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Biomedical subjects

Masafumi Kitakaze

Publications and source records attributed to Masafumi Kitakaze.

At least 19 recordsLinked to original sources
PubMed2007

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. Open-chest anesthetized dogs subjected to 90-min occlusion of the left anterior descending coronary artery and 6-h reperfusion were divided into four groups: 1) control group; no intervention after reperfusion (n = 6); 2) postconditioning (Postcon) group; four cycles of 1-min reperfusion and 1-min reocclusion (n = 7); 3) Postcon + sodium bicarbonate (NaHCO(3)) group; four cycles of 1-min reperfusion and 1-min reocclusion with the administration of NaHCO(3) (n = 8); and 4) NaHCO(3) group; administration of NaHCO(3) without postconditioning (n = 6). Infarct size, the area at risk (AAR), collateral blood flow during ischemia, and pH in coronary venous blood were measured. The phosphorylation of Akt and extracellular signal-regulated kinase (ERK) in ischemic myocardium was assessed by Western blot analysis. Systemic hemodynamic parameters, AAR, and collateral blood flow were not different among the four groups. Postconditioning induced prolonged transient acidosis during the early reperfusion phase. Administration of NaHCO(3) completely abolished the infarct size-limiting effects of postconditioning. Furthermore, the phosphorylation of Akt and ERK in ischemic myocardium induced by postconditioning was also blunted by the cotreatment of NaHCO(3). In conclusion, postconditioning mediates its cardioprotective effects possibly via prolonged transient acidosis during the early reperfusion phase with the activation of Akt and ERK.

Acidosis↗
PubMed2006

Long-term stimulation of adenosine A2b receptors begun after myocardial infarction prevents cardiac remodeling in rats.

BACKGROUND: Adenosine inhibits proliferation of cardiac fibroblasts and hypertrophy of cardiomyocytes, both of which may play crucial roles in cardiac remodeling. In the present study, we investigated whether chronic stimulation of adenosine receptors begun after myocardial infarction (MI) prevents cardiac remodeling. METHODS AND RESULTS: MI was produced in Wistar rats by permanent ligation of the left anterior descending coronary artery. One week after the onset of MI, animals were randomized into 8 groups: vehicle, dipyridamole (DIP; the adenosine uptake inhibitor, 50 mg/kg), 2-chroloadenosine (CADO; the stable analogue of adenosine, 2 mg/kg), and CADO in the presence of the nonselective adenosine receptor antagonist 8-sulfophenyltheophylline (8-SPT) or the selective antagonist for adenosine A1, A2a, A2b, or A3 receptor. Three weeks after treatment, hemodynamic and echocardiographic parameters in the DIP and CADO groups were significantly improved compared with the vehicle group. These hemodynamic and echocardiographic improvements were blunted by either 8-SPT or the selective adenosine A2b antagonist MRS1754 but not by the selective antagonists for other subtypes of adenosine receptors. The collagen volume fraction was smaller, and gene expression of the molecules associated with cardiac remodeling such as matrix metalloproteinase in noninfarcted areas was reduced in the DIP and CADO groups compared with the vehicle group, both of which were attenuated by either 8-SPT or MRS1754. CONCLUSIONS: Long-term stimulation of adenosine A2b receptors begun after MI attenuates cardiac fibrosis in the noninfarcted myocardium and improves cardiac function. Drugs that stimulate adenosine A2b receptors or increase adenosine levels are new candidates for preventing cardiac remodeling after MI.

2-Chloroadenosine↗
PubMed2006

Delayed onset of beating and decreased expression of T-type Ca2+ channel in mouse ES cell-derived cardiocytes carrying human chromosome 21.

The mouse ES cell line hcgp7/#21, which carries a human chromosome 21 (hChr.21), was used as an in vitro model to examine the effects of hChr.21 on cardiomyocyte differentiation. Cardiomyocytes derived from hcgp7/#21 showed a significant delay in the onset of spontaneous beating. The number of Nkx2.5/GFP(+) cardiac progenitor cells was comparable to that in control ES cells and they also expressed comparable mRNA levels for mesodermal markers, cardiac specific transcription factors, contractile proteins, and L-type Ca(2+) channels. However, cells from hcgp7/#21 expressed significantly reduced levels of mRNA for Cav3.1 and Cav3.2, which was consistent with the decreased number of cells expressing T-type Ca(2+) channels and decreased T-type Ca(2+) channel currents. These findings suggest that the presence of human chromosome 21 suppresses expression of T-type Ca(2+) channels in cardiomyocytes during differentiation, which may be responsible for delayed onset of spontaneous beating.

