Vasodilation Of Microvessels Research Articles

Microcirculatory Liver Bloodstream in Hyperhomocysteinemia and Administration of Tautomeric Forms of Orotic Acid

The aim of the study was to analyze the microvasculation of the liver in administration of tautomeric forms of orotic acid for a methionine-induced liver pathology to assess the efficacy of the modified drugs and the potentialof their clinical use.Material and methods. The study included 30 white outbred rats, that were simulated methionine induced hyperhomocysteinemia by the administration of methionine, dosage 0.15 g/100 g of the body we ight, via food during 4 weeks. Animals with hyperhomocysteinemia were divided into 4 groups: animals of group 1 received orotic acid (OA) in the initial form (oxo-tautomer), animals of group 2 received hydroxy–tautomer OA after mechanomodification for 1 hour, animals of group 3 received dihydroxy-tautomer OA after mechanomodification for 6 hours. Histological preparations of the liver were used to evaluate the area of hepatocytes; diameters and areas of the central vein, the interlobular vein and artery, the bile duct, and the Visotto coefficient were calculated.Results. Morphometric data of the hepatic microvascular bloodstream with simulated hyperhomocysteinemia evidenced a general increase in the diameter and area of blood vessels, changes affected the system of blood inflow and outflow at the organ level. Administration of OA had a normalizing effect on the liver bloodflow, but the effects were different: the most pronounced effect was detected in administration of the hydroxy-form of the preparation, this can be explained by a modificationin the dispersion of the preparation (without changing the crystal lattice), an increase in the rate of dissolution in water and aqueous solutions, an increasein the number of functionally active groups in the heterocycle of the hydroxy-form of OA. Thus, the hydroxy-tautomer of orotic acid had the greatest efficacy relating to vasodilation of microvessels of the liver bloodstream in hyperhomocysteinemia; the fact suggesting feasibility of its further study in the clinical environment.

EFFECT OF A WHEY-BASED BIOPRODUCT ON METABOLIC PROCESSES IN THE MICROCIRCULATION

Aim. The article deals with the effect of a whey-based product on the metabolic processes, character, and local mechanisms of the microcirculation in athletes involved in track-and-field athletics. Materials and methods. 32 male athletes participated in the study. The microcirculation was studied with the help of the LAKK-M laser analyzer. The calculations were conducted by using a special software package (version 2.0.0.423, LAZMA, Russia). Results. It is established that a course of the MDX Multicomplex bioproduct increases blood perfusion in the microcirculatory bloodstream by 34% and erythrocyte fluctuation by 66%, which improve the efficiency of metabolic processes. Bloodstream modulation is provided by the enhanced performance of the local active regulatory mechanisms. A statistically significant increase of 42% is registered in the endothelium-dependent mechanism, the increase of 32% and 23% is found in the myogenic and neurogenic mechanisms respectively. The contribution of the passive regulatory mechanisms reduces as a result of chest and heart muscle performance. The physiologically active substances of the bioproduct are involved in the vasodilation of microvessels and redox reactions at the cellular level. A 22% increase in NADH reduced coenzyme and a 9% decrease in FAD oxidized coenzyme indicate a decrease in mitochondrial activity in the absence of physical exertion and, indirectly, confirm the complete restoration of the energy reserves. Conclusion. The data obtained proves the optimization of metabolic processes in the microcirculation as an effect of the MDX Multicomplex bioproduct.

Low-Fat Diet Designed for Weight Loss But Not Weight Maintenance Improves Nitric Oxide-Dependent Arteriolar Vasodilation in Obese Adults.

Obesity is associated with microvascular dysfunction. While low-fat diet improves cardiovascular risk, its contributions on microvascular function, independent of weight loss, is unknown. We tested the hypothesis that nitric oxide (NO)-dependent vasodilation in microvessels is improved by low-fat diets designed for weight loss (LFWL) compared to low-fat weight maintenance (LFWM) diet. Obese adults were randomly assigned to either a LFWL diet (n = 11) or LFWM diet (n = 10) for six weeks. Microvessels were obtained from gluteal subcutaneous fat biopsies before and after the intervention for vascular reactivity measurements to acetylcholine (Ach) and flow, with and without L-NAME or indomethacin. Vascular and serum NO and C-reactive protein (CRP) were also measured. LFWL diet increased flow-induced (FID) and ACh-induced dilation (AChID); an effect that was inhibited by L-NAME. Conversely, LFWM diet did not affect FID or AChID. Indomethacin improved FID and AChID in the baseline and this effect was minimized in response to both diets. Serum NO or CRP did not change in response to either diet. In conclusion, LFWL diet improves microvascular reactivity compared to LFWM diet and increased vascular NO contribution to the improved microvascular dilation. These data suggest that weight reduction on low fat diet is critical for microvascular health.

