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OBJECTIVE--Endothelin (ET)-1 is a vasoconstrictor and proin-flammatory peptide that may interfere with glucose uptake. Our objective was to investigate whether exogenous ET-1 affects glucose uptake in the forearm of individuals with insulin resistance and in cultured human skeletal muscle cells. RESEARCH DESIGN AND METHODS--Nine male subjects (aged 61 ± 3 years) with insulin resistance (M value <5.5 mg/kg/min or a homeostasis model assessment of insulin resistance index >2.5) participated in a protocol using saline infusion followed by ET-1 infusion (20 pmol/min) for 2 h into the brachial artery. Forearm blood flow (FBF), endothelium-dependent vasodilatation, and endothelium-independent vasodilatation were assessed. Molecular signaling and glucose uptake were determined in cultured skeletal muscle cells. RESULTS--ET-1 decreased forearm glucose uptake (FGU) by 39% (P < 0.05) after the 2-h infusion. ET-1 reduced basal FBF by 36% after the 2-h infusion (P < 0.05) and impaired both endothelium-dependent vasodilatation (P < 0.01) and endothelium-independent vasodilatation (P < 0.05). ETA and ETB receptor expression was detected on cultured skeletal muscle cells. One-hour ET-1 incubation increased glucose uptake in cells from healthy control subjects but not from type 2 diabetic patients. Incubation with ET-1 for 24 h reduced glucose uptake in cells from healthy subjects. ET-1 decreased insulin-stimulated Akt phosphorylation and increased phosphorylation of insulin receptor substrate-1 serine 636. CONCLUSIONS--ET-1 not only induces vascular dysfunction but also acutely impairs FGU in individuals with insulin resistance and in skeletal muscle cells from type 2 diabetic subjects. These findings suggest that ET-1 may contribute to the development of insulin resistance in skeletal muscle in humans. [ABSTRACT FROM AUTHOR]

Background Small studies suggest that postconditioning reperfusion interrupted by brief repetitive cycles of reocclusions, may protect the myocardium in the clinical setting. Objective To test the hypothesis that postconditioning limits infarct size in relation to the area at risk in patients with ST elevation myocardial infarction (STEMI). Methods 76 patients (aged 37 · 87 years) eligible for primary percutaneous coronary intervention due to STEMI were randomised to standard percutaneous coronary intervention (n=38) or postconditioning, consisting of four cycles of 60 s reperfusion and 60 s of reocclusion before permanent reperfusion (n=38). Results The area at risk was determined from angiographic abnormally contracting segments. Infarct size was quantified from delayed enhancement MRI on days 6·9. Infarct size, expressed in relation to the area at risk, did not differ between the control group (44%; 30, 56) (median and quartiles) and the post-conditioned group (47%; 23, 63). The slope of the regression lines relating infarct size to the area at risk differed between the two groups. Infarct size was significantly (p=0.001) reduced by postconditioning in patients with large areas at risk. The area under the curve and peak troponin T release and CKMB during 48 h did not differ between patients in the control and postconditioning groups. Conclusions This prospective, randomised trial suggests that postconditioning does not reduce infarct size in patients with STEMI in the overall study group. The data indicate that postconditioning may be of value in patients with large areas at risk. [ABSTRACT FROM AUTHOR]

Background: In order to determine myocardial salvage, accurate quantification of myocardium at risk (MaR) is necessary. We present a validated novel automatic segmentation algorithm for quantification of MaR by myocardial perfusion SPECT (MPS) in patients with acute coronary occlusion. Methods and Results: Twenty-nine patients with coronary occlusion were injected with a perfusion tracer before reperfusion, and underwent rest MPS within 4 hours. The MaR was quantified using the proposed algorithm (Segment software), the software Quantitative Perfusion SPECT (QPS) and by manual segmentation. The Segment MaR algorithm used a threshold of 55% of maximal counts and an a priori model based on normal coronary artery perfusion territories. The MaR was 30 ± 10% left ventricular mass (%LVM) by manual segmentation, 31 ± 12%LVM by Segment, and 36 ± 14%LVM by QPS. There was a good agreement between automatic and manual segmentation for both of the algorithms with a lower bias for Segment (.8 ± 4.0%LVM) than for QPS (5.8 ± 5.8%LVM) when compared to manual segmentation. Conclusions: The Segment MaR algorithm can be used to correctly assess MaR from MPS images in patients with acute coronary occlusion without access to tracer-specific normal database. The MaR in relation to final infarct size enables determination of myocardial salvage. [ABSTRACT FROM AUTHOR]

