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Biomedical subjects

Tetsuo Minamino

Publications and source records attributed to Tetsuo Minamino.

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

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

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

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

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↗
PubMed2006

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. Ten-week-old male Wistar-Kyoto rats were randomly divided into 4 groups: a control group (no treatment), an Nomega-nitro-L-arginine methyl ester (L-NAME) group (administered L-NAME, an inhibitor of nitric oxide synthase, 1 g/l in drinking water), an L-NAME+candesartan group (L-NAME plus candesartan-an angiotensin II receptor blocker (ARB)-at 0.1 mg/kg/day), and an L-NAME + hydralazine group (L-NAME plus hydralazine at 120 mg/l in drinking water). Eight weeks after treatment, the L-NAME group showed significantly higher systolic blood pressure than the control group (197 +/- 12 vs.138 +/- 5 mmHg, p < 0.05). Candesartan or hydralazine with L-NAME reduced systolic blood pressure to baseline. Chronic inhibition of NO synthesis increased the extent of fibrosis and transforming growth factor-beta expression in atrial tissue, and both of these effects were prevented by candesartan, but not by hydralazine. Cardiac hypertrophy and dysfunction were induced in the L-NAME group, and these effects were also prevented by candesartan, but not by hydralazine. In contrast, the decrease in thrombomodulin expression in the atrial endocardium in hypertensive rats was restored by candesartan and hydralazine. The ARB prevented atrial structural remodeling, a possible contributing factor for the development of AF, in the hearts of rats with hypertension induced by long-term inhibition of NO synthesis.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

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. We found that proteasome activities already depressed before the onset of cardiac dysfunction in pressure-overloaded hearts of mice. Cardiomyocyte apoptosis was observed along with depression of proteasome activities and elevation of proapoptotic/antiapoptotic protein ratio in failing hearts. In cultured cardiomyocytes, pharmacological inhibition of proteasome accumulated proapoptotic proteins such as p53 and Bax. Gene silencing of these proapoptotic proteins by RNA interference prevented the accumulation of respective proteins and attenuated cardiomyocyte apoptosis induced by proteasome inhibition. We conclude that depression of proteasome activities contributes to cardiac dysfunction resulting from cardiomyocyte apoptosis through accumulation of proapoptotic proteins by impaired degradation.

Adult↗
PubMed2005

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). Either cromakalim or diazoxide activated both PKC and ecto-5'-nucleotidase, which was blunted by either GF109203X or 5-hydroxydecanoate, but not by HMR-1098. We concluded that the opening of mitoK(ATP) channels contributes to either activation of ecto-5'-nucleotidase or the infarct size-limiting effect via activation of PKC in canine hearts.

5'-Nucleotidase↗
PubMed2005

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. In open chest dogs, the selective infusion of aldosterone into the left anterior descending coronary artery (LAD) reduced coronary blood flow (CBF) in the nonischemic hearts in a dose-dependent manner. Also, in the ischemic state that CBF was decreased to 33% of the baseline, the intracoronary administration of aldosterone (0.1 nmol/L) rapidly decreased CBF (37.4+/-3.8 to 19.3+/-5.2 mL/100 g/min; P<0.05), along with decreases in fractional shortening (FS) (8.4+/-0.7 to 5.4+/-0.4%; P<0.05) and lactate extraction rate (LER) (-31.7+/-2.9 to -41.4+/-3.7%; P<0.05). The decrease in CBF was reproduced by the infusion of bovine serum albumin-conjugated aldosterone. Notably, these aldosterone-induced deteriorations of myocardial contractile and metabolic functions were blunted by the co-administration of GF109203X, an inhibitor of PKC, but not spironolactone. In addition, aldosterone activated vascular PKC. These results indicate that aldosterone nongenomically induces vasoconstriction via PKC-dependent pathways possibly through membrane receptors, which leads to the worsening of the cardiac contractile and metabolic functions in the ischemic hearts. Elevation of plasma or cardiac aldosterone levels may be deleterious to ischemic heart disease through its nongenomic effects.

