Common occurrence of everolimus-associated aphthous stomatitis in Japanese heart transplant recipients.

Mammalian target of rapamycin (mTOR) inhibitors display antiproliferative effects with less nephrotoxicity than calcineurin inhibitors. However, clinical use of mTOR inhibitors can be associated with a series of adverse events. We experienced cases of aphthous stomatitis associated with everolimus (EVL) in four Japanese heart transplant recipients treated at the target trough EVL blood level after a switch from mycophenolate mofetil between April and December 2007. All four patients developed aphthous stomatitis; three required reduction of the exposure and one, EVL discontinuation due to stomatitis as well as other side effects. All patients recovered from stomatitis after reduction or withdrawal of EVL. Thus, we considered that EVL-related stomatitis might occur commonly among the Japanese population. The proper dosage, effects, and frequency of the side effects of mTOR inhibitors may vary by ethnic population.

Which factors predict the recovery of natural heart function after insertion of a left ventricular assist system?

BACKGROUND: Recent reports have demonstrated that use of a left ventricular assist system (LVAS) can initiate recovery of cardiac function, and subsequent weaning from the LVAS has attracted considerable interest. In this study we investigated reliable predictors of LVAS weaning. METHODS: Eighty-two patients underwent LVAS implantation between April 1994 and July 2006 at our institution. Cardiac function was restored in 8 patients, who were weaned from LVAS after a mean of 5 months (Group R). Thirty-three patients remained on LVAS support for >1 year (Group N) because natural heart function did not show adequate improvement. We retrospectively evaluated the differences between these two groups. Group R was younger, and had a shorter duration of heart failure than Group N (23.4 vs 36.7 years and 13.3 vs 56.1 months, p < 0.01, respectively). Pathologic findings showed that the interstitial fibrosis score was lower in Group R (p < 0.01). Three months after LVAS insertion, B-type natriuretic peptide (BNP) and fractional shortening (FS) were more favorable (66.6 +/- 46 vs 264.5 +/- 170 pg/ml, p < 0.01, and 23 +/- 17.1 vs 12 +/- 9.1%, p < 0.05, respectively) in Group R. Furthermore, Group R received a higher dose of beta-blocker (15.4 +/- 8.4 vs 5.8 +/- 3.9 mg, p < 0.05). CONCLUSIONS: Younger age, shorter history of heart failure, and less interstitial fibrosis were effective predictors of weaning from LVAS. Restoration of natural heart function was more rapid and more persistent in candidates for LVAS explantation, and presence of beta-blocker played a prominent role in improving cardiac function after LVAS implantation.

Heterogeneity of regional systolic function detected by tissue Doppler imaging is linked to impaired global left ventricular relaxation in hypertrophic cardiomyopathy.

OBJECTIVE: To evaluate regional and global left ventricular (LV) function and LV wall thickness (LVWT) in patients with hypertrophic cardiomyopathy (HCM). DESIGN AND SETTING: Observational study at the National Cardiovascular Centre and Nagoya University Hospital in Japan. PARTICIPANTS: Thirty-six patients with HCM and 16 patients with hypertensive LV hypertrophy (LVH). MAIN OUTCOME MEASURES: Conventional echocardiography and strain rate (SR) imaging derived from tissue Doppler imaging were performed. Systolic strain (epsilon(sys)), peak systolic SR (SR(sys)), peak early diastolic SR (SR(dia)) and LVWT were obtained from eight LV segments. LV pressure was simultaneously recorded with a high-fidelity micromanometer. RESULTS: The regional epsilon(sys) and SR(sys) were correlated with LVWT in patients with HCM (r = 0.50, p<0.001 and r = 0.63, p<0.001, respectively) but not in patients with hypertensive LVH. The standard deviations of LVWT, epsilon(sys) and SR(sys) obtained from the eight LV segments of each subject were greater for patients with HCM than for patients with hypertensive LVH. The standard deviation of LVWT was correlated with those of epsilon(sys) and SR(sys) (r = 0.55, p<0.001 and r = 0.56, p<0.001, respectively). The standard deviations of LVWT, epsilon(sys) and SR(sys) were correlated with tau (r = 0.35, p<0.05; r = 0.47, p<0.001; and r = 0.39, p<0.005, respectively). CONCLUSIONS: Heterogeneity of regional LV systolic function detected by SR imaging is in part attributable to heterogeneity of LVH and may be linked to impaired global LV relaxation in HCM.

