Synthesis and antihyperglycemic activity of erythrose, ribose and substituted pyrrolidine containing thiazolidinedione derivatives. (49/1087)

A series of erythrose, ribose, and substituted pyrrolidine containing 2,4-thiazolidinediones were synthesized. Among them, thirteen unsaturated thiazolidinediones, six saturated thiazolidinediones and two unsaturated malonates were evaluated for their ability to enhance glucose utilization in cultured L6 myocytes. On the basis of the in vitro activity, 5-[4-[2-(1-benzyl-3,4-bis-benzyloxypyrrolidin-2-yl)ethoxy]benzylidene]thiazolidin e-2,4-dione 24b was selected as the candidate for further pharmacological studies.  (+info)

Ca2+ current-mediated regulation of action potential by pacing rate in rat ventricular myocytes. (50/1087)

OBJECTIVE: Pacing rate regulates the duration of the cardiac action potential (AP). It also regulates the decay kinetics of the L-type Ca(2+) current (I(Ca-L)) which occurs via modulation of Ca(2+)-dependent inactivation. We investigated whether and how this latter process contributes to frequency-dependent (FD) changes in the AP waveform in rat ventricular cells. METHODS: We recorded APs using a microelectrode technique in rat papillary muscles, and using the whole-cell current patch-clamp technique in single rat ventricular cells. RESULTS: The AP duration (APD) was increased by high rates encompassing the physiological range (0.1-5.7 Hz) in both papillary muscles and single cells. This prolongation was accompanied by concomitant depolarisation (approximately 7 mV at 5.7 Hz) of the membrane potential (MP) in papillary muscles. Equivalent artificial depolarisation of the MP enhanced the FD prolongation in single cells. The FD prolongation was enhanced in presence of the K(+) current blocker 4-aminopyridine (5 mmol/l), and decreased in absence of extracellular Ca(2+). It was antagonised by Ca(2+) channel blockers (Co(2+), nifedipine, nitrendipine) and decreased by use of high EGTA (10 vs. 0.5 mmol/l EGTA) or BAPTA (20 mmol/l) in the patch-pipette. It was prevented by ryanodine or thapsigargin, two drugs that reduce or abolish SR-Ca(2+) function. CONCLUSION: I(Ca-L) contributes to the FD modulation of the AP, which occurs following a sudden change in cardiac frequency in rat ventricular cells. This highly dynamic physiological process is related to SR-Ca(2+) release and occurs through beat-to-beat adaptation of Ca(2+)-dependent inactivation of I(Ca-L).  (+info)

Nonuniform Ca2+ transients in arrhythmogenic Purkinje cells that survive in the infarcted canine heart. (51/1087)

OBJECTIVE AND METHODS: In this study, we investigated whether Ca(2+) transients are altered in Purkinje cell aggregates dispersed from the subendocardium overlying the infarcted zone of the left ventricle (IZPCs) 48 h after coronary artery occlusion. To do so, we combined epifluorescent imaging with microelectrode recordings of IZPCs and normal canine Purkinje cell aggregates (NZPCs). RESULTS: NZPCs respond to an action potential (AP) by a small Ca(2+) transient at the cell surface immediately after the AP upstroke followed by a large [Ca(2+)] transient, which propagates to the cell core. In addition, focal Ca(2+) waves can originate spontaneously later during the AP or during the diastolic interval (Circ Res 2000;86:448-55) and then propagate throughout the aggregate as 'cell-wide Ca(2+) waves'. Electrically-evoked Ca(2+) transients in IZPCs arose significantly faster than those in NZPCs, and showed substantial spatiotemporal nonuniformity within an IZPC aggregate as well as between IZPC aggregates. IZPCs showed, hitherto undetected, low amplitude, micro Ca(2+) transients (extent +info)

New insights into beta2-adrenoceptor signaling in the adult rat heart. (52/1087)

