Relationship between endogenous concentrations of vasoactive substances and measures of peripheral vasodilator function in patients with coronary artery disease

• 1 The aim of the present study was to determine the relationship between plasma concentrations of nitrite/nitrate (NO_x) and endothelin (ET)‐1 and non‐invasive measures of peripheral vasodilator function in patients with coronary artery disease (CAD).
• 2 Twenty‐two patients with angiographic CAD underwent non‐invasive measurement of peripheral vasodilator function in the brachial conduit artery (flow‐mediated dilation (FMD) testing via ultrasound) and in the forearm resistance arteries (via venous occlusion plethysmography) during reactive hyperaemia after 5 min ischaemia. In addition, plasma NO_x and ET‐1 concentrations were determined.
• 3 The plasma concentration of NO_x was related to the peak brachial FMD response when expressed as either the relative (%) or absolute (mm) change in diameter (r = 0.73, P < 0.001; and r = 0.64, P < 0.01, respectively). Moreover, plasma concentrations of NO_x demonstrated a relationship with forearm vasodilation estimated by total forearm blood flow following 5 min ischaemia (r = 0.63, P < 0.01) and the flow debt repayment of the forearm (r = 0.54, P < 0.01). Finally, ET‐1 concentrations were inversely related to FMD% (r = –0.45, P < 0.05).
• 4 The findings of the present study demonstrate a relationship between the plasma concentrations of NO_x and measures of vascular reactivity in conduit and resistance arteries in patients with CAD. Therefore, measurement of plasma NO_x may serve as a reliable marker for peripheral vasodilator dysfunction in patients with CAD.

     

Higher circulating resistin protein and PBMCs resistin mRNA levels are associated with increased prevalence of small dense LDL particles in coronary artery disease patients

Recent in vitro experiments have indicated that human resistin increases the number of lipoprotein particles secreted by the human hepatocytes and also influences their quality, in terms of generating more proatherogenic lipid particles. The aim of this study is to investigate associations of plasma resistin and peripheral blood mononuclear cells (PBMCs) resistin messenger RNA (mRNA) levels with different prevalence of small, dense low‐density lipoprotein particles (sdLDL) in patients with indications for coronary angiography. This study included 65 patients requiring coronary angiography. There were 41 patients without significant stenosis and 24 patients with significant stenosis in at least one major coronary artery. Circulating resistin was measured by enzyme‐linked immunosorbent assay; PBMC resistin mRNA was determined by real‐time polymerase chain reaction. The LDL and high density lipoprotein subclasses were determined by gradient gel electrophoresis. Plasma resistin (P = 0.031) and PBMCs resistin mRNA (P = 0.004) were significantly higher in patients with proportion of sdLDL particles ≥ 50%, compared to the group with relative proportion of sdLDL particles < 50%. Plasma resistin correlated positively with creatinine (r = 0.456, P < 0.001) and resistin mRNA (r = 0.298, P = 0.014) but negatively with body mass index (r = ?0.254, P = 0.034) and total cholesterol (r = ?0.286, P = 0.021). Multiple linear regression analysis revealed LDL particle diameter as the only independent predictor of resistin mRNA (R² = 0.258; adjR² = 0.190). A significant association between resistin, both PBMCs mRNA and plasma protein, and the relative proportion of sdLDL particles in the circulation of coronary artery disease patients has been established, which implies that increased gene expression of resistin in PBMCs and higher resistin concentration in plasma are related to pro‐atherogenic LDL particle phenotype.     