Micro-Magnetocardiography System With a Single-Chip SQUID Magnetometer Array for QT Analysis and Diagnosis of Myocardial Injury in Small Animals.

Development of drugs requires electrophysiological studies of small animals like mice, rats or guinea pigs. Electrocardiography (ECG) of hirsute animals is time-consuming. We have developed a micro magnetometer array with a 9-channel superconducting quantum interference device (SQUID) with a 2.5-mm diameter pickup-coil for noncontacting measurement of magnetocardiograms (MCGs) in small animals. The micro-MCG successfully recorded the PQRST complex in mice, rats and guinea pigs. A regional myocardial injury was made in rat hearts with a cryoinjury probe, and the characteristic pattern of the injury was recorded in the MCG. An anterior myocardial injury created a QS pattern in the MCG, and a posterior myocardial injury created a QR pattern in the MCG. Quinidine-induced QT prolongation was successfully detected by micro-MCG in mice and rats. Simultaneous recording of ECG and MCG was conducted after intraperitoneal administration of quinidine (60 mg/kg) in guinea pigs. QT interval corrected for heart rate (QTc) in both ECG and MCG correlated well. The newly developed micro-MCG may facilitate electrophysiological studies of small animals, and may enable high-throughput screening of drug-induced QT abnormality.

Genetic variations and haplotype structures of the ABCB1 gene in a Japanese population: an expanded haplotype block covering the distal promoter region, and associated ethnic differences.

As functional ABCB1 haplotypes were recently reported in the promoter region of the gene, we resequenced the ABCB1 distal promoter region, along with other regions (the enhancer and proximal promoter regions, and all 28 exons), in a total of 533 Japanese subjects. Linkage disequilibrium (LD) analysis based on 92 genetic variations revealed 4 LD blocks with the same make up as previously described (Blocks -1, 1, 2 and 3), except that Block 1 was expanded to include the distal promoter region, and that a new linkage between polymorphisms -1,789G>A in the distal promoter region and IVS5 + 123A>G in intron 5 was identified. We re-assigned Block 1 haplotypes, and added novel haplotypes to the other 3 blocks. The reported promoter haplotypes were further classified into several types according to tagging variations within Block 1 coding or intronic regions. Our current data reconfirm the haplotype profiles of the other three blocks, add more detailed information on functionally-important haplotypes in Block 1 and 2 in the Japanese population, and identified differences in haplotype profiles between ethnic groups. Our updated analysis of ABCB1 haplotype blocks will assist pharmacogenetic and disease-association studies carried out using Asian subjects.

Serum amiodarone and desethylamiodarone concentrations following nasogastric versus oral administration.

OBJECTIVE: Hospitalized patients unable to ingest anything by mouth require nutritional support by enteral feeding and administration of drugs through a nasogastric tube inserted into the digestive tract. Nasogastric administration of amiodarone may not always be equivalent to oral administration of amiodarone. METHODS: We collected 162 observations of serum amiodarone and desethylamiodarone metabolite concentrations from 93 patients within 60 days of starting treatment with amiodarone. Eight patients were given the drug nasogastrically and 85 patients, orally. The two groups, were compared in terms of their serum concentration/(dose/weight) (C/D) value. A ratio of serum amiodarone concentration to serum desethylamiodarone concentration (AMD/DEA) was calculated for each sample. In addition, the percentage drug recovery after nasogastric administration of amiodarone was analysed. RESULTS: Significant differences were observed in C/D values of amiodarone and desethylamiodarone and in AMD/DEA values of patients given amiodarone orally when compared with those given the drug nasogastrically. The C/D values of patients who received their medication nasogastrically were approximately 30% of the C/D values of patients who received their medication orally. Approximately 70% of the drug was recovered after it had passed through the nasogastric tube. CONCLUSIONS: To achieve similar concentrations, an approximately 3-fold increase in dosage of amiodarone was required when patients were given the drug nasogastrically rather than orally. This suggests that the absorption of amiodarone following nasogastric administration is poor when compared with oral administration. Therapeutic drug monitoring is necessary to optimize dose particularly during the early stages of amiodarone therapy.

Heart-type fatty acid binding protein is a novel prognostic marker in patients with non-ischaemic dilated cardiomyopathy.

