascular reactivity (MR) of a group of patients in the chronic phase of CD with healthy volunteers, matched for sex and age. In addition, we sought to evaluate the association between MR and left ventricular ejection fraction (LVEF) in CD patients. Methods Systemic microvascular flow and endothelium-dependent vasodilation were assessed using laser speckle contrast imaging, coupled with acetylcholine (Ach) iontophoresis in the forearm skin. Vascular reactivity data were expressed as area under the curve (AUC) of Ach-induced vasodilation. Anthropometry, medications, biochemistry, and echocardiographic data were obtained from medical records. Results Thirty-six patients were compared to 25 healthy individuals (controls). Ach-induced vasodilation was higher in controls, when compared to patients (maximum increase of microvascular flow from baseline of 106% and of 48% respectively, P&amp;lt;0.0001; Mann Whitney test). There was a significant association between LVEF, stratified into quartiles, and MR (P value for linear trend = 0.002; one way ANOVA, Figure 1). In addition, there was no difference in MR between CD patients with normal LVEF and the control group. In CD patients, MR was independent of the presence of arterial hypertension or diabetes. Conclusion We have shown that the reduction of MR is associated with a decrease of LVEF in a group of chronic CD patients. The results were not affected by comorbidities, such as hypertension or diabetes. The evaluation of systemic endothelial function may be useful to tailor therapeutic and preventive approaches, targeted at systolic left ventricular failure associated with chronic CD cardiomyopathy. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro

Previous recreational cold exposure does not alter endothelial function or sensory thermal thresholds in the hands or feet.

What is the central question of this study? Does recreational cold exposure result in cold sensitivity and is this associated with endothelial dysfunction and impaired sensory thermal thresholds? What is the main finding and its importance? Previous cold exposure was correlated with cold sensitivity of the foot, which might indicate the development of a subclinical non-freezing cold injury. Endothelial function and thermal detection were not impaired in cold-sensitive individuals; therefore, further research is required to understand the pathophysiology of subclinical and clinical forms of non-freezing cold injury. In this study, we investigated whether cold-sensitive (CS) individuals, who rewarm more slowly after a mild cold challenge, have impaired endothelial function and sensory thermal thresholds (STTs) and whether this is related to reported cold exposure. Twenty-seven participants with varying previous cold exposure undertook three tests: an STT test, i.e. determination of warm and cold STTs of the fingers and dorsal foot; an endothelial function test, i.e. measurement of cutaneous vascular conductance (CVC) during iontophoresis of ACh on the forearm, finger and foot; and a CS test, involving immersion of a foot for 2min in water at 15°C followed by 10min of rewarming in air at 30°C. Toe skin temperature (Tsk ) measured during the CS test was used to form a CS group (<32°C before and 5min after immersion) and an otherwise closely matched control group [Tsk >32°C; n=9 (four women) for both groups]. A moderate relationship was found between cold exposure ranking and Tsk rewarming (r=0.408, P=0.035, n=27) but not STT or endothelial function. The Tsk and blood flow were lower in CS compared with control subjects before and after foot immersion [Tsk , mean (SD): 30.3(0.9) versus 34.8(0.8) and 27.9(0.8) versus 34.3(0.8)°C, P<0.001; and CVC: 1.08(0.79) versus 3.82(1.21) and 0.79(0.52) versus 3.45(1.07)fluxmmHg-1 , n=9, P<0.001, respectively]. However, no physiologically significant differences were observed between groups for endothelial function or STT. A moderate correlation between previous cold exposure and toe Tsk rewarming after foot immersion was observed; however, CS was not associated with impaired endothelial function or reduced thermal detection.