Abstract 18339: Weight Loss with Low Carbohydrate Diets Improves Flow Induced Vasodilation in Resistance Arteries

Introduction: Obesity is associated with microvascular dysfunction and reduced nitric oxide (NO). We tested the hypothesis that NO-dependent, flow induced vasodilation in microvessels is improved by low carbohydrate diets designed for weight loss. Methods: Obese female adults (BMI = 32.0 ± 0.6 kg/m 2 , pre & post, n=22) were randomly assigned to a low carbohydrate (LC) diet for weight loss (LCWL, n=11, 500 calorie/day deficit). All meals were prepared for 6 weeks (10% carbohydrate, 30% protein, 60% fat). Resistance arteries (RAs, internal diameter of 16021 μm, n=22) were dissected from gluteal subcutaneous fat biopsies at weeks 0 (pre) and 6 (post). Vessels were cannulated and exposed to pressure gradients (Δ10-Δ100 cmH 2 O), with or without L-NAME (10 -4 M, inhibitor of eNOS), PEG-catalase (PEG-CAT, 500 Units/ml, scavenger of H 2 O 2 ), indomethacin (INDO, 10 -5 M, inhibitor of cyclooxygenase), or pioglitazone (PIOG, 10 -5 M, PPARγ agonist) and to papaverine (10 -4 M), pre and post LC. NO or H 2 O 2 in RAs was measured by fluorescence microscopy. Results: LC diets reduced BMI (post 32.7±0.8% vs. pre 31.4±1.0%, p<0.01), and increased flow-induced vasodilation (FID, post 81 ± 3% vs. pre 63 ± 4%, at Δ100 cmH 2 O (p<0.01) that was reduced by L-NAME and PEG-CAT (p<0.05). Consistently, vascular NO (fluorescence ratio: 1.5 ± 0.3, post vs. pre, p<0.05) and H 2 O 2 (2.6 ± 1.2, p<0.05) were increased with flow, and inhibited by L-NAME and PEG-CAT, respectively. INDO reduced FID in post, less (p<0.05) than in pre LC. There was no effect of pioglitazone on FID both in pre and in post (p>0.05). Endothelium independent responses to papaverine were similar in pre and post LC. Conclusion: We found that after 6 weeks of WL on low carbohydrate diet, 1) BMI was reduced, and microvascular vasodilator reactivity was improved; 2) microvascular NO and H 2 O 2 generation were increased; and 3) there was no effect of pioglitazone on FID in resistance arteries. These data indicate that weight reduction on low carbohydrate diet is critical for improved and endothelium-dependent microvascular function. NIH ( R01HL095701 ).

Acute exertion elicits a H2O2-dependent vasodilator mechanism in the microvasculature of exercise-trained but not sedentary adults.

Brachial artery flow-mediated vasodilation in exercise-trained (ET) individuals is maintained after a single bout of heavy resistance exercise compared with sedentary individuals. The purpose of this study was to determine whether vasodilation is also maintained in the microcirculation of ET individuals. A total of 51 sedentary and ET individuals underwent gluteal subcutaneous fat biopsy before and after performing a single bout of leg press exercise. Adipose arterioles were cannulated in an organ bath, and vasodilation to acetylcholine was assessed±the endothelial nitric oxide inhibitorl-NG-nitroarginine methyl ester, the cyclooxygenase inhibitor indomethacin, or the hydrogen peroxide scavenger polyethylene glycol catalase. Separate vessels (isolated from the same groups) were exposed to an intraluminal pressure of 150 mm Hg for 30 minutes to mimic the pressor response, which occurs with isometric exercise. Vasodilation to acetylcholine was reduced in microvessels from sedentary subjects after either a single weight lifting session or exposure to increased intraluminal pressure, whereas microvessels from ET individuals maintained acetylcholine-mediated vasodilation. Before weight lifting, vasodilation of microvessels from ET individuals was reduced in the presence of l-NG-nitroarginine methyl ester and indomethacin. After weight lifting or exposure to increased intraluminal pressure, polyethylene glycol catalase significantly reduced vasodilation, whereas l-NG-nitroarginine methyl ester and indomethacin had no effect. These results indicate that (1) endothelium-dependent vasodilation in the microvasculature is maintained after heavy resistance exercise in ET individuals but not in sedentary subjects and that (2) high pressure alone or during weight lifting may induce a mechanistic switch in the microvasculature to favor hydrogen peroxide as the vasoactive mediator of dilation.