Animals↗
PubMed2006

Evaluation of transmural distribution of viable muscle by myocardial strain profile and dobutamine stress echocardiography.

Transmural distribution of viable myocardium in the ischemic myocardium has not been quantified and fully elucidated. To address this issue, we evaluated transmural myocardial strain profile (TMSP) in dogs with myocardial infarction using a newly developed tissue strain imaging. TMSP was obtained from the posterior wall at the epicardial left ventricular short-axis view in 13 anesthetized open-chest dogs. After control measurements, the left circumflex coronary artery was occluded for 90 min to induce subendocardial infarction (SMI). Subsequently, latex microbeads (90 microm) were injected in the same artery to create transmural infarction (TMI). In each stage, measurements were done before and after dobutamine challenge (10 microg.kg(-1).min(-1) for 10 min) to estimate transmural myocardial viability. Strain in the subendocardium in the control stage increased by dobutamine (from 53.6 +/- 17.1 to 73.3 +/- 21.8%, P < 0.001), whereas that in SMI and TMI stages was almost zero at baseline and did not increase significantly by dobutamine [from 0.8 +/- 8.8 to 1.3 +/- 7.0%, P = not significant (NS) for SMI, from -3.9 +/- 5.6 to -1.9 +/- 6.0%, P = NS for TMI]. Strain in the subepicardium increased by dobutamine in the control stage (from 23.9 +/- 6.1 to 26.3 +/- 6.4%, P < 0.05) and in the SMI stage (from 12.4 +/- 7.3 to 27.1 +/- 8.8%, P < 0.005), whereas that in the TMI stage did not change (from -1.0 +/- 7.8 to -0.7 +/- 8.3%, P = NS). In SMI, the subendocardial contraction was lost, but the subepicardium showed a significant increase in contraction with dobutamine. However, in TMI, even the subepicardial increase was not seen. Assessment of transmural strain profile using tissue strain imaging was a new and useful method to estimate transmural distribution of the viable myocardium in myocardial infarction.

Animals↗
PubMed2006

Impact of blockade of histamine H2 receptors on chronic heart failure revealed by retrospective and prospective randomized studies.

OBJECTIVES: The goal of this work was to determine whether the blockade of histamine H2 receptors is beneficial for the pathophysiology of chronic heart failure (CHF). BACKGROUND: Because CHF is one of the major life-threatening diseases, we need to find a novel effective therapy. Intriguingly, our previous study, which predicts the involvement of histamine in CHF, suggests that we should test this hypothesis in patients with CHF. METHODS: We selected 159 patients who received famotidine among symptomatic CHF patients for the retrospective study. We blindly selected age- and gender-matched CHF patients receiving drugs for gastritis other than histamine H2 receptor blockers as a control group. For the prospective study, 50 symptomatic CHF patients were randomly divided into 2 groups. One group received famotidine of 30 mg/day for 6 months, and the other group received teprenone. RESULTS: In the retrospective study, famotidine of 20 to 40 mg decreased both left ventricular end-diastolic and end-systolic lengths (LVDd and LVDs, respectively) and the plasma B-type natriuretic peptide (BNP) levels (182 +/- 21 vs. 259 +/- 25 pg/ml, p < 0.05) with unaltered fractional shortening (FS). In a randomized, open-label study, compared with teprenone, famotidine of 30 mg prospectively decreased both New York Heart Association functional class (p < 0.05) and plasma BNP levels (183 +/- 26 pg/ml vs. 285 +/- 41 pg/ml, p < 0.05); this corresponded to decreasing both LVDd (57 +/- 2 mm vs. 64 +/- 2 mm, p < 0.05) and LVDs (47 +/- 2 mm vs. 55 +/- 2 mm, p < 0.05) with unaltered FS (15 +/- 1% vs. 17 +/- 1%). The frequency of readmission because of worsening of CHF was lower in the famotidine group (4% and 24%, p < 0.05). On the other hand, teprenone had no effects on CHF. CONCLUSIONS: Famotidine improved both cardiac symptoms and ventricular remodeling associated with CHF. Histamine H2 receptor blockers may have therapeutic benefits for CHF.