Effects of insulin analogs as an add-on to metformin on cutaneous microcirculation in type 2 diabetic patients

BackgroundA single insulin injection was shown to improve microcirculatory blood flow. Our aim was to examine the effects of 4weeks of insulin therapy by three randomly assigned insulin analog regimens (Detemir, Aspart, and their combination) on cutaneous blood flow (CBF) and microcirculatory endothelial function as an add-on to metformin in type 2 diabetic patients poorly controlled on oral antidiabetic treatment. MethodsFourty-two type 2 diabetic patients with no history of cardiovascular disease in secondary failure to oral antidiabetic agents had CBF measurements before and after acetylcholine (Ach) iontophoretic administration. CBF measurements were performed at fasting and after a standardized breakfast during the post-prandial period. Before randomization (Visit 1, V1) during the tests, participants took only metformin. The same tests were repeated after 4weeks of insulin treatment (Visit 2, V2). ResultsThirty-four patients had good quality recordings for both visits. During V1, CBF and CBF response to Ach increased in the post-prandial period. After 4weeks of insulin treatment, metabolic parameters improved. Compared to V1, CBF at fasting did not increase at V2 but there was an improvement in endothelial function at fasting after Ach iontophoresis, without difference across insulin regimens. Oxidative stress markers were not modified, and E-selectin and vascular cell adhesion molecule 1 levels decreased after insulin treatment, without differences between insulin groups. ConclusionsA strategy of improving glycemic control for 4weeks with insulin analogs improves microcirculatory endothelial reactivity and reduces endothelial biomarkers at fasting, whatever the insulin regimen used. Insulin therapy associated to metformin is able to improve fasting microvascular endothelial function even before complete metabolic control.

Marked regional endothelial dysfunction in mottled skin area in patients with severe infections

BackgroundMottling around the knee, reflecting a reduced skin blood flow, is predictive of mortality in patients with septic shock. However, the causative pathophysiology of mottling remains unknown. We hypothesized that the cutaneous hypoperfusion observed in the mottled area is related to regional endothelial dysfunction.MethodsThis was a prospective, observational study in a medical ICU in a tertiary teaching hospital. Consecutive adult patients with sepsis admitted to ICU were included. After resuscitation, endothelium-dependent vasodilation in the skin circulation was measured before and after iontophoresis of acetylcholine (Ach) in the forearm and the knee area. We analyzed the patterns of induced vasodilatation according to the presence or absence of mottling and vital status at 14 days.ResultsWe evaluated 37 septic patients, including 11 without and 26 with septic shock. Overall 14-day mortality was 22%. Ten patients had mottling around the knee (10/37, 27%). In the knee area, the increased skin blood flow following iontophoresis of Ach was lower in patients with mottled skin as compared to patients without mottled skin (area under curve (AUC) 3280 (2643–6440) vs. 7980 (4233–19,707), both P < 0.05). In the forearm area, the increased skin blood flow following iontophoresis of Ach was similar in patients with and without mottled skin. Among patients with septic shock, the increased skin blood flow following iontophoresis of Ach in the knee area was significantly lower in non-survivors as compared to survivors at 14 days (AUC 3256 (2600–4426) vs. 7704 (4539–15,011), P < 0.01). In patients with septic shock, the increased skin blood flow in the forearm area following iontophoresis of Ach was similar in survivors and non-survivors at 14 days.ConclusionMottling is associated with regional endothelial dysfunction in patients with septic shock. Endothelial dysfunction in the knee skin area was more pronounced in non-survivors than in survivors.

Does third generation left ventricular assist device alter heart failure-related microvascular dysfunction?

Background Left ventricular assist device (LVAD) is a promising new therapy in patients with advanced heart failure. Previous studies suggested that continuous blood flow impairs endothelial function. Whether the third-generation LVAD (HeartWare®, HeartWare Inc., Framingham, MA, USA) system affects endothelial regulation of microvascular flow, endothelial nitric oxide (NO) bioavailability and endothelial production of vWF is not known. Methods Fifteen LVAD-supported heart failure patients and 13 age/body mass index matched heart failure patients (HF) were included. The microvascular endothelial function of skin vessels was assessed with laser Doppler imager (LDI) using 3 different hyperaemic challenges: acetylcholine (Ach) iontophoresis, sodium nitroprusside (SNP) iontophoresis and local heating to 44°C. NO-mediated vasodilation was further evaluated by comparing heating hyperaemic response in skin area pretreated either by a saline solution (control) or a specific NO-synthase inhibitor (L-N-arginine-methyl-ester, L-NAME). vWF antigen was also measured in LVAD and HF patients. Results SNP-induced vasodilation did not differ between LVAD and HF patients, and we observed a trend towards an increased vasodilator response to Ach in LVAD patients (P = 0.06). Compared to HF patients, skin thermal hyperaemia was increased in LVAD patients in both control and L-NAME pretreated skin (all P

Does third generation left ventricular assist device alter heart failure-related microvascular dysfunction?