Aims: Nitric oxide (NO) is vital for the integrity of the cardiovascular system and protection against ischaemic heart disease. Arginase is up-regulated during ischaemia–reperfusion (IR) and this enzyme might compete with NO synthase (NOS) for arginine. The present study investigated whether arginase blockade protects from myocardial IR injury and whether such an effect is coupled to increased NO bioavailability. [ABSTRACT FROM PUBLISHER]

Background: Overweight and the metabolic syndrome (MS) represent dramatically increasing problems in children and adolescents. Waist circumference (WC) is an important factor to determine MS. So far, WC is a predictor of blood pressure, high-density lipoprotein (HDL), insulin concentration, and visceral fat in adolescents. We investigated whether WC and body mass index standard deviation score (BMI-SDS) are predictors of adiponectin, stromal-derived factor (SDF-1), and soluble E-selectin (sE-selectin) as parameters for beginning insulin resistance and endothelial damage. Methods: Seventy-nine male Caucasian adolescents were studied, aged 13–17 yr. Thirty-eight (48%) of them had a WC above 90th age percentile. All participants were enrolled in one consultation, recording various parameters and collecting one blood sample. Results: Differences in systolic blood pressure, HDL, high sensitive C-reactive protein, and hemoglobin A1c could be found between groups above or below the 90th WC percentile. Linear regression analysis revealed that WC and BMI-SDS predict traditional risk factors, as well as reduced adiponectin, lower SDF-1, and higher sE-selectin levels. Multiple linear regression analyses show that SDF-1 is in closest correlation to WC and BMI-SDS. Conclusions: WC and BMI-SDS predict various alterations of traditional and new cardiovascular risk factors. SDF-1 might be a new marker for diagnosis of obesity-related diseases and help understand pathophysiologic mechanisms. [ABSTRACT FROM AUTHOR]

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Aims: Endothelin-1 levels are elevated in patients with type 2 diabetes mellitus and may contribute to impaired microvascular function. We investigated the effect of selective endothelin-A (ETA) receptor blockade (BQ123) on skin microcirculation in patients with type 2 diabetes and albuminuria. Methods: Ten type 2 diabetes patients and 8 non-diabetic controls were investigated. Nutritive skin capillary circulation, investigated by videophotometric capillaroscopy, and total skin microcirculation, assessed by laser Doppler fluxmetry (LDF), were studied during intra-arterial infusion of saline for 15 min, followed by BQ123 infusion for 60 min. Results: Following BQ123 infusion there was a significant increase in resting capillary blood cell velocity (CBV) in patients with type 2 diabetes from 0.24 (0.20–0.34) mm/s at baseline to 0.61 (0.46–0.88) mm/s at 60 min, but no significant change in the control subjects [0.55 (0.10–0.68) vs. 0.38 (0.13–0.88) mm/s; p < 0.005 for difference between groups]. Peak CBV following arterial occlusion and skin temperature increased significantly in the type 2 diabetes group but not in the control group during BQ123 infusion. There were no significant changes in LDF parameters during infusion of BQ123 in either group. Conclusion: ETA receptor blockade improves nutritive skin capillary circulation in patients with type 2 diabetes and microangiopathy. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aims: Cardiovascular disease and type 2 diabetes mellitus are associated with low plasma concentration of adiponectin. The aim of this study was to investigate whether adiponectin exerts cardioprotective effects during myocardial ischaemia-reperfusion and whether this effect is related to the production of nitric oxide (NO). [ABSTRACT FROM PUBLISHER]

Abstract: Endothelin (ET)-1 is a potent vasoconstrictor peptide originally isolated from endothelial cells. Its production is stimulated in a variety of different cell types under the influence of risk factors for cardiovascular disease and during the development of cardiovascular disease. Based on these observations and the biological effects induced by ET-1, including profound vasoconstriction, pro-inflammatory actions, mitogenic and proliferative effects, stimulation of free radical formation and platelet activation, ET-1 has been implicated as an important factor in the development of vascular dysfunction and cardiovascular disease. In the following the pathogenic role of ET-1, the mechanisms underlying the involvement of ET-1 for the development of vascular dysfunction and the potentially beneficial therapeutic effects of selective ETA and dual ETA/ETB receptor antagonists will be discussed. In particular the changes of pathophysiological importance mediated by ET-1 in clinical studies are reviewed. These changes may be of significance for the development of various cardiovascular diseases beyond pulmonary arterial hypertension which is the currently approved indication for ET receptor antagonists. [Copyright &y& Elsevier]