Aged↗
PubMed2006

Impaired glucose tolerance: a possible contributor to left ventricular hypertrophy and diastolic dysfunction.

BACKGROUND: Approximately 40% of patients with heart failure have preserved left ventricular systolic function with latent diastolic dysfunction associated with left ventricular hypertrophy, suggesting that diastolic dysfunction participates in the pathophysiology of heart failure. However, the cause or prerequisite status of diastolic dysfunction has not been resolved. This study was designed to investigate whether impaired glucose tolerance is related to left ventricular hypertrophy and abnormal diastolic function. METHODS: An age/sex-matched study was performed in subjects who underwent health screening, including both a 75-g oral glucose tolerance test and Doppler echocardiography. Using the WHO criteria, the subjects were classified into the diabetic group (n=112, 77 men/35 women, mean aged: 57.3+/-7.6 years), the impaired glucose tolerance group (n=226, 155 men/71 women, mean aged 56.8+/-7.5 years), and the normal glucose tolerance group (n=639, 438 men/201 women, mean aged 56.7+/-7.5 years). The subjects had no symptoms or signs of chronic heart failure. RESULTS: There were no significant differences of ejection fraction, fractional shortening, and left ventricular dimensions among the three groups. However left ventricular mass was larger in the impaired glucose tolerance and the diabetic groups compared with the normal group, while the mitral E/A wave ratio was lower in the impaired glucose tolerance and the diabetic groups compared with the normal group even after adjustment for the values of blood pressure and body mass index and left ventricular mass. CONCLUSIONS: These results suggest that impaired glucose tolerance is a possible contributor to left ventricular hypertrophy and diastolic dysfunction.

Analysis of Variance↗
PubMed2006

Blockade of angiotensin II receptors reduces the expression of receptors for advanced glycation end products in human endothelial cells.

OBJECTIVE: Receptors for advanced glycation end products (RAGEs) play crucial roles in atherogenesis. Because tumor necrosis factor alpha (TNFalpha) is expressed and upregulates RAGE expression in atherosclerotic lesions, the TNFalpha-RAGE interaction might be involved in the inflammatory process of atherogenesis. On the other hand, an angiotensin II type-1 receptor blocker (ARB), widely used as an antihypertensive drug, has been reported to have also antiatherosclerotic effects. Thus we investigated whether an ARB exerts antiatherosclerotic effects via inhibiting the TNFalpha-RAGE interaction. METHODS AND RESULTS: Stimulation of human endothelial cells with candesartan as well as olmesartan decreased TNFalpha-induced RAGE expression in both mRNA and protein levels along with the decrease in the activity of nuclear factor kappaB and the expression of inflammatory mediators such as vascular cell adhesion molecule (VCAM)-1. Both candesartan and olmesartan inhibited the binding of nuclear factor kappaB to the RAGE gene promoter. Furthermore, gene silencing of RAGE by RNA interference decreased the expression of TNFalpha-induced VCAM-1 in both mRNA and protein levels. CONCLUSIONS: RAGE contributes at least partially to the TNFalpha-induced VCAM-1 expression in both mRNA and protein levels. Blockade of angiotensin II receptors might exert antiatherosclerotic effects via reducing TNFalpha-RAGE interaction.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2006