Background Left ventricular assist device (LVAD) is a promising new therapy in patients with advanced heart failure. Previous studies suggested that continuous blood flow impairs endothelial function. Whether the third-generation LVAD (HeartWareR, HeartWare Inc., Framingham, MA, USA) system affects endothelial regulation of microvascular flow, endothelial nitric oxide (NO) bioavailability and endothelial production of vWF is not known.Methods Fifteen LVAD-supported heart failure patients and 13 age/body mass index matched heart failure patients (HF) were included. The microvascular endothelial function of skin vessels was assessed with laser Doppler imager (LDI) using 3 different hyperaemic challenges: acetylcholine (Ach) iontophoresis, sodium nitroprusside (SNP) iontophoresis and local heating to 44°C. NO-mediated vasodilation was further evaluated by comparing heating hyperaemic response in skin area pretreated either by a saline solution (control) or a specific NO-synthase inhibitor (L-N-arginine-methyl-ester, L-NAME). vWF antigen was also measured in LVAD and HF patients.Results SNP-induced vasodilation did not differ between LVAD and HF patients, and we observed a trend towards an increased vasodilator response to Ach in LVAD patients (P =0.06). Compared to HF patients, skin thermal hyperaemia was increased in LVAD patients in both control and L-NAME pretreated skin (all P < 0.001). The hyperaemic reaction attributable to NO-mediated vasodilation correlated negatively with HF duration (r = –0.50, P < 0.01, n = 28), but did not differ between LVAD and HF patients. Both groups disclosed also similar vWF antigen serum levels.Conclusion This case-control study indicates that third-generation LVAD therapy does not alter skin microvascular endothelial function and vWF production of patients with HF

Effects of Dietary Supplementation with Brazil Nuts on Microvascular Endothelial Function in Hypertensive and Dyslipidemic Patients: A Randomized Crossover Placebo-Controlled Trial.

To investigate the effects of dietary supplementation with GBNs on microvascular endothelial function in hypertensive and dyslipidemic patients. Ninety-one patients of both sexes aged 62.1 ± 9.3 years received 13 g/day of GBNs or a placebo for three months with a washout period of one month between treatments. Microvascular endothelial function was assessed using LSCI coupled with iontophoresis of ACh and PORH. We also used skin video capillaroscopy to measure capillary density and recruitment at rest and during PORH. Plasma concentrations of NOx were also measured as a marker of nitric oxide bioavailability. Supplementation with GBNs significantly increased the plasma levels of Se (p < 0.05) and NOx (p < 0.05). However, we did not observe any effects of GBN consumption on microvascular vasodilator responses to ACh or PORH (p > 0.05), and GBNs did not improve capillary density at baseline or recruitment during PORH (p > 0.05). Supplementation with GBNs induced significant increases in the plasma Se concentration and systemic bioavailability of nitric oxide. Nevertheless, GBN supplementation did not lead to any improvement in systemic microvascular reactivity or density in patients with arterial hypertension and dyslipidemia who were undergoing multiple drug therapies.

Modeling Perfusion Dynamics in the Skin During Iontophoresis of Vasoactive Drugs Using Single-Pulse and Multiple-Pulse Protocols.

After iontophoresis of vasoactive drugs into the skin, a decrease in perfusion is commonly observed. We delivered vaso-active drugs by iontophoresis using different delivery protocols to study how these affect this decrease in perfusion as measured using LDF. We measured skin perfusion during iontophoresis of (ACh), MCh, and NA using a single pulse or separate pulses at different skin sites, and during repeated delivery of ACh at the same site. Perfusion half-life was 6.1 (5.6-6.6) minutes for ACh and 41 (29-69) minutes for MCh (p < 0.001). The maximum response with multiple pulses of ACh iontophoresis was lower than with a single pulse, 30 (22-37) PU vs. 43 (36-50) PU, p < 0.001. Vasoconstriction to NA was more rapid with a single pulse than with multiple pulses. The perfusion half-life of ACh decreased with repeated delivery of ACh at the same site-first 16 (14-18), second 5.9 (5.1-6-9) and third 3.2 (2.9-3.5) minutes, p < 0.001. The drug delivery protocol affects microvascular responses to iontophoresis, possibly as a result of differences in the dynamics of local drug concentrations. Perfusion half-life may be used as a measure to quantify the rate of perfusion recovery after iontophoresis of vasoactive drugs.

