Decreased mobilization of endothelial progenitor cells contributes to impaired neovascularization in diabetes

• 1 Circulating bone marrow (BM)‐derived endothelial progenitor cells (EPCs) play an important role in neovascularization. In the present study, we investigated the mechanisms underlying the reduction in circulating EPCs in a mouse model of diabetes induced by streptozotocin.
• 2 Compared with non‐diabetic controls, diabetic mice had reduced circulating EPCs (0.59 ± 0.11 vs 0.94 ± 0.21%, respectively; P < 0.01) and increased plasma endothelial microparticles (18 642 ± 6809 vs 5692 ± 1862/mL, respectively; P < 0.01). In a mouse bone marrow (BM) transplantation model, increased adhesion of transplanted BM cells to aortas of diabetic mice was observed compared with control (900 ± 194 vs 431 ± 109 cells/mm², respectively; P < 0.01).
• 3 Following hindlimb ischaemia, diabetic mice exhibited suppressed EPC mobilization, a reduction in the expected increase in capillary density and suppressed restoration of transcutaneous oxygen pressure in the ischaemic tissue. Diabetic mice also showed impaired ischaemia‐induced upregulation of vascular endothelial growth factor (VEGF), hypoxia‐inducible factor (HIF)‐1α and interleukin‐1β, an exaggerated increase in matrix metalloproteinase (MMP)‐2 and ‐9 and a suppressed increase in tissue inhibitor of matrix metalloproteinase (TIMP)‐1. On multivariate analysis, VEGF expression was the only independent factor related to circulating EPC count.
• 4 In conclusion, the data indicate that the decrease in basal circulating EPCs in diabetes may be attributable, in part, to consumptive loss of EPCs due to increased endothelial damage. Impairment of ischaemia‐induced EPC mobilization in the diabetic mouse model is associated with altered HIF‐1α/VEGF and MMP/TIMP regulation and represents a novel mechanism underlying defective postischaemic neovascularization in diabetes.

     

Cholinergic stimulation with pyridostigmine improves autonomic function in infarcted rats

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OBESITY INDUCED RENAL OXIDATIVE STRESS CONTRIBUTES TO RENAL INJURY IN SALT-SENSITIVE HYPERTENSION

• 1 In the present study, we determined the role of hypertension, oxidative stress and inflammation on kidney damage in a rodent model of obesity and diabetes. Hypertension was induced in male obese (db/db) mice and lean (db/m) mice by implantation of deoxycorticosterone acetate (DOCA) pellets and mice were allowed to drink water containing 1% salt. Mice were divided into six groups as follows: obese and lean control, obese and lean 1% salt (salt) and obese and lean DOCA plus 1% salt (DOCA‐salt).
• 2 Blood pressure was significantly increased in lean and obese DOCA‐salt groups relative to their respective controls; however, there was no difference in blood pressure between the lean and obese control and salt groups. Urinary 8‐isoprostane was increased in obese control compared with lean control mice (1464 ± 267 vs 493 ± 53 pg/µmol creatinine, respectively) and this elevation was further increased in the obese DOCA‐salt treated mice (2430 ± 312 pg/µmol creatinine). Urinary monocyte chemoattractant protein‐1 excretion and CD68‐positive cells were also increased in both obese and lean DOCA‐salt groups compared with their respective controls. Furthermore, DOCA‐salt treatment increased collagen IV excretion in both obese and lean mice compared with controls, but there was no difference between obese and lean DOCA‐salt groups. Urinary albumin excretion was significantly increased in the obese compared with the lean DOCA‐salt mice (507 ± 160 vs 202 ± 48 µg/day, respectively).
• 3 These data suggest that obese DOCA‐salt hypertensive mice exhibit greater renal injury than lean DOCA‐salt hypertensive mice in a manner independent of blood pressure and that this renal injury is associated with obesity related pre‐existing renal oxidative stress.