Abstract: Background: Large burns cause systemic inflammation and myocardial depression. We hypothesized that small burns affect cardiac tolerance to ischemia, and that tumor necrosis factor alpha (TNFα) signaling through endothelin-1 (ET) and nuclear factor kappa B (NFκB) are associated. Methods: Mice were randomly assigned to four groups: burn (caused by boiling water on <2% of the body surface area), sham, burn+etanercept (TNFα blocker) treatment and sham+etanercept treatment. Twenty-four hours later, hearts were isolated and subjected to global ischemia followed by reperfusion. Additional hearts and burned skin lesions were sampled to evaluate expression of TNFα (immunoblotting) and endothelin-1 (radioimmunoassay). A NFκB-luciferase reporter mouse was used to evaluate NFκB activation. Results: Baseline cardiac function before ischemia (BI) was only negligibly influenced by burn or etanercept, but was reduced by burn+etanercept. Burn markedly impaired post-ischemic left ventricular function and increased infarct size in comparison with sham-treated mice. Cardiac, but nut cutaneous, expression of TNFα was increased in burned mice, while cardiac NFκB and endothelin-1 were not influenced. TNFα blockade reduced the detrimental effects of burn on cardiac tolerance to ischemia. Conclusions: Small cutaneous burns, that did not influence baseline heart function, impaired the tolerance to ischemia. This effect may be mediated through TNFα, but does not involve signaling through NFκB or endothelin-1. [Copyright &y& Elsevier]

Hydroxymethyl glutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) protect the myocardium against ischemia-reperfusion injury via a mechanism unrelated to cholesterol lowering. Statins may inhibit isoprenylation and thereby prevent activation of proteins such as RhoA. We hypothesized that statins protect the myocardium against ischemia-reperfusion injury via a mechanism involving inhibition of geranylgeranyl pyrophosphate synthesis and translocation of RhoA to the plasma membrane. Sprague-Dawley rats were given either the HMG-CoA reductase inhibitor rosuvastatin, geranylgeranyl pyrophosphate dissolved in methanol, the combination of rosuvastatin and geranylgeranyl pyrophosphate, rosuvastatin and methanol, or distilled water (control) by intraperitoneal injection for 48 h before ischemia-reperfusion. Animals were anesthetized and either subjected to 30 min of coronary artery occlusion followed by 2 h of reperfusion whereat infarct size was determined, or the expression of RhoA protein was determined in cytosolic and membrane fractions of nonischemic myocardium. There were no significant differences in hemodynamics between the control group and the other groups before ischemia or during ischemia and reperfusion. The infarct size was 80 ± 3% of the area at risk in the control group. Rosuvastatin reduced infarct size to 64 ± 2% (P < 0.001 vs. control). Addition of geranylgerapyl pyrophosphate (77 ± 2%, P < 0.01 vs. rosuvastatin) but not methanol (65 ± 2%, not significant vs. rosuvastatin) abolished the cardioprotective effect of rosuvastatin. Geranylgeranyl pyrophosphate alone did not affect infarct size per se (84 ± 2%). Rosuvastatin increased the cytosol-to-membrane ratio of RhoA protein in the myocardium (P < 0.05 vs. control). These changes were abolished by addition of geranylgeranyl pyrophosphate. We conclude that the cardioprotection and the increase of the RhoA cytosol-to-membrane ratio induced by rosuvastatin in vivo are blocked by geranylgeranyl pyrophosphate. The inhibition of geranylgeranyl pyrophosphate formation and subsequent modulation of cytosol/membrane-bound RhoA are of importance for the protective effect of statins against myocardial ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]