Peripheral microvascular function is altered in young individuals at risk for hypertrophic cardiomyopathy and correlates with myocardial diastolic function.

Hypertrophic cardiomyopathy (HCM) is a major cause of sudden cardiac death in the young. Based on previous reports of functional abnormalities in not only coronary but also peripheral vessels in adults with HCM, we aimed to assess both peripheral vascular and myocardial diastolic function in young individuals with an early stage of HCM and in individuals at risk for HCM. Children, adolescents, and young adults (mean age: 12 yr) with a family history of HCM who either had (HCM group; n = 36) or did not have (HCM-risk group; n = 30) echocardiography-documented left ventricular (LV) hypertrophy as well as healthy matched controls (n = 85) and healthy young athletes (n = 12) were included in the study. All underwent assessment with 12-lead electrocardiography, two-dimensional echocardiography, tissue Doppler imaging and laser Doppler with transdermal iontophoresis of ACh and sodium nitroprusside. LV thickness and mass were increased in HCM and athlete groups compared with control and HCM-risk groups. The mitral E-to-e' ratio, measured via tissue Doppler, was increased in HCM (P < 0.0001) and HCM-risk (P < 0.01) groups compared with control and athlete groups, as were microvascular responses to ACh (HCM group: P = 0.045 and HCM-risk group: P = 0.02). Responses to ACh correlated with the E-to-e' ratio (r = 0.5, P = 0.001). Microvascular responses to sodium nitroprusside were similar in all groups (P > 0.2). HCM-causing mutations or its familial history are associated with changes in cardiac diastolic function and peripheral microvascular function even before the onset of myocardial hypertrophy. Tissue Doppler can be used to differentiate HCM from physiological LV hypertrophy in young athletes.

Ethnic differences in microvascular function in apparently healthy South African men and women.

Microvascular dysfunction precedes the clinical manifestations of cardiovascular disease. Given the ethnic disparities in cardiovascular disease, we aimed to investigate ethnic differences in microvascular endothelial function in a group of young (18-33years old), apparently healthy individuals (n=33, nine Black African, 12 mixed ancestry and 12 Caucasian). Microvascular endothelium-dependent and -independent function was assessed by laser Doppler imagery and iontophoresis of ACh and sodium nitroprusside (SNP), respectively, adjusting for skin resistance. Microvascular reactivity was expressed as maximum absolute perfusion, percentage change from baseline and area under the curve (AUC). Skin resistance was significantly lower in the Caucasian group in response to ACh (Caucasian, mean 0.16±0.03Ω versus Black, 0.21±0.04Ω and mixed ancestry, 0.20±0.02Ω, P<0.01) and SNP (Caucasian, 0.08±0.01Ω versus Black, 0.11±0.02Ω and mixed ancestry, 0.12±0.01Ω, P<0.01). Microvascular function in response to ACh was significantly higher in the Caucasian group compared with the other two groups; however, after adjusting for skin resistance these differences were no longer significant. Conversely, the microvascular SNP response remained significantly higher in the Caucasian group, even after adjusting for skin resistance (P<0.01). Diastolic blood pressure was inversely associated with the AUC of ACh (r=-0.4) and all SNP responses (r=-0.3 to -0.6). Skin resistance was inversely associated with AUC and maximum absolute ACh response (r=-0.59 and -0.64, respectively) and all SNP responses (r=-0.37 to -0.79). Ethnic differences in endothelium-independent microvascular function may contribute to ethnic disparities in cardiovascular disease. Moreover, skin resistance plays a significant role in the interpretation of the microvascular response to outcomes of iontophoresis in a multiethnic group.

