Artery Vasomotor Research Articles

The preconditioning pulmonary protective effect of volatile isoflurane in acute lung injury is mediated by activation of endogenous iNOS

There is still a lack of evidence to support the use of specific anesthetic agents during major operations that could affect the development of postoperative acute lung injury (ALI). This study determined the protective effect of inhaled isoflurane in a rat model of endotoxin-induced ALI. Rats were exposed to volatile isoflurane (1.5% in oxygen) or pure oxygen via a facemask for 2h. After a 3-h recovery period, rats were reanesthetized and ALI was induced by intratracheal instillation of lipopolysaccharide (LPS, 1mg/kg in 0.5ml saline). In some animals, a specific inducible nitric oxide synthase (iNOS) inhibitor, 1400W, (10mg/kg, i.p.) was administered before exposure to isoflurane. Animals were sacrificed 12h later for analysis. Pulmonary artery vasomotor function and alveolocapillary permeability were assessed. Expression of iNOS and CD11b, and activity of myeloperoxidase in the lung were analyzed. The maximal relaxation response to acetylcholine was significantly potentiated in rats pretreated with isoflurane. Lung wet-to-dry ratio was reduced in the lung of isoflurane-treated animals. Expression of iNOS and CD11b were attenuated in the lung tissue obtained from rats receiving isoflurane. Furthermore, enzymatic activity of myeloperoxidase was also reduced in the lung preexposed to isoflurane. However, these pulmonary protective effects of isoflurane were significantly abolished by pretreatment with 1400W. Pretreatment with volatile isoflurane attenuated inflammatory process in the lung tissue of rats with LPS-induced ALI, and this preconditioning pulmonary protective effect was mainly mediated by activation of endogenous iNOS in the lung.

PERTINENT (a substudy of the EUROPA trial): a persistent legacy: EXPERTS' PERSPECTIVE

This editorial refers to an article by C. Ceconi et al . [9][1] published in Cardiovascular Research in 2007. It is accompanied by a retrospective editorial by two authors of that original article, R. Ferrari and C. Ceconi (doi: 10.1093/cvr/CVS165) as part of this Spotlight on Landmark Papers in Cardiovascular Research . Endothelial activation and dysfunction—usually associated with traditional cardiovascular disease risk factors and increased oxidative stress—initiate the atherosclerotic process. In patients with coronary artery disease (CAD), endothelial dysfunction results in abnormal coronary artery vasomotion, increased leucocyte adhesion to the vascular wall, platelet activation, and the release of pro-inflammatory molecules, all of which contribute to both the atherogenic process and atheromatous plaque growth. These events largely result from reduced nitric oxide (NO) production and bioavailability as well as the reduced expression and activity of endothelial nitric oxide synthase (eNOS), which can itself become a pro-atherogenic stimulus promoting an increase in oxidative stress.1,2 Prior to the publication of the EUROPA trial, several relatively small studies had suggested a correlation between coronary endothelial dysfunction and the occurrence of adverse events in patients with CAD.3–5 The important goal of improving endothelial dysfunction stimulated the development of therapies aimed at reversing or slowing down the processes leading to atherogenesis and vascular dysfunction. In this regard, the large EUROPA trial6 made an important contribution to the field. The study assessed whether the administration of the angiotensin-converting enzyme (ACE) inhibitor perindopril reduced … [1]: #ref-9

Influence of Sex and ERK MAPK on the Pressure Reactivity Index in Newborn Piglets After Fluid Percussion Injury.

Greater impairment in autoregulation is seen in male versus female piglets following fluid percussion injury (FPI). This is partially mediated by a greater upregulation of extracellular signal-related kinase mitogen-activated protein kinase (ERK MAPK). We hypothesized that these trends would be reflected by the pressure reactivity index (PRx), a clinical measure of autoregulation. We further hypothesized that PRx values would correlate well with pial artery dilatory responses to hypotension. Male and female piglets were subjected to FPI and treated with a vehicle or ERK MAPK antagonist U 0126 (1 mg/kg IV) 30 min post-injury. FPI led to upregulation of CSF ERK MAPK in untreated piglets of both sexes, however significantly higher PRx values were seen in male versus female piglets. Following administration of U 0126, elevation of ERK MAPK levels was blocked in both sexes and PRx values were significantly improved in the male. A strong correlation was seen between the PRx and pial artery vasomotor activity. These data support previous observations that male piglets demonstrate reversible ERK MAPK-mediated impairment in autoregulation following FPI, which is reflected by the PRx. The strong correlation between the PRx and pial artery vasomotor activity supports the practice of continuously monitoring cerebrovascular autoregulation in patients using this index.

