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Contractile Dysfunction (contractile + dysfunction)
Selected AbstractsCardiac Overexpression of Alcohol Dehydrogenase Exacerbates Cardiac Contractile Dysfunction, Lipid Peroxidation, and Protein Damage After Chronic Ethanol IngestionALCOHOLISM, Issue 7 2003Kadon K. Hintz Background: Alcoholic cardiomyopathy is manifested as ventricular dysfunction, although its specific toxic mechanism remains obscure. This study was designed to examine the impact of enhanced acetaldehyde exposure on cardiac function via cardiac-specific overexpression of alcohol dehydrogenase (ADH) after alcohol intake. Methods: ADH transgenic and wild-type FVB mice were placed on a 4% alcohol or control diet for 8 weeks. Mechanical and intracellular Ca2+ properties were evaluated in cardiac myocytes. Levels of acetaldehyde, lipid peroxidation, and protein carbonyl formation were determined. Results: FVB and ADH mice consuming ethanol exhibited elevated blood ethanol/acetaldehyde, cardiac acetaldehyde, and cardiac hypertrophy compared with non-ethanol-consuming mice. However, the levels of cardiac acetaldehyde and hypertrophy were significantly greater in ADH ethanol-fed mice than FVB ethanol-fed mice. ADH transgene itself did not affect mechanical and intracellular Ca2+ properties with the exception of reduced resting intracellular Ca2+ and Ca2+ re-sequestration at low pace frequency. Myocytes from ethanol-fed mice showed significantly depressed peak shortening, velocity of shortening/relengthening, rise of intracellular Ca2+ transients, and sarco(endo)plasmic reticulum Ca2+ load associated with similar duration of shortening/relengthening compared with myocytes from control mice. Strikingly, the ethanol-induced mechanical and intracellular Ca2+ defects were exacerbated in ADH myocytes compared with the FVB group except velocity of shortening/relengthening. The lipid peroxidation end products malondialdehyde and protein carbonyl formation were significantly elevated in both livers and hearts after chronic ethanol consumption, with the cardiac lipid and protein damage being exaggerated by ADH transgene. Conclusion: These data suggest that increased cardiac acetaldehyde exposure due to ADH transgene may play an important role in cardiac contractile dysfunctions associated with lipid and protein damage after alcohol intake. [source] Junctin and the histidine-rich Ca2+ binding protein: potential roles in heart failure and arrhythmogenesisTHE JOURNAL OF PHYSIOLOGY, Issue 13 2009Tracy J. Pritchard Contractile dysfunction and ventricular arrhythmias associated with heart failure have been attributed to aberrant sarcoplasmic reticulum (SR) Ca2+ cycling. The study of junctin (JCN) and histidine-rich Ca2+ binding protein (HRC) becomes of particular importance since these proteins have been shown to be critical regulators of Ca2+ cycling. Specifically, JCN is a SR membrane protein, which is part of the SR Ca2+ release quaternary structure that also includes the ryanodine receptor, triadin and calsequestrin. Functionally, JCN serves as a bridge between calsequestrin and the Ca2+ release channel, ryanodine receptor. HRC is a SR luminal Ca2+ binding protein known to associate with both triadin and the sarcoplasmic reticulum Ca2+ -ATPase, and may thus mediate the crosstalk between SR Ca2+ uptake and release. Indeed, evidence from genetic models of JCN and HRC indicate that they are important in cardiophysiology as alterations in these proteins affect SR Ca2+ handling and cardiac function. In addition, downregulation of JCN and HRC may contribute to Ca2+ cycling perturbations manifest in the failing heart, where their protein levels are significantly reduced. This review examines the roles of JCN and HRC in SR Ca2+ cycling and their potential significance in heart failure. [source] Effect of letrozole on urinary bladder function in the female rabbitBJU INTERNATIONAL, Issue 6 2007Wei-Yu Lin OBJECTIVE To investigate the effect of letrozole (a potent aromatase inhibitor that effectively inhibit the synthesis of oestrogen) on bladder contraction with changes in morphology and biochemistry. MATERIALS AND METHODS Sixteen female New Zealand white rabbits were separated into four equal groups; groups 1,3 were given oral letrozole for 1, 2 and 3 weeks, and group 4 was given saline and served as the control group. At the end of the medication period each rabbit was anaesthetized and the bladder muscle strips were used for contractile, histological and biochemical studies. RESULTS The concentration of serum oestrogen was significantly lower and testosterone was significantly higher in letrozole-treated rabbits than in the control group. The rabbits treated for 