P70: Molecular and physiological aspects connecting red cell eNOS, red blood cell deformability and decreased microvascular function in patients with essential hypertension

Background Arterial hypertension (HT) is a complex multifactorial condition associated with cardiovascular disease. Independent studies show that HT is associated with microcirculatory and hemorheological alterations, such as decreased red blood cell (RBC) deformability, as well as decreased endothelial function and nitric oxide (NO) bioavailability. Recently we found RBC carry an active endothelial nitric oxide synthase (eNOS), which is decreased in cardiovascular disease.Hypothesis: We hypothesized that a reduced RBC deformability may contribute to induce a hypertensive phenotype via impairment of microcirculatory conductance. Methods To evaluate hemorehological alterations in HT, patients ( n = 10) with HT and age-and risk factors-matched subjects ( n = 10) without HT (control) were recruited. High BP was defined as systolic BP > 135 mm Hg and diastolic BP > 85 mm in 24 h BP measurements. RBC deformability was measured by laser-assisted optical rotational cell analyzer (LORCA) and assessed as elongation index (EI) at 1.73 Pa. RBC redox state (ROS, GSH) was assessed by labeling with diclorodihydrofluorescein and thiol-tracker and flow cytometry. Cutaneous microvascular function as post-occlusion reactive hyperemia was measured by noninvasive laser Doppler Perfusion imaging and quantified as area under the curve (AUC). Endothelial function of the brachial artery was assessed as flow-mediated dilatation (FMD) by high resolution ultrasound. Deformability of RBC from eNOS −/− mice was evaluated and compared to wild type (WT) C57Bl/6 mice. To evaluate NO and NOS-dependent changes in RBC deformability, RBC from healthy individuals ( n = 6) were treated with NO donors, NOS inhibitors and guanylate cyclase inhibitors. Measurements of cGMP production in RBC were assessed by ELISA. A stepwise linear regression as well as a multivariate linear regression model were performed to identify independent predictors for systolic BP. Results In the HT group EI (0.300 ± 0.007 vs. 0.326 ± 0.007, p = 0.013), AUC (1657 ± 422 vs. 2313 ± 473 PU; p = 0.009). and FMD (6.2% ± 0.7% vs. 5.0% ± 0.3 % p = 0.010) was reduced in the HT group, suggesting decreased deformability, shorter lasting vasodilation of microvessels and endothelial dysfunction. In RBC from HT patients the ROS levels increased and the GSH levels decreased, indicating increased oxidative stress. Univariate inverse correlations were found between systolic BP and AUC ( r = −0.485; p r = 0.726; p R 2 = 0.607, p = 0.004). In a translational approach we analyzed deformability in eNOS −/− mice, characterized by a dysfunctional endothelium and hypertension. eNOS −/− RBC are less deformable than WT RBC, show increased ROS and decreased GSH, similarly to the HT grouP Moreover, NO donors increased EI of RBC from healthy individuals, while NOS inhibition as well as guanlyte cyclase inhibition decreased cGMP levels and EI indicating that NO/NOS/cGMP dependent pathways control deformability in RBC. Conclusion The NO/NOS/cGMP pathway controls RBC mechanoproperties, and RBC deformability is an independent predictor of increased blood pressure in patients with arterial hypertension. Disclosure Nothing to disclose.

