Simvastatin reduces neointimal thickening in low-density lipoprotein receptor-deficient mice after experimental angioplasty without changing plasma lipids.

BACKGROUND: Statins exert antiinflammatory and antiproliferative actions independent of cholesterol lowering. To determine whether these actions might affect neointimal formation, we investigated the effect of simvastatin on the response to experimental angioplasty in LDL receptor-deficient (LDLR-/-) mice, a model of hypercholesterolemia in which changes in plasma lipids are not observed in response to simvastatin. METHODS AND RESULTS: Carotid artery dilation (2.5 atm) and complete endothelial denudation were performed in male C57BL/6J LDLR-/- mice treated with low-dose (2 mg/kg) or high-dose (20 mg/kg) simvastatin or vehicle subcutaneously 72 hours before and then daily after injury. After 7 and 28 days, intimal and medial sizes were measured and the intima to media area ratio (I:M) was calculated. Total plasma cholesterol and triglyceride levels were similar in simvastatin- and vehicle-treated mice. Intimal thickening and I:M were reduced significantly by low- and high-dose simvastatin compared with vehicle alone. Simvastatin treatment was associated with reduced cellular proliferation (BrdU), leukocyte accumulation (CD45), and platelet-derived growth factor-induced phosphorylation of the survival factor Akt and increased apoptosis after injury. CONCLUSIONS: Simvastatin modulates vascular repair after injury in the absence of lipid-lowering effects. Although the mechanisms are not yet established, additional research may lead to new understanding of the actions of statins and novel therapeutic interventions for preventing restenosis.

Effects of percutaneous coronary arterial thrombectomy during acute myocardial infarction on left ventricular remodeling.

The benefit of primary angioplasty for acute myocardial infarction (AMI) is limited by the no-reflow phenomenon, resulting in chronic left ventricular (LV) remodeling. The aim of this study was to evaluate the impact of thrombectomy with the Rescue percutaneous thrombectomy catheter on LV function after AMI. We performed a retrospective study comparing conventional angioplasty with the combination of angioplasty and thrombectomy using the Rescue catheter. The study population was comprised of 109 consecutive patients with AMI who underwent angioplasty and thrombectomy and 86 controls treated with conventional angioplasty. Baseline clinical and lesion characteristics were similar in the 2 groups. Postprocedural restoration of normal flow (Thrombolysis In Myocardial Infarction grade 3) was more frequent in the thrombectomy group (82% vs 69%, p = 0.03). No differences were observed in cardiac events, including death, reinfarction, and target vessel revascularization (thrombectomy vs controls, 27% vs 33%; p = 0.44) or changes in ejection fraction (p = 0.22) during 6-month follow-up. The incidence of LV remodeling, defined as an increase in LV end-diastolic volume index of >20%, was significantly lower in the thrombectomy group (22% vs 44%; p = 0.01). Multiple logistic regression analysis revealed that thrombectomy with the Rescue catheter contributed significantly to reduction of both no-reflow and LV remodeling. In the setting of primary angioplasty, adjunctive pretreatment with a rescue catheter reduces the no-reflow phenomenon and protects against LV remodeling.

Effects of carvedilol on plasma B-type natriuretic peptide concentration and symptoms in patients with heart failure and preserved ejection fraction.