     

ACUTE EFFECTS OF NICOTINE ON ARTERIAL STIFFNESS AND WAVE REFLECTION IN HEALTHY YOUNG NON-SMOKERS

• 1 Recently, we have demonstrated that cigarette smoke exposure proportionally increases plasma nicotine levels and arterial wave reflection to the aorta. However, the exact contribution of nicotine to the smoke‐induced enhancement of wave reflection and the potential underlying mechanisms have not been fully investigated.
• 2 The present study was a prospective study in 15 healthy male non‐smokers. All received a placebo and a 2 mg nicotine tablet, according to a randomized double‐blind cross‐over study design. Each subject underwent repeated measurements at baseline and for 1 h after nicotine or placebo intake, using carotid–femoral pulse wave velocity (PWV) to assess arterial compliance. Concurrently, aortic pressures and the augmentation index were evaluated using applanation tonometry.
• 3 Plasma nicotine concentrations achieved 1 h after intake of the nicotine tablet reached comparable levels to those achieved after 1 h exposure to passive smoke (3.6 ± 0.4 vs 3.2 ± 0.4 ng/mL, respectively; P = 0.4).
• 4 Nicotine enhanced arterial wave reflection to the aorta, as assessed by the augmentation index corrected for heart rate (4.2 ± 1.3 vs–0.7 ± 0.8% with placebo; P = 0.001). In addition, a progressive increase in carotid–femoral PWV was noted after nicotine administration (0.3 ± 0.1 vs–0.02 ± 0.1 m/s with placebo; P = 0.04). This remained significant even after adjustment for changes in mean blood pressure and heart rate (P = 0.01).
• 5 Plasma nicotine concentrations comparable to those achieved after exposure to passive smoke enhance arterial wave reflection to the aorta. This is accompanied by an increase in carotid–femoral PWV, denoting a deterioration of arterial compliance by nicotine.

     

PREVENTION OF AORTIC ELASTIC LAMINA DEFECTS BY LOSARTAN IN APOLIPOPROTEIN E-DEFICIENT MOUSE

• 1 In a previous study, we identified prevalent internal elastic lamina (IEL) defects in the aorta of hyperlipidaemic apolipoprotein E (ApoE)‐deficient mice that are thought to provide a structural basis for the development of atherosclerosis and intimal thickening. In the present study, we examined the effects of losartan, an angiotensin AT₁ receptor antagonist, on the development of IEL defects.
• 2 Male 18‐week‐old ApoE‐deficient mice (maintained on a normal diet) were treated with losartan (3 or 30 mg/kg per day) for 10 weeks via the drinking water. The IEL defects were quantified histologically by measuring the continuity of the IEL within the inner curvature of the aortic arch.
• 3 In untreated animals, there was an age‐dependent increase in IEL defects from 7.2 ± 2.1% at 18 weeks to 13.8 ± 4.0% at 28 weeks. Treatment with the high dose of losartan significantly prevented the development of IEL defects (4.7 ± 1.3% at 28 weeks; P < 0.05 vs untreated). This effect was independent of changes in blood pressure or plasma lipid levels. Using quantitative real‐time polymerase chain reaction, we found that the effects of losartan were not associated with changes in levels of matrix metalloproteinase (MMP)‐2 and MMP‐9, tissue inhibitor of matrix metalloproteinase‐1 or inflammatory markers in the aorta.
• 4 The results suggest that the renin–angiotensin system may contribute to the development of aortic IEL defects in a blood pressure‐independent manner.