A novel, non-invasive diagnostic clinical procedure for the determination of an oxygenation status of chronic lower leg ulcers using peri-ulceral transcutaneous oxygen partial pressure measurements: results of its application in chronic venous insufficiency (CVI).

The basis for the new procedure is the simultaneous transcutaneous measurement of the peri-ulceral oxygen partial pressure (tcPO2), using a minimum of 4 electrodes which are placed as close to the wound margin as possible, additionally, as a challenge the patient inhales pure oxygen for approximately 15 minutes. In order to evaluate the measurement data and to characterise the wounds, two new oxygen parameters were defined: (1) the oxygen characteristic (K-PO2), and (2) the oxygen inhomogeneity (I-PO2) of a chronic wound. The first of these is the arithmetic mean of the two lowest tcPO2 measurement values, and the second is the variation coefficient of the four measurement values. Using the K-PO2 parameter, a grading of wound hypoxia can be obtained. To begin with, the physiologically regulated (and still compensated) hypoxia with K-PO2 values of between 35 and 40 mmHg is distinguished from the pathological decompensated hypoxia with K-PO2 values of between 0 and 35 mmHg; the first of these still stimulates self-healing (within the limits of the oxygen balance). The decompensated hypoxia can be (arbitrarily) divided into “simple” hypoxia (Grade I), intense hypoxia (Grade II) and extreme hypoxia (Grade III), with the possibility of intermediate grades (I/II and II/III).Measurements were carried out using the new procedure on the skin of the right inner ankle of 21 healthy volunteers of various ages, and in 17 CVI (chronic venous insufficiency) wounds. Sixteen of the 17 CVI wounds (i.e., 94%) were found to be pathologically hypoxic, a state which was not found in any of the healthy volunteers. The oxygen inhomogeneity (I-PO2) of the individual chronic wounds increased exponentially as a function of the hypoxia grading (K-PO2), with a 10-fold increase with extreme hypoxia in contrast to a constant value of approximately 14% in the healthy volunteers. This pronounced oxygen inhomogeneity explains inhomogeneous wound healings, resulting in the so-called mosaic wounds. The hypoxia grades found in all of the chronic wounds was seen to be evenly distributed with values ranging from 0 to 40 mmHg, and therefore extremely inhomogeneous. In terms of oxygenation, chronic wounds are therefore inhomogeneous in two respects: (1) within the wound itself (intra-individual wound inhomogeneity) and (2) between different wounds (inter-individual wound inhomogeneity). Due to the extreme oxygen inhomogeneity, single measurements are not diagnostically useful. In healthy individuals the oxygen inhalation challenge (see above) results in synchronised tcPO2 oscillations occurring at minute rhythms, which are not seen in CVI wounds. These oscillations can be interpreted as a sign of a functioning arterial vasomotor system.The new procedure is suitable for the routine characterisation of chronic wounds in terms of their oxygen status, and correspondingly, their metabolically determining (and limiting) potential for healing and regeneration. The oxygen characteristic K-PO2 can furthermore be used as a warning of impending ulceration, since the oxygen provision worsens over time prior to the demise of the ulcerated tissue, thus making a controlled prophylaxis possible.

Increased endothelin-1 vasoconstriction in mesenteric resistance arteries after superior mesenteric ischaemia-reperfusion.