1 week with letrozole showed significant decreases in the contractile responses to electrical field stimulation, ATP and carbachol, but not to KCl. Contractility returned to normal in the rabbits treated for 2 and 3 weeks. Letrozole resulted in an increased volume percentage of collagens and decreased bladder compliance. The volume percentage of the smooth muscle component also changed, with a significant decrease at 1 week and then a gradual increase at 2 and 3 weeks. Contractile dysfunction was absent at 2 and 3 weeks, which was consistent with no change in sarcoplasmic reticulum Ca2+ -ATPase content or mitochondrial function. CONCLUSIONS The bladder contractility decline in the first week and was restored at 2 and 3 weeks. The present study unexpectedly showed the possibility that testosterone might be as important as oestrogen in the contractile function of the female bladder. [source] miR133a regulates cardiomyocyte hypertrophy in diabetesDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 1 2010Biao Feng Abstract Background Diabetic cardiomyopathy, characterized by cardiac hypertrophy and contractile dysfunction, eventually leads to heart failure. We have previously shown that alterations of a number of key molecules are involved in producing cardiomyocyte hypertrophy in diabetes. The aim of the present study was to determine whether microRNAs (miRNA) play a role in mediating altered gene expression and structural/functional deficits in the heart in diabetes. Methods STZ-induced diabetic mice were haemodynamically investigated after 2 months of diabetes to establish the development of cardiomyopathy. The tissues were then examined for gene expression and microRNA analysis. We further investigated neonatal rat cardiomyocytes to identify the mechanisms of glucose-induced hypertrophy and the potential role of miR133a. Results Diabetic mice showed myocardial contractile dysfunction and augmented mRNA expression of atrial and brain natriuretic peptides (ANP, BNP), MEF2A and MEF2C, SGK1 and IGF1R compared to age- and sex-matched controls. Cardiac tissues from these mice showed alteration of multiple miRNAs by array analysis including miR133a, which was confirmed by RT-PCR. In vitro exposure of cardiomyocytes to high levels of glucose produced hypertrophic changes and reduced expression of miRNA133a. Finally, transfection of miR133a mimics prevented altered gene expression and hypertrophic changes. Conclusion Data from these studies demonstrate a novel glucose-induced mechanism regulating gene expression and cardiomyocyte hypertrophy in diabetes which is mediated through miR133a. Copyright © 2009 John Wiley & Sons, Ltd. [source] The Use of Anatomic M-Mode Echocardiography to Determine the Left Atrial Appendage Functions in Patients with Sinus RhythmECHOCARDIOGRAPHY, Issue 2 2005Yekta Gurlertop M.D. Left atrial appendage (LAA) contractile dysfunction is associated with thrombus formation and systemic embolism. LAA function is determined by its flow velocities and fractional area change. This study was performed in order to determine the LAA functions with the anatomic M-mode echocardiography (AMME). Our study comprised 74 patients who had sinus rhythm and underwent transesophageal echocardiography (TEE) for various reasons. LAA fractional change (LAAFAC) was measured by manual planimetry in a transverse basal short-axis approach and LAA emptying and filling velocities also were measured. The AMME values were determined by an M-mode cross section from a cursor placed beneath the orifice of the LAA in transverse basal short-axis imaging. From these values LAA fractional shortening (LAAFS) and ejection fraction (LAAEF) were calculated. LAAEF was calculated by the Teicholz method. The comparisons were conducted, and no correlations between the LAA late filling and the anatomic M-mode values were found (for LAAFS r = 0.18; P > 0.05 and for LAAEF r = 0.19; P > 0.05). There were significant but poor correlations among the LAA late emptying with the anatomic M-mode measurements (for LAAFS r = 0.26; P < 0.05 and for LAAEF r = 0.30; P < 0.01), whereas, there were significant and good correlations between the LAAFAC and the anatomic M-mode values (for LAAFS r = 0.75; P < 0.01 and for LAAEF r = 0.78; P < 0.01). There were significant differences between the valvular heart disease group and the normal group, and between the valvular heart disease group and the ASD group (for LAAFAC P < 0.01, for LAAEF P < 0.01, for LAAFS P < 0.01). There was no difference between the normal group and the ASD group. Our study showed that the LAAEF and LAAFS in patients with sinus rhythm obtained via anatomical M-mode echocardiography is a new method, which can be used instead of left