DEVELOPMENT OF CARDIAC DYSFUNCTION INDUCED BY REPETITIVE TRANSIENT MYOCARDIAL ISCHAEMIA IS INHIBITED BY EDARAVONE IN CONSCIOUS RATS

• 1 In the present study, we investigated the effects of treatment with the hydroxyl radical scavenger 3‐methyl‐1‐phenyl‐2‐pyrazolin‐5‐one (edaravone) on myocardial dysfunction induced by transient but frequent ischaemia in conscious rats.
• 2 Conscious male Wistar rats were subjected to repetitive ischaemia (RI; 40 s ischaemia every 20 min for 72 h). After the ninth episode of RI, edaravone (1 mg/kg, i.v., at each ischaemic event) or vehicle control (acetate buffer solution, i.v.) was administered. Dilation of the left ventricle (LV) after the eighth RI (fractional area change; %FAC_initial) and after the final RI (%FAC_final) was determined by comparing measurements (12 MHz echocardiogram) at these time‐points with baseline LV area prior to RI.
• 3 In controls, %FAC_final was correlated with %FAC_initial (r = 0.98; P < 0.0001), making %FAC_initial a predictor of %FAC_final. Edaravone treatment shifted the %FAC_initial–%FAC_final relationship downward (P < 0.0001), indicating that edaravone inhibited progression of LV dilation. In addition, %FAC_final was correlated with myocardial generation of reactive oxygen species (ROS) in control samples (r = 0.88, P = 0.008), although both %FAC_final and ROS were suppressed by edaravone treatment (P = 0.016).
• 4 We conclude that repetitive transient ischaemia in conscious rats induced development of cardiac dysfunction and that this phenomenon was inhibited by edaravone. We speculate that edaravone is a potential therapeutic agent that may interfere with the progression of cardiac dysfunction in high‐risk patients with RI.

     

Effects of 1,8-cineole on electrophysiological parameters of neurons of the rat superior cervical ganglion

• 1 1,8‐Cineole is a non‐toxic small terpenoid oxide believed to have medicinal properties in folk medicine. It has been shown to have various pharmacological effects, including blockade of the compound action potential (AP). In the present study, using intracellular recording techniques, we investigated the effects of 1,8‐cineole on the electrophysiological parameters of neurons of the superior cervical ganglion (SCG) in rats.
• 2 1,8‐Cineole (0.1–6 mmol/L) showed reversible and concentration‐dependent effects on various electrophysiological parameters. At 3 and 6 mmol/L, but not at 0.1 and 1 mmol/L, 1,8‐cineole significantly diminished the input resistance (R_i) and altered the resting potential (E_m) to more positive values. At 6 mmol/L, 1,8‐cineole completely blocked all APs within 2.7 ± 0.6 min (n = 12). In neurons exposed to 3 and 1 mmol/L 1,8‐cineole, the effects regarding excitability varied from complete AP blockade to minor inhibition of AP parameters. The depolarization of E_m and the decrease in R_i induced by 6 mmol/L 1,8‐cineole were unaltered by 200 µmol/L niflumic acid, a well known blocker of Ca²⁺‐activated Cl^? currents.
• 3 Significant correlations (Pearson correlation test) were found between changes in E_m and decreases in AP amplitude (r = –0.893; P < 0.00282) and maximum ascendant inclination (r = –0.799; P < 0.0173), but not for maximum descendant inclination (r = 0.598; P < 0.117). Application of current to restore the transmembrane potential equal to control E_m values in the presence of 6 mmol/L 1,8‐cineole resulted in the partial recovery of AP.
• 4 The present study shows that 1,8‐cineole effectively blocks the excitability of SCG neurons, probably through various mechanisms, one of which acts indirectly via depolarization of the neuronal cytoplasmatic membrane.

     

Effect of the Arg389Gly β(1) -adrenoceptor polymorphism on plasma renin activity and heart rate, and the genotype-dependent response to metoprolol treatment

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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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In vitro effects of cilostazol,a phosphodiesterase 3A inhibitor,on mouse oocyte maturation and morphology

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Oral nitrate therapy does not affect glucose metabolism in healthy men

