Abstract-We previously reported that combined blockade of adenosine receptors and ATP-sensitive Kϩ channels (K ϩ ATP channels) blunted but did not abolish the response of coronary blood flow to exercise. This study tested the hypothesis that the residual increase in coronary flow in response to exercise after adenosine receptor and K ϩ ATP channel blockade is dependent on endogenous NO. Dogs were studied at rest and during a four-stage treadmill exercise protocol under control conditions, during K ϩ ATP channel blockade with glibenclamide (50 g ⅐ kg Ϫ1 ⅐ min Ϫ1 IC) in the presence of adenosine receptor blockade with 8-phenyltheophylline (8-PT, 5 mg/kg IV), and after the addition of the NO synthase inhibitor N G -nitro-L-arginine (LNNA, 1.5 mg/kg IC). During control conditions, coronary blood flow was 49Ϯ3 mL/min at rest and increased to 92Ϯ8 mL/min at peak exercise. LNNA alone or in combination with 8-PT did not alter resting coronary flow and did not impair the normal increase in flow during exercise, indicating that when K ϩ ATP channels are intact, neither NO nor adenosine-dependent mechanisms are obligatory for maintaining coronary blood flow. Combined K ϩ ATP channel and adenosine blockade decreased resting coronary flow to 27Ϯ3 mL/min (PϽ.05), but exercise still increased flow to 45Ϯ5 mL/min (PϽ.05). The subsequent addition of LNNA further decreased resting coronary flow to 20Ϯ2 mL/min and markedly blunted exercise-induced coronary vasodilation (coronary vascular conductance, 0.20Ϯ0.03 mL ⅐ min Ϫ1 ⅐ mm Hg Ϫ1 at rest versus 0.24Ϯ0.04 mL ⅐ min Ϫ1 ⅐ mm Hg Ϫ1 during the heaviest level of exercise; Pϭ.22), so that coronary flow both at rest and during exercise was below the control resting level. The findings suggest that K Key Words: blood flow Ⅲ endothelium Ⅲ K ϩ channel Ⅲ ischemia Ⅲ reactive hyperemia R ecent evidence indicates that hyperpolarization of the vascular smooth muscle cell membrane caused by opening of K ϩ ATP channels is an important mechanism for metabolic coronary vasodilation. 1 We previously reported that blockade of vascular smooth muscle K ϩ ATP channels in chronically instrumented dogs decreased resting coronary blood flow but did not attenuate the increase in flow that occurred in response to treadmill exercise.2 However, after K ϩ ATP channel blockade had been established, the subsequent addition of adenosine receptor blockade reduced the exercise-induced increase in coronary flow by more than half, 3 indicating increased importance of adenosine in causing metabolic vasodilation after K ϩ ATP channels are blocked. Nevertheless, even after the combination of K ϩ ATP channel blockade and adenosine receptor blockade, exercise still produced a substantial increase in coronary flow.Bernstein et al 4 have reported that exercise causes increased NO production across the coronary circulation. We have previously observed that NO contributes to coronary vasodilation distal to a coronary artery stenosis, which results in hypoperfusion during exercise. 5 It is possible that NO could similarly contr...

In this new model of heart failure/hypertrophy, the abnormal myocardial HEP metabolism is related to the decreased CK-Mt protein level, which in turn is related to the severity of the hypertrophy.

Stromal-derived factor 1alpha (SDF-1alpha) is a key stem cell homing factor that is crucial for mobilization of stem cells from bone marrow to peripheral blood and subsequent engraftment to the tissue of diseased organs. It has been reported that SDF-1alpha is transiently over-expressed in ischemic myocardium. Therefore, there may be a limited time window after acute myocardial infarction (AMI) during which stem cells are recruited to injured myocardium for repair. This study aimed at investigating whether controlled release of SDF-1alpha via a novel conjugated poly(ethylene glycol) (PEG) (PEGylated) fibrin patch at the infarct site would increase the rate of stem cell recruitment and offer potential therapeutic benefits. Recombinant mouse SDF-1alpha was covalently bound to the PEGylated fibrinogen as evidenced by immunoprecipitation and western blotting. The PEGylated fibrinogen, bound with recombinant mouse SDF-1alpha, was mixed with thrombin to form the PEGylated fibrin patch. The release kinetics of SDF-1alpha were detected in vitro using enzyme-linked immunosorbent assay. Using a mouse AMI model produced by a ligature on the left anterior descending coronary artery, a PEGylated fibrin patch bound with SDF-1alpha (100 ng) was placed on the surface of the infarct area of the left ventricle. Infarct size, left ventricular (LV) function, and the percentage of sca-1(+)/c-kit(+) cells within the infarct area were measured at days 7, 14, and 28 after AMI. In vitro results showed that SDF-1alpha was successfully bound to the PEGylated fibrin patch and can be released from the patch constantly for up to 10 days. Two weeks after infarction, the myocardial recruitment of c-kit(+) cells was significantly higher in the group treated with the SDF-1alpha PEGylated fibrin patch (n = 9) than in the AMI control group (n = 10) (p < 0.05; 11.20 +/- 1.71% vs. 4.22 +/- 0.96%, respectively). At day 28 post-AMI, unlike the control group, the group with the SDF-1alpha-releasing patch maintained stable release of SDF-1alpha concurrent with additional stem cell homing. Moreover, LV function was significantly better than in the control group. These data demonstrate that the PEGylated fibrin patch based SDF-1alpha delivery can improve the rate of c-kit(+) cell homing and improve LV function in hearts with postinfarction LV remodeling.

Bone marrow-derived mononuclear cell (BMNC) transplantation provides the possibility of rescue or regeneration of myocardium lost during acute myocardial infarction (AMI). The extensive death of transplanted cells and the lack of sustained engraftment may limit its application. We investigated whether delivery of BMNCs by an injectable PEGylated fibrin biomatrix that covalently binds hepatocyte growth factor (HGF) would enhance the rate of cell engraftment and improve cardiac function. Balb/C female mice with AMI secondary to left anterior descending coronary ligation were randomly assigned to one of six groups: the Saline control group (n = 8) received a myocardial injection of saline (50 microL); the Cell group (n = 10) received a myocardial injection in the peri-infarct and infarct zones consisting of 500,000 murine BMNCs suspended in 50 microL saline; and the Biomatrix + HGF (n = 9) and Biomatrix + HGF + Cell (n = 9) group hearts received the HGF-loaded injectable biomatrix (identical volume) with or without entrapped BMNCs. Control groups consisting of the biomatrix alone (n = 9) and Biomatrix + Cells (n = 9) without HGF were also included for comparison. The left ventricular (LV) function was measured by echocardiography at days 14 and 28 post-MI. All animals were euthanized 4 weeks after AMI and transplantation for evaluation of angiogenesis, apoptosis, and fibrosis by immunohistochemistry. Cell prevalence rate at 4 weeks increased 15-fold in hearts receiving the Biomatrix + HGF + Cell delivery (p < 0.01), which was accompanied by the lowest levels of apoptosis and the highest LV function recovery among the treated groups.