Activation of peroxisome proliferator-activated receptor (PPAR) gamma protects from myocardial ischemia/reperfusion injury. The aim of the study was to investigate whether the cardioprotective effect of PPARgamma is related to nitric oxide (NO). Wild type (WT) and endothelial NO synthase (eNOS) knockout (KO) mice received 3 mg/kg of the PPARgamma agonist rosiglitazone or vehicle (n = 6–9 in each group) i. p. 45 min before anesthesia. The hearts were isolated, perfused in a Langendorff mode and subjected to global ischemia and 30 min reperfusion. The hearts of another two groups ofWT mice received the NOS inhibitor L-NNA (100 ìmol/l) or vehicle in addition to pre-treatment with vehicle or rosiglitazone. In the WT heart, rosiglitazone increased the recovery of left ventricular function and coronary flow following ischemia in comparison with the vehicle group.L-NNA did not affect recovery per se but significantly blunted the improvement in the recovery of left ventricular function induced by rosiglitazone. In the KO group rosiglitazone suppressed the recovery of myocardial function following ischemia. Expression of eNOS was not affected, but phosphorylated eNOS was significantly increased by rosiglitazone in the WT hearts (P < 0.05). These results suggest that the cardioprotective effect of the PPARgamma agonist rosiglitazone is mediated via NO by phosphorylation of eNOS. [ABSTRACT FROM AUTHOR]

Background Ligands of peroxisome proliferator-activated receptor alpha (PPAR-α) have been shown to reduce ischaemia/reperfusion injury. The mechanisms behind this effect are not well known. We hypothesized that activation of PPAR-α exerts cardioprotection via a mechanism related to nitric oxide (NO) and endothelin-1 (ET-1). Methods Five groups of anaesthetized open-chest Sprague-Dawley rats were given the PPAR-α agonist WY 14643 1 mg/kg (WY; n = 7), dimethyl sulfoxide (DMSO, vehicle for WY; n = 6), the combination of WY and the NO synthase inhibitor N-nitro-L-arginine (L-NNA, 2 mg/kg) (n = 7), L-NNA only (n = 8) or 0.9% sodium chloride (NaCl, vehicle for DMSO and L-NNA; n = 8) i.v. before a 30 min period of coronary artery occlusion followed by 2 h of reperfusion. Infarct size (IS), eNOS and iNOS protein and ET-1 mRNA expression were determined. Results There were no haemodynamic differences between the groups during the experiment. The IS was 78 ± 3% of the area at risk in the DMSO group and 77 ± 2% in the NaCl group (P = NS). WY reduced IS to 56 ± 3% (P < 0.001 vs. DMSO group). When WY was administered in combination with L-NNA the cardioprotective effect was abolished (IS 73 ± 3%, P < 0.01 vs. WY 14643). L-NNA did not affect IS per se (78 ± 2%, P = NS). The expression of eNOS but not iNOS protein in ischaemic myocardium from rats was increased in the group given WY (P < 0.05). ET-1 mRNA levels were lower in the ischaemic myocardium following WY administration. Conclusion The results suggest that the PPAR-α activation protects the rat myocardium against ischaemia/reperfusion injury via a mechanism related to production of NO, and possibly ET-1. [ABSTRACT FROM AUTHOR]

Endothelin (ET) receptor antagonism protects from ischemia reperfusion injury. We hypothesized that the cardioprotective effect is related to nitric oxide (NO) bioavailability Buffer perfused rat and mouse hearts were subjected to ischemia and reperfusion At the onset of ischemia, the rat hearts received vehicle, the dual endothelin type A/type B (ETA/ETB) receptor antagonist bosentan (10 μM), the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 100 μM), the combination of bosentan and L- NMMA or the combination of bosentan, L-NMMA, and the NO substrate L-arginine (1 mM). Hearts from wild-type and endothelial NO synthase (eNOS)-deficient mice received either vehicle or bosentan. Myocardial performance, endothelial function, NO outflow, and eNOS expression were monitored bosentan significantly improved myocardial function during reperfusion in rats and in wild type mice. but not in eNOS-deficient mice. The functional protection afforded by bosentan was inhibited by L-NMMA, whereas it was restored by L-arginine Myocardial expression of eNOS (immunoblotting) increased significantly in bosentan treated rat hearts compared with vehicle hearts. Recovery of NO outflow during reperfusion was enhanced in the bosentan treated rat heart. The endothelium dependent vasodilator adenosine diphosphate increased coronary flow by 18 ± 9% at the end of reperfusion in the bosentan group, whereas it reduced coronary flow by 7 ± 5% in the vehicle group (P < 0.001 ). The response to the endothelium independent dilator sodium nitroprusside was not different between the two groups. In conclusion, the dual ETA/ETB receptor antagonist bosentan preserved endothelial and cardiac contractile function during ischemia and reperfusion via a mechanism dependent on endothelial NO production. [ABSTRACT FROM AUTHOR]