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. Control animals received saline immediately after the ligation. RESULTS: The infarct size 6 h after MI was significantly smaller in the EPO(0) group than in the control group (61.5 +/- 6.0% vs. 22.9 +/- 2.2%). One week after MI, the circulating CD34-positive mononuclear cell numbers in both the EPO(0) and the EPO(6h) groups were significantly higher than in the control group. In the ischemic region, the capillary density and myocardial blood flow 4 weeks after MI was significantly higher in both the EPO(0) and the EPO(6h) groups than in the control group. Four weeks after MI, left ventricular (LV) ejection fraction in the EPO(6h) (48.6 +/- 1.9%) group was significantly higher than that in either the control (41.9 +/- 0.9%) or the EPO(1wk) (42.6 +/- 1.2%) group but significantly lower than that in the EPO(0) group (56.1 +/- 2.3%). The LV end-diastolic pressure 4 weeks after MI in both the EPO(0) and the EPO(6h) groups was significantly lower than either the control or the EPO(1wk) group. Hematologic parameters did not differ among the groups. CONCLUSIONS: In addition to its acute infarct size-limiting effect, EPO enhances neovascularization, likely via EPC mobilization, and improves cardiac dysfunction in the chronic phase, although it has time-window limitations.

Animals↗
PubMed2006

Impaired systolic torsion in dilated cardiomyopathy: reversal of apical rotation at mid-systole characterized with magnetic resonance tagging method.

Left ventricular (LV) torsion plays an important role in squeezing the blood out of the heart. To characterize the systolic torsion in LV dysfunction, we studied using magnetic resonance imaging myocardial tagging method in 26 subjects: 17 patients with dilated cardiomyopathy (DCM, LV ejection fraction [EF], 27 +/- 8%) and 9 healthy control subjects. Grid-tagged LV short-axis cine images were acquired at base, mid and apex levels. Tag-intersections were tracked during the systole, thereby determining rotation angle (positive indicated clockwise from the apex). Peak torsion was defined as the maximum difference in rotation angle between the base and apex. Time to peak torsion was expressed as % systole by dividing the time by a total systolic time. Amplitude of the rotation at peak was less in DCM than in controls at both the base (0.1 +/- 2.9 vs. 2.6 +/- 1.6 degrees , P < 0.05) and apex (-5.9 +/- 5.3 vs. -11.2 +/- 2.5 degrees , P < 0.01). Amplitude of peak torsion was then less in DCM than in controls (6.1 +/- 3.4 vs. 13.6 +/- 2.5 degrees , P < 0.001), and the timing of peak was earlier (66 +/- 22 vs. 104 +/- 16% systole, P < 0.001). The amplitude of peak torsion was correlated with LVEF (r=0.74, P < 0.001). In conclusion, amplitude of systolic torsion was impaired in proportion to LV function. Systolic torsion in LV dysfunction was characterized by the discontinuing counter-rotation of the apex to the base before end-systole.

Adult↗
PubMed2006

Glycosaminoglycan modification of neuropilin-1 modulates VEGFR2 signaling.

Neuropilin-1 (NRP1) is a co-receptor for vascular endothelial growth factor (VEGF) that enhances the angiogenic signals cooperatively with VEGFR2. VEGF signaling is essential for physiological and pathological angiogenesis through its effects on vascular endothelial cells (ECs) and smooth muscle cells (SMCs), but the mechanisms coordinating this response are not well understood. Here we show that a substantial fraction of NRP1 is proteoglycan modified with either heparan sulfate or chondroitin sulfate on a single conserved Ser. The composition of the NRP1 glycosaminoglycan (GAG) chains differs between ECs and SMCs. Glycosylation increased VEGF binding in both cell types, but the differential GAG composition of NRP1 mediates opposite responsiveness to VEGF in ECs and SMCs. Finally, NRP1 expression and its GAG modification post-transcriptionally regulate VEGFR2 protein expression. These findings indicate that GAG modification of NRP1 plays a critical role in modulating VEGF signaling, and may provide new insights into physiological and pathological angiogenesis.

Amino Acid Sequence↗
PubMed2006

Unusual appearance of mitral annular calcification mimicking intracardiac tumor prompting early surgery.

Although mitral annular calcification (MAC) is usually easy to diagnose by transthoracic echocardiography, we experienced a rare case with MAC which looked like an intracardiac tumor. The patient who had been on chronic hemodialysis for 20 years was admitted to our hospital because of dyspnea. Transthoracic echocardiography showed a mass with severe calcification on the anterior mitral annulus and mean mitral gradient of 20 mm Hg. Because of the suspicion of the intracardiac calcified tumor that restricted mitral valve motion causing mitral obstruction, she underwent resection of the mass and mitral valve replacement. Pathological findings showed that the mass had a calcified envelope containing liquefied necrotic eosinophilic material with lympocytic infiltrate inside consistent with MAC. We should consider a possibility of MAC when we see a severe calcified mass attached to the mitral annulus in a patient on long-term hemodialysis.