• 1 Previously, we demonstrated that nitric oxide (NO) may be an important mediator of peripheral glucose disposal. The aim of the present study was to determine whether acute oral nitrate therapy improves glucose metabolism in healthy individuals.
• 2 Healthy men (n = 10), aged between 19 and 46 years, participated in a randomized cross‐over placebo‐controlled study. During Visit 1, participants received a dose‐graded intravenous infusion of sodium nitroprusside (SNP; titrated from a dose of 0.5 μg/kg per min to a maximum of 2 μg/kg per min and delivered at a rate of 2 mL/min over 30 min). On Visits 2, 3 and 4, participants received oral extended‐release isosorbide mononitrate (120 mg), pentaerythritol tetranitrate (160 mg) and placebo in a randomized Latin square design (one treatment per visit). The main outcome measures were plasma glucose and insulin levels and glucose tolerance determined by an oral glucose tolerance test following the SNP infusion and 3 h after nitrate/placebo administration. Exhaled NO, cGMP and pulmonary blood flow were also measured for 3 h after administration of nitrate/placebo and after SNP infusion.
• 3 None of the nitrate interventions influenced measures of glucose metabolism. Following SNP infusion, there was no change in plasma glucose (P = 0.42) or insulin (P = 0.25) levels, and the response to a glucose load did not different from baseline (P = 0.46). Similarly, neither of the oral nitrates altered plasma glucose (P = 0.24) or insulin levels (P = 0.90) or glucose tolerance (P = 0.56) compared with placebo.
• 4 In conclusion, these results indicate that acute oral nitrate therapy does not influence glucose metabolism. Studies using NO donors in a chronic setting are required to clarify the role of NO in mediating peripheral glucose uptake.

     

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.

     

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

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SIMULTANEOUS ACTION OF THE FLAVONOID QUERCETIN ON CYTOCHROME P450 (CYP) 1A2, CYP2A6, N-ACETYLTRANSFERASE AND XANTHINE OXIDASE ACTIVITY IN HEALTHY VOLUNTEERS

• 1 Quercetin, one of the most abundant natural flavonoids, has been reported to modulate the activity of several drug‐metabolising enzymes. The aim of the present study was to investigate the effects of quercetin on cytochrome P450 (CYP) 1A2, CYP2A6, N‐acetyltransferase (NAT2) and xanthine oxidase (XO) activity in healthy volunteers using caffeine as a probe drug.
• 2 Twelve unrelated, healthy volunteers were recruited to the study. There were two phases to the study; in the first phase, each subject was given a single oral dose of caffeine (one 100 mg capsule) with 150 mL water; in the second phase, each subject was give a 500 mg quercetin capsule once daily for 13 continuous days and was coadministered a 100 mg caffeine capsule on the 13th day. Urinary caffeine metabolite ratios were used as indicators of the activity of CYP1A2, CYP2A6, NAT2 and XO. The pharmacokinetics of caffeine and its metabolites were determined by HPLC.
• 3 In the quercetin‐treated group, CYP1A2 activity was decreased by 10.4% (95% confidence interval (CI), 1.1–29.8%; P = 0.039), whereas increases were observed in CYP2A6 (by 25.3%; 95% CI, 6.2–34.5%; P = 0.002), NAT2 (by 88.7%; 95% CI, 7.1–160.2%; P = 0.010) and XO activity (by 15.0%; 95% CI, 1.6–21.6%; P = 0.007). Plasma C_max and the AUC_(0–24 h) of 1,7‐dimethylxanthine were decreased by 17.2% (95% CI, 6.4–28.0%; P = 0.024) and 16.2% (95% CI, 3.9–28.5%; P = 0.032), respectively. The urinary excretion of 1,7‐dimethylxanthine and 1‐methylxanthine was significantly decreased by 32.4% (95% CI, 2.5–62.1%; P = 0.036) and 156.1% (95% CI, 53.3–258.9%; P = 0.004), respectively. The urinary excretion of 1,7‐dimethylurate and 1‐methylurate was increased by 82.9% (95% CI, 56.0–165.4%; P = 0.030) and 97.8% (95% CI, 12.1–183.5%; P = 0.029), respectively. No changes were observed in the urinary excretion of caffeine and 5‐acetylamino‐6‐formylamino‐3‐methyluracil between the two study phases.
• 4 The results of the present study indicate that quercetin inhibits CYP1A2 function, but enhances CYP2A6, NAT2 and XO activity. Simultaneously, some pharmacokinetic parameters relating to 1,7‐dimethylxanthine were affected by quercetin. Thus, we conclude that quercetin affects CYP1A2, CYP2A6, NAT2 and XO activity in vivo.

