Beneficial effects of intracoronary nicorandil on microvascular dysfunction after primary percutaneous coronary intervention: demonstration of its superiority to nitroglycerin in a cross-over study.

Purpose: In patients undergoing primary percutaneous coronary intervention (PCI) for the treatment of ST-segment elevation myocardial infarction (STEMI), coronary microvascular dysfunction is associated with poor prognosis. Coronary microvascular resistance is predominantly regulated by ATP-sensitive potassium (KATP) channels. The aim of this study was to clarify whether nicorandil, a hybrid KATP channel opener and nitric oxide donor, may be a good candidate for improving microvascular dysfunction even when administered after primary PCI.

Distal protection during primary coronary intervention can preserve the index of microcirculatory resistance in patients with acute anterior ST-segment elevation myocardial infarction.

Background: The objective of this study was to investigate whether a distal protection (DP) device can preserve the index of microcirculatory resistance (IMR) after primary percutaneous coronary intervention (PCI) in patients with anterior ST-segment elevation myocardial infarction (STEMI).

Methods And Results: The study group of 36 consecutive patients with anterior STEMI were randomized into 2 groups of primary PCI with or without DP: stenting without DP (non-DP group, n = 17) and with DP (DP group, n = 19). The DP in all cases was Filtrap (Nipro, Japan).

Ablation of C/EBP homologous protein attenuates endoplasmic reticulum-mediated apoptosis and cardiac dysfunction induced by pressure overload.

Background: Apoptosis may contribute to the development of heart failure, but the role of apoptotic signaling initiated by the endoplasmic reticulum in this condition has not been well clarified.

Methods And Results: In myocardial samples from patients with heart failure, quantitative real-time polymerase chain reaction revealed an increase in messenger RNA for C/EBP homologous protein (CHOP), a transcriptional factor that mediates endoplasmic reticulum-initiated apoptotic cell death. We performed transverse aortic constriction or sham operation on wild-type (WT) and CHOP-deficient mice.

High index of microcirculatory resistance level after successful primary percutaneous coronary intervention can be improved by intracoronary administration of nicorandil.

Background: Although microvascular dysfunction following percutaneous coronary intervention (PCI) can be evaluated with the index of microcirculatory resistance (IMR), no method of treatment has been established. We hypothesized that intracoronary administration of nicorandil can improve IMR after successful primary PCI in patients with ST-segment elevation myocardial infarction (STEMI).

Methods And Results: In 40 patients with first STEMI after successful primary PCI, IMR was measured using PressureWire(TM) Certus (St.

X-box binding protein 1 regulates brain natriuretic peptide through a novel AP1/CRE-like element in cardiomyocytes.

The unfolded protein response (UPR) is triggered to assist protein folding when endoplasmic reticulum (ER) function is impaired. Recent studies demonstrated that ER stress can also induce cell-specific genes. In this study, we examined whether X-box binding protein 1 (XBP1), a major UPR-linked transcriptional factor, regulates the expression of brain natriuretic peptide (BNP) in cardiomyocytes.

Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome.

Background: The endoplasmic reticulum (ER) responds to various stresses by upregulation of ER chaperones, but prolonged ER stress eventually causes apoptosis. Although apoptosis is considered to be essential for the progression and rupture of atherosclerotic plaques, the influence of ER stress and apoptosis on rupture of unstable coronary plaques remains unclear.

Methods And Results: Coronary artery segments were obtained at autopsy from 71 patients, and atherectomy specimens were obtained from 40 patients.

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.

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.

Angiotensin II type 1 receptor blocker prevents atrial structural remodeling in rats with hypertension induced by chronic nitric oxide inhibition.

The prevalence of atrial fibrillation (AF) increases in patients with hypertension. Angiotensin II is involved in structural atrial remodeling, which contributes to the onset and maintenance of AF in paced animal models. We investigated the role of angiotensin II in atrial structural remodeling in rats with hypertension.

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.

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).

Depression of proteasome activities during the progression of cardiac dysfunction in pressure-overloaded heart of mice.

The ubiquitin-proteasome system contributes to regulation of apoptosis degrading apoptosis-regulatory proteins. Marked accumulation of ubiquitinated proteins in cardiomyocytes of human failing hearts suggested impaired ubiquitin-proteasome system in heart failure. Since cardiomyocyte apoptosis contributes to the progression of cardiac dysfunction in pressure-overloaded hearts, we investigated the role of ubiquitin-proteasome system in such conditions.

Aldosterone nongenomically worsens ischemia via protein kinase C-dependent pathways in hypoperfused canine hearts.

Rapid nongenomic actions of aldosterone independent of mineralocorticoid receptors (MRs) on vascular tone are divergent. Until now, the rapid nongenomic actions of aldosterone on vascular tone of coronary artery and cardiac function in the in vivo ischemic hearts were not still fully estimated. Furthermore, although aldosterone can modulate protein kinase C (PKC) activity, there is no clear consensus whether PKC is involved in the nongenomic actions of aldosterone on the ischemic hearts.

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.

Ablation of MEK kinase 1 suppresses intimal hyperplasia by impairing smooth muscle cell migration and urokinase plasminogen activator expression in a mouse blood-flow cessation model.