OBJECTIVE: The role of cAMP in beta(2)-adrenoceptor signaling and its functional relevance in adult rat heart has been the subject of considerable controversy. Therefore, we investigated the beta(2)-adrenoceptor pathways in both adult cardiomyocytes and in the intact hearts of Wistar rats with respect to protein kinase A (at Ser16)-, the key event in shortening of relaxation time, and CaM kinase II (at Thr17)-dependent phospholamban phosphorylation. METHODS: Contractile and cellular beta(1)/beta(2)-adrenergic responses were studied in parallel on the same perfused rat heart. (-)Isoproterenol and the beta(2)-adrenergic agonists zinterol and procaterol were used to discriminate the beta-adrenoceptor subtype-related actions. RESULTS: Beta(2)-adrenoceptor stimulation induces protein kinase A-dependent phospholamban phosphorylation in both adult cardiomyocytes and in adult hearts of rats. The beta(2)-adrenoceptor-mediated shortening of relaxation time in the heart correlates with Ser16 phosphorylation. Adenosine elicited antiadrenergic action on both beta(1)- and beta(2)-adrenergic signaling cascades by reducing the phosphorylation status of phospholamban. Only beta(1)-adrenoceptor stimulation produced significant CaM kinase II-related Thr17 phosphorylation, troponin I phosphorylation and activation of phosphorylase a. CONCLUSIONS: Our findings clearly show that beta(2)-adrenoceptor signaling is coupled to phospholamban phosphorylation and shortening of relaxation time in the adult rat heart.  (+info)

Differential regulation of p38 mitogen-activated protein kinase mediates gender-dependent catecholamine-induced hypertrophy. (53/1087)

OBJECTIVE: Exogenous catecholamine exposure has been associated with p38 mitogen-activated protein kinase (MAPK) and cardiac hypertrophy. In this study, we investigated the regulation of p38 MAPK in cardiac remodeling elicited by endogenous adrenergic mechanisms. METHODS: Transgenic male and female mice with fourfold phospholamban (PLB) overexpression exhibited enhanced circulating norepinephrine (NE), as a physiological compensatory mechanism to attenuate PLB's inhibitory effects. This enhanced noradrenergic state resulted in left ventricular hypertrophy/dilatation and depressed function. RESULTS: Male transgenics exhibited ventricular hypertrophy and mortality at 15 months, concurrent with cardiac p38 MAPK activation. Female transgenics, despite similar contractile dysfunction, displayed a temporal delay in p38 activation, hypertrophy, and mortality (22 months), which was associated with sustained cardiac levels of MAP Kinase Phosphatase-1 (MKP-1), a potent inhibitor of p38. At 22 months, decreases in cardiac MKP-1 were accompanied by increased levels of p38 activation. In vitro studies indicated that preincubation with 17-beta-estradiol induced high MKP-1 levels, which precluded NE-induced p38 activation. CONCLUSION: These findings suggest that norepinephrine-induced hypertrophy is linked closely with p38 MAP kinase activation, which can be endogenously modulated through estrogen-responsive regulation of MKP-1 expression.  (+info)

Effect of vasopeptidase inhibitor omapatrilat on cardiomyocyte apoptosis and ventricular remodeling in rat myocardial infarction. (54/1087)

We have shown earlier that cardiomyocyte apoptosis continues at a high level late after myocardial infarction and contributes to adverse cardiac remodeling. Here we studied whether this process can be inhibited by the vasopeptidase inhibitor omapatrilat, a drug which causes simultaneous inhibition of both angiotensin converting enzyme and neutral endopeptidase. Our hypothesis was that omapatrilat-treated rats would have less cardiomyocyte apoptosis, and less adverse cardiac remodeling compared to rats treated with selective inhibitors of angiotensin converting enzyme, neutral endopeptidase or placebo. Myocardial infarction was produced by ligation of the left anterior descending coronary artery. Rats were randomized to receive omapatrilat, captopril, neutral endopeptidase inhibitor SQ-28603 or vehicle. Rats treated with omapatrilat and captopril had reduced cardiac BNP mRNA levels and less myocardial fibrosis by comparison with the vehicle-treated rats. However, omapatrilat was more effective than captopril in attenuating hypertrophy as measured by relative cardiac weight (3.0+/-0.2 vs. 3.8+/-0.2 mg/g, P<0.01) or by echocardiographically determined left ventricular mass (0.61+/-0.05 vs. 0.83+/-0.06 g, P<0.01). Myocardial apoptosis was elevated both in the infarction border zone (0.129+/-0.017%) and in the remote area (0.035+/-0.005%) still 4 weeks after myocardial infarction. Angiotensin converting enzyme inhibition proved to be important in the prevention of apoptosis since both omapatrilat and captopril reduced the number of apoptotic myocytes whereas selective neutral endopeptidase inhibitor SQ-28603 had no effect. In conclusion, myocardial apoptosis, remaining increased 4 weeks after myocardial infarction, was reduced by angiotensin converting enzyme inhibition. Vasopeptidase inhibition was more effective than selective angiotensin converting enzyme inhibition in preventing adverse cardiac remodeling after myocardial infarction.  (+info)

