Novel Synthesized Radical-Containing Nanoparticles Limit Infarct Size Following Ischemia and Reperfusion in Canine Hearts.

Purpose: Although nitroxyl radicals such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) scavenge free radicals, their short half-life and considerable side effects such as systemic hypotension and bradycardia have limited their clinical application. Since a radical-containing nanoparticle (RNP) delivers nitroxyl radicals with a prolonged half-life specific to ischemic hearts, we investigated whether RNPs reduce infarct size without the occurrence of substantial side effects and whether nitric oxide (NO) contributes to the cardioprotective effects of RNPs.

Methods: The left anterior descending coronary arteries of dogs were occluded for 90 min, followed by reperfusion for 6 h.

Evaluation of Intracranial Microvessel Visualization in Mouse and Dog Models by Using a New Rotating Cerium Anode X-ray System.

Objective: Lacunar stroke may be caused by infarction of small perforating branches of the middle cerebral artery. We developed a microangiographic X-ray system using a cerium anode to evaluate the perforating branches.

Methods: Iodine has K-edges at 33.

A rotating cerium anode X-ray system allows visualization of intramural coronary vessels after cardiac stem cell therapy for myocardial infarction.

Conventional angiography is insufficient for evaluating the therapeutic effect of cardiac regeneration therapy. A microangiographic X-ray system using a cerium anode was developed. Cerium has a characteristic X-ray with a peak at 34.

Altered blood flow in cerebral perforating arteries of rat models of diabetes: A synchrotron radiation microangiographic study toward clinical evaluation of white matter hyperintensities.

Aim: As altered blood flow in the cerebral perforating arteries (PA) might be related to development of cerebral white matter hyperintensities, we examined whether the hemodynamic relationship of the PA and middle cerebral artery (MCA) is altered in rat models of diabetes, compared with normal rats and a rat model of sinoatrial denervation (blood pressure fluctuation model).

Methods: We used microangiography with monochromatic synchrotron radiation to measure the diameters of the PA and MCA at 4.5 μm resolution in five groups of rats: (i) Long-Evans Tokushima Otsuka (LETO); (ii) Otsuka Long-Evans Tokushima Fatty (a model of type 2 diabetes with obesity); (iii) LETO with sinoaortic denervation (LETO + SAD); (iv) F344; and (v) F344 + streptozotocin (a model of type 1 diabetes).

Development of Fingertip Synchrotron Radiation Microangiography toward Clinical Prediction of Diabetic Microangiopathy.

Objectives: The spatial resolution of conventional angiographic systems is not enough to predict diabetic microangiopathy in arterioles (20-200 µm).

Methods: To determine whether fingertip synchrotron (SR) radiation microangiography has enough spatial resolution to quantitate arteriolar diameter changes, and whether an arteriolar paradoxical vasoconstriction is a characteristic observation for diabetic microangiopathy, diameter reduction as arteriolar branching and difference of the diameter changes induced by acetylcholine between control (n = 5) and diabetic rats (n = 5) were analyzed.

Results: Fingertip SR microangiography visualized the arterioles with a diameter range of 30-300 µm and demonstrated vascular diameter reduction as branching with a fixed ratio (r = 0.

Visualization of microvessels by angiography using inverse-Compton scattering X-rays in animal models.

The fundamental performance of microangiography has been evaluated using the S-band linac-based inverse-Compton scattering X-ray (iCSX) method to determine how many photons would be required to apply iCSX to human microangiography. ICSX is characterized by its quasi-monochromatic nature and small focus size which are fundamental requirements for microangiography. However, the current iCSX source does not have sufficient flux for microangiography in clinical settings.

Carperitide induces coronary vasodilation and limits infarct size in canine ischemic hearts: role of NO.

Carperitide is effective for heart failure (HF) owing to its diuretic and vasodilatory effects. This recombinant peptide may also have direct cardioprotective effects because carperitide reduces the severity of heart failure and limits infarct size. Because coronary vasodilation is an important cardioprotective treatment modality, we investigated whether carperitide increased coronary blood flow (CBF) and improved myocardial metabolic and contractile dysfunction during ischemia in canine hearts.

H(2) mediates cardioprotection via involvements of K(ATP) channels and permeability transition pores of mitochondria in dogs.

Purpose: Inhalation of hydrogen (H(2)) gas has been shown to limit infarct size following ischemia-reperfusion injury in rat hearts. However, H(2) gas-induced cardioprotection has not been tested in large animals and the precise cellular mechanism of protection has not been elucidated. We investigated whether opening of mitochondrial ATP-sensitive K+ channels (mK(ATP)) and subsequent inhibition of mitochondrial permeability transition pores (mPTP) mediates the infarct size-limiting effect of H(2) gas in canine hearts.

Effect of systemic blood pressure on microcollateral circulation evaluated by real-time contrast echocardiography.