Calcinosis↗
PubMed2006

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. Administration of famotidine and cimetidine from 10 minutes before occlusion until after 1 hour of reperfusion reduced infarct size (17.0 +/- 4.1% and 17.8 +/- 2.9% vs. 36.9 +/- 5.9% of the solvent group, respectively) Famotidine administration only during the reperfusion period for 1 hour also attenuated infarct size (22.5 +/- 3.5%). There were no differences in either area at risk or collateral flow among the groups. In another set of experiments, we decreased coronary perfusion pressure in dogs so that the coronary blood flow decreased to 50% of the non-ischemic level. In such conditions, we observed the increases in histamine release compared with non-ischemic conditions (0.04 +/- 0.03 to 0.28 +/- 0.13 ng/ml, p < 0.05). Famotidine improved anaerobic myocardial metabolism gauged by both lactate extraction ratio and myocardial oxygen consumption. We conclude that the blockade of histamine H(2) receptors mediates improvements in the anaerobic myocardial metabolism, and thus protects against ischemia and reperfusion injury.

Animals↗
PubMed2006

Tricyclic pharmacophore-based molecules as novel integrin alphavbeta3 antagonists. Part IV: preliminary control of alphavbeta3 selectivity by meta-oriented substitution.

To establish the in vivo efficacy of alphavbeta3/alphaIIbbeta3 dual antagonists possessing a tricyclic pharmacophore, a corresponding alphavbeta3-selective antagonist was required as a control. We initially took two synthetic approaches to obtain alphavbeta3-selective antagonists based on the RGD recognition pattern or on modification of the dihedral angle between the central benzene ring and the adjacent heterocycle, but both proved unsuccessful. However, synthesis of novel antagonists with meta-substitution of the central benzene ring generated weak selectivity for alphavbeta3 over alphaIIbbeta3 for the first time in the family of compounds with the tricyclic pharmacophore. Optimization of meta-oriented antagonists furnished an alphavbeta3-selective antagonist exhibiting inhibitory activity not only in a receptor-binding assay, but also in a cell adhesion assay.

Aorta↗
PubMed2006

Control of plasma glucose with alpha-glucosidase inhibitor attenuates oxidative stress and slows the progression of heart failure in mice.

OBJECTIVE: It has been suggested that reduction in glucose levels contributes to the prolongation of life span of rodents in conjunction with restricted food intake, and hyperglycemia has been confirmed as a risk factor for cardiovascular disease (CVD), raising the possibility that better glycemic control could slow the progression of CVD. This study was designed to determine whether impaired glucose tolerance develops during the progression of cardiac hypertrophy and heart failure, and whether tight glycemic control could reduce the severity of heart failure. METHODS: In male C57BL/6 mice, transverse aortic constriction (TAC) was employed to create cardiac hypertrophy and heart failure. The involvement of NADPH in TAC mice and cardiac myocytes in the neonatal rat was investigated. RESULTS: The random-fed plasma glucose concentration was higher in TAC mice, and it was reduced to about 100 mg/dL by voglibose (an alpha-glycosidase inhibitor). Four weeks after TAC, both the heart weight/body weight ratio and the lung weight/body weight ratio were lower in the voglibose group than in the TAC group. Echocardiographic and invasive hemodynamic examination showed improvement of left ventricular function in voglibose-treated mice. Voglibose treatment decreased the myocardial expression of an NADPH oxidase subunit (p47phox). Glucose dose-dependently increased both neonatal rat myocyte protein synthesis and the expression of p47phox protein, while apocynin (an NADPH oxidase inhibitor) blocked the enhancement of protein synthesis by high glucose. CONCLUSION: Improvement of glycemic control through voglibose therapy inhibited cardiac remodeling by decreasing myocardial oxidative stress in mice with cardiac pressure overload.