Although the benefits of carvedilol in patients with heart failure and depressed ejection fraction (EF) have been elucidated, those in patients with preserved EF are not understood. We enrolled 40 patients with mild or moderate heart failure and EF >/=45%. They were randomly assigned to carvedilol (n = 19) or conventional therapy (n = 21). After 12 months of treatment, carvedilol significantly improved all end points (plasma concentration of B-type natriuretic peptide [BNP] from 175 (35 to 209) to 106 (52 to 160) pg/ml, mean (95% confidence interval) p <0.01; New York Heart Association functional class from 2.37 (2.13 to 2.61) to 1.56 (1.21 to 1.91), p <0.01; exercise capacity estimated with the Specific Activity Scale from 4.75 (4.50 to 5.00) to 5.68 (5.22 to 6.14) METs, p <0.02), whereas conventional therapy did not (plasma BNP concentration from 150 (114 to 186) to 174 (100 to 248) pg/ml; New York Heart Association functional class from 2.29 (2.08 to 2.50) to 2.11 (1.73 to 2.49); exercise capacity from 4.57 (4.34 to 4.80) to 4.72 (4.41 to 5.03) METs). Univariate regression analyses showed that only the use of carvedilol was correlated with the decrease in plasma BNP concentration (p <0.03). Multivariate analyses demonstrated that an ischemic cause of heart failure (p <0.02), high plasma concentration of BNP (p <0.02), left ventricular dilation (p <0.03), and use of carvedilol (p <0.04) at baseline were predictive of a decrease in plasma concentration of BNP. In conclusion, carvedilol potentially decreased neurohumoral activation, decreased symptoms, and increased exercise capacity in patients with heart failure and preserved EF.

Plasma concentrations of LPL and LCAT are in putative association with females and alcohol use which are independent negative risk factors for coronary atherosclerosis among Japanese.

BACKGROUND: Coronary heart disease (CHD) prevalence appears low among Japanese. Analysis of their negative risk factors is therefore important for public health strategy. METHODS: We analyzed the impact on coronary atherosclerosis of sex, alcohol intake, plasma lipoproteins and enzymes to regulate cholesterol transport, lipoprotein lipase (LPL) and lecithin:cholesterol acyltransferase (LCAT) for the 110 patients who underwent coronary angiography, consecutively enrolled by excluding those >70 years or under hypolipidemic-drug treatment. Subgroup combinations compared were males vs. females in non-drinkers, and drinkers vs. non-drinkers in males. RESULTS: Coronary stenosis was less in females and in drinkers, accompanied by high-density lipoprotein (HDL) in the respective comparison. LPL associated with sex (females>males) and LCAT with alcohol intake (drinkers>non-drinkers) although neither enzyme demonstrated direct correlation with coronary stenosis. LPL positively associated only with HDL in most of subgroups and LCAT correlated with low-density lipoprotein (LDL) in all subgroups but with HDL only in males. CONCLUSIONS: Among non-drinkers, females are at lower risk for coronary atherosclerosis than males mainly due to higher HDL in potential association with high LPL, and that drinkers are protected among males also by high HDL that is in apparent association with LCAT.

Cerivastatin ameliorates high insulin-enhanced neutrophil-endothelial cell adhesion and endothelial intercellular adhesion molecule-1 expression by inhibiting mitogen-activated protein kinase activation.

BACKGROUND AND AIMS: There is growing evidence that hyperinsulinemia is linked to the development of atherosclerosis in patients with diabetes. We demonstrated previously that high insulin exacerbates neutrophil-endothelial cell adhesion and endothelial intercellular adhesion molecule (ICAM)-1 expression through activation of protein kinase C (PKC) and mitogen-activated protein (MAP) kinase. Though 3-hydroxymethyl-3-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been employed as therapeutic agents in the treatment of dyslipidemia, which is frequently accompanied by diabetes mellitus; it is not known whether statins protect against leukocyte-endothelial interactions, especially in hyperinsulinemia. In this study, we determined which statin(s) could protect against endothelial reactions to high insulin. METHODS: Studies of adhesion between neutrophils from healthy volunteers and human umbilical vein endothelial cells incubated in regular insulin-rich medium with or without statins were performed. Adhered neutrophils were quantified by measuring their myeloperoxidase (MPO) activities, and endothelial expression of ICAM-1 was examined using an enzyme immunoassay. RESULTS: Both the increased neutrophil-endothelial cell adhesion and ICAM-1 expression caused by high insulin (100 microU/ml) for 48 h were significantly attenuated by pretreatment with cerivastatin (0.01 microM), but not by fluvastatin (0.5 microM) or pravastatin (0.05 microM). These protective actions of cerivastatin were attenuated by a key intermediate in the cholesterol biosynthesis pathway, mevalonate (400 microM). In addition, cerivastatin attenuated both neutrophil-endothelial cell adhesion and endothelial ICAM-1 expression enhanced by a MAP kinase activator, anisomycin (1 microM) but not by a PKC activator, PMA (10 nM). CONCLUSIONS: These results suggest that through inhibiting MAP kinase but not PKC activation therapy with cerivastatin would be promising strategy for inhibiting neutrophil-endothelial cell adhesion and endothelial ICAM-1 expression enhanced by high insulin, which is closely correlated with atherosclerosis.