Aldosterone↗
PubMed2005

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. The intimal areas 28 days after ligation were significantly decreased in the ligated MEKK1-/- arteries compared with WT arteries (28+/-8 versus 65+/-17 microm2, P<0.05). There were no differences in the ratios of proliferating cell nuclear antigen (PCNA)-positive cells to total cells within the arterial wall between WT and MEKK1-/- arteries. Proliferation capacity also did not differ between WT and MEKK1-/- cultured aortic smooth muscle cells (AoSMCs). In contrast, the number of intimal PCNA-positive cells 7 days after ligation was significantly smaller in MEKK1-/- arteries. Three different migration assays revealed that migration and invasion of MEKK1-/- AoSMCs were markedly impaired. Addition of full-length MEKK1 restored the migration capacity of MEKK1-/- AoSMCs. The number of MEKK1-/- AoSMCs showing lamellipodia formation by epithelial growth factor was significantly smaller compared with those of WT SMCs. Furthermore, uPA expression after ligation was markedly decreased in MEKK1-/- arteries. CONCLUSIONS: MEKK1 is implicated in vascular remodeling after blood-flow cessation by regulating the migration and uPA expression of SMCs. MEKK1 is a potential target for drug development to prevent vascular remodeling.

Animals↗
PubMed2005

Benidipine, a long-acting calcium channel blocker, inhibits cardiac remodeling in pressure-overloaded mice.

OBJECTIVE: The effects of long-acting calcium channel blockers (CCBs) on pressure overload-induced cardiac remodeling are seldom studied in animals. We evaluated the effects of benidipine, a long-acting CCB, on cardiac remodeling. METHODS: Rat neonatal cardiac myocytes were used to examine the influence of benidipine on protein synthesis. Cardiac remodeling was induced in C57 B6/J mice by transverse aortic constriction (TAC). Then the effects of benidipine (10 mg/kg/d) were assessed on myocardial hypertrophy and heart failure, cardiac histology, and gene expression. RESULTS: Benidipine significantly inhibited protein synthesis by cardiac myocytes stimulated with phenylephrine (PE), and this effect was partially abolished by cotreatment with a nitric oxide synthase (NOS) inhibitor [N(G)-nitro-l-arginine methylester (l-NAME)]. Four weeks after the onset of pressure overload, benidipine therapy potently inhibited cardiac hypertrophy and prevented heart failure. The heart to body weight ratio was 6.89+/-0.48 mg/g in treated mice vs. 8.76+/-0.33 mg/g in untreated mice (P<0.01), and the lung to body weight ratio was 7.39+/-0.93 mg/g vs. 10.53+/-0.99 mg/g, respectively (P<0.05). Left ventricular fractional shortening (LVFS) was improved on echocardiography. Plasma NO levels were increased, while B type natriuretic peptide, protein inhibitor of neuronal NOS, and procollagen IV alpha were down-regulated in benidipine-treated mice. CONCLUSION: These results indicate that benidipine inhibits cardiac remodeling due to pressure overload at least partly by acting on the nitric oxide signaling pathway.

Animals↗
PubMed2005

Amlodipine ameliorates myocardial hypertrophy by inhibiting EGFR phosphorylation.

The effects of long-acting calcium channel blockers on pressure overload-induced cardiac hypertrophy have been little studied in experimental animals and the underlying mechanisms are not fully understood. We previously reported that cardiomyocyte hypertrophy could be induced via phosphorylation of the epidermal growth factor receptor (EGFR). In this study, we investigated whether amlodipine attenuates cardiac hypertrophy by inhibiting EGFR phosphorylation. We found that amlodipine dose-dependently inhibited epinephrine-induced protein synthesis and EGFR phosphorylation in cultured neonatal rat cardiomyocytes. Our in vivo study revealed that amlodipine could ameliorate myocardial hypertrophy induced by transverse aortic constriction (TAC) in C57/B6 mice. One week after TAC, amlodipine treatment (3 mg/kg/day) significantly reduced the heart-to-body weight ratio (6.04 +/- 0.16 mg/g vs. 6.90 +/- 0.45 mg/g in untreated TAC mice, P < 0.01). These results indicate that amlodipine ameliorates cardiomyocyte hypertrophy via inhibition of EGFR phosphorylation.

Amlodipine↗