Endothelin-1 (ET-1) plays an important role in the maintenance of vascular tone. We aimed to evaluate the influence of superior mesenteric artery (SMA) ischaemia-reperfusion (I/R) on mesenteric resistance artery vasomotor function and the mechanism involved in the changes in vascular responses to ET-1. SMA from male Sprague-Dawley rats was occluded (90 min) and following reperfusion (24h), mesenteric resistance arteries were dissected. Vascular reactivity was studied using wire myography. Protein and mRNA expression, superoxide anion (O(2) (•-) ) production and ET-1 plasma concentration were evaluated by immunofluorescence, real-time quantitative PCR, ethidium fluorescence and elisa, respectively. I/R increased ET-1 plasma concentration, ET-1-mediated vasoconstriction and ET(B) mRNA expression, and down-regulated ET(A) mRNA expression. Immunofluorescence confirmed mRNA results and revealed an increase in ET(B) receptors in the mesenteric resistance artery media layer after I/R. Therefore, the ET(B) receptor agonist sarafotoxin-6 induced a contraction that was inhibited by the ET(B) receptor antagonist BQ788 only in vessels, with and without endothelium, from I/R rats. Furthermore, BQ788 potentiated ET-1 vasoconstriction only in sham rats. Endothelium removal in rings from I/R rats unmasked the inhibition of ET-1 vasoconstriction by BQ788. Endothelium removal, N(ω) -nitro-L-arginine methyl ester and superoxide dismutase abolished the differences in ET-1 vasoconstriction between sham and I/R rats. We also found that I/R down-regulates endothelial NOS mRNA expression and concomitantly enhanced O(2) (•-) production by increasing NADPH oxidase 1 (NOX-1) and p(47phox) mRNA. Mesenteric I/R potentiated the ET-1-mediated vasoconstriction by a mechanism that involves up-regulation of muscular ET(B) receptors and decrease in NO bioavailability.

Modulation of vasomotive activity in rabbit external ophthalmic artery by neuropeptides.

Purpose. To investigate the vasomotive activity upon the external ophthalmic artery of vasointestinal peptide (VIP) and neuropeptide Y (NPY) using a previously developed model. Methods. Isolated rabbit eyes (n = 12) were perfused in situ with tyrode through the external ophthalmic artery. Effects of intra-arterial injections of NPY 200 μg/ml (Group A; n = 6) and VIP 200 μg/ml (Group B; n = 6) on the recorded pressure were obtained. For statistical analysis, Student's paired t-test and Fast Fourier Transform were used. Results. Spontaneous oscillations were observed before any drug administration in the 12 rabbit models. NPY produced an increase in total vascular resistance and a higher frequency and amplitude of oscillations, while VIP evoked the opposite effects. Conclusions. This study provides evidence of vasomotion in basal conditions in rabbit external ophthalmic artery. Concerning drug effects, NPY increased arterial resistance and enhanced vasomotion while VIP produced opposite effects which demonstrates their profound influence in arterial vasomotion.

Human epicardial fat: what is new and what is missing?

1. Putative physiological functions of human epicardial adipose tissue (EAT) include: (i) lipid storage for the energy needs of the myocardium; (ii) thermoregulation, whereby brown fat components of EAT generate heat by non-shivering thermogenesis in response to core cooling; (iii) neuroprotection of the cardiac autonomic ganglia and nerves; and (iv) regulation of vasomotion and luminal size of the coronary arteries. Under pathophysiological circumstances, EAT may play an adverse paracrine role in cardiac arrhythmias and in lipotoxic cardiomyopathy, but of major current interest is its hypothetical role as an immunological organ contributing to inflammation around coronary artery disease (CAD). 2. The amount of EAT measured either by echocardiographic thickness over the free wall of the right ventricle or as volume by computed tomography expands in patients with obesity both without and with CAD. The mechanisms other than obesity governing the increase in EAT volume in CAD are unknown, but EAT around CAD is infiltrated by chronic inflammatory cells and overexpresses genes for adipokines that have pro- or anti-inflammatory actions and regulate oxidative stress plus angiogenesis. 3. Many cross-sectional studies have shown positive associations between increased EAT mass and stable CAD burden. One prospective population-based epidemiological study suggested that EAT volume at baseline is a predictor of acute myocardial infarction, but was without significant incremental predictive value after adjustment for established cardiovascular risk factors. However, strategies are needed to obtain robust epidemiological, interventional and experimental evidence to prove or disprove the hypothesis that EAT is a cardiovascular risk factor locally contributing to CAD.