Participation of high glucose concentrations in neutrophil adhesion and surface expression of adhesion molecules on cultured human endothelial cells: effect of antidiabetic medicines.

BACKGROUND: Atherosclerosis and vascular inflammation induced by hyperglycemia are important factors in the promotion of diabetic complications. One of the earliest events in the inflammatory process is increased binding of neutrophils to endothelial cells. Since vascular inflammation has been recently reported to be crucial for the onset of atherosclerosis-mediated serious diseases (acute myocardial infarction, stroke), in this study, we examined the effects of high glucose concentrations on endothelial-neutrophil cell adhesion and surface expression of endothelial adhesion molecules. We also evaluated the effects of various antidiabetic medicines on these events. METHODS: Human umbilical vein endothelial cells (HUVECs) were first cultured for 48 h in the glucose-rich medium, and neutrophils from healthy volunteers were then added and allowed to adhere for 30 min. Adhered neutrophils were quantified by measuring myeloperoxidase (MPO) activities, and surface expression of endothelial adhesion molecules was determined using an enzyme immunoassay. RESULTS: High glucose concentrations (over 27.8 mM) increased endothelial-neutrophil cell adhesion and expression of endothelial adhesion molecules (intercellular adhesion molecule-1 (ICAM-1), P-selectin, E-selectin). These events were protein kinase C (PKC) dependent, because PKC inhibitors, but not other intracellular second messenger inhibitors, significantly blocked them. Among antidiabetic medicines, a sulfonylurea, gliclazide (but not glibenclamide or glimepiride), and an aldose reductase inhibitor, epalrestat, significantly inhibited these events; however, a new K(ATP)-channel blocker, netegulinide, a biguanide, metformine, or an insulin sensitizer, troglitazone, did not. CONCLUSIONS: Our data is consistent with hyperglycemia-mediated vascular inflammation through increases in neutrophil adhesion and expression of endothelial adhesion molecules. These events might lead to the onset of atherosclerosis-mediated serious diseases, but could be inhibited by something perhaps, such as gliclazide and epalrestat.

The mechanisms of inhibitory actions of gliclazide on neutrophils-endothelial cells adhesion and surface expression of endothelial adhesion molecules mediated by a high glucose concentration.

BACKGROUND: We previously reported that culture of endothelial cells in the presence of high glucose concentrations (27.8 and 55.5 mM) increase neutrophils adhesion because of the increase in endothelial adhesion molecules expression via activation of a protein kinase C (PKC) pathway. The antidiabetic sulfonylurea gliclazide, but not glibenclamide, inhibited these events, but the mechanisms involved were not clarified then. We present hereafter the results of further investigations of that effect with special reference to PKC activation. METHODS: Human umbilical vein endothelial cells (HUVEC) were cultured for 48 h in a glucose-rich medium and neutrophils from healthy volunteers were then added and allowed to adhere for 30 min. Adhered neutrophils were quantified by measuring myeloperoxidase (MPO) activities and the surface expression of endothelial adhesion molecules was determined by enzyme immunoassay. RESULTS: Culture in the presence of a high glucose concentration (27.8 mM for 48 h) increased neutrophils-endothelial cells adhesion and the surface expression of intercellular adhesion molecule-1 (ICAM-1), P-selectin, and E-selectin on the endothelial cells. These phenomena were significantly inhibited by gliclazide (20 microM). On the other hand, phorbol 12-myristate 13-acetate (PMA), a PKC activator, had an effect similar to a high glucose concentration and that effect was also inhibited by gliclazide. CONCLUSIONS: These data suggest that gliclazide inhibits high glucose-mediated neutrophils-endothelial cells adhesion and expression of endothelial adhesion molecules through inhibition of a PKC pathway.