atrial appendage area change. [source] Structural myocardial changes after coronary artery surgeryEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 11 2000F. Eberhardt Background Postoperative contractile dysfunction or ,myocardial stunning' has been described after coronary artery bypass grafting (CABG). In the present study we sought to determine if and to what extent clinical, structural and histochemical evidence of myocardial changes associated with stunning could be found in patients after CABG and cold crystalloid cardioplegia. Materials and methods Left ventricular (LV) biopsies were obtained from CABG patients (n = 10) prior to and at the end of cardiopulmonary bypass (CPB). These biopsies were immunostained for the inducible heat-shock protein 70 (HSP-70i), intercellular adhesion molecule-1 (ICAM-1) and actin. ATP was measured by bioluminescence. Results Biopsies pre-CPB showed no evidence of myocardial damage as HSP-70i was absent and a regular actin cross-striation pattern and only constitutive ICAM-1-expression were present. After CPB we found significantly increased HSP-70i and ICAM-1 levels as well as a deranged actin cross-striation pattern with a widening of actin bands. ATP levels declined from 10 mmol L,1 pre-CPB to 4.9 mmol L,1 after CPB. Correspondingly, coronary sinus effluent showed a significant lactate production. Although, cardiac function determined by transoesophageal echocardiography did not deteriorate, significant inotropic support was necessary to maintain cardiac output. Conclusions Our results present clinical and structural evidence of ,myocardial stunning' after CABG and cold crystalloid cardioplegia. Increased HSP-70i and ICAM-1 expression, as well as a deranged actin cross-striation pattern, might be structural markers to determine ,myocardial stunning' in clinical settings. [source] Human Heart Cytosolic Reductases and Anthracycline CardiotoxicityIUBMB LIFE, Issue 1 2001Alvaro Mordente Abstract Anthracyclines are a class of antitumor drugs widely used for the treatment of a variety of malignancy, including leukemias, lymphomas, sarcomas, and carcinomas. Different mechanisms have been proposed for anthracycline antitumor effects including freeradical generation, DNA intercalation/binding, activation of signaling pathways, inhibition of topoisomerase II and apoptosis. A life-threatening form of cardiomyopathy hampers the clinical use of anthracyclines. According to the prevailing hypothesis, anthracyclines injure the heart by generating damaging free radicals through iron-catalyzed redox cycling. Although the "iron and freeradical hypothesis" can explain some aspects of anthracycline acute toxicity, it is nonetheless disappointing when referred to chronic cardiomyopathy. An alternative hypothesis implicates C-13 alcohol metabolites of anthracyclines as mediators of myocardial contractile dysfunction ("metabolite hypothesis"). Hydroxy metabolites are formed upon two-electron reduction of the C-13 carbonyl group in the side chain of anthracyclines by cytosolic NADPH-dependent reductases. Anthracycline alcohol metabolites can affect myocardial energy metabolism, ionic gradients, and Ca 2+ movements, ultimately impairing cardiac contraction and relaxation. In addition, alcohol metabolites can impair cardiac intracellular iron handling and homeostasis, by delocalizing iron from the [4Fe-4S] cluster of cytoplasmic aconitase. Chronic cardiotoxicity induced by C-13 alcohol metabolite might be primed by oxidative stress generated by anthracycline redox cycling ("unifying hypothesis"). Putative cardioprotective strategies should be aimed at decreasing C-13 alcohol metabolite production by means of efficient inhibitors of anthracycline reductases, as short-chain coenzyme Q analogs and chalcones that compete with anthracyclines for the enzyme active site, or by developing novel anthracyclines less susceptible to reductive metabolism. [source] Twenty-Four Hours Postoperative Results After Orthotopic Cardiac Transplantation in SwineJOURNAL OF CARDIAC SURGERY, Issue 4 2007Matthias Siepe M.D. However, there is no functional data available for a longer time period after transplantation. We have established a pig model to investigate myocardial function 24 hours after orthotopic transplantation.Materials and Methods: Orthotopic cardiac transplantations (HTx) in pigs were performed with a postoperative observation period of 24 hours (n = 6). To analyze myocardial function after transplantation, hemodynamical parameters (Swan-Ganz- and impedance-catheter data) as well as tissue and blood samples were obtained. Regional myocardial blood flow (RMBF) was assessed using fluorescent microspheres. Results: The impedance-catheter parameters