     

EFFECTS OF ANTI-HYPERTENSIVE DRUGS ON PRODUCTION OF SOLUBLE FMS-LIKE TYROSINE KINASE 1 AND SOLUBLE ENDOGLIN FROM HUMAN NORMAL AND PRE-ECLAMPTIC PLACENTAS IN VITRO

• 1 Increases in soluble fms‐like tyrosine kinase 1 (sFlt‐1) and soluble endoglin (sEng) contribute to the pathogenesis of pre‐eclampsia. Soluble Flt‐1 binds to circulating free vascular endothelial growth factor and placenta growth factor and this is associated with endothelial dysfunction. Soluble endoglin, a transforming growth factor (TGF)‐β coreceptor, was reported to synergize with sFlt‐1 to amplify endothelial dysfunction by inhibiting TGF‐β1‐mediated vasorelaxation.
• 2 The aim of the present study was to examine whether the antihypertensive drugs clonidine (0.08–1.3 µg/mL), diazoxide (25–300 µg/mL), frusemide (60–1000 µg/mL) and hydralazine (6.3–100 µg/mL) have any effect on placental production of sFlt‐1 and sEng in placentas from normal and pre‐eclamptic pregnancies.
• 3 Explants were taken from non‐laboured term placentas of normal pregnancy (n = 5) and women with pre‐eclampsia (n = 5). Villous explants were cultured with increasing doses of antihypertensive drugs. Placental sFlt‐1 and sEng production was examined using ELISA.
• 4 Baseline sFlt‐1 production was higher in placentas from women with pre‐eclampsia than from normal pregnancy (4.5 ± 1.4 vs 3.2 ± 0.6 ng/mg of total protein, respectively; P < 0.001), as was sEng production (9.0 ± 2.3 vs 4.1 ± 0.6 ng/mg of total protein, respectively; P < 0.001). With the exception of frusemide, none of the antihypertensive drugs tested had any effect on sFlt‐1 and sEng production from placental explants of normal pregnancy and women with pre‐eclampsia. Increasing frusemide concentrations were correlated with increased sEng production in normal pregnancy (P < 0.005).
• 5 In conclusion, placental sFlt‐1 and sEng production was higher in pre‐eclampsia and antihypertensive drugs had no effect on placental production of sFlt‐1 and sEng in vitro.

     

Beneficial effect of adenosine on myocardial perfusion in patients treated with primary percutaneous coronary intervention for acute myocardial infarction

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DILATED CARDIOMYOPATHY WITH HYPERTENSION: PREVALENCE AND RESPONSE TO HIGH-DOSE β1-ADRENOCEPTOR ANTAGONIST THERAPY

• 1 The aim of the present study was to investigate the prevalence of hypertension in patients with dilated cardiomyopathy (DCM) and to determine the tolerance and efficacy of a high dose of the β₁‐adrenoceptor antagonist metoprolol in the long‐term treatment of DCM patients.
• 2 The prevalence of hypertension in DCM patients (n = 362) and age‐matched controls (n = 401) was evaluated and compared. To investigate the effects of metoprolol, DCM patients were divided into hypertensive (DCM‐H) or normotensive (DCM‐N) subgroups. Metoprolol was administered at a starting dosage of 6.25 mg/day and increased gradually to 250 mg/day or the maximum tolerable dose. Blood pressure (BP), heart rate (HR), left ventricular (LV) end‐diastolic dimension (LVEDD), left atrial end‐diastolic dimension (LAEDD), LV ejection fraction (LVEF), LV posterior wall thickness (LVPWT) and ventricular septal thickness (VST) were determined at baseline and 6 and 12 months after metoprolol treatment.
• 3 The prevalence of hypertension was significantly higher in DCM patients than in age‐matched controls (32.8 vs 20.1%, respectively; P < 0.01). Resting HR and a family history of hypertension were highest in the DCM‐H group. There were no significant differences in age, gender and occupation between the DCM‐H, DCM‐N and age‐matched control groups.
• 4 The tolerable dose for metoprolol was significantly higher in the DCM‐H group than the DCM‐N group (189.6 ± 14.8 vs 133.9 ± 12.0 mg/day, respectively; P < 0.05). Metoprolol significantly reduced BP and HR in the DCM‐H group and improved LVEDD, LAEDD and LVEF in all DCM patients, with a greater effect seen in the DCM‐H group.
• 5 In conclusion, DCM patients have a higher prevalence of hypertension than the general population. Patients in the DCM‐H subgroup were characterized by a higher resting HR and a family history of hypertension and were more tolerant of and more responsive to metoprolol treatment. These data suggest that this subgroup of DCM patients could have higher sympathetic nerve activity and is suitable for treatment with a higher dose of metoprolol.