Acetophenones↗
PubMed2006

Circadian variation of endothelial function in idiopathic dilated cardiomyopathy.

This study measured flow-mediated dilation (FMD) of the brachial artery 3 times a day (6:30 a.m., 11:30 a.m., and 9 p.m.) in 7 normal subjects and 14 patients with idiopathic dilated cardiomyopathy (7 in New York Heart Association [NYHA] functional class I or II and 7 in NYHA functional class III or IV). FMD in normal subjects and patients in NYHA class I or II showed a circadian variation, being lowest in the morning and highest at night. Compared with them, FMD in patients in NYHA class III or IV was lower and almost constant during the day, showing loss of significant circadian variation in endothelial function in patients with congestive heart failure.

Adult↗
PubMed2006

The antagonism of aldosterone receptor prevents the development of hypertensive heart failure induced by chronic inhibition of nitric oxide synthesis in rats.

Aldosterone promotes cardiovascular inflammation and remodeling, both of which are characteristic changes in hypertensive and failing hearts. Since chronic inhibition of nitric oxide (NO) synthase with N(omega)-nitro-L-arginine methyl ester (L-NAME) induces systemic hypertension associated with cardiovascular inflammation and remodeling, we examined the potential role of aldosterone in this process using eplerenone, a selective aldosterone receptor antagonist. Ten-week-old male Wistar-Kyoto rats were randomly divided into 3 groups: the control group (no treatment), the L-NAME group (received L-NAME 1 g/L in drinking water), and the L-NAME+Eplerenone group (L-NAME plus eplerenone at 100 mg/kg/day). After 8 weeks of the treatment, the L-NAME group showed significantly higher systolic blood pressure than the control group (198 +/- 7 vs. 141 +/- 3 mmHg, P < 0.05). Eplerenone did not affect the increase in blood pressure caused by L-NAME (189 +/- 12 mmHg). Chronic inhibition of NO synthesis increased the plasma aldosterone concentration and CYP11B2 mRNA in adrenal glands. Cardiac inflammation and fibrosis were detected in the L-NAME group, while both changes were completely prevented by eplerenone. Cardiac hypertrophy was induced in L-NAME group, but was partially prevented by eplerenone. In the L-NAME group, left ventricular fractional shortening (LVFS: 27 +/- 2 vs. 38 +/- 1%) and E/A ratio (1.7 +/- 0.1 vs. 2.1 +/- 0.1) were significantly lower and LV end-diastolic pressure (LVEDP) was higher (4.9 +/- 0.6 vs. 13.9 +/- 0.5 mmHg) without LV enlargement, compared with those in the control group (P < 0.05). Eplerenone completely normalized LVFS (36 +/- 2%), E/A ratio (2.2 +/- 0.1), and LVEDP (6.2 +/- 0.7 mmHg). These results suggest that chronic inhibition of NO synthesis induces cardiac inflammation and dysfunction via an aldosterone receptor-dependent mechanism.

Actins↗
PubMed2006

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. METHODS: In open-chest dogs, left anterior descending coronary artery (LAD) was occluded for 90 minutes followed by 6 hours of reperfusion. We intravenously administered G-CSF (0.33 micro/kg/min) for 30 minutes from the onset of reperfusion. Wortmannin, a PI3K inhibitor, was selectively administered into the LAD after the onset of reperfusion. RESULTS: G-CSF significantly (p<0.05) reduced myocardial infarct size (38.7+/-4.3% to 15.7+/-5.3%) and the incidence of ventricular fibrillation during reperfusion periods (50% to 0%) compared with the control. G-CSF enhanced Akt phospholylation in ischemic canine myocardium. Wortmannin blunted both the infarct size-limiting and anti-arrhythmic effects of G-CSF. G-CSF did not change myeloperoxidase activity, a marker of neutrophil accumulation, in the infarcted myocardium. CONCLUSION: An intravenous administration of G-CSF at the onset of reperfusion attenuates ischemia/reperfusion injury through PI3K/Akt pathway in the in vivo model. G-CSF administration can be a promising candidate for the adjunctive therapy for patients with acute myocardial infarction.

Animals↗