demonstrated a preserved contractility in both ventricles 24 hours post-transplantation. In contrast, cardiac output 24 hours after HTx was diminished by 50% as compared to the preoperative value. Conversely, pulmonary vascular resistance increased significantly. The RMBF was increased in both ventricles. Metabolic and histological analyses indicate myocardial recovery 24 hours after HTx with no irreversible damage. Conclusions: For the first time, we were able to establish a porcine model to investigate myocardial function 24 hours after heart transplantation. While the contractility of the transplanted hearts was well-preserved, impaired cardiac output was going along with an increase in pulmonary vascular resistance. Using this clinical relevant model, improvements of human cardiac transplantation and post-transplant contractile dysfunction, especially, could be investigated. [source] AMP-activated protein kinase deficiency exacerbates aging-induced myocardial contractile dysfunctionAGING CELL, Issue 4 2010Subat Turdi Summary Aging is associated with myocardial dysfunction although the underlying mechanism is unclear. AMPK, a key cellular fuel sensor for energy metabolism, is compromised with aging. This study examined the role of AMPK deficiency in aging-associated myocardial dysfunction. Young or old wild-type (WT) and transgenic mice with overexpression of a mutant AMPK ,2 subunit (kinase dead, KD) were used. AMPK , isoform activity, myocardial function and morphology were examined. DCF and JC-1 fluorescence probes were employed to quantify reactive oxygen species (ROS) and mitochondrial membrane potential (,,m), respectively. KD mice displayed significantly reduced ,2 but not ,1 AMPK isoform activity at both ages with a greater effect at old age. Aging itself decreased ,1 isoform activity. Cardiomyocyte contractile function, intracellular Ca2+ handling, and SERCA2a levels were compromised with aging, the effects of which were exacerbated by AMPK deficiency. H&E staining revealed cardiomyocyte hypertrophy with aging, which was more pronounced in KD mice. TEM micrographs displayed severe disruption of mitochondrial ultrastructure characterized by swollen, irregular shape and disrupted cristae in aged KD compared with WT mice. Aging enhanced ROS production and reduced ,,m, the effects of which were accentuated by AMPK deficiency. Immunoblotting data depicted unchanged Akt phosphorylation and a significant decrease in mitochondrial biogenesis cofactor PGC-1, in aged groups. AMPK deficiency but not aging decreased the phosphorylation of ACC and eNOS. Expression of membrane Glut4 and HSP90 was decreased in aged KD mice. Moreover, treatment of the AMPK activator metformin attenuated aging-induced cardiomyocyte contractile defects. Collectively, our data suggest a role for AMPK deficiency in aging-induced cardiac dysfunction possibly through disrupted mitochondrial function and ROS production. [source] Proteomics of ischemia/reperfusion injury in rabbit myocardium reveals alterations to proteins of essential functional systemsPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 5 2005Melanie Y. White Abstract Brief periods of myocardial ischemia prior to timely reperfusion result in prolonged, yet reversible, contractile dysfunction of the myocardium, or "myocardial stunning". It has been hypothesized that the delayed recovery of contractile function in stunned myocardium reflects damage to one or a few key sarcomeric proteins. However, damage to such proteins does not explain observed physiological alterations to myocardial oxygen consumption and ATP requirements observed following myocardial stunning, and therefore the impact of alterations to additional functional groups is unresolved. We utilized two-dimensional gel electrophoresis and mass spectrometry to identify changes to the protein profiles in whole cell, cytosolic- and myofilament-enriched subcellular fractions from isolated, perfused rabbit hearts following 15 min or 60 min low-flow (1 mL/min) ischemia. Comparative gel analysis revealed 53 protein spot differences (> 1.5-fold difference in visible abundance) in reperfused myocardium. The majority of changes were observed to proteins from four functional groups: (i) the sarcomere and cytoskeleton, notably myosin light chain-2 and troponin C; (ii) redox regulation, in particular several components of the NADH ubiquinone oxidoreductase complex; (iii) energy metabolism, encompassing creatine kinase; and (iv) the stress response. Protein differences appeared to be the result of isoelectric point shifts most probably resulting from chemical modifications, and molecular mass shifts resulting from proteolytic or physical fragmentation. This is consistent