Influence of obesity on insulin‐mediated dilation in the human microcirculation

Obesity is known to reduce both insulin sensitivity to glucose and endothelial‐derived NO‐dependent vasorelaxation to insulin, but little is known about the effect of obesity on insulin‐induced dilation mediated by endothelial‐derived hyperpolarizing factors (EDHFs). We examined the influence of obesity on insulin‐mediated dilation in human adipose arterioles. Vasodilation in microvessels from human adipose tissue were examined in response to physiological concentrations of insulin (0.3 – 100 ng/ml) using videomicroscopy. Endothelial denudation or treatment with high K+ (45 mM) abolished dilation to insulin in obese subjects, indicating an EDHF mechanism. Treatment with PEG‐catalase reduced insulin dilation in arterioles from lean (BMI 22.5 ± 1.1; m ± SE) and obese (BMI 31.0 ± 1.0) subjects by 47% and 45% respectively. In the presence of L‐NAME and indomethacin (INDO), PEG‐catalase abolished the remaining dilation to insulin in arterioles of lean subjects; but had no further effect in obese subjects. The mono‐oxygenase inhibitor MS‐PPOH had no effect on insulin dilation in obese subjects. We conclude that H2O2 contributes significantly to EDHF dilation to insulin in lean subjects, but obesity induces a mechanistic switch to a non‐H2O2, non‐epoxyeicosatrienoic acid EDHF. (Supported by NHLBI grants HL‐094971 and HL‐080704 (DDG) and AHA Midwest Postdoctoral Fellowship Award).

Estimation of the microcirculation state in cerebrovascular disorders using laser doppler flowmetry data and hemorheological parameters

The microcirculation state was assessed in the group of patients with ischemic stroke (n = 30) and the control group of healthy individuals (n = 27) using laser Doppler flowmetry and the wavelet analysis of the amplitude-frequency range of microvascular blood flow oscillations combined with absorption spectroscopy. The hemorheological parameters (blood and plasma viscosity, the degree of red blood cell aggregability and deformability) were assessed in both groups, as were their correlations with the microcirculation parameters. Decreased tissue perfusion (by 25%) and specific oxygen consumption (by 21%) were revealed in a cerebrovascular accident. Changes in the tone-forming regulatory mechanisms of microcirculation of vasodilating nature (decreased microvascular tone, activation of the secretory function of endothelium) may be regarded as a compensatory reaction aimed at maintaining the blood supply of organs and tissues in stroke. The blood viscosity increase in patients due to the plasma viscosity increase and increased red blood cell aggregability and their decreased deformability cause the blood flow to slow down and the wall shear stress to increase, which activates the endothelial secretory function and vasodilation of microvessels. Correlation between the rheological parameters and the passive (respiratory and cardiac) rhythm amplitudes was observed in the control group. In patients, the hemorheological parameters were correlated with the characteristics of the active factors of microvascular blood flow modulation (endothelial, neurogenic, and myogenic), which confirms the role of changed blood properties and regulatory tone-forming mechanisms in the maintenance of tissue perfusion in cerbrovascular accidents.

Metoprolol impairs resistance artery function in mice

Acute β-blockade with metoprolol has been associated with increased mortality by undefined mechanisms. Since metoprolol is a relatively high affinity blocker of β(2)-adrenoreceptors, we hypothesized that some of the increased mortality associated with its use may be due to its abrogation of β(2)-adrenoreceptor-mediated vasodilation of microvessels in different vascular beds. Cardiac output (CO; pressure volume loops), mean arterial pressure (MAP), relative cerebral blood flow (rCBF; laser Doppler), and microvascular brain tissue Po(2) (G2 oxyphor) were measured in anesthetized mice before and after acute treatment with metoprolol (3 mg/kg iv). The vasodilatory dose responses to β-adrenergic agonists (isoproterenol and clenbuterol), and the myogenic response, were assessed in isolated mesenteric resistance arteries (MRAs; ∼200-μm diameter) and posterior cerebral arteries (PCAs ∼150-μm diameter). Data are presented as means ± SE with statistical significance applied at P < 0.05. Metoprolol treatment did not effect MAP but reduced heart rate and stroke volume, CO, rCBF, and brain microvascular Po(2), while concurrently increasing systemic vascular resistance (P < 0.05 for all). In isolated MRAs, metoprolol did not affect basal artery tone or the myogenic response, but it did cause a dose-dependent impairment of isoproterenol- and clenbuterol-induced vasodilation. In isolated PCAs, metoprolol (50 μM) impaired maximal vasodilation in response to isoproterenol. These data support the hypothesis that acute administration of metoprolol can reduce tissue oxygen delivery by impairing the vasodilatory response to β(2)-adrenergic agonists. This mechanism may contribute to the observed increase in mortality associated with acute administration of metoprolol in perioperative patients.