OBJECTIVE: To determine whether concentrations of heart-type fatty acid binding protein (H-FABP) measured before hospital discharge predict critical cardiac events in patients with idiopathic dilated cardiomyopathy (DCM). PATIENTS: 92 consecutive patients with DCM were enrolled and followed up for four years. MAIN OUTCOME MEASURES: Serum concentrations of H-FABP, brain natriuretic peptide (BNP), cardiac troponin T before hospital discharge and survival rate. RESULTS: 23 patients died of cardiac causes, received a left ventricular assist device or underwent heart transplantation during the four-year follow up. Univariate analyses showed that New York Heart Association functional class, heart rate, ejection fraction, serum H-FABP and plasma BNP were significant variables. According to multivariate analysis, serum H-FABP and plasma BNP concentrations were independent predictors of critical cardiac events. Cardiac troponin T before hospital discharge was not a predictor. The area under the receiver operating characteristic curve for death from critical cardiac events was similar between H-FABP and BNP. Patients with an H-FABP concentration at or above the median (> or = 5.4 ng/ml) had a significantly lower survival rate than those below the median, according to analysis by log rank test (p < 0.0001). When combined with BNP concentration at or above the median (> or = 138 pg/ml), H-FABP below the median predicted the worst prognosis among the combinations. CONCLUSIONS: The concentration of serum H-FABP before discharge from hospital may be an independent predictor for critical cardiac events in DCM.

Haplotype structures of the UGT1A gene complex in a Japanese population.

Genetic polymorphisms of UDP-glucuronosyltransferases (UGTs) are involved in individual and ethnic differences in drug metabolism. To reveal co-occurrence of the UGT1A polymorphisms, we first analyzed haplotype structures of the entire UGT1A gene complex using the polymorphisms from 196 Japanese subjects. Based on strong linkage disequilibrium between UGT1A8 and 1A10, among 1A9, 1A7, and 1A6, and between 1A3 and 1A1, the complex was divided into five blocks, Block 8/10, Block 9/6, Block 4, Block 3/1, and Block C, and the haplotypes for each block were subsequently determined/inferred. Second, using pyrosequencing or direct sequencing, additional 105 subjects were genotyped for 41 functionally tagged polymorphisms. The data from 301 subjects confirmed the robustness of block partitioning, but several linkages among the haplotypes with functional changes were found across the blocks. Thus, important haplotypes and their linkages were identified among the UGT1A gene blocks (and segments), which should be considered in pharmacogenetic studies.

Genetic polymorphisms and haplotypes of the human cardiac sodium channel alpha subunit gene (SCN5A) in Japanese and their association with arrhythmia.

Genetic variations in cardiac ion channels have been implicated not only as the causes of inherited arrhythmic syndromes, but also as genetic risk factors for some acquired arrhythmias. To elucidate the potential roles of genetic polymorphisms of the alpha subunit of the voltage-gated sodium channel type V (SCN5A) in cardiac rhythm disturbance, the entire SCN5A coding exons and their flanking introns were sequenced in 166 Japanese arrhythmic patients and 232 healthy controls. We detected 69 genetic variations, including 54 novel ones. Out of the 12 novel nonsynonymous single nucleotide polymorphisms (SNPs), p.Leu1988Arg was found at a frequency of 0.015. The other 11 SNPs were rare (0.001), with 6 found in arrhythmic patients and 5 in healthy controls. The frequency of a novel intronic SNP, c.703+130G>A, was significantly higher in the patients than in the controls, suggesting this SNP is associated with an unknown risk factor for arrhythmia. Following linkage disequilibrium analysis, the haplotype structure of SCN5A was inferred using high-frequency SNPs. The frequency of the haplotype harbouring both p.Leu1988Arg and the common SNP p.His558Arg (haplotype GG) was significantly lower in the patients than in the controls. This finding suggests that this haplotype (GG) might have been positively selected in the controls because of its protective effect against arrhythmias. This study provides fundamental information necessary to elucidate the effect of genetic variations in SCN5A on channel function and cardiac rhythm in Japanese, and probably in the Asian population.

Comparative left ventricular functional and neurohumoral effects of chronic treatment with carvedilol versus metoprolol in patients with dilated cardiomyopathy.