with our hypothesis that the time course for the onset of injury associated with myocardial stunning is too brief to be mediated by large changes to gene/protein expression, but rather that more subtle, rapid and potentially transient changes are occurring to the proteome. The physical manifestation of stunned myocardium is therefore the likely result of the summed functional impairment resulting from these multiple changes, rather than a result of damage to a single key protein. [source] High temperature does not alter fatigability in intact mouse skeletal muscle fibresTHE JOURNAL OF PHYSIOLOGY, Issue 19 2009Nicolas Place Intense activation of skeletal muscle results in fatigue development, which involves impaired function of the muscle cells resulting in weaker and slower contractions. Intense muscle activity also results in increased heat production and muscle temperature may rise by up to ,6°C. Hyperthermia is associated with impaired exercise performance in vivo and recent studies have shown contractile dysfunction and premature fatigue development in easily fatigued muscle fibres stimulated at high temperatures and these defects were attributed to oxidative stress. Here we studied whether fatigue-resistant soleus fibres stimulated at increased temperature show premature fatigue development and whether increasing the level of oxidative stress accelerates fatigue development. Intact single fibres or small bundles of soleus fibres were fatigued by 600 ms tetani given at 2 s intervals at 37°C and 43°C, which is the highest temperature the muscle would experience in vivo. Tetanic force in the unfatigued state was not significantly different at the two temperatures. With 100 fatiguing tetani, force decreased by ,15% at both temperatures; the free cytosolic [Ca2+] (assessed with indo-1) showed a similar ,10% decrease at both temperatures. The oxidative stress during fatigue at 43°C was increased by application of 10 ,m hydrogen peroxide or tert-butyl hydroperoxide and this did not cause premature fatigue development. In summary, fatigue-resistant muscle fibres do not display impaired contractility and fatigue resistance at the highest temperature that mammals, including humans, would experience in vivo. Thus, intrinsic defects in fatigue-resistant muscle fibres cannot explain the decreased physical performance at high temperatures. [source] Myocardial metabolism of triacylglycerol-rich lipoproteins in type 2 diabetesTHE JOURNAL OF PHYSIOLOGY, Issue 13 2009You-Guo Niu Cardiac utilisation of very-low-density lipoprotein (VLDL) and chylomicrons (CM) was investigated in the ZDF rat model of type 2 diabetes, in order to define the role of triacylglycerol (TAG) metabolism in the development of contractile dysfunction. Hearts from obese diabetic and lean littermate control rats were perfused with VLDL and CM from diabetic and control rats. Metabolic fate of the lipoprotein TAG and contractile function were examined. Myocardial utilisation of both VLDL- and CM-TAG was increased in the diabetic state. Diabetic hearts oxidised diabetic lipoprotein-TAG to a greater extent than control lipoproteins; glucose oxidation was decreased. There was no difference in lipoprotein-TAG assimilation into diabetic heart lipids; diabetic lipoproteins were, however, a poor substrate for control heart tissue lipid accumulation. Although the proportion of exogenous lipid incorporated into tissue TAG was increased in diabetic hearts perfused with control lipoproteins, this effect was not seen in diabetic hearts perfused with diabetic lipoproteins. Myocardial heparin-releasable lipoprotein lipase (LPL) activity was moderately increased in the diabetic state, and diabetic lipoproteins increased tissue-residual LPL activity. Cardiac hydraulic work was decreased only in diabetic hearts perfused with diabetic CM. Compositional analysis of diabetic variant lipoproteins indicated changes in size and apoprotein content. Alterations in cardiac TAG-rich lipoprotein metabolism in type 2 diabetes are due to changes in both the diabetic myocardium and the diabetic lipoprotein particle; decreased contractile function is not related to cardiac lipid accumulation from TAG-rich lipoproteins but may be associated with changes in TAG-fatty acid oxidation. [source] Impaired myofibrillar function in the soleus muscle of mice with collagen-induced arthritisARTHRITIS & RHEUMATISM, Issue 11 2009Takashi Yamada Objective Progressive muscle weakness is a common feature in patients with rheumatoid arthritis (RA). However, little is known about whether the intrinsic contractile properties of muscle fibers are affected in RA. This study was undertaken to investigate muscle contractility and the myoplasmic free