     

PREMATURE VENTRICULAR CONTRACTIONS ORIGINATING FROM THE RIGHT VENTRICULAR OUTFLOW TRACT: THREE-DIMENSIONAL DISTRIBUTION OF THE TARGET SITES AND THEIR ELECTROCARDIOGRAPHIC CHARACTERISTICS

• 1 The purpose of the present study was to explore the relationship between electrocardiogram (ECG) patterns of right ventricular outflow tract (RVOT) premature ventricular contractions and the three‐dimensional distribution of the target sites.
• 2 Thirty‐three consecutive patients were included in the study. The target sites were identified by non‐contact mapping and confirmed by successful ablation. The distribution of the target sites in the three‐dimensional reconstructed geometry of the RVOT was classified in three directions: (i) anterior (A)/posterior (P); (ii) free wall (F)/septal (Se); and (iii) superior (Su)/inferior (I). The ECG characteristics were then analysed according to the three‐dimensional distribution of the target sites.
• 3 The following indices were helpful to identify the position of the target site: (i) QRS duration (≥ 150 msec = F; < 150 msec = Se; P < 0.05); (ii) the R wave pattern in the inferior leads (RR′ or Rr′ = F; R = Se; P < 0.05); (iii) the R wave amplitude in the inferior leads (high = Se; low = F; P < 0.05); (iv) the initial r wave width in lead V₁ (wide = F; narrow = Se; P < 0.05); (v) the QS wave amplitude in aVR and aVL (if aVR < aVL, A; if aVR ≥ aVL, P; P < 0.05); and (vi) the initial r wave amplitude in lead V₁ and V₂ (if V₁ ≥ 0.15 mV and V₂ ≥ 0.3 mV, Su; if V₁ < 0.15 mV or V₂ < 0.3 mV, I; P < 0.05).
• 4 In conclusoin, the ECG characteristics were associated with target site locations in all three directions.

     

Pulse pressure variation does not reflect stroke volume variation in mechanically ventilated rats with lipopolysaccharide‐induced pneumonia

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Hydroxyethylvaline adduct formation in haemoglobin as a biological monitor of cigarette smoke intake

The ethylene oxide adduct formed on the N-terminal valine in haemoglobin was investigated as a biological monitor of tobacco smoke intake. The modified method developed for the determination of the hydroxyethylvaline adduct (HOEtVal) involved reaction of globin with pentafluorophenyl isothiocyanate, extraction of the HOEtVal thiohydantoin product, derivatization of this by trimethylsilylation and quantitation by capillary gas chromatography with selective ion monitoring mass spectrometry using a tetradeuterated internal standard. The method was applied to globin samples from 26 habitual cigarette smokers and 24 non-smokers. There was a significant correlation between cigarette smoke intake as measured by the average number of cigarettes smoked per day and HOEtVal levels (r=0.537, p<0.01). Background levels were found in non-smokers (mean 49.9 pmol/g Hb, range 22–106 pmol/g Hb). Smoking increased these levels by 71 pmol/g Hb/ 10 cigarettes per day.Cotinine levels in plasma of the smokers were determined by GC-NPD using 2-methyl-4-nitroaniline as internal standard. For non-smokers cotinine was determined by GC-MS selective ion monitoring using d₃-methylcotinine as internal standard. There was no correlation between number of cigarettes smoked per day and cotinine levels (r=0.297, p>0.05) although cotinine was correlated with HOEtVal (r=0.43, p<0.01).The HOEtVal adduct levels thus appear to be a suitable biomonitor for exposure to hydroxyethylating agents in cigarette smoke, reflecting an integrated dose over the erythrocyte lifetime. This is in contrast to plasma cotinine determinations which reflect only the previous day's exposure to nicotine in smoke.     