Flow-Mediated Vasodilation in End-Stage Renal Disease

An intact endothelium is essential for adaptations between arterial vasomotor tone and shear stress (SS), i.e., flow-mediated vasodilation (FMD). Endothelial dysfunction occurs in hypertension, cardiac insufficiency, diabetes, atherosclerosis, and in end-stage renal disease (ESRD) patients, whose renal failure is associated with many of those cardiovascular diseases (CVD). Using a progressive hand-warming protocol and repeated measures ANOVA, we analyzed SS-mediated increase of brachial artery diameter (ΔBA) in 22 healthy controls, 18 CVD-negative ESRD patients (ESRD-CVD(-)), and 17 CVD-positive ESRD patients (ESRD-CVD(+)) to analyze the role of uremia versus CVD on FMD. Hand-warming increased SS (P < 0.001) and ΔBA (P < 0.001). Negative interactions were observed between ΔBA and ESRD (P < 0.001), and between ΔBA and CVD(+) (P < 0.02), but there was no interaction between ESRD and CVD(+) (P = 0.69). For low and mild SS increases, ESRD-CVD(-) patients were characterized by similar ΔBA as controls, but it was lower than controls at higher SS (P < 0.01). In ESRD-CVD(+) patients, brachial artery diameter did not respond to mild and moderate SS increases, and showed "paradoxical" vasoconstriction at higher SS (P < 0.05). In ESRD, a positive and independent interaction was observed between ΔBA and 25(OH) vitamin D(3) insufficiency (≤15 μg/L; P < 0.02). These observations indicate that, independently of each other, ESRD and CVD(+) history are associated with endothelial dysfunction. They also suggest the importance of considering the relationships between SS and endothelial function in different clinical conditions.

Prediction of Coronary Conduit Artery Endothelial Cell Phenotype by Phenotypic Assessment in the Systemic Vasculature

Human studies have established a correlation between endothelial vasomotor function assessed at the brachial and coronary arteries. This relationship spurred widespread investigation of brachial artery vasomotor function and, more recently, the isolation and phenotypic analysis of endothelial cells harvested invasively from the brachial artery (presumably with the application of understanding the coronary vascular endothelium). However, notwithstanding the correlation between vasomotor function in brachial and coronary arteries, the degree to which markers of endothelial cell phenotype correlate between systemic and coronary arteries is unknown. PURPOSE: Determine the degree to which endothelial cell phenotype assessed in peripheral conduit vessels is predictive of phenotype in the coronary artery endothelium in swine. METHODS: Isolated segments of thoracic and abdominal aorta, carotid, brachial, femoral, renal, internal mammary, and right coronary arteries were harvested at the time of sacrifice from 19 swine. Vessels were placed in a dissection buffer, cleaned of excess connective tissue, cut longitudinally, and the endothelium was mechanically scraped yielding an endothelial enriched sample of vascular cells. Samples were subsequently probed for eNOS, HSP90, p67phox, SOD1 and SOD3 protein expression via immunobloting. RESULTS: Expression of eNOS, HSP90, SOD1, and SOD3 was on average well correlated (p < 0.05 vs. coronary artery for each vessel) between systemic conduit arteries and the right coronary artery (mean rho value = 0.71 ± 0.02, 0.83 ± 0.02, 0.72 ± 0.02, and 0.91 ± 0.01 for eNOS, HSP90, SOD1, and SOD3, respectively). In contrast, expression of p67phox in systemic conduit artery endothelium was not correlated to that in the right coronary artery (mean rho value = 0.24 ± 0.04, p > 0.05 vs. coronary artery for each vessel). CONCLUSION: We conclude that endothelial cell protein expression assessed in peripheral conduit arteries is predictive of expression levels in the conduit coronary arteries in the cases of some (e.g., eNOS, HSP90, SOD1 and SOD3) but not all (e.g., p67phox) markers of endothelial cell phenotype. Supported by: P01-HL052490 (M.H.L.) and T32-AR048523 (G.H.S. and J.P.).

Bestrophin is important for the rhythmic but not the tonic contraction in rat mesenteric small arteries

We have previously characterized a cGMP-dependent Ca(2+)-activated Cl(-) current in vascular smooth muscle cells (SMCs) and have shown its dependence on bestrophin-3 expression. We hypothesize that this current is important for synchronization of SMCs in the vascular wall. In the present study, we aimed to test this hypothesis by transfecting rat mesenteric small arteries in vivo with siRNA specifically targeting bestrophin-3. The arteries were tested 3 days after transfection in vitro for isometric force development and for intracellular Ca(2+) in SMCs. Bestrophin-3 expression was significantly reduced compared with arteries transfected with mutated siRNA. mRNA levels for bestrophin-1 and -2 were also significantly reduced by bestrophin-3 down-regulation. This is suggested to be secondary to specific bestrophin-3 down-regulation since siRNAs targeting different exons of the bestrophin-3 gene had identical effects on bestrophin-1 and -2 expression. The transfection affected neither the maximal contractile response nor the sensitivity to norepinephrine and arginine-vasopressin. The amplitude of agonist-induced vasomotion was significantly reduced in arteries down-regulated for bestrophins compared with controls, and asynchronous Ca(2+) waves appeared in the SMCs. The average frequency of vasomotion was not different. 8Br-cGMP restored vasomotion in arteries where the endothelium was removed, but oscillation amplitude was still significantly less in bestrophin-down-regulated arteries. Thus, vasomotion properties were consistent with those previously characterized for rat mesenteric small arteries. Data from our mathematical model are consistent with the experimental results. This study demonstrates the importance of bestrophins for synchronization of SMCs and strongly supports our hypothesis for generation of vasomotion.