Ca2+ concentration ([Ca2+]i) in the soleus, a major postural muscle, in mice with collagen-induced arthritis (CIA). Methods Muscle contractility and [Ca2+]i were assessed in whole muscle and intact single-fiber preparations, respectively. The underlying mechanisms of contractile dysfunction were assessed by investigating redox modifications using Western blotting and antibodies against nitric oxide synthase (NOS), superoxide dismutase (SOD), 3-nitrotyrosine (3-NT), carbonyl, malondialdehyde (MDA), and S-nitrosocysteine (SNO-Cys). Results The tetanic force per cross-sectional area was markedly decreased in the soleus muscle of mice with CIA, and the change was not due to a decrease in the amplitude of [Ca2+]i transients. The reduction in force production was accompanied by slowing of the twitch contraction and relaxation and a decrease in the maximum shortening velocity. Immunoblot analyses showed a marked increase in neuronal NOS expression but not in inducible or endothelial NOS expression, which, together with the observed decrease in SOD2 expression, favors peroxynitrite formation. These changes were accompanied by increased 3-NT, carbonyl, and MDA adducts content in myofibrillar proteins from the muscles of mice with CIA. Moreover, there was a significant increase in SNO-Cys content in myosin heavy-chain and troponin I myofibrillar proteins from the soleus muscle of mice with CIA. Conclusion These findings show impaired contractile function in the soleus muscle of mice with CIA and suggest that this abnormality is due to peroxynitrite-induced modifications in myofibrillar proteins. [source] Positive inotropic effect of coenzyme Q10, omega-3 fatty acids and propionyl-L-carnitine on papillary muscle force-frequency responses of BIO TO-2 cardiomyopathic Syrian hamstersBIOFACTORS, Issue 1-4 2008Romina Vargiu Abstract The inability of heart muscle to generate ventricular pressure to adequately propel blood through the cardiovascular system is a primary defect associated with congestive heart failure (CHF). Force-frequency relationship (FFR) is one of the main cardiac defects associated with congestive heart failure. Thus FFR is a convenient methodological tool for evaluating the severity of muscle contractile dysfunction and the effectiveness of therapeutic agents. Papillary muscle isolated from BIO TO-2 cardiomyopathic Syrian hamsters (CMSHs), show a depressed FFR and represents an animal model of human idiopathic dilated cardiomyopathy. In the present study we investigated the effect of CoQ10, omega-3 fatty acids, propionyl-L-carnitine (PLC) and a combination of these 3 agents (formulation HS12607) on FFR in 8 month old BIO TO-2 CMSHs. Papillary muscles isolated from the anesthetized animals were placed in an incubation bath and attached to an isometric force transducer. A digital computer with an analog/digital interface allowed control of both muscle developed force and electrical stimulus parameters. Force-frequency response was evaluated, at Lmax, with increasing frequencies: 0.06, 0.12, 0.25, 0.5, 1, 2 and 4 Hz. HS12607-treatment produced a positive inotropic effect resulting in a significant enhancement (p < 0.05) of the peak force at the highest frequencies (1,4 Hz). In the range of frequency of 1,4 Hz also CoQ10 and omega-3 significantly(p < 0.05) attenuated the fractional decline in developed force. The significant improvement (p < 0.05) of the timing parameter peak rate of tension rise (+T') and peak rate of tension fall (,T') indicating a faster rate of muscle contraction and relaxation respectively, found in CoQ10, omega-3 and PLC-treated CMSHs, may be due to the positive effects of these substances on sarcoplasmic reticulum functions. These findings suggest that naturally occurring CoQ10, omega-3 and PLC, particularly when administered together in a coformulation, might be a valid adjuvant to conventional therapy in dilated cardiomyopathy especially when considering that they are natural substances, devoid of side effects. [source] Effects of chronic treatment with vardenafil, a phosphodiesterase 5 inhibitor, on female rat bladder in a partial bladder outlet obstruction modelBJU INTERNATIONAL, Issue 7 2009Seiji Matsumoto OBJECTIVES To investigate whether vardenafil, a phosphodiesterase 5 (PDE-5) inhibitor, would protect the bladder from decompensatory changes in a 4-week rat bladder outlet obstruction (BOO) model, as evidence has been accumulating that PDE-5 inhibitors improve lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS In all, 50 12-week-old female Sprague-Dawley rats were divided into five equal groups; group 1, sham operated vehicle control rats; group 2, BOO vehicle rats; group 3,5, BOO rats given oral vardenafil at 5, 20, 80 