β3 Receptors: role in cardiometabolic disorders

Pharmacological and molecular approaches have shown that an atypical β-adrenoceptor (AR), called β(3)-AR, that is distinct from β(1)-ARs and β(2)-ARs, exists in some tissues in heterogeneous populations such as β(3a)-ARs and β(3b)-ARs. β(3)-ARs belong to a superfamily of receptors linked to guanine nucleotide binding proteins (G proteins). The β(3)-AR gene contains two introns whereas the β(1)-AR and β(2)-AR genes are intronless, leading to splice variants. β(3)-ARs can couple to G(i) and G(s) and they are reported to be present in brown adipose tissue, vasculature, the heart, among other tissues. β(3)-ARs cause vasodilation of microvessels in the islets of Langerhans and may participate in the pathogenesis of cardiac failure, during which modification of β(1)-AR and β(2)-AR expression occurs. The development of β(3)-AR agonists has led to the elaboration of promising new drugs, including antiobesity and antidiabetic drugs. This article reviews the various pharmacological actions of β(3)-ARs and their clinical implications for diabetes and cardiovascular diseases.

Derangements of post-ischemic cerebral blood flow by protein kinase C delta

Cerebral ischemia causes blood flow derangements characterized by hyperemia (increased cerebral blood flow, CBF) and subsequent hypoperfusion (decreased CBF). We previously demonstrated that protein kinase C delta (δPKC) plays an important role in hippocampal neuronal death after ischemia. However, whether part of this protection is due to the role of δPKC on CBF following cerebral ischemia remains poorly understood. We hypothesized that δPKC exacerbates hyperemia and subsequent hypoperfusion resulting in CBF derangements following ischemia. Sprague–Dawley (SD) rats pretreated with a δPKC specific inhibitor (δV1-1, 0.5 mg/kg) exhibited attenuation of hyperemia and latent hypoperfusion characterized by vasoconstriction followed by vasodilation of microvessels after 2-vessel occlusion plus hypotension measured by 2-photon microscopy. In an asphyxial cardiac arrest model (ACA), SD rats treated with δV1-1 (pre- and post-ischemia) exhibited improved perfusion after 24 h and less hippocampal CA1 neuronal death 7 days after ACA. These results suggest possible therapeutic potential of δPKC in modulating CBF and neuronal damage after cerebral ischemia.

Characterization of the Non-Invasive Assessment of the Cutaneous Microcirculation by Laser Doppler Perfusion Scanner

Microcirculatory dysfunction contributes to morbidity and mortality in vascular diseases. Here, we aimed at establishing a sensitive and valid method to measure microvascular reactivity during post-occlusive reactive hyperemia (PORH) using scanning laser Doppler perfusion imaging (LDPI) of the forearm. In a first series, LDPI was methodologically evaluated on the volar forearm of healthy volunteers (n = 10) before and after one to five minutes of upper arm occlusion. In a second series, readings were performed in 20 healthy subjects and 20 patients with coronary artery disease (CAD). Three minutes of forearm occlusion were sufficient to induce maximal vasodilation during PORH as indicated by maximal increase in perfusion unit (PU) amplitude that did not further increase after five-minute occlusion. Five-minute occlusion led to a significant prolongation of PORH with greater area under curve (AUC) suggesting longer lasting vasodilation of microvessels. The five-minute occlusion was associated with lower variability as compared with three minutes (intraindividual variability: 9-17% vs. 12-21%; interindividual variability: 13-24% vs. 14-26%). CAD patients exhibited significantly reduced amplitude (105 +/- 49 vs. 164 +/- 35 PU; p < 0.001), ratio (4.7 +/- 1.8 vs. 7.1 +/- 1.8; p < 0.001), and AUC (1656 +/- 1070 vs. 2723 +/- 864 PU x minutes; p = 0.001). Scanning LDPI is a feasible and reproducible method for non-invasive assessment of the cutaneous microcirculatory response during PORH.