Long-term exercise training does not alter brachial and femoral artery vasomotor function and endothelial phenotype in healthy pigs

Although the beneficial effects of exercise training on conduit artery endothelial function are well-established in animals and humans with compromised basal function, whether exercise exerts favorable effects on a healthy endothelium is inconclusive. We sought to determine whether long-term exercise training enhances endothelial function in peripheral conduit arteries of healthy pigs. Using a retrospective analysis of data collected in our laboratory (n = 127), we compared in vitro brachial and femoral artery endothelium-dependent and -independent relaxation between a group of pigs that exercise-trained for 16-20 wk and a group that remained sedentary. No differences in vasomotor function were found between the 2 groups (P > 0.05). Additionally, in a subset of pigs (n = 16), expression levels of 18 proteins that are typically associated with the atherosclerotic process were measured by immunoblot analysis of endothelial cell scrapes obtained from the brachial and femoral arteries. We found no differences (P > 0.05) in endothelial gene expression between these exercise-trained and sedentary healthy pigs. These results indicate that pigs exhibiting the classic training-induced adaptations do not demonstrate enhanced endothelium-dependent dilation nor reveal a more atheroprotected endothelial cell phenotype in their brachial and femoral arteries than their sedentary but otherwise healthy counterparts.

Response to Letter Regarding Article, “Donor Pretreatment With Hypertonic Saline Attenuates Primary Allograft Dysfunction: A Pilot Study in a Porcine Model”

We thank Drs Deutsch and Kaczmarek for their careful review of our article.1 As they note, we observed enhanced ventricular recovery in addition to preserved coronary artery vasomotor function with donor pretreatment with hypertonic saline in a porcine heart transplant model. They postulate that a mechanism to explain our positive results is the prevention of intracellular Ca2+ accumulation induced by extracellular hypernatremia. Furthermore, they present the results of 2 retrospective studies2,3 that examined the correlation between donor serum sodium levels immediately before organ procurement and primary graft failure and note that the lowest incidence of primary graft failure occurred with the most severely hypernatremic donors, although this did not reach statistical significance. Although we …

Vasomotion in rat small mesenteric arteries is bestrophin‐3 dependent.

We have hypothesized the importance of a cGMP‐dependent Ca‐activated Cl current for synchronization of smooth muscle cells (SMCs) in the vascular wall and have shown that cGMP‐dependent Ca‐activated Cl current dependens on bestrophin‐3 (Best‐3) expression.To study the role of Best‐3 for vascular tone, we transfected rat small mesenteric arteries in vivo with siRNA against Best‐3 and with non‐functional mutated Best‐3 siRNA, as a control. The arteries were tested 3 days after in vitro for isometric force development and for [Ca2+]i.Best‐3 protein expression was downregulated with specific siRNA by 65.0±5.8 % versus control arteries transfected with mutated siRNA. The transfection did not affect either maximal contractile response or sensitivity to noradrenalin (NA). Relaxation to acetylcholine was not affected either. The amplitude of NA‐induced vasomotion in arteries downregulated for Best‐3 was significantly lower than in the controls, while frequency was not different. The downregulation of Best‐3 partly desynchronized the global [Ca2+]i oscillations in SMCs and asynchronous Ca waves appeared.Our study demonstrates the importance of Best‐3 for synchronization of SMCs and, thus, generation of vasomotion.