The efficacy of treating dilated cardiomyopathy with metoprolol was compared with that of carvedilol. Metoprolol was administered to 29 patients, and carvedilol to 62. Patients who could not be dosed with up to 40 mg daily of metoprolol or 20 mg daily of carvedilol were defined as intolerant. As well as the tolerability of these beta-blockers, the effects on left ventricular end-diastolic dimension (LVDd), fractional shortening (FS), plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations, the delayed heart and mediastinum (H/M) ratio determined from metaiodobenzylguanidine imaging were compared. Drug intolerance occurred in 24% of patients in the metoprolol group and 19% in the carvedilol group. Among the drug-tolerant patients, LVDd, FS and plasma BNP concentration improved in both groups and to the same degree. Only 25% of drug-tolerant patients in the metoprolol group had a delayed H/M ratio below 1.9 compared with 57% in the carvedilol group. Both metoprolol and carvedilol, when tolerated, improve cardiac function and neurohumoral factors to the same degree. However, carvedilol is preferable to metoprolol for patients with a low delayed H/M ratio.

Vascular cell adhesion molecule-1 as a biochemical marker of left ventricular mass in the patients with hypertension.

Plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular adhesion molecule-1 (sVCAM-1), and E-selectin were measured in 80 outpatients with uncomplicated essential hypertension. Although the levels of E-selectin and sICAM-1 were similar between the patients with and without left ventricular (LV) hypertrophy, sVCAM-1 level was significantly elevated in the patients with LV hypertrophy (759.7+/-154.6 ng/mL nu 984.4+/-240.6 ng/mL, P < .0001). The LV mass normalized to body surface area or height were significantly correlated with sVCAM-1 (r=0.615, P < .0001 and r=0.571, P < .0001, respectively). These results indicate that a soluble adhesion molecule is correlated with LV mass in uncomplicated essential hypertensive patients.

[Clinical significance of measuring inferior vena cava dimension in patients with acute exacerbation of chronic heart failure].

OBJECTIVES: This study determined the clinical significance of measuring the inferior vena cava dimension in patients with heart failure. METHODS: The subjects were 373 patients admitted due to acute exacerbation of chronic heart failure. The relationships were examined between inferior vena cava dimension in the end-expiratory phase on admission and in the stable state and etiology of heart failure, age, New York Heart Association (NYHA) functional classification in the stable state (before exacerbation), body weight, grade of tricuspid regurgitation, left ventricular end-diastolic dimension and left ventricular ejection fraction measured by two-dimensional echocardiography in the stable state and on admission, severity of lung congestion (Killip's classification) on admission, and clinical course during treatment. RESULTS: The inferior vena cava dimension was not correlated with etiology, age, NYHA functional classification, body weight, left ventricular end-diastolic dimension or left ventricular ejection fraction, but was correlated with the grade of tricuspid regurgitation (r = 0.78, p < 0.0001 in the stable state, r = 0.60, p < 0.0001 and on admission). The severity of lung congestion did not correlate with inferior vena cava dimension on admission or the increase in inferior vena cava dimension. The increase in body weight on admission was correlated with the increase in inferior vena cava dimension (r = 0.83, p < 0.0001), but did not correlate with inferior vena cava dimension on admission. Tricuspid regurgitation grade and inferior vena cava dimension were restored to the stable state when body weight reached stable state after treatment in patients (n = 202) with inferior vena cava dimension increased by over 5 mm on admission. CONCLUSIONS: Inferior vena cava dimension in patients with heart failure is correlated with the tricuspid regurgitation grade in the stable state and at acute exacerbation. The increase in inferior vena cava dimension between stable and exacerbated states, but not the actual value, is clinically useful to evaluate patients with acute exacerbation of chronic heart failure.

Improvement in cardiac function and free fatty acid metabolism in a case of dilated cardiomyopathy with CD36 deficiency.

A 27-year-old man diagnosed as having dilated cardiomyopathy (DCM) without myocardial accumulation of 123I-beta-methyl-iodophenylpentadecanoic acid, and he was found to have type I CD36 deficiency. This abnormality of cardiac free fatty acid metabolism was also confirmed by other methods: 18F-fluoro-2-deoxyglucose positron emission tomography, measurements of myocardial respiratory quotient and cardiac fatty acid uptake. Although the type I CD36 deficiency was reconfirmed after 3 months, the abnormal free fatty acid metabolism improved after carvedilol therapy and was accompanied by improved cardiac function. Apart from a cause-and-effect relationship, carvedilol can improve cardiac function and increase free fatty acid metabolism in patients with both DCM and CD36 deficiency.