Background: In acute myocardial infarction, residual collateral-derived myocardial blood flow (CBF) within the ischemic area is one of the major determinants of infarct size. Management of systemic blood pressure (sBP) related to maintain collateral circulation is still difficult. The aim of this study was to reveal the influence of sBP on the rescue of area at risk by collateral circulation.

Role of Cu,Zn-SOD in the synthesis of endogenous vasodilator hydrogen peroxide during reactive hyperemia in mouse mesenteric microcirculation in vivo.

We have recently demonstrated that endothelium-derived hydrogen peroxide (H2O2) is an endothelium-derived hyperpolarizing factor and that endothelial Cu/Zn-superoxide dismutase (SOD) plays an important role in the synthesis of endogenous H2O2 in both animals and humans. We examined whether SOD plays a role in the synthesis of endogenous H2O2 during in vivo reactive hyperemia (RH), an important regulatory mechanism. Mesenteric arterioles from wild-type and Cu,Zn-SOD(-/-) mice were continuously observed by a pencil-type charge-coupled device (CCD) intravital microscope during RH (reperfusion after 20 and 60 s of mesenteric artery occlusion) in the cyclooxygenase blockade under the following four conditions: control, catalase alone, N(G)-monomethyl-L-arginine (L-NMMA) alone, and L-NMMA + catalase.

Important role of endogenous hydrogen peroxide in pacing-induced metabolic coronary vasodilation in dogs in vivo.

Objectives: We examined whether endogenous hydrogen peroxide (H2O2) is involved in pacing-induced metabolic vasodilation in vivo.

Background: We have previously demonstrated that endothelium-derived H2O2 is an endothelium-derived hyperpolarizing factor in canine coronary microcirculation in vivo. However, the role of endogenous H2O2 in metabolic coronary vasodilation in vivo remains to be examined.

Edaravone preserves coronary microvascular endothelial function after ischemia/reperfusion on the beating canine heart in vivo.

We examined whether edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, exerts its protective effect on coronary microvessels after ischemia/reperfusion (I/R) in vivo. Ninety-minute coronary occlusion followed by reperfusion was performed in 16 open-chest dogs with and without edaravone administration. Coronary small artery (> or = 100 microm in size) and arteriolar (< 100 microm) vasodilation, in the presence of endothelium-dependent (acetylcholine) or -independent (papaverine) vasodilators, was directly observed using intravital microscopy before and after I/R.

Prolonged transient acidosis during early reperfusion contributes to the cardioprotective effects of postconditioning.

We have previously reported that the prolonged transient acidosis during early reperfusion mediates the cardioprotective effects in canine hearts. Recently, postconditioning has been shown to be one of the novel strategies to mediate cardioprotection. We tested the contribution of the prolonged transient acidosis to the cardioprotection of postconditioning.

Erythropoietin enhances neovascularization of ischemic myocardium and improves left ventricular dysfunction after myocardial infarction in dogs.

Objectives: We investigated the effects of erythropoietin (EPO) on neovascularization and cardiac function after myocardial infarction (MI).

Background: Erythropoietin exerts antiapoptotic effects and mobilizes endothelial progenitor cells (EPCs).

Methods: We intravenously administered EPO (1,000 IU/kg) immediately [EPO(0) group], 6 h [EPO(6h) group], or 1 week [EPO(1wk) group] after the permanent ligation of the coronary artery in dogs.

Granulocyte colony-stimulating factor mediates cardioprotection against ischemia/reperfusion injury via phosphatidylinositol-3-kinase/Akt pathway in canine hearts.

Purpose: Recent studies suggest that G-CSF prevents cardiac remodeling following myocardial infarction (MI) likely through regeneration of the myocardium and coronary vessels. However, it remains unclear whether G-CSF administered at the onset of reperfusion prevents ischemia/reperfusion injury in the acute phase. We investigated acute effects of G-CSF on myocardial infarct size and the incidence of lethal arrhythmia and evaluated the involvement of the phosphatidylinositol-3 kinase (PI3K) in the in vivo canine models.

Cardioprotective role of endogenous hydrogen peroxide during ischemia-reperfusion injury in canine coronary microcirculation in vivo.

We have recently demonstrated that endogenous H2O2 plays an important role in coronary autoregulation in vivo. However, the role of H2O2 during coronary ischemia-reperfusion (I/R) injury remains to be examined. In this study, we examined whether endogenous H2O2 also plays a protective role in coronary I/R injury in dogs in vivo.

Triiodothyronine acutely increases blood flow in the ventricles and kidneys of anesthesized rabbits.

Thyroid hormone (triiodothyronine [T(3)]) has various nongenomic effects, including alterations in glucose and fatty acid metabolism, augmentation of intracellular Ca(2+), enhancement of myocardial contractility, and vascular dilatation. However, its effect on regional blood flow remains to be established. We have measured the effect of T(3) on blood flow in major organs of anesthetized rabbits in vivo using the microsphere method.

Blockade of histamine H2 receptors protects the heart against ischemia and reperfusion injury in dogs.