Propagation Mechanisms of Calcium Waves Arising During Arterial Vasomotion

Vasomotion consists in cyclic arterial diameter variations induced by synchronous contractions and relaxations of smooth muscle cells (SMCs) present in the arterial wall. These contractions have been shown to be due to an increase in the intracellular cytosolic calcium concentration. However, the arteries do not contract simultaneously on macroscopic distances and a propagation of the diameter variations can be observed. Our aim was to investigate this propagation. We stimulated endothelium denuded rat mesenteric arterial strips with the vasoconstrictor, phenylephrine (PE) to obtain vasomotion and observed that the contraction waves are linked to intercellular calcium waves through the SMCs. A velocity of about 100 μm/s was measured for the two kinds of waves which could propagate either from the distal to the proximal side of the artery or in the opposite direction. To investigate the calcium wave propagation mechanisms, we used a method allowing a PE stimulation of a small area of the strip. No calcium propagation could be induced by this local stimulation when the strip was in its resting state. However, if a low PE concentration was added to the whole strip, local PE stimulations induced calcium waves spreading over finite distances. The calcium wave velocity induced by local stimulation was identical to the velocity observed during vasomotion. This suggests that the propagation mechanisms are similar in the two cases. Using inhibitors of gap junctions and of voltage operated calcium channels, we showed that the locally induced calcium propagation likely depends on the propagation of the SMCs depolarization. Finally, from the experimental data gathered, it is possible to propose a model of the mechanisms underlying the propagation.

Thromboxane receptor-mediated vasomotion and cerebrocortical blood flow oscillations in NO-deficiency

Event Abstract Back to Event Thromboxane receptor-mediated vasomotion and cerebrocortical blood flow oscillations in NO-deficiency Gábor Lenzsér1, Béla Horváth1, András Iring1, Péter Hermán1, Katalin Komjáti1, Péter Sándor1 and Zoltán Benyó1* 1 Semmelweis University, Institute of Human Physiology and Clinical Experimental Research, Hungary The effect of the thromboxane-receptor agonist U-46619 on the development of vasomotion of middle cerebral arteries (MCAs) in vitro and cerebrocortical blood flow (CoBF)-oscillations in vivo was studied under physiological conditions and after NO synthase (NOS) blockade. CoBF was measured in the parietal cortex of anesthetized, spontaneously breathing adult male Wistar rats by laser Doppler (LD) flowmetry. The dominant frequency and the corresponding magnitude of the LD flux (LDF) oscillations were evaluated by Fourier-analysis before and after the administration of U-46619. In vitro experiments were performed in isolated MCA segments by isometric tension recording in a conventional myograph system. Under physiological conditions the administration of U-46619 (1 μg/kg i.v.) failed to change the LDF or induce LDF oscillations. After NOS blockade by NG-nitro-L-arginine methyl ester (L-NAME, 100 mg/kg i.v.) the LDF decreased and oscillations appeared with a dominant frequency of 0.144±0.023 Hz and a magnitude of 5.99±0.66 AU. Administration of U-46619 resulted in a significant (p<0.05) increase of the magnitude of the oscillation to 8.84±0.94 AU without changing the frequency (0.144±0.026 Hz) or the mean LDF. Similarly, in isolated MCA segments 1 μM U-46619 had no effect under physiological conditions but induced marked vasomotion in the presence of 100 μM L-NAME. Our results demonstrate that activation of the thromboxane-receptors with a low dose of U-46619, which has no major effect on the cerebrovascular tension or cerebrocortical blood flow under physiological conditions, evokes strong vasomotion and CoBF-oscillations in the absence of NO. Supported by NKTH OMFB-00770/2009, TÁMOP 4.2.2. - 08/1/KMR-2008-004, OTKA K62375 and an EFSD/Servier Grant Award. Conference: IBRO International Workshop 2010, Pécs, Hungary, 21 Jan - 23 Jan, 2010. Presentation Type: Poster Presentation Topic: Disorders of the nervous system Citation: Lenzsér G, Horváth B, Iring A, Hermán P, Komjáti K, Sándor P and Benyó Z (2010). Thromboxane receptor-mediated vasomotion and cerebrocortical blood flow oscillations in NO-deficiency. Front. Neurosci. Conference Abstract: IBRO International Workshop 2010. doi: 10.3389/conf.fnins.2010.10.00026 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 19 Apr 2010; Published Online: 19 Apr 2010. * Correspondence: Zoltán Benyó, Semmelweis University, Institute of Human Physiology and Clinical Experimental Research, Budapest, Hungary, zoltan.benyo@pharma.uni-heidelberg.de Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Gábor Lenzsér Béla Horváth András Iring Péter Hermán Katalin Komjáti Péter Sándor Zoltán Benyó Google Gábor Lenzsér Béla Horváth András Iring Péter Hermán Katalin Komjáti Péter Sándor Zoltán Benyó Google Scholar Gábor Lenzsér Béla Horváth András Iring Péter Hermán Katalin Komjáti Péter Sándor Zoltán Benyó PubMed Gábor Lenzsér Béla Horváth András Iring Péter Hermán Katalin Komjáti Péter Sándor Zoltán Benyó Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Influence of exercise and perivascular adipose tissue on coronary artery vasomotor function in a familial hypercholesterolemic porcine atherosclerosis model