Pro-insulin C-peptide has been shown to increase muscle blood flow in type 1 diabetic patients. The Underlying mechanism is not fully understood. The aim of this study was to evaluate if the vasodilator effect of C-peptide is mediated by nitric oxide (NO). Eleven type 1 diabetic patients were studied two times and randomized to administration of intravenous and intraarterial infusion of C-peptide or saline. Forearm blood flow (FBF) was measured by venous occlusion plethysmography during infusion of C-peptide or saline before, during, and after NO synthase (NOS) blockade. Endothelium-dependent and -independent vasodilatation was evaluated by administration of acetylcholine and sodium nitroprusside, respectively. FBF increased by 35% during intravenous C-peptide (P < 0.01) but not during saline infusion (-2%, not significant). NOS blockade resulted in a more pronounced reduction in FBF during intravenous C-peptide than during saline infusion (-41 vs. -26%, P < 0.05). Intra-arterial C-peptide failed to increase FBF during NOS blockade. However, when C-peptide was given after the recovery from NOS blockade, FBF rose by 30% (P < 0.001). The vasodilator effects of acetylcholine and nitroprusside were not influenced by Cpeptide. It is concluded that the stimulatory effect of Cpeptide on FBF in type 1 diabetic patients is mediated via the NO system and that C-peptide increases basal endothelial NO levels. [ABSTRACT FROM AUTHOR]

Reperfusion through thrombolysis or percutananeous coronary angioplasty is standard treatment in impending acute myocardial infarction. Although restoration of blood flow to the jeopardised myocardial area is a perquisite for myocardial salvage, reperfusion itself may lead to accelerated and additional myocardial injury beyond that generated by ischemia alone. This is referred to as the “reperfusion injury”. Since the reperfusion injury is initiated by the treatment of myocardial infarction, it is of importance to limit the extent of the injury. Several studies aimed at preventing reperfusion injury by means of pharmacological agents have therefore been conducted. The design of such studies is crucial for the results. Factors of importance are the timing of drug administration, animal species used, the degree of collateral flow and the duration of ischemia. A variety of pharmacological compounds have been investigated in different experimental models of myocardial ischemia and reperfusion. These include oxygen free radical scavengers, antioxidants, calcium channel blockers, inhibitors of neutrophils, nitric oxide, adenosine-related agents, inhibitors of the renin-angiotensin system, endothelin receptor antagonists, Na+/H+ exchange inhibitors, and anti-apoptotic agents. All these groups of pharmacological agents have been demonstrated to protect from reperfusion injury determined as limitation of infarct size, improved myocardial and endothelial function, and reduced incidence of arrhythmias. The mechanism behind the protective effect may differ between different groups of compounds, but some compounds may exert cardioprotection via common pathways. Such a pathway may be via maintained bioavailability of nitric oxide. [Copyright &y& Elsevier]

Background: Calcium antagonists may, in addition to their classical actions, release nitric oxide (NO) from coronary arteries. The aim of this study was to elucidate the possible interaction between the cardioprotective effect of a short-acting calcium antagonist and NO during myocardial ischaemia and reperfusion. Methods: Anaesthetised pigs were subjected to 45 min ligation of the left anterior descending coronary artery (LAD) followed by 4 h of reperfusion. Five groups were given vehicle (n=9), clevidipine (n=8), the NO synthase inhibitor l-NMMA (n=6), clevidipine in combination with l-NMMA (n=6) or clevidipine in combination with l-NMMA and NO precursor l-arginine (n=6) into the LAD during the last 10 min of ischaemia and the first 5 min of reperfusion. Results: There were no significant differences in LAD blood flow, mean arterial pressure, rate–pressure product or dP/dt between the groups before ischaemia or during reperfusion. The infarct size (IS) was 86±2% of the area at risk in the vehicle group. Clevidipine reduced the IS to 59±3% (P<0.001). When clevidipine was administered together with l-NMMA, the protective effect of clevidipine was abolished (IS, 87±3%; P<0.001 vs. clevidipine), whereas addition of l-arginine restored its cardioprotective effect (IS 60±3%; P<0.001 vs. vehicle). l-NMMA did not affect IS per se (88±5%). Endothelium-dependent coronary vasodilation induced by substance P was significantly larger in the clevidipine group than in the other groups. Conclusion: Local administration of a calcium antagonist during the late ischaemia and early reperfusion reduces IS and preserves coronary endothelial function. The cardioprotective effect of clevidipine is suggested to be dependent on maintained local bioavailability of NO. [ABSTRACT FROM PUBLISHER]