     

Effects of fatty acids on cardioprotection by pre‐ischaemic inhibition of the malate–aspartate shuttle

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Effects of sodium valproate on synaptic transmission and neuronal excitability in rat hippocampus

• 1 Valproate (VPA) has long been used in the treatment of both generalized and partial seizures. However, its cellular mechanisms of action remain unclear.
• 2 In the present study, the effects of VPA on synaptic transmission and neuronal excitability were examined in the hippocampal CA1 region using whole‐cell patch clamp recordings.
• 3 Perfusion with VPA, at therapeutically attainable concentrations (i.e. 0.3 and 0.6 mmol/L), significantly increased the frequency (112 ± 2 and 133 ± 2% of control, respectively; n = 5; both P < 0.05), but not the average amplitude, of miniature inhibitory post‐synaptic currents (mIPSCs). Perfusion with VPA had no effect on either the amplitude or the frequency of miniature excitatory post‐synaptic currents (mEPSCs).
• 4 In acutely dissociated CA1 pyramidal neurons, VPA had no effect on 10 µmol/L GABA‐induced currents. Furthermore, following the administration of 0.3 and 0.6 mmol/L VPA, the frequency of action potential firing was significantly reduced from 18.0 ± 1.1 to 15.3 ± 0.9 and from 18.6 ± 0.9 to 12.6 ± 0.6, respectively (n = 8; both P < 0.05). In contrast, 0.3 and 0.6 mmol/L VPA significantly increased spike frequency adaptation from 4.02 ± 0.47 to 4.72 ± 0.55 and from 3.47 ± 0.41 to 4.48 ± 0.58, respectively (n = 8; P < 0.05).
• 5 The results of the present study suggest that VPA presynaptically increases inhibitory synaptic activity without modifying excitatory synaptic transmission and reduces neuronal excitability. Any or all of these effects may contribute to its anticonvulsant action.

     

Temporal development of baroreceptor dysfunction in a rodent model of chronic kidney disease

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EPIGALLOCATECHIN-3-GALLATE ATTENUATES CARDIAC HYPERTROPHY IN HYPERTENSIVE RATS IN PART BY MODULATION OF MITOGEN-ACTIVATED PROTEIN KINASE SIGNALS

• 1 It has been demonstrated that epigallocatechin‐3‐gallate (EGCG) inhibits cardiac hypertrophy through its antihypertensive and anti‐oxidant effects. However, the underlying molecular mechanism is not clear.
• 2 In the present study, we tested the hypothesis that EGCG attenuates transaortic abdominal aortic constriction (TAC)‐induced ventricular hypertrophy by regulating mitogen‐activated protein kinase (MAPK) signal pathways in hypertensive rats. Four groups of rats were used: (i) a sham‐operated control group; (ii) an EGCG‐treated (50 mg/kg per day, i.p., for 21 days) sham‐operated group; (iii) a TAC group; and (iv) an EGCG‐treated TAC group. Histological analysis of whole hearts and biochemical analyses of left ventricular (LV) tissue were used to investigate the effects of EGCG.
• 3 The results showed that the LV myocyte diameter and the expression of atrial natriuretic peptide, brain natriuretic peptide and β‐myocardial heavy chain were significantly decreased in the EGCG‐treated (50 mg/kg per day, i.p.) TAC group. Levels of reactive oxygen species and malondialdehyde in the lV were significantly reduced by EGCG in the TAC group. Total superoxide dismutase, catalase and glutathione peroxidase activities were decreased in the TAC group, and this decrease was significantly restored by EGCG treatment. Phosphorylation of extracellular signal‐regulated kinase 2, p38 and c‐Jun N‐terminal kinase 1 was significantly reversed in the LV of EGCG‐treated TAC rats (40%, 53% and 52%vs TAC, respectively), accompanied by significant inhibition of nuclear factor‐κB and activator protein‐1. Transaortic abdominal aortic constriction significantly upregulated LV expression of matrix metalloproteinase‐9 from 32 ± 6 to 100 ± 12% and this increase was inhibited by EGCG treatment (from 100 ± 12 to 50 ± 15%). In addition, TAC decreased mitochondrial DNA copy number and the activity of respiratory chain complexes I (from 100 ± 7 to 68 ± 5%), III (from 100 ± 4 to 2 ± 5%) and IV (from 766 ± 2 to 100 ± 5%); this decrease was reversed by EGCG treatment to levels seen in sham‐operated rats.
• 4 In conclusion, EGCG attenuates TAC‐induced ventricular hypertrophy in hypertensive rats in part by suppression of anti‐oxidant enzymes and regulation of MAPK signals.