Our lab has shown that left circumflex coronary artery (LCX) perivascular adipose tissue (PAT) blunts endothelin-1 (ET-1)-induced maximal contractions in normal pigs on low- and high-fat diets. Other studies report that PAT exerts anticontractile effects on agonist-induced arterial contraction via release of a relaxing factor that acts on the underlying vasculature. The purpose of this study was to test the hypotheses that PAT blunts LCX contraction in familial hypercholesterolemic pigs and that exercise training (Ex) augments this anticontractile effect. Male familial hypercholesterolemic pigs were divided into Ex (n = 13) and sedentary (Sed) (n = 15) groups. LCX reactivity to angiotensin II (ANG II), bradykinin (BK), ET-1, and sodium nitroprusside (SNP) was evaluated in vitro with intact or removed PAT in Sed and Ex familial hypercholesterolemic pigs. LCX relaxation induced by BK and SNP was not altered by Ex or PAT removal. LCX contractions stimulated by ANG II and ET-1 were not significantly altered by Ex or PAT removal across doses; however, Ex did act to significantly reduce ET-1 maximal contractions in familial hypercholesterolemic pig LCX compared with Sed familial hypercholesterolemic pig LCX, independent of PAT (P < 0.05). We conclude that LCX PAT in Sed and Ex familial hypercholesterolemic pigs exerts no substantial anticontractile influence over LCX vasomotor responses to endogenous constrictors such as ANG II and ET-1. Our results suggest that exercise training significantly reduces familial hypercholesterolemic pig LCX maximal contractile responses to the endogenous constrictor ET-1, independent of PAT.

Abstract 5252: Long-Term Administration of Thiazolidinedione Improves Vasomotion of Coronary Arteries Irrespective of Improvements in Diabetic Status for Patients Receiving an Angiotensin-II Receptor Blocker

Background: Effects of insulin sensitizing agents on coronary artery pathophysiology have marked attention, but the long-term effects remain uncertain. We previously reported clinical effects of thiazolidinedione, and adverse prognostic impacts of vasomotor dysfunction in coronary arteries. This study evaluated long-term effects of thiazolidinedione, an insulin sensitizer, on vasomotion of coronary arteries frequently affected by diabetes mellitus, in patients treated with an angiotensin-II receptor blocker, one of the best possible antiatherosclerotic therapies. Methods: Twenty-two type-2 diabetic patients treated with an angiotensin-II receptor blocker, were randomized where they received troglitazone (400mg/ day) or pioglitazone (30mg/day) (group-T), or they received therapy without thiazolidinedione for more than 1 year (group-C). We measured reactive changes in coronary blood flow (coronary flow reserve: CFR) or reactive endothelium-dependent dilatation (FMD) of coronary arteries to infusion of ATP (50 μ g) into the study (normal or minimally diseased) left coronary artery. CFR (maximal hyperemic flow-baseline flow/baseline flow) was quantified by coronary angiography and intracoronary doppler-guidewire. Changes in CFR and FMD were compared between the 2 groups. Results: All the enrolled patients manifested good compliance to the treatment and there were improvements in some of metabolic variables in group-T (n=11). CFR increased in group-T (p=0.027) but not in group-C (p=0.102). FMD also increased in group-T (p&lt;0.001), while it remained unchanged in group-C (p=0.768). Changes of CFR or FMD did not correlate to those of HbA1c (CFR: r=0.19, p=0.66, FMD: r=0.15, p=0.80). Conclusion: This study suggests that long-term thiazolidinedione use improves vasomotion of coronary arteries irrespective of glucose metabolic status, which may have beneficial potentials for management of coronary artery disease with type-2 diabetes mellitus.