Antihypertensive Treatment Improves Microvascular Rarefaction and Reactivity in Low‐Risk Hypertensive Individuals

To test whether long-term antihypertensive treatment with metoprolol succinate (a β₁-adrenoceptor blocker) or olmesartan medoxomil (an angiotensin II AT₁-receptor blocker) reverses microvascular dysfunction in hypertensive patients. This study included 44 hypertensive outpatients and 20 age and sex-matched healthy controls. We used skin capillaroscopy to measure capillary density and recruitment at rest and during PORH. Endothelium-dependent vasodilation of skin microcirculation was evaluated with a LDPM system in combination with ACh iontophoresis, PORH, and LTH. Pretreatment capillary density in hypertensive patients was significantly reduced compared with controls (71.3 ± 1.5 vs. 80.6 ± 1.8 cap/mm²; p < 0.001), as was PORH (71.7 ± 1.5 vs. 79.5 ± 2.6 cap/mm²; p < 0.05). After treatment for six months, capillary density increased to 75.4 ± 1.1 cap/mm² (p < 0.01) at rest and 76.8 ± 1.1 cap/mm² during PORH. During LTH, CVC in perfusion units (PU)/mmHg was similar in patients (1.71 [1.31-2.12]) and controls (1.60 [1.12-1.91]) and increased significantly (1.82 [1.30-2.20]) after treatment. Maximal CVC during PORH was reduced in hypertensive patients (0.30 [0.22-0.39]) compared to controls (0.39 [0.31-0.49], p < 0.001) and increased (0.41 [0.29-0.51], p < 0.001) after treatment. Capillary rarefaction and microvascular endothelial dysfunction in hypertensive patients responded favorably to long-term pharmacological treatment.

Regular pace training increases endothelium-dependent vasodilatation in untrained women

Almost all scientific research that investigates how exercise training affects the circulatory system estimates main arteries, like brachial artery and few focus on the cutaneous microvascular function. The aim of this study was to estimate the impact of 25 Programmed Aerobic/Anaerobic/Accommodating Circuit Exercise (PACE) training sessions on changes in vasomotor reactions (microvascular beds of the skin) in healthy untrained women. PACE training is a short duration (∼30 min), intense physical activity that includes both aerobic and anaerobic states, that changes after every 30 s. 20 women participated in this study (age 35±10 years; body mass index 26.7±4.2). The laser Doppler flow technique (MoorLDI2) was used to estimate the regional blood flow changes on the upper part of the palm induced by local acetylcholine (1% Ach) and sodium nitroprusside (1% SNP) iontophoresis; assessment of concentrations of C reactive protein and cortisol were made with the Immulite 2500. There was an increase in endothelium-dependent vasodilatation after 25 PACE training sessions, that was estimated by laser dopplerography test with 1% Ach iontophoresis (292±80 PU vs 335±88 PU, p&lt;0.01). 25 PACE training sessions did not cause any significant changes in endothelium-independent vasodilatation (1% SNP iontophoresis). There was a negative correlation between 1% Ach-induced vasodilatation and C reactive protein (p&lt;0.05; r=−0.38), but there was a positive correlation between 1% SNP-induced vasodilatation and cortisol (p&lt;0.01; r=0.53), when data from pre and post 25 PACE training sessions are taken together (n=40). In conclusion, 25 PACE training sessions improve endothelium-dependent vasodilatation, but have no effect on endothelium-independent vasodilatation. Inflammatory processes (higher C reactive protein level) reduce the capacity of endothelium-dependent vasodilatation.