We have previously reported that histamine H(2) blockers may be cardioprotective in patients with chronic heart failure. Since both endogenous histamine and histamine H(2) receptors are present in heart tissue, we tested the hypothesis that the blockade of histamine H(2) receptors mediates protection against reversible or irreversible ischemia and reperfusion injury. In open-chest dogs, the left anterior descending coronary artery was occluded for 90 minutes, followed by reperfusion for 6 hours.

A role of opening of mitochondrial ATP-sensitive potassium channels in the infarct size-limiting effect of ischemic preconditioning via activation of protein kinase C in the canine heart.

The opening of mitochondrial ATP-sensitive K+ (mitoK(ATP)) channels triggers or mediates the infarct size (IS)-limiting effect of ischemic preconditioning (IP). Because ecto-5'-nucleotidase related to IP is activated by PKC, we tested whether the opening of mitoK(ATP) channels activates PKC and contributes to either activation of ecto-5'-nucleotidase or IS-limiting effect. In dogs, IP procedure decreased IS and activated ecto-5'-nucleotidase, both of which were mimicked by transient exposure to either cromakalim or diazoxide, and these effects were blunted by either GF109203X (a PKC inhibitor) or 5-hydroxydecanoate (a mitoK(ATP) channel blocker), but not by HMR-1098 (a surface sarcolenmal K(ATP) channel blocker).

Erythropoietin just before reperfusion reduces both lethal arrhythmias and infarct size via the phosphatidylinositol-3 kinase-dependent pathway in canine hearts.

Although recent studies suggest that erythropoietin (EPO) may reduce multiple features of the myocardial ischemia/reperfusion injury, the cellular mechanisms and the clinical implications of EPO-induced cardioprotection are still unclear. Thus, in this study, we clarified dose-dependent effects of EPO administered just before reperfusion on infarct size and the incidence of ventricular fibrillation and evaluated the involvement of the phosphatidylinositol-3 (PI3) kinase in the in vivo canine model. The canine left anterior descending coronary artery was occluded for 90 min followed by 6 h of reperfusion.

Beneficial effect of hydroxyfasudil, a specific Rho-kinase inhibitor, on ischemia/reperfusion injury in canine coronary microcirculation in vivo.

Objectives: We examined whether hydroxyfasudil, a specific Rho-kinase inhibitor, exerts cardioprotective effect on coronary ischemia/reperfusion (I/R) injury and, if so, whether nitric oxide (NO) is involved.

Background: Recent studies have demonstrated that Rho-kinase is substantially involved in the pathogenesis of cardiovascular diseases; however, it remains to be examined whether it is also involved in ischemia/reperfusion (I/R) injury.

Methods: Canine subepicardial small arteries (SA, >or=100 microm) and arterioles (A, <100 microm) were observed by a charge-coupled device intravital microscope during I/R.

Opening of Ca2+-activated K+ channels is involved in ischemic preconditioning in canine hearts.

Brief periods of ischemia that precede sustained ischemia can markedly reduce infarct size (IS), a phenomenon that is known as ischemic preconditioning (IP). Several investigators have shown that elevation of the intracellular Ca(2+) level ([Ca(2+)](i)) during the antecedent brief periods of ischemia triggers the cardioprotective mechanism of IP. Since opening of Ca(2+) activated K(+) (K(Ca)) channels is reported to be cardioprotective, we hypothesized that these channels may be involved in the cardioprotective mechanism of IP.

Optimal windows of statin use for immediate infarct limitation: 5'-nucleotidase as another downstream molecule of phosphatidylinositol 3-kinase.

Background: Although statins are reported to have a cardioprotective effect, their immediate direct influence on ischemia-reperfusion injury and the underlying mechanisms remain obscure. We investigated these issues an in vivo canine model.

Methods And Results: Dogs were subjected to coronary occlusion (90 minutes) and reperfusion (6 hours) immediately after injection of pravastatin (0.

Protein kinase A as another mediator of ischemic preconditioning independent of protein kinase C.

Background: We and others have reported that transient accumulation of cyclic AMP (cAMP) in the myocardium during ischemic preconditioning (IP) limits infarct size independent of protein kinase C (PKC). Accumulation of cAMP activates protein kinase A (PKA), which has been demonstrated to cause reversible inhibition of RhoA and Rho-kinase. We investigated the involvement of PKA and Rho-kinase in the infarct limitation by IP.

Beta-adrenoceptor blocker carvedilol provides cardioprotection via an adenosine-dependent mechanism in ischemic canine hearts.

Background: Carvedilol is a beta-adrenoceptor blocker with a vasodilatory action that is more effective for the treatment of congestive heart failure than other beta-blockers. Recently, carvedilol has been reported to reduce oxidative stress, which may consequently reduce the deactivation of adenosine-producing enzymes and increase cardiac adenosine levels. Therefore, carvedilol may also have a protective effect on ischemia and reperfusion injury, because adenosine mediates cardioprotection in ischemic hearts.