Association of Ornithine Transcarbamylase Gene Polymorphisms With Hypertension and Coronary Artery Vasomotion

Previous studies have suggested that the activity of enzymes involved in the urea cycle may modulate nitric oxide (NO) production, arterial vasomotion, and hypertension. Our aim was to determine whether hypertension and coronary vasomotion could be associated with polymorphisms within the ornithine transcarbamylase (OTC) gene, located on chromosome X and coding for a key-enzyme of the urea cycle. Among 11 OTC polymorphisms that were originally selected from databases, the tag single-nucleotide polymorphism (SNP) rs5963409 and the independent SNP rs1800321 were tested for association with hypertension in two independent population samples recruited in Northern (Multinational MONItoring of trends and determinants in CArdiovascular disease (MONICA) study, n = 1,138) and Western (Etude du Vieillissement Artériel (EVA) study, n = 1,166) France. The vasomotor response of coronary arteries to methylergonovine maleate and isosorbide dinitrate was also evaluated in an independent sample (the vasomotion study, n = 121). In males, the frequency of the rs5963409 minor allele was consistently higher in hypertensive (HT) than in normotensive subjects in the MONICA and EVA studies. In the combined sample, the rs5963409 minor allele was associated with an increased risk of hypertension (odds ratio (OR) (95% confidence interval (CI)) = 1.45 (1.10-1.90); P = 0.008). This association was independent of classical confounding factors. Consistently, rs5963409 minor allele was associated with a greater susceptibility to vasoconstriction in response to methylergonovine maleate (P = 0.0072). In contrast, no significant association between rs5963409 and hypertension could be detected in females. Our results suggest that the OTC rs5963409 polymorphism may be associated with hypertension and coronary vasomotion in males.

TRPV4-dependent dilation of peripheral resistance arteries influences arterial pressure

Transient receptor potential vanilloid 4 (TRPV4) channels have been implicated as mediators of calcium influx in both endothelial and vascular smooth muscle cells and are potentially important modulators of vascular tone. However, very little is known about the functional roles of TRPV4 in the resistance vasculature or how these channels influence hemodynamic properties. In the present study, we examined arterial vasomotor activity in vitro and recorded blood pressure dynamics in vivo using TRPV4 knockout (KO) mice. Acetylcholine-induced hyperpolarization and vasodilation were reduced by approximately 75% in mesenteric resistance arteries from TRPV4 KO versus wild-type (WT) mice. Furthermore, 11,12-epoxyeicosatrienoic acid (EET), a putative endothelium-derived hyperpolarizing factor, activated a TRPV4-like cation current and hyperpolarized the membrane of vascular smooth muscle cells, resulting in the dilation of mesenteric arteries from WT mice. In contrast, 11,12-EET had no effect on membrane potential, diameter, or ionic currents in the mesenteric arteries from TRPV4 KO mice. A disruption of the endothelium reduced 11,12-EET-induced hyperpolarization and vasodilatation by approximately 50%. A similar inhibition of these responses was observed following the block of endothelial (small and intermediate conductance) or smooth muscle (large conductance) K(+) channels, suggesting a link between 11,12-EET activity, TRPV4, and K(+) channels in endothelial and smooth muscle cells. Finally, we found that hypertension induced by the inhibition of nitric oxide synthase was greater in TRPV4 KO compared with WT mice. These results support the conclusion that both endothelial and smooth muscle TRPV4 channels are critically involved in the vasodilation of mesenteric arteries in response to endothelial-derived factors and suggest that in vivo this mechanism opposes the effects of hypertensive stimuli.

Endothelium-dependent vasomotor dysfunction in pig coronary arteries with paclitaxel-eluting stents is associated with inflammation and oxidative stress

Objectives We sought to evaluate coronary epicardial and intramyocardial resistance, arterial vasomotor function, local inflammatory reaction, and superoxide anion (O2· −) production after overlapping paclitaxel-eluting stent (PES) implantation in a porcine model. Background PES implantation has been shown to elicit coronary vasomotor dysfunction. However, underlying mechanisms remain largely unknown. Methods Nine pigs received overlapping PES and bare-metal stents (BMS) in the coronary arteries, and 3 sham animals were naive. At 1 month, inflammatory response at the overlapped region was assessed by histopathology and scanning electron microscopy. Endothelial vasomotor function and O2· − at nonstented coronary reference segments were measured by angiography and organ chamber tensiometry, and lucigenin luminometry; vasomotor function of distal resistance arteries was measured by myography. Results Paclitaxel-eluting stents showed reduced late lumen loss, but inflammation and luminal inflammatory cell adherence were higher than for BMS (p Conclusions Abnormal endothelium-dependent relaxation at both coronary conduit and resistance arteries was demonstrated after overlapping PES implantation. Profound localized inflammatory reaction, as well as enhanced local oxidative stress, may contribute to vasomotor dysfunction.