mg/L, respectively. Vardenafil was given in drinking water from the day of surgery. At 4-weeks after the introduction of BOO, vardenafil was washed-out by giving water for 24,48 h, and then the bladder was excised and dissected into four longitudinal strips for isometric organ-bath assay. Contractile responses of bladder strips to electrical field stimulation (EFS), carbachol and KCl was determined for each group. RESULTS BOO induced a significant increase in bladder weight in group 2 compared with group 1. Bladder weights of groups 3,5 were not significantly different from that of group 2. The contractile forces in response to EFS, carbachol and KCl in group 2 were 30.7,51.7% of those in group 1. Vardenafil treatment in groups 3,5 generally did not block the BOO-induced reduction of contractile force in the bladder strips. However, treatment with a high dose of vardenafil resulted in a significant increase in the contractile response to carbachol (78.4% group 5 vs 51.7% group 2). CONCLUSION Chronic treatment with a high dose of vardenafil protected the rat bladder from BOO-induced contractile dysfunction to carbachol. [source] Combined blockade of endothelin-1 and thromboxane A2 receptors against postischaemic contractile dysfunction in rat heartsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2001Pius S Hornstein Endothelin-1 (ET-1) may play a role in myocardial ischaemia/reperfusion injury because both the release and vasoconstrictor effect of ET-1 are increased after ischaemia. Since the increased vasoconstrictor effect of ET-1 can be mediated by ET-1-induced release of thromboxane A2 (TXA2), the aim of this study was to test whether combined blockade of ET and TXA2 receptors protects the coronary flow, contractile performance, and cardiac energy metabolism during ischaemia and reperfusion. Bosentan (antagonist for ETA and ETB receptors, 1 ,M based on concentration-response curves of ET-1), SQ 30,741 (antagonist of TXA2 receptors, 0.1 ,M), or the combination thereof was administered to isolated perfused rat hearts undergoing 15 min of global ischaemia and 60 min of reperfusion. Neither bosentan or SQ 30,741 alone, nor the combination thereof, improved the incomplete postischaemic recovery of coronary flow, left ventricular developed pressure, phosphocreatine, or ATP. However, they attenuated ischaemia-induced acidosis but this did not translate into a measurable effect on haemodynamic or metabolic variables. Thus, combined blockade of ET and TXA2 receptors does not protect the coronary flow, contractile performance, and cardiac energy metabolism during ischaemia and reperfusion in isolated perfused rat hearts. This finding suggests that neither ET-1 nor ET-1-induced release of TXA2 play a major role in the postischaemic recovery of the cardiac contractile function and energy metabolism. British Journal of Pharmacology (2001) 132, 234,240; doi:10.1038/sj.bjp.0703773 [source] Abnormal myocardial perfusion and contractile recruitment during exercise in type 1 diabetic patientsCLINICAL CARDIOLOGY, Issue 2 2005Roldano Scognamiglio M.D. Abstract Background: No data are available on the relationship between myocardial perfusion and left ventricular (LV) function in type 1 diabetes mellitus (T1DM), which may constitute a factor explaining the progressive contractile dysfunction to the overt phase of diabetic cardiomyopathy. Hypothesis: This study was undertaken to test whether myocardial perfusion abnormalities are present at rest and during exercise and whether they are related to contractile dysfunction in T1DM. Methods: Twenty-two patients with T1DM, aged 32 ± 8.3 years, without macro-or microvascular complications, and 10 controls, aged 31 ± 3 years, were studied. Left ventricular function and myocardial perfusion were assessed by two-dimensional and myocardial contrast echocardiography at rest and during handgrip (HG). Results: Fourteen patients with T1DM showed a decline in LV ejectionfraction (LVEF) during HG (Group 1) while 8 had a normal response (Group 2). Both basal myocardial blood volume (MBV) and velocity ((3) were normal inT1DM. During exercise, MBV and (3 increased and were associated with an increase in myocardial blood flow (MBF) in controls. In T1DM, (3 did not change and MBV increased only in Group 2, while this increase was not observed in Group 1 (controls: 14.9 ±2.3 vs. Group 1:7.6± 1.6, p< 0.001; and vs. Group2:10.2± 2.8, p<0.001), (3(0.86±0.12vs.0.68±0.14, p<0.001;and vs. 0.67±0.15, p<0.001). A correlation between the ratio exercise MBF/resting MBF and LVEF at peak exercise in T1DM was observed (r=0.805, p< 0.001). Conclusions: A large proportion of patients with T1DM exhibit abnormalities in myocardial adaptable capacity to match