Role of CD1d in coxsackievirus B3-induced myocarditis. (55/1087)

The myocarditic (H3) variant of Coxsackievirus B3 (CVB3) causes severe myocarditis in BALB/c mice and BALB/c mice lacking the invariant J alpha 281 gene, but minimal disease in BALB/c CD1d(-/-) animals. This indicates that CD1d expression is important in this disease but does not involve the invariant NKT cell often associated with CD1d-restricted immunity. The H3 variant of the virus increases CD1d expression in vitro in neonatal cardiac myocytes whereas a nonmyocarditic (H310A1) variant does not. V gamma 4(+) T cells show increased activation in both H3-infected BALB/c and J alpha 281(-/-) mice compared with CD1d(-/-) animals. The activated BALB/c V gamma 4(+) T cells from H3-infected mice kill H3-infected BALB/c myocytes and cytotoxicity is blocked with anti-CD1d but not with anti-MHC class I (K(d)/D(d)) or class II (IA/IE) mAbs. In contrast, H3 virus-infected CD1d(-/-) myocytes are not killed. These studies demonstrate that CD1d expression is essential for pathogenicity of CVB3-induced myocarditis, that CD1d expression is increased early after infection in vivo in CD1d(+) mice infected with the myocarditic but not with the nonmyocarditic CVB3 variant, and that V gamma 4(+) T cells, which are known to promote myocarditis susceptibility, appear to recognize CD1d expressed by CVB3-infected myocytes.  (+info)

Increased myocardial apoptosis in patients with unfavorable left ventricular remodeling and early symptomatic post-infarction heart failure. (56/1087)

OBJECTIVES: The purpose of this study was to evaluate a potential correlation between apoptotic rate (AR), post-infarction left ventricular (LV) remodeling, and clinical characteristics in subjects who died late (>or=10 days) after an acute myocardial infarction (AMI) with evidence of persistent occlusion of the infarct-related artery at autopsy. BACKGROUND: Apoptosis contributes to myocardiocyte loss in cardiac disease and may have a pathophysiologic role in post-infarction LV remodeling. METHODS: The AR was calculated at the site of infarction and in remote unaffected LV regions, using co-localization of in situ end labeling for deoxyribonucleic acid fragmentation and immunohistochemistry for caspase-3, in 14 subjects who died within two months after AMI. Correlation between AR and clinical characteristics such as age, site of AMI, transmural extension, multivessel coronary disease, and signs and/or symptoms of heart failure (HF), at the time of initial hospitalization for AMI or subsequently before death, was assessed using non-parametric statistical tests. Parameters of LV remodeling including diameters, free wall thickness, diameter-to-wall-thickness ratio, and mass were measured at gross examination at autopsy. Values are expressed as median (interquartile range). RESULTS: Among clinical variables, early symptomatic post-infarction HF (9 cases, 64%) was associated with nearly fourfold increased AR at the site of infarction (26.2% [24.5% to 28.8%] vs. 6.4% [1.9% to 13.3%], p = 0.001). Moreover, AR both at the site of infarction and in unaffected regions was significantly correlated with parameters of progressive LV remodeling (p < 0.05). CONCLUSIONS: Our data show that in patients dying >or=10 days after AMI, myocardial apoptosis is strongly associated with and may be a major determinant of unfavorable LV remodeling and early symptomatic post-infarction HF.  (+info)