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 COMBINATION THERAPY WITH PERINDOPRIL AND LOSARTAN ON LEFT VENTRICULAR REMODELLING IN PATIENTS WITH MYOCARDIAL INFARCTION

• 1 Inhibiting the renin–angiotensin–aldosterone system prevents left ventricular (LV) remodelling after myocardial infarction (MI).
• 2 The present study was designed to assess the effects of a combination of perindopril and losartan on LV remodelling, cardiac function and serum procollagen type III amino terminal peptide (PIIINP) levels in patients with acute MI.
• 3 Patients with anterior MI were divided into three groups: (i) MI + perindopril; (ii) MI + losartan; and (iii) MI + perindopril + losartan. After successful intervention therapy, perindopril (2–4 mg daily), losartan potassium (25–50 mg daily) or their combination were administered. All patients received aspirin, clopidogrel and statins, and some patients were given beta‐blockers, nitrate and a platelet glycoprotein IIb/IIIa receptor antagonist. Three months later, LV dimensions and LV ejection fraction (LVEF) were measured by ultrasonography. Plasma B‐type natriuretic peptide (BNP), serum C‐reactive protein (CRP) and PIIINP levels were evaluated using enzyme‐linked immunosorbent assay or radioimmunoassay.
• 4 The baseline characteristics of the three groups were the same. Three months after the initiation of therapy, all patients showed decreased CRP, increased BNP and PIIINP levels and LV dilation and dysfunction. Compared with the two monotherapy groups, patients in the combination group showed significantly lower CRP, BNP and PIIINP levels, less LV dilation and higher LVEF. Serum PIIINP levels were positively correlated with CRP levels (r = 0.597; P < 0.01) and LV end‐diastolic volume index (r = 0.543; P < 0.01) and were negatively correlated with LVEF (r = –0.565; P < 0.01).
• 5 For patients with acute MI, combination treatment with perindopril and losartan significantly inhibited LV remodelling and improved LV function. Inhibition of myocardial interstitial fibrosis may be part of the underlying mechanism.

     

Microvascular resistance in response to iodinated contrast media in normal and functionally impaired kidneys

Contrast‐induced nephropathy (CIN) is considered to result from intrarenal vasoconstriction, and occurs more frequently in impaired than in normal kidneys. It was hypothesized that iodinated contrast media would markedly change renal blood flow and vascular resistance in functionally impaired kidneys. Thirty‐six patients were enrolled (32 men; mean age, 75.3 ± 7.6 years) undergoing diagnostic coronary angiography and were divided into two groups based on the presence of chronic kidney disease (CKD), defined as an estimated glomerular filtration rate (eGFR) of < 60 mL/min per 1.73 m² (CKD and non‐CKD groups, n = 18 in both). Average peak velocity (APV) and renal artery resistance index (RI) were measured by Doppler flow wire before and after administration of the iodinated contrast media. The APV and the RI were positively and inversely correlated with the eGFR at baseline, respectively (APV, R = 0.545, P = 0.001; RI, R = ?0.627, P < 0.001). Mean RI was significantly higher (P = 0.015) and APV was significantly lower (P = 0.026) in the CKD than in the non‐CKD group. Both APV (P < 0.001) and RI (P = 0.002) were significantly changed following contrast media administration in the non‐CKD group, but not in the CKD group (APV, P = 0.258; RI, P = 0.707). Although renal arterial resistance was higher in patients with CKD, it was not affected by contrast media administration, suggesting that patients with CKD could have an attenuated response to contrast media.     

Comprehensive analysis of the association of SCN1A gene polymorphisms with the retention rate of carbamazepine following monotherapy for new-onset focal seizures in the Chinese Han population

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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.