Background: Migration, proliferation, and matrix-degrading protease expression of smooth muscle cells (SMCs) are major features of intimal hyperplasia after vascular injury. Although MEK kinase 1 (MEKK1) has been shown to regulate cell migration and urokinase plasminogen activator (uPA) expression, the precise role of MEKK1 in this process remains unknown.

Methods And Results: We triggered a vascular remodeling model by complete ligation of the right common carotid artery in wild-type (WT) and MEKK1-null (MEKK1-/-) mice.

Selective blockade of serotonin 5-HT2A receptor increases coronary blood flow via augmented cardiac nitric oxide release through 5-HT1B receptor in hypoperfused canine hearts.

Serotonin (5-hydroxytryptamine [5-HT]), which induces vasoconstriction via 5-HT2A receptors in smooth muscle cells and vasodilation through activating nitric oxide (NO) synthase (NOS) via 5-HT1B receptors in endothelial cells, possesses divergent effects on regulating vascular tone. These facts lead us to consider that sarpogrelate, a 5-HT2A receptor blocker, may increase coronary blood flow (CBF) via either attenuation of vasoconstriction through 5-HT2A receptor blockade or augmentation of vasodilation by relative stimulation of NOS through 5-HT1B receptor and we tested this hypothesis in ischemic canine hearts. In open chest dogs, coronary perfusion pressure was reduced so that CBF was decreased to 33% of the baseline and kept constant.

Id2 haploinsufficiency in mice leads to congenital hydronephrosis resembling that in humans.

Congenital hydronephrosis is one of the most common anomalies found in humans and may cause renal failure in childhood. Half of the cases are due to obstruction at the ureteropelvic junction (UPJ). Here we report that mice lacking Id2, an inhibitor of basic helix-loop-helix (bHLH) transcription factors, exhibit hydronephrosis mimicking the characteristics of human cases such as unilaterality and male preponderance.

Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis.

Background: The endoplasmic reticulum (ER) is recognized as an organelle that participates in folding secretory and membrane proteins. The ER responds to stress by upregulating ER chaperones, but prolonged and/or excess ER stress leads to apoptosis. However, the potential role of ER stress in pathophysiological hearts remains unclear.

Prognostic value of nuclear area index in patients with bladder cancer.

Background: To assess the prognostic usefulness of the nuclear area index (NAI), a new nuclear morphometric parameter expressed as the mean nuclear area (MNA) ratio of cancer to normal transitional cells in patients with bladder cancer, who have undergone radical cystectomy.

Methods: Measurements of the nuclear areas of cancer and normal transitional cells were carried out on the histological slides of 73 patients with bladder cancer. The clinical usefulness of MNA, NAI, grade, and TNM categories for the prediction of the cause-specific survival of the patients was examined.

Prognostic value of 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography imaging for patients with prostate cancer.

Purpose: The purpose of this study was to investigate the prognostic value of measuring glucose metabolism of primary prostate cancer lesions, using 2-Deoxy-2-[F-18]Fluoro-D-Glucose positron emission tomography (FDG-PET).

Procedures: Forty-two patients with prostate cancer were investigated with FDG-PET, and standardized uptake value (SUV) of the prostate was calculated. After PET study, radical prostatectomy was performed in 17 patients (RPT group), and endocrine therapy in 25 patients (ET group).

Pharmacological characterization of unique prazosin-binding sites in human kidney.

In human kidney, we found unique prazosin-binding sites that were insensitive to phentolamine and were thus unlikely to be alpha(1)-adrenoceptors. As the binding of [(3)H]prazosin to phentolamine-insensitive sites was prevented by 100 microM guanabenz, the insensitive sites were evaluated by subtracting [(3)H]prazosin binding in the presence of 100 microM guanabenz from that in the presence of 10 microM phentolamine. [(3)H]Prazosin bound to the phentolamine-insensitive sites monophasically with a high affinity (pK(d); 9.

Pharmacological characterization of TA-0201, an endothelin receptor antagonist, with recombinant and human prostate endothelin receptors.

The pharmacological profile of N-(6-(2-(5-bromopyrimidine-2-yloxy)ethoxy)-5-(4-methylphenyl)pyrimidin-4-yl)-4-(2-hydroxy-1,1-dimethylethyl) benzensulfonamide sodium salt sesquihydrate (TA-0201), a new antagonist of endothelin receptors, was examined, using human recombinant and prostate endothelin receptors. In binding experiments with [125I]endothelin-1, TA-0201 showed extremely high affinity for recombinant endothelin ET(A) receptors (pK(i)=10.7), as compared with that for recombinant endothelin ET(B) receptors (pK(i)=7.

Genomic structure and analysis of transcriptional regulation of the mouse zinc-fingers and homeoboxes 1 (ZHX1) gene.

The mouse zinc-fingers and homeoboxes 1 (ZHX1) gene was cloned and its transcriptional regulatory mechanism analysed. The mouse ZHX1 gene spans approximately 29 kb and consists of five exons. Exons 1-3 contain the nucleotide sequence of the 5'-noncoding region of mouse ZHX1 cDNA, exon 4 contains a part of the 5'-noncoding region, an entire coding sequence, and a part of the 3'-noncoding sequence, and exon 5 contains the resulting 3'-noncoding sequence.