EFFECTS OF PHYSIOLOGICAL HYPERINSULINAEMIA ON THE MICROCIRCULATION: PP.11.424

Objective: Steady state hyperinsulinaemia during a hyperinsulinaemic euglycaemic clamp stimulates endothelium-dependent vasomotion and vasodilation as well as capillary recruitment, which contribute to increased glucose uptake; these phenomena have been shown to be blunted in obesity. The aim of the present study was to investigate whether similar results can be obtained during dynamic hyperinsulinaemia as induced by a glucose load or a mixed meal. Design and Methods: A randomised, placebo-controlled trial was performed in 18 healthy (BMI 22.5 ± 1.7 kg/m2) and 13 obese (BMI 34.0 ± 3.5 kg/m2) subjects, to examine the effects of a glucose drink (75 g glucose), a 495-kcal liquid mixed meal (60% carbohydrates, 25% proteins, 15% fat) or placebo (a similar amount of tap water) on microvascular function. Skin endothelium-(in)dependent vasodilatation was evaluated by laser Doppler flowmetry (LDF) with iontophoresis of acetylcholine (Ach) and sodium nitroprusside (SNP). Vasomotion was examined by Fourier analysis of the LDF signal. Results: Both the glucose drink and the liquid mixed meal, but not placebo, induced hyperinsulinaemia. The levels of hyperinsulinaemia were higher in obese compared to healthy subjects (peak levels glucose drink: 95.9 vs. 54.2 mU/l, P < 0.05; mixed meal: 107.6 vs. 59.7 mU/l P < 0.05). Compared to placebo, vasomotion analysis showed increased endothelial activity in healthy subjects following the glucose drink (delta energy density (median (interquartile range) +0.11 (−0.04 – +0.25); P < 0.05) and meal drink (+0.16 (0.05 – 0.29); P = 0.001). Compared to healthy subjects, a significant decrease of endothelial activity was found in obese subjects following the meal drink (−0.09 (−0.23–0.13) vs 0.16 (0.05 – 0.29); P < 0.05). No changes in endothelium-(in)dependent vasodilatation following iontophoresis of Ach or SNP were found in either group. Conclusion: A glucose load and a mixed meal, which are accompanied by non-steady state hyperinsulinaemia, increase endothelial vasomotion in healthy individuals. These responses are blunted in obese subjects. These data suggest impairment of microvascular function in the postprandial state in obese individuals.

유산소성 훈련이 활동한선밀도 및 한선의 출력기능에 미치는 영향

The sweat volume of indirectly activated(AXR) and directly activated(DIR) of sweating that occurs in the aerobic exercise-trained as compared to the sedentary subjects has been attributed to differences in the peripheral sweating mechanisms, although such mechanisms have not been completely investigated in comparative terms. The aim of this study was to investigate quantitatively the peripheral sudomotor adaptive mechanisms attributed for AXR and DIR sweating that is found in the aerobic exercise- trained runner(Trainee) in contrast to the health control(HC) subjects. QSART by 2 mA for 5 min of 10% ACh were applied to determine AXR by nicotinic receptor mediated sweating activity(axon reflex-mediated) and DIR by muscarinic receptor mediated sweating activity sweating during ACh iontophoresis. The sweat volumes of AXR(1), AXR(2) and DIR were higher in the aerobic exercise-trained Trainees as compared to those for the sedentary subjects. Furthermore, number of activated sweat gland density was higher in the aerobic exercise-trained Trainees as compared to sedentary subjects(p0.001). The activated single sweat gland output was higher in the aerobic-trained Trainees as compared to the output for the sedentary subjects(p0.001). These findings suggest that aerobic exercise-trained Trainees had higher sweat volume due to the combinations of a higher sweat gland output per activated sweat gland and more increased density of activated sweat gland.

Platelet inhibition by low-dose aspirin but not by clopidogrel reduces the axon-reflex current-induced vasodilation in humans

We previously showed a prolonged inhibition of current-induced vasodilation (CIV) after a single oral high dose of aspirin. In this study, we tested the hypothesis of platelet involvement in CIV. Nine healthy volunteers took 75 mg aspirin/day, 98 mg of clopidogrel bisulfate/day, or placebo for 4 days. CIV was induced by two consecutive 1-min anodal current applications (0.08 mA/cm(2)) through deionized water with a 10-min interval. CIV was measured with laser Doppler flowmetry and expressed as a percentage of baseline cutaneous vascular conductance: %C(b). In a second experiment in 10 volunteers, aspirin and placebo were given as in experiment 1, but a 26-h delay from the last aspirin intake elapsed before ACh iontophoresis and postocclusive hyperemia were studied in parallel to CIV. In experiment 1, the means +/- SE amplitude of CIV was 822 +/- 314, 313 +/- 144, and 746 +/- 397%C(b) with placebo, aspirin (P < 0.05 from placebo and clopidogrel), and clopidogrel (NS from placebo), respectively. In experiment 2, CIV impairment with aspirin was confirmed: CIV amplitudes were 300 +/- 99, and 916 +/- 528%C(b) under aspirin and placebo, respectively (P < 0.05), whereas vasodilation to ACh iontophoresis (322 +/- 74 and 365 +/- 104%C(b)) and peak postocclusive hyperemia (491 +/- 137 and 661 +/- 248%C(b)) were not different between aspirin and placebo, respectively. Low-dose aspirin, even 26 h after oral administration, impairs CIV, while ACh-mediated vasodilation and postocclusive hyperemia are preserved. If platelets are involved in the neurovascular mechanism triggered by galvanic current application in humans, it is likely to occur through the cyclooxygenase but not the ADP pathway.