     

CARDIOPROTECTIVE EFFECT OF l-GLUTAMATE IN OBESE TYPE 2 DIABETIC ZUCKER FATTY RATS

• 1 Because diabetic hearts have an increased threshold for cardioprotection by ischaemic preconditioning (IPC), we hypothesized that protection by l ‐glutamate during reperfusion is restricted in Type 2 diabetic hearts. Previously, we found that l ‐glutamate‐mediated postischaemic cardioprotection mimics IPC.
• 2 Rat hearts were studied in a Langendorff preparation perfused with Krebs’–Henseleit solution and subjected to 40 min global no‐flow ischaemia, followed by 120 min reperfusion. l ‐Glutamate (0, 15 and 30 mmol/L) was added to the perfusate during reperfusion of hearts from non‐diabetic (Wistar‐Kyoto) and diabetic (Zucker diabetic fatty (ZDF)) rats, studied at 16 weeks of age. The infarct size (IS)/area‐at‐risk (AAR) ratio was the primary end‐point. Expression of l ‐glutamate excitatory amino acid transporter (EAAT) 1 (mitochondrial) and EAAT3 (sarcolemmal) was determined by quantitative polymerase chain reaction and immunoblotting.
• 3 The ISS/AAR ratio did not differ between control hearts from Wistar‐Kyoto and ZDF rats (0.52 ± 0.03 and 0.51 ± 0.04, respectively; P = 0.90). l ‐Glutamate (15 mmol/L) significantly reduced the IS/AAR ratio in non‐diabetic hearts, but not in diabetic hearts, compared with their respective controls. The higher concentration of l ‐glutamate (30 mmol/L) reduced infarct size in diabetic hearts to the same degree as in non‐diabetic hearts (IS/AAR 0.35 ± 0.03 (P = 0.002) and 0.34 ± 0.03 (P = 0.004), respectively). The mitochondrial l ‐glutamate transporter EAAT1 was downregulated in hearts from ZDF rats at both the mRNA and protein levels (P < 0.0005 and P < 0.0001, respectively). However, there was no change in EAAT3 expression at the protein level. Myocardial l ‐glutamate content was increased by 43% in diabetic hearts (P < 0.0001).
• 4 Hearts from obese diabetic rats have an elevated threshold for metabolic postischaemic cardioprotection by l ‐glutamate. These findings may reflect underlying mechanisms of inherent resistance against additional cardioprotection in the diabetic heart.