The mechanisms underlying endothelial dysfunction in Type 1 and Type 2 diabetes (T1DM and T2DM) are unresolved. The red blood cells (RBCs) with increased arginase activity induce endothelial dysfunction in T2DM, but the implications of RBCs and the role of arginase inhibition in T1DM are unexplored. We aimed to investigate the differences in endothelial function in patients with T1DM and T2DM, with focus on RBCs and arginase. Thirteen patients with T1DM and twenty-six patients with T2DM, matched for HbA1c and sex were included. In vivo endothelium-dependent and -independent vasodilation (EDV and EIDV) were assessed by venous occlusion plethysmography before and after administration of an arginase inhibitor. RBCs were co-incubated with rat aortic segments for 18h followed by evaluation of endothelium-dependent (EDR) and -independent relaxation (EIDR) in isolated organ chambers. In vivo EDV, but not EIDV, was significantly impaired in patients with T2DM compared with patients with T1DM. Arginase inhibition resulted in improved EDV only in T2DM. RBCs from patients with T2DM induced impaired EDR but not EIDR in isolated aortic segments, whereas RBCs from patients with T1DM did not affect EDR nor EIDR. The present study demonstrates markedly impaired EDV in patients with T2DM in comparison with T1DM. In addition, it highlights the divergent roles of RBCs and arginase in mediating endothelial dysfunction in T1DM and T2DM. While endothelial dysfunction is mediated via RBCs and arginase in T2DM, these phenomena are not prominent in T1DM thereby indicating distinct differences in underlying mechanisms. [ABSTRACT FROM AUTHOR]

Human cytomegalovirus (HCMV) is an opportunistic pathogen that has been implicated in the pathogenesis of atherosclerosis. Endothelin-1 (ET-1), a potent vasoconstrictive peptide, is overexpressed and strongly associated with many vasculopathies. The main objective of this study was to investigate whether HCMV could affect ET-1 production. As such, both endothelial and smooth muscle cells, two primary cell types involved in the pathogenesis of atherosclerosis, were infected with HCMV in vitro and ET-1 mRNA and proteins were assessed by quantitative PCR assay, immunofluorescence staining and ELISA. HCMV infection significantly decreased ET-1 mRNA and secreted bioactive ET-1 levels from both cell types and promoted accumulation of the ET-1 precursor protein in infected endothelial cells. This was associated with inhibition of expression of the endothelin converting enzyme-1 (ECE-1), which cleaves the ET-1 precursor protein to mature ET-1. Ganciclovir treatment did not prevent the virus suppressive effects on ET-1 expression. Consistent with this observation we identified that the IE2-p86 protein predominantly modulated ET-1 expression. Whether the pronounced effects of HCMV in reducing ET-1 expression in vitro may lead to consequences for regulation of the vascular tone in vivo remains to be proven. [ABSTRACT FROM AUTHOR]

Objective: Endothelin-1 (ET-1) is not only a potent vasoconstrictor but also a stimulator of polymorphonuclear leukocyte (PMN) aggregation and adhesion. The aim of this study was to investigate whether an ETA receptor antagonist attenuates the PMN-mediated contractile dysfunction following myocardial ischaemia. Methods: Isolated rat hearts were perfused according to the Langendorff method. The hearts were subjected to global ischaemia and reperfused with buffer solution only, or human PMNs dissolved in rat plasma (HNRP). Results: In an initial study, the ETA receptor antagonist LU 135252 (1 and 10 μmol/l) or ET-1 (1 and 10 nmol/l) did not significantly affect the recovery of left ventricular developed pressure (LVDP), end-diastolic pressure (LVEDP), the first derivative of left ventricular pressure (dP/dt) or the rate pressure product (RPP) during reperfusion with buffer solution only compared to a vehicle group. In a second study on hearts reperfused with HNRP, administration of LU 135252 (10 μmol/l) significantly enhanced the recovery of LVDP, dP/dt and RPP in hearts reperfused with HNRP. LVEDP was 20 mmHg lower in hearts given LU 135252 than vehicle in combination with HNRP (P<0.05). The outflow of PMNs in the coronary effluent during reperfusion was 41±8% in hearts given LU 135252 compared to 9±5% in vehicle-treated hearts (P<0.01). There was a significant correlation between the myocardial functional recovery and the outflow of PMNs. Administration of ET-1 (0.1 and 1 nmol/l) in combination with HNRP resulted in complete loss of contractile function and no outflow of PMNs during reperfusion. Conclusion: The ETA receptor antagonist LU 135252 protects from ischaemia/reperfusion injury in the isolated rat heart in the presence of PMNs. It is suggested that inhibition of PMN-induced injury during reperfusion is an important cardioprotective action of LU 135252. [ABSTRACT FROM PUBLISHER]

Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide derived from vascular endothelial cells. ET-1 can also be produced by other cell types such as smooth muscle cells and cardiomyocytes. Plasma levels of ET-1 are elevated during several different cardiovascular disorders like atherosclerosis, myocardial infarction and congestive heart failure. During and following myocardial ischaemia and reperfusion, the myocardial production and release of ET-1 is stimulated and the coronary constrictor response to ET-1 is enhanced. These findings all favour a pathophysiological role for ET-1 in the development of ischaemia/reperfusion injury. Accordingly, by using different pharmacological tools (monoclonal antibody, ET converting enzyme inhibitor or ET receptor antagonists) that block the biological actions of ET-1, myocardial ischaemia/reperfusion injury has been demonstrated to be reduced in experimental animal models, in terms of both reduction in final infarct size and improved recovery of myocardial performance and coronary flow. However, some studies have shown no cardioprotective effects of ET receptor antagonists. Possible explanations for these apparently conflicting results are differences in animal species used, route and timing of drug administration, experimental protocol and chemical nature of the antagonists. The potential mechanisms underlying the cardioprotective effects of ET antagonists are discussed and include prevention of no-reflow, inhibition of ET-induced neutrophil activation, abolishment of direct pro-ischaemic actions of ET on myocytes, and interruption of interference of ET with the renin-angiotensin system. [ABSTRACT FROM PUBLISHER]

Objective: The aim was to investigate the effects of the non-peptide endothelin receptor antagonist bosentan (Ro 47-0203) on haemodynamic variables, infarct size, myocardial overflow, and tissue content of endothelin-like immunoreactivity (ET-LI) during ischaemia and reperfusion in anaesthetised pigs, and to study the inhibitory effect of bosentan on ET-1 induced coronary constriction in vitro. Methods: Ischaemia was induced by ligation of the left anterior descending coronary artery for 45 min, followed by 4 h of reperfusion. Bosentan was given either intravenously (5 mg·kg−1) 15 min before ischaemia or as a 25 min local coronary venous retroinfusion (10−4 M) starting at 30 min of ischaemia. ET-LI was analysed in myocardial tissue and in plasma from the anterior interventricular coronary vein and aorta. The effect of bosentan on endothelin-1 induced vasoconstriction was evaluated in isolated diagonal branches of left anterior descending coronary artery. Results: Intravenous bosentan slightly reduced arterial blood pressure (P < 0.05) but did not affect basal coronary vascular resistance. Local retroinfusion of bosentan did not change blood pressure. Intravenous and retroinfused bosentan significantly reduced infarct size by 58% and 48% respectively (P < 0.01) and enhanced the recovery of coronary blood flow by 65–90% compared to vehicle treated controls at the end of 4 h reperfusion. The basal plasma levels of ET-LI and the myocardial overflow of ET-LI during reperfusion increased twofold after bosentan. A threefold increase in the concentration of ET-LI was observed in the ischaemic/reperfused myocardium and this enhancement was significantly attenuated by bosentan. Bosentan effectively antagonised the endothelin-1 induced but not the serotonin induced, contractions of isolated coronary arteries and reversed the established contraction induced by endothelin-1. Conclusions: The non-peptide endothelin receptor antagonist bosentan markedly protects the myocardium from ischaemia/reperfusion injury and improves blood flow to the reperfused area, indicating the involvement of endogenous endothelin-1 and the therapeutic value of bosentan in the treatment of ischaemia/reperfusion injury. [ABSTRACT FROM PUBLISHER]