Mechanisms of inhibitory activity of the aldose reductase inhibitor, epalrestat, on high glucose-mediated endothelial injury: neutrophil-endothelial cell adhesion and surface expression of endothelial adhesion molecules.

BACKGROUND: We have previously reported that endothelial cells cultured in the presence of high concentrations of glucose (27.8 and 55.5 mM) exhibited enhanced neutrophil adhesion through increased expression of endothelial adhesion molecules via the activation of a protein kinase C (PKC)-dependent pathway. We also found that the aldose reductase inhibitor, epalrestat, inhibited these events, but the mechanisms for this inhibition remained unclear. In this study, we further investigated the inhibitory mechanisms of epalrestat with reference to PKC activation and nitric oxide (NO) production. METHODS: Human umbilical vein endothelial cells (HUVECs) were cultured for 48 h in glucose-rich medium and neutrophils from healthy volunteers were then added and allowed to adhere for 30 min. Adhered neutrophils were quantified by measuring myeloperoxidase (MPO) activity and surface expression of endothelial adhesion molecules was determined by enzyme immunoassay. RESULTS: Culture in the presence of a high concentration of glucose (27.8 mM for 48 h) increased neutrophil-endothelial cell adhesion and surface expression of intercellular adhesion molecule-1 (ICAM-1), P-selectin, and E-selectin on endothelial cells. These phenomena were significantly inhibited by epalrestat (10 microM), while NO synthase (NOS) inhibitors reduced the inhibitory effects of this compound. In contrast, 10 nM phorbol 12-myristate 13-acetate (PMA), a PKC activator, showed similar effects as high glucose, and these effects were also inhibited by epalrestat. CONCLUSIONS: Our data suggested that epalrestat inhibited high glucose-mediated neutrophil-endothelial cell adhesion and expression of endothelial adhesion molecules not only through inhibition of a PKC-dependent pathway, but also through increased endothelial NO production.

Effects of insulin on the acetylcholine-induced hyperpolarization in the guinea pig mesenteric arterioles.

BACKGROUND: Insulin induces endothelium-dependent vasodilatation, which may be casually related to the insulin resistance and hypertension. Endothelium-derived nitric oxide (NO) is the most important mechanism of insulin-induced vasodilatation, and a possible contribution of endothelium-derived hyperpolarizing factor (EDHF) is also considered. Attempts were made to observe the effects of insulin on acetylcholine (ACh)-induced hyperpolarization in the submucosal arteriole of the guinea pig ileum, the objective being to investigate possible involvement of EDHF in the actions of insulin. METHODS: Conventional microelectrode techniques were applied to measure the membrane potential of smooth muscle cells in the submucosal arteriole. EDHF-induced hyperpolarization was elicited by ACh in the presence of both N(omega)-nitro-L-arginine (L-NNA) (100 microM) and diclofenac (1 microM). RESULTS: The resting membrane potential was -70.9 mV, and Ba(2+) (0.5 mM) depolarized the membrane to -33.0 mV. Insulin (10 microU/ml to 100 mU/ml) did not change the membrane potential in the absence or presence of Ba(2+). In the presence of Ba(2+), ACh (3 microM) hyperpolarized the membrane with two components, an initial large hyperpolarization followed by a slow and small one. Low concentration of insulin (100 microU/ml) did not alter the ACh-induced hyperpolarization. High concentration of insulin (100 mU/ml) shortened the time required to reach the peak amplitude and tended to increase the peak amplitude of the ACh-induced hyperpolarization. CONCLUSIONS: The data show that insulin enhances the ACh-induced hyperpolarization in the submucosal arterioles of the guinea pig ileum. The results suggested that EDHF also accounts for one of the endothelial factors involved in the insulin-induced vasodilatation.