     

Captopril attenuates hypertension and renal injury induced by the vascular endothelial growth factor inhibitor sorafenib

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Routine early versus deferred provisional tirofiban treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention

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Topical anaesthesia does not affect cutaneous vasomotor or sudomotor responses in human skin

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Curcumin ameliorates high glucose‐induced acute vascular endothelial dysfunction in rat thoracic aorta

• 1 The aims of the present study were to explore the protective effect of curcumin against the acute vascular endothelial dysfunction induced by high glucose and to investigate the possible role of heme oxygenase (HO)‐1 in this protective action.
• 2 Thoracic aortic rings, with or without endothelium, obtained from male Sprague‐Dawley rats were mounted in an organ bath. Isometric contraction of the rings was recorded. After completion of the organ bath studies, rings were homogenized and centrifuged (30 000 g, 4°C, 15 min) and HO activity was determined in the supernatant.
• 3 After 2 h incubation of aortic rings in the presence of high glucose (44 mmol/L), the relaxation evoked by acetylcholine (3 × 10^?8 to 3 × 10^?5 mol/L) was significantly decreased only in rings with an intact endothelium. When rings were coincubated in the presence of curcumin (10^?13 to 10^?11 mol/L) and high glucose, curcumin reversed the vasodilator dysfunction induced by high glucose dose dependently.
• 4 Curcumin (10^?11 mol/L) increased HO activity in the aortic rings compared with activity in control rings (63.1 ± 3.6 vs control 43.2 ± 2.9 pmol/mg per h, respectively; P < 0.01). Protoporphyrin IX zinc (10^?6 mol/L), an inhibitor of HO‐1, offset the protective effects of curcumin. In addition, the non‐selective guanylate cyclase (GC) inhibitor methylene blue (10^?6 mol/L) completely abolished the protective effects of curcumin.
• 5 In conclusion, the results of the present study show that curcumin alleviates the acute endothelium‐dependent vasodilator dysfunction induced by high glucose in rat aortic rings. Increased HO‐1 activity and stimulation of GC may be involved in the protective effects of curcumin.

     

Remote per‐conditioning reduces oxidative stress,downregulates cyclo‐oxygenase‐2 expression and attenuates ischaemia–reperfusion‐induced acute kidney injury

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MEASUREMENT OF PULMONARY FLOW RESERVE IN HIGHER PRIMATES

• 1 There are currently limited diagnostic methods for assessing the integrity of the pulmonary microvasculature. We hypothesized that a novel, invasively determined physiological index of ‘pulmonary flow reserve’ (PFR = maximal hyperaemic pulmonary blood flow divided by basal pulmonary flow) may facilitate microvascular assessment in the lung. Therefore, we developed a baboon model in which to: (i) validate the use of Doppler flow velocity for PFR assessment; (ii) define the optimal drug and dose regimen for attainment of maximal pulmonary hyperaemia; and (iii) demonstrate the feasibility of measuring PFR in healthy higher primates.
• 2 Doppler sensor guidewires were placed in segmental pulmonary arteries of 11 ketamine‐anaesthetized baboons. Vessel diameter, flow velocity and haemodynamics were recorded before and after direct intrapulmonary artery administration of saline, adenosine (50–500 µg/kg per min) and papaverine (3–60 mg), enabling calculation of PFR.
• 3 Saline (either bolus injection or infusion) did not alter vessel diameter or flow velocity (P > 0.1), validating local drug administration. Both adenosine and papaverine induced dose‐dependent increases in flow velocity from baseline (from 22.5 ± 2.3 to 32.7 ± 4.8 cm/s for 400–500 µg/kg per min adenosine; and from 23.9 ± 1.1 to 34.6 ± 4.0 cm/s for 24 mg papaverine; both P < 0.0001), without affecting pulmonary artery pressure or vessel diameter (P > 0.3). Healthy primate PFR values were 1.35 ± 0.10 and 1.39 ± 0.10 using 200 µg/kg per min adenosine and 24 mg papaverine, respectively (P > 0.8).
• 4 In conclusion, pulmonary flow reserve in higher primates can be assessed using Doppler sensor guidewire and either adenosine or papaverine as microvascular hyperaemic agents. Measurements of PFR may facilitate pulmonary microvascular assessments.

     

Non‐adrenergic,non‐cholinergic,non‐purinergic contractions of the urothelium/lamina propria of the pig bladder

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