It is well established that altered purinergic signaling contributes to vascular dysfunction in type 2 diabetes (T2D). Red blood cells (RBCs) serve as an important pool for circulating ATP and the release of ATP from RBCs in response to physiological stimuli is impaired in T2D. We recently demonstrated that RBCs from patients with T2D (T2D RBC) serve as key mediators of endothelial dysfunction. However, it remains unknown whether altered vascular purinergic signaling is involved in the endothelial dysfunction induced by dysfunctional RBCs in T2D. Here, we evaluated acetylcholine-induced endothelium-dependent relaxation (EDR) of isolated rat aortas after 18 h ex vivo co-incubation with human RBCs, and aortas of healthy recipient rats 4 h after in vivo transfusion with RBCs from T2D Goto-Kakizaki (GK) rats. Purinergic receptor (PR) antagonists were applied in isolated aortas to study the involvement of PRs. EDR was impaired in aortas incubated with T2D RBC but not with RBCs from healthy subjects ex vivo, and in aortas of healthy rats after transfusion with GK RBCs in vivo. The impairment in EDR by T2D RBC was attenuated by non-selective P1R and P2R antagonism, and specific A1R, P2X7R but not P2Y6R antagonism. Transfusion with GK RBCs in vivo impaired EDR in aortas of recipient rats, an effect that was attenuated by A1R, P2X7R but not P2Y6R antagonism. In conclusion, RBCs induce endothelial dysfunction in T2D via vascular A1R and P2X7R but not P2Y6R. Targeting vascular purinergic singling may serve as a potential therapy to prevent endothelial dysfunction induced by RBCs in T2D. [ABSTRACT FROM AUTHOR]

We recently showed that red blood cells (RBCs) from patients with type 2 diabetes mellitus (T2DM-RBCs) induce endothelial dysfunction through a mechanism involving arginase I and reactive oxygen species. Peroxynitrite is known to activate arginase in endothelial cells. Whether peroxynitrite regulates arginase activity in RBCs, and whether it is involved in the cross-talk between RBCs and the vasculature in T2DM, is unclear and elusive. The present study was designed to test the hypothesis that endothelial dysfunction induced by T2DM-RBCs is driven by peroxynitrite and upregulation of arginase. RBCs were isolated from patients with T2DM and healthy age matched controls. RBCs were co-incubated with aortae isolated from wild type rats for 18 h in the absence and presence of peroxynitrite scavenger FeTTPS. Evaluation of endothelial function in organ chambers by cumulative addition of acetylcholine as well as measurement of RBC and vessel arginase activity was performed. In another set of experiments, RBCs isolated from healthy subjects (Healthy RBCs) were incubated with the peroxynitrite donor SIN-1 with subsequent evaluation of endothelial function and arginase activity. T2DM-RBCs, but not Healthy RBCs, induced impairment in endothelial function, which was fully reversed by scavenging of RBC but not vascular peroxynitrite with FeTPPS. Arginase activity was up-regulated by the peroxynitrite donor SIN-1 in Healthy RBCs, an effect that was inhibited by FeTTPS. Healthy RBCs co-incubated with aortae in the presence of SIN-1 caused impairment of endothelial function, which was inhibited by FeTTPS or the arginase inhibitor ABH. T2DM-RBCs induced up-regulation of vascular arginase, an effect that was fully inhibited by FeTTPS. Collectively, our data indicate that RBCs impair endothelial function in T2DM via an effect that is driven by a peroxynitrite-mediated increase in arginase activity. This mechanism may be targeted in patients with T2DM for improvement in endothelial function. [ABSTRACT FROM AUTHOR]

Diets containing nutrients such as polyunsaturated fatty acids, polyphenols, or vitamins have been shown to have cardiovascular benefits. Micro (mi)RNAs are fundamental regulators of gene expression and function in the cardiovascular system. Diet-induced cardiovascular benefits are associated with changes in endogenous expression of miRNAs in the cardiovascular system. In addition, emerging studies have shown that miRNAs present in the food can be transported in the circulation to tissues. These exogenous miRNAs may also affect cardiovascular function contributing to the diet-induced benefits. This review discusses the emerging role of both endogenous and exogenous miRNAs as mediators of diet-induced cardiovascular protection. Understanding the mechanisms of diet-mediated actions through modulation of miRNA may provide a potential strategy for new therapies. • Diets containing nutrients affect endogenous miRNA levels in the cardiovascular system. • miRNAs present in diets can be delivered to cardiovascular tissues. • Diet-induced benefits may be mediated by the endogenous and exogenous miRNAs. [ABSTRACT FROM AUTHOR]