High-amplitude QRS complex in the electrocardiograms of normotensive people and risk of subsequent hypertension.

BACKGROUND: Left ventricular hypertrophy sometimes develops in normotensive people with a genetic background for hypertension. The aim of this case-control study was to test the hypothesis that a high-amplitude QRS complex (high-QRS) is indicative of risk of eventual hypertension. METHODS: We reviewed medical charts that included blood pressure data obtained every 6 months from 7011 Japanese workers. The cases were all of 24 normotensive people showing an electrocardiogram with SV1+RV5>4.0 mV (high-QRS). The 24 controls chosen presented normal electrocardiograms and were matched for blood pressure, body mass index, age, gender, glycated hemoglobin A1c fraction, and parental occurrence of hypertension. The incidence of hypertension and change in blood pressure during a 5-year study period were compared in the two groups. RESULTS: The cases were more likely than the controls to have a parent with hypertension (18/24 [75.0%] and 686/5704 [12.0%], respectively; P<0.01, odds ratio=21.8 [95% CI: 8.6-55.2]). At the end of the study period, hypertension was more frequent (18/24 [75.0%] and 3/24 [12.5%], respectively; P<0.01, odds ratio=21.0 [95% CI; 4.6-96.2]) and both systolic and diastolic blood pressures were higher (149.0+/-17.1 mmHg vs. 139+/-17.1 mmHg, P<0.01; and 89.5+/-9.2 mmHg vs. 81.7+/-11.5 mmHg, P=0.01, respectively) in the cases than in the controls. CONCLUSIONS: High-QRS may be indicative of risk of eventual hypertension, and may therefore be useful for screening purposes.

Comparison of dilatation mechanism and long-term vessel remodeling between directional coronary atherectomy and balloon angioplasty assessed by volumetric intravascular ultrasound.

Although acute and late outcomes of coronary interventions have been determined by coronary angiography, this method cannot determine changes in vessel and plaque volume. Volumetric intravascular analysis has the potential to evaluate the morphology and redistribution of plaque after coronary intervention as well as longitudinal vessel remodeling. We used 3-dimensional intravascular ultrasound (3-D IVUS) to delineate the mechanism of coronary dilatation and long-term (> 1 year) remodeling in 25 patients. Ten patients underwent directional coronary atherectomy (DCA), and 15 underwent balloon angioplasty (POBA). No patients exhibited restenosis at 6-month angiographic follow-up. Validated Netra 3-D IVUS was performed pre- and post-intervention, at 6-months and at > 1-year. There were some differences in mechanism of dilatation and time course of change in vessel size between DCA and POBA patients. The principal mechanism was vessel stretching and longitudinal plaque redistribution in the POBA group and plaque debulking in the DCA group. In the POBA group, vessel volume increased just after the procedure; this increase was maintained at 6 months and at > 1-year. However, in the DCA group, vessel volume increased initially 6 months after the procedure. 3-D IVUS revealed a difference in mechanism of dilatation between POBA and DCA; this difference might affect late-term vessel remodeling even in patients without restenosis.

High density lipoprotein cholesterol and apolipoprotein A-I are persistently elevated during long-term treatment with pitavastatin, a new HMG-CoA reductase inhibitor.

Although a low level of high density lipoprotein-cholesterol (HDL-C) is an important risk factor for coronary heart disease, few available agents are capable of significantly increasing HDL-C. This multicenter study demonstrated that administration of pitavastatin, a new HMG-CoA reductase inhibitor, significantly and persistently increased HDL-C (from 36.0+/-5.9 to 40.5+/-9.1 mg/dL: p<0.001) and apolipoprotein A-I levels (from 108.4+/-18.0 to 118.7+/-19.3 mg/dL: p<0.01) in 43 hypercholesterolemic patients with low HDL-C over the course of 12 months of treatment. This suggests that pitavastatin may contribute to reduction in coronary heart disease.