Cardiac transplantation under new legislation for organ transplantation in Japan: report of two cases.

During the past 2 years since new legislation for organ transplantation from brain-dead donors came into effect in Japan, 3 cardiac transplants have been carried out, 2 of which were performed at the National Cardiovascular Center (NCVC). The recipient cases were 46- and 25-year-old male patients who suffered from end-stage dilated cardiomyopathy and had been listed for cardiac transplantation in the Japan Organ Transplantation Network as status I candidates. The first patient was supported by the use of a paracorporeal air-driven left ventricular assist device of the NCVC type, and had a moderate degree of renal and hepatic dysfunction at the time of transplantation. Donor hearts were transported from distant hospitals (Tokyo and Miyagi prefecture) and the transportation time was 1 h 33 min and 2h 4 min, respectively. The operation was performed by the standard technique (Lower-Shumway) in the first patient and by the bicaval anastomosis technique in the second patient. Reperfusion of the transplanted heart was performed retrogradely through the coronary sinus utilizing leukocyte-depleted blood with a gradual increase in temperature. Total ischemic time was 3 h 34 min and 3 h 35 min, respectively. Weaning from the cardiopulmonary bypass was easy and uneventful in each patient. Immunosuppressive therapy was conducted with OKT-3 induction in the first patient because of the coexisting renal dysfunction and with a triple immunosuppressive regimen for both patients. Routine endomyocardial biopsy showed acute rejection of less than grade Ib, and the patients were discharged on the 65th and 46th postoperative day, respectively. At present, both patients are in the NYHA class I state and are ready to return to work. The uneventful recovery seen in these patients shows the advances made in transplant medicine, including the progress and improvement of immunosuppressive therapy, surgical techniques, myocardial protection, and detection and treatment of infection. Further efforts are required to fully establish the cardiac transplantation program in Japan.

Improvement in left ventricular function in response to carvedilol is accompanied by attenuation of neurohumoral activation in patients with dilated cardiomyopathy.

BACKGROUND: We sought to evaluate whether improvement in ejection fraction (EF) with carvedilol therapy is accompanied by improvement in neurohumoral factors. METHODS AND RESULTS: Forty-two patients with dilated cardiomyopathy were given carvedilol for 3 to 5 months. Changes in EF, plasma atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and norepinephrine levels were determined. Iodine-123 metaiodobenzylguanidine (MIBG) images were also obtained before and after carvedilol therapy. Myocardial uptake of MIBG was calculated as the heart to mediastinal activity ratio (H/M). Storage and release of MIBG was calculated as percent myocardial MIBG washout rate (WR). We divided patients into 2 groups: 27 responders whose EF increased by more than 5% and 15 nonresponders whose EF increased by 5% or less. EF of responders increased by 15 +/- 5% and that of nonresponders by 1 +/- 4%. Although MIBG image-derived indexes of nonresponders remained unchanged, the delayed H/M (1.91 +/- 0.34 v 2.24 +/- 0.53, P < .01) and WR (49 +/- 11 v 39 +/- 9%, P < .01) of responders improved, respectively. The plasma ANP (51 +/- 50 v 27 +/- 24 pg/mL, P < .01) and BNP (194 +/- 197 v 49 +/- 62 pg/mL, P < .01) levels of responders decreased. The degree of changes in the plasma BNP level correlated with changes in EF (r = -.698, P < .01). CONCLUSION: The improvement in EF with carvedilol therapy was proved to be accompanied by an improvement in neurohumoral factors.

Enhanced methods for visualizing myocardial perfusion with peripheral venous injection of levovist: application of triggered harmonic imaging and triggered harmonic power Doppler imaging techniques.