Microalbuminuria in Type 2 diabetes indicates impaired microvascular vasomotion and perfusion

Vascular oscillation (vasomotion) occurs in the microcirculation and is thought to be a significant contributor to tissue perfusion. Our aims were to assess the relationship of vasomotion to perfusion in the cutaneous microcirculation of diabetic patients, to determine the influence on it of endothelium-dependent and nonendothelium-dependent vasodilatory stimuli, and to assess the relationship to perfusion and vasomotion of various biochemical markers of vascular function (HbA1c, LDL- and HDL-cholesterol, triglycerides, insulin resistance, high sensitive C-reactive protein, L- and E-selectin, soluble ICAM, von Willebrand factor) and microalbuminuria. Perfusion and vasomotion (spectral density at low and very low frequencies) were measured by laser-Doppler flowmetry after local heat and iontophoresis of ACh and sodium nitroprusside. Perfusion responses to all stimuli were impaired in patients with Type 2 diabetes (heat: F = 28.0, P < 0.001; ACh: F = 7.11, P = 0.003; sodium nitroprusside: F = 4.0, P = 0.028). Responses to endothelium-dependent stimuli were further impaired in microalbuminuric patients (heat: P = 0.035; ACh: P = 0.034). Vasomotion responses at low frequencies after endothelium-dependent stimuli were impaired in diabetic patients compared with that shown in controls (heat: F = 5.62, P = 0.002; ACh: F = 4.32, P = 0.015). Multivariate modeling showed microalbuminuria to be the only consistent predictor of perfusion and vasomotion responses. The results suggest that microalbuminuria in Type 2 diabetes reflects a generalized disturbance of microvascular function related to endothelium-dependent mechanisms.

Digital iontophoresis of vasoactive substances as measured by laser Doppler imaging--a non-invasive technique by which to measure microvascular dysfunction in Raynaud's phenomenon.

To test the hypothesis that microvascular vasodilation is impaired in patients with systemic sclerosis (SSc) compared with patients with primary Raynaud's phenomenon (PRP) and healthy controls, using the technique of laser Doppler imaging to quantify blood flow responses to iontophoresis of vasoactive agents. Microvascular blood flow was measured by laser Doppler imaging before, during and after 120 s iontophoresis (30 microA) of 1% acetylcholine chloride (ACh, endothelium-dependent) and 1% sodium nitroprusside (NaNP, endothelium-independent). Two adjacent fingers of the left hand were studied, and the procedure then repeated on the right. Ten patients with limited cutaneous SSc (LCSSc), 10 patients with PRP and 11 healthy control subjects were studied. Vasodilation in response to both ACh and NaNP iontophoresis, as measured by 'area under the blood flow.time curve' (AUC), normalized for baseline flux, was similar in the control and PRP groups, but was diminished in the LCSSc group compared with both control and PRP groups (ACh results: control vs LCSSc P = 0.028, PRP vs LCSSc P = 0.005; NaNP results: control vs LCSSc P = 0.004, PRP vs LCSSc P = 0.005). There were no differences between groups in baseline flux values nor in voltages required to drive the 30 microA current. Both endothelium-dependent and endothelium-independent vasodilation are impaired in patients with LCSSc. Vasodilatory responses in patients with PRP are similar to those in controls. If reproducibility is confirmed to be satisfactory, then these techniques could be used to examine disease progression over time and responsiveness to vasoactive treatment, thus facilitating clinical trials.