On the mechanism for PPAR agonists to enhance ABCA1 gene expression.

Expression of ATP binding cassette transporter A1 (ABCA1), a major regulator of high density lipoprotein (HDL) biogenesis, is known to be up-regulated by the transcription factor liver X receptor (LXR) alpha, and expression is further enhanced by activation of the peroxisome proliferator activated receptors (PPARs). We investigated this complex regulatory network using specific PPAR agonists: four fibrates (fenofibrate, bezafibrate, gemfibrozil and LY518674), a PPAR delta agonist (GW501516) and a PPAR gamma agonist (pioglitazone). All of these compounds increased the expression of LXRs, PPARs and ABCA1 mRNAs, and associated apoA-I-mediated lipid release in THP-1 macrophage, WI38 fibroblast and mouse fibroblast. When mouse fibroblasts lacking expression of PPAR alpha were examined, the effects of fenofibrate and LY518674 were markedly diminished while induction by other ligands were retained. The PPAR alpha promoter was activated by all of these compounds in an LXR alpha-dependent manner, and partially in a PPAR alpha-dependent manner, in mouse fibroblast. The LXR responsive element (LXRE)-luciferase activity was enhanced by all the compounds in an LXR alpha-dependent manner in mouse fibroblast. This activation was exclusively PPAR alpha-dependent by fenofibrate and LY518674, but nonexclusively by the others. We conclude that PPARs and LXRs are involved in the regulation of ABCA1 expression and HDL biogenesis in a cooperative signal transduction pathway.

Predictors of congestive heart failure in patients on maintenance hemodialysis.

BACKGROUND: Cardiovascular disease is a major cause of death in patients on maintenance hemodialysis (HD). Predictors of congestive heart failure (CHF) events in patients on HD were investigated, focusing on left ventricular (LV) function. METHODS AND RESULTS: One hundred consecutive patients on HD were followed for at least 5 years after index examination performed 1 day after the last HD session. Tests included M-mode and Doppler echocardiography and plasma brain natriuretic peptide (BNP) and hemoglobin (Hb) concentration measurements. Patients with atrial fibrillation or poor echocardiographic images were excluded. Confounding factors included diabetes mellitus (DM), hypertension, age, HD duration, LV fractional shortening, E/A of transmitral flow velocity pattern, Tei index, LV mass index (LVMI), BNP level, Hb, and use of antihypertensive or antiarrhythmic drugs. Six CHF events occurred during 1,703+/-565 days. DM and Hb <10 g/dl were identified as independent predictors of CHF events in a stepwise Cox regression model after DM, LVMI, BNP, and Hb <10 g/dl were selected in the univariate analysis. The hazard ratio (confidence interval) was 10.96 (1.49-80.44) for DM, and 23.00 (2.41-219.76) for Hb <10 g/dl. The estimated hazard across time was constant (T_COV*DM; p=0.726, T_COV*Hb <10 g/dl; p=0.681) by time-dependent covariates analysis. CONCLUSION: In patients on maintenance HD, DM and anemia (Hb <10 g/dl), but not echo-derived cardiac function, predicted CHF events.

The relationship between variables of 123-I-metaiodobenzylguanidine cardiac imaging and clinical status of the patients with diastolic heart failure.