OBJECTIVES: The purpose of this study was to determine whether triggered harmonic imaging (THI) or triggered harmonic power Doppler imaging (THPDI) could obtain the myocardial contrast enhancement using peripheral venous injection of a first generation echocardiographic contrast agent, Levovist. METHODS: In a phantom model, we examined the influence of an acoustic power, harmonic filters, transmitted frequencies and focus positions of transducer on Levovist. Then fundamental, harmonic or harmonic power Doppler imaging were performed with ECG-triggered imaging in eight closed-chest dogs using bolus injection of Levovist. RESULTS: In a phantom model, the highest transmission power (Mechanical index 1.6), a medium harmonic filter and a focus position (6 cm) resulted in the best enhanced contrast in both THI and THPDI. Furthermore, higher pulse repetition frequency (5500 Hz) of harmonic power Doppler made clearer enhancement. In animal models, we could not observe the apparent myocardial contrast using triggered fundamental imaging, and the intensity of each region of interest (ROI) of myocardium had not changed significantly. However, homogeneous myocardial contrast could be obtained using THI, which was conditioned on the highest transmission power, a medium harmonic filter same as the phantom model, at a lower transmitted frequency (1.8 MHz) and a focus position, which were located in the middle portion of the left ventricle. The peak intensity of each ROI increased significantly in a gray level. Furthermore, THPDI caused emphasized myocardial contrast visually. CONCLUSIONS: These results indicate that THI and THPDI produce obvious MCE using peripheral venous injection of Levovist.

Pravastatin restored the infarct size-limiting effect of ischemic preconditioning blunted by hypercholesterolemia in the rabbit model of myocardial infarction.

OBJECTIVES: We tested to find out whether pravastatin restores the infarct size (IS)-limiting effect of ischemic preconditioning (IP) and if it has any effect on the IP-induced activation of adenosine producing enzyme ecto-5'-nucleotidase which plays a key role in the IP-induced cardioprotection. BACKGROUND: The IS-limiting effect of IP is blunted by hypercholesterolemia. Recently, HMG-CoA reductase inhibitors are shown to have direct cytoprotective effects. METHODS: Rabbits were fed with a normal or cholesterol (1%) added diet with or without pravastatin (5 mg/kg/day) treatment. Infarct size was measured after 30 min occlusion and 3 h reperfusion of circumflex coronary artery with or without the IP procedure (5 min occlusion and 10 min reperfusion). Additionally, ecto-5'-nucleotidase activities of ischemic and nonischemic myocardium were measured immediately after IP procedure. RESULTS: This dose of pravastatin did not normalize the increased level of serum cholesterol. The IS-limiting effect of preceding IP (IS reduced from 36.7% to 9.6%, p < 0.001) was abolished by hypercholesterolemia (from 46.1% to 31.3%, p = NS) and restored by pravastatin treatment (from 35.2% to 9.4%, p < 0.001). Pravastatin treatment did not affect IS or the effect of IP under normocholesterolemia. The activation of ecto-5'-nucleotidase presented as the activity ratio of ischemic to nonischemic myocardium (3.1-fold in normocholesterolemia) was blunted by hypercholesterolemia (1.8-fold, p < 0.05) and restored by pravastatin treatment (2.9-fold). CONCLUSIONS: Pravastatin, at the dose serum cholesterol was not normalized, restored the IS-limiting effect of IP and IP-induced ecto-5'-nucleotidase activation, which were both blunted by hypercholesterolemia. The activation of ecto-5'-nucleotidase may be worth further investigation as a possible mechanism for the hypercholesterolemia-induced retardation and pravastatin-mediated restoration of the cardioprotective effect of IP.

Intracoronary administration of adenosine triphosphate increases coronary blood flow and attenuates the severity of myocardial ischemic injury in dogs.

ATP generates nitric oxide (NO) via activation of P2y receptors, and is degraded to adenosine. This study was undertaken to examine whether ATP causes coronary hyperemic flow via purinoceptors-, NO- and adenosine-dependent mechanisms, and attenuates the severity of contractile and metabolic dysfunction in the ischemic myocardium. In the non-ischemic canine hearts, the infusions of ATP into the coronary artery dose-dependently increased coronary blood flow. The levels of adenosine and end-product of NO in coronary venous blood over the arterial blood also increased. This hyperemic flow was partially attenuated by either 8-sulfophenyltheophylline (8SPT) or L(omega)-nitro arginine methyl ester (L-NAME), and completely blocked by the treatment with 8SPT, L-NAME and suramin (SRM). During myocardial ischemia, exogenous ATP increased coronary blood flow, and attenuated myocardial metabolic and contractile dysfunction, which was completely blunted by the treatment with 8SPT, L-NAME and SRM. We conclude that exogenous ATP increases coronary blood flow in the non-ischemic and ischemic myocardium mainly via either NO- or adenosine-dependent mechanisms.