BACKGROUND: The status of cardiac sympathetic nerve activity in patients with diastolic heart failure has not been fully understood. 123-I-metaiodobenzylguanidine cardiac images are valuable for evaluating cardiac sympathetic nerve activity. METHODS: We obtained 123-I-metaiodobenzylguanidine cardiac images from 34 consecutive patients with moderate heart failure and an ejection fraction of > or = 45%. RESULTS: The decay-corrected washout rate of 123-I-metaiodobenzylguanidine correlated with each plasma concentration of brain natriuretic peptide (standardized correlation coefficient=0.305, p<0.05), New York Heart Association functional class (standardized correlation coefficient=0.364, p<0.02), and exercise capacity (standardized correlation coefficient=-0.388, p<0.04). A multiple regression analysis revealed that the washout rate independently predicted plasma concentration of brain natriuretic peptide (standardized regression coefficient=0.367, p<0.02). In a univariate regression, the washout rate did not significantly correlate with the presence of ischemic heart disease (p=0.254); in a multivariate regression, the presence of ischemic heart disease did not predict the washout rate. For the 14 patients with sinus rhythm, there was a marginal negative correlation between the E/A velocity ratio of the transmitral flow and washout rate (standardized correlation coefficient=-0.518, p<0.07). CONCLUSIONS: In diastolic heart failure, cardiac sympathetic nerve activity increases proportionally to severity of the disease.

Relationship between Doppler transmitral flow velocity pattern and plasma atrial and brain natriuretic peptide concentrations in anuric patients on maintenance hemodialysis.

Plasma atrial (ANP) and brain (BNP) natriuretic peptide levels were compared to determine if transmitral flow velocity pattern is an instantaneous marker of body fluid balance in anuric patients on hemodialysis (HD). We measured plasma ANP and BNP levels and performed Doppler echocardiography in 38 anuric patients before and after HD. Patients with valvular disease, left ventricular systolic dysfunction having a fractional shortening < 0.3, arrhythmia, or left ventricular hypertrophy were excluded. The relationships between plasma ANP or BNP levels and the transmitral flow velocity pattern were evaluated. We also determined if the magnitude of the decrease in plasma ANP level was related to that in the early peak of transmitral flow velocity (peak E). The mean age of the subjects was 61.1 +/- 9.7 years. The ANP level of 213.6 +/- 146.1 pg/mL was related to peak E of 61 +/- 15 cm/s before HD (R = 0.504, P < 0.001), but not after HD. Plasma ANP level was not related to peak late transmitral flow velocity (peak A) or peak E/peak A before or after HD. BNP level was not related to the transmitral flow velocity pattern. The magnitude of decrease in hANP level during HD was significantly related to that in peak E (R = 0.342, P < 0.05). Before HD, peak E was related to the plasma ANP level, reflecting volume overload. Change in peak E showed a weak relationship with that of plasma ANP level in the same HD patient. The measurement of peak E during a HD session may potentially enable the assessment of hydration status during HD.

Increased gene expression of collagen Types I and III is inhibited by beta-receptor blockade in patients with dilated cardiomyopathy.

AIMS: To elucidate the cellular mechanisms of cardioprotection of beta-blockers in patients with heart failure, we investigated the effects of beta-blockers on collagen synthesis in patients with dilated cardiomyopathy (DCM). METHODS AND RESULTS: We examined the gene expression before and 4 months after the administration of a beta-blocker in 17 DCM patients. The messenger ribonucleic acid expression of collagen Types I and III (Col I and III) and transforming growth factor-beta(1) (TGF-beta(1)) of right ventricular tissues obtained by the endomyocardial biopsy were assessed by quantitative reverse transcriptase-polymerase chain reaction. Cardiac sympathetic nerve activity was assessed by the washout rate (WR) of (123)I-metaiodobenzylguanidine from the heart. Left ventricular ejection fraction (21 +/- 7 vs. 35 +/- 9%) and WR (53+/-14 vs. 42 +/- 13%) improved significantly. Before the beta-blocker treatment, the expressions of both Col I (r = 0.560, P = 0.041) and Col III (r = 0.630, P = 0.008) genes were correlated with WR. The expression levels of both Col I (1.08 +/- 0.72 vs. 0.65 +/- 0.26, P = 0.024) and Col III (2.06 +/- 1.81 vs. 1.05 +/- 0.74, P = 0.018) were reduced by a beta-blocker. Changes in TGF-beta(1) correlated with those in WR (r = 0.606, P = 0.002). CONCLUSION: beta-Blockers are considered to inhibit the expression of collagen-related genes in DCM, which seems to be mediated by TGF-beta(1).

The antidiabetic agent, gliclazide, reduces high insulin-enhanced neutrophil-transendothelial migration through direct effects on the endothelium.

BACKGROUND AND AIM: Many lines of evidence indicate that hyperinsulinemia might be associated with coronary atherosclerosis, and, currently, there are no effective strategies for preventing this. We previously reported that high insulin enhances neutrophil-transendothelial migration, a process that involves increased surface presentation of platelet endothelial cell adhesion molecule-1 (PECAM-1) through a mitogen-activated protein (MAP) kinase-dependent event. In this current study, we examined if antidiabetic agents, especially K(ATP) channel blockers, might similarly protect against the leukocyte-endothelial cell interactions enhanced by high insulin. METHODS: Neutrophils transmigration across umbilical vein endothelial cells (in high insulin medium) with or without K(ATP) channel blockers was performed. Neutrophil migration was quantified by measuring myeloperoxidase, and surface expression of endothelial PECAM-1 was examined using cell-surface enzyme immunoassay. RESULTS: Neutrophil-transendothelial migration and PECAM-1 expression were enhanced by insulin (100 micro U/mL, 24 h) and were attenuated by gliclazide (20 micro M), but not by other K(ATP) channel blockers (glibenclamide, nateglinide, and glimepiride). Neutrophil migration and PECAM-1 expression were also increased by the mitogen-activated protein (MAP) kinase activator, anisomycin (1 micro M), and also attenuated by gliclazide. Nitric oxide (NO) synthase inhibitors did not modify either gliclazide effect. CONCLUSIONS: Our results suggest that the K(ATP) channel blocker, gliclazide, blocks high insulin-mediated neutrophil migration and PECAM-1 expression. These gliclazide effects may be mediated through the inhibition of MAP kinase activation and are unrelated to NO production.

Protective actions of gliclazide on high insulin-enhanced neutrophil-endothelial cell interactions through inhibition of mitogen activated protein kinase and protein kinase C pathways.

BACKGROUND AND AIM: There are many lines of evidence indicating that hyperinsulinemia but not hyperglycemia is linked to the development of atherosclerotic diseases such as coronary events in diabetic patients. K(ATP) channel blockers of the sulphonylurea class are used widely to treat type 2 diabetes mellitus even with hyperinsulinemia. In this study, we determined whether K(ATP) channel blockers can protect against atherosclerotic processes enhanced by hyperinsulinemia, namely leukocyte-endothelial cell interactions. In addition, we characterized the intracellular mechanisms involved in protective actions of the K(ATP) channel blocker(s). METHOD: Studies of adhesion between neutrophils and human umbilical vein endothelial cells incubated in insulin-rich medium with or without K(ATP) channel blockers were performed. Adhered neutrophils were quantified by measuring their myeloperoxidase activities, and surface expression of endothelial ICAM-1 was examined using an enzyme immunoassay. RESULTS: Both neutrophil adhesion and ICAM-1 expression enhanced by high insulin (100 microU/ml, 48 h) were attenuated by gliclazide (20 microM), but not by other K(ATP) channel blockers (glibenclamide, nateglinide, and glimepiride). In addition, both neutrophil adhesion and ICAM-1 expression which were increased by a MAP kinase activator, anisomycin (1 microM), or a PKC activator, phorbol 12-myristate 13-acetate (10 nM) were also attenuated by gliclazide. Nitric oxide (NO) synthase inhibitors did not affect these effects of gliclazide. CONCLUSIONS: These results suggest that among K(ATP) channel blockers, only gliclazide can act directly on endothelial cells to inhibit neutrophil-endothelial cell adhesion and ICAM-1 expression enhanced by hyperinsulinemia. These effects of gliclazide are mediated through inhibiting activation of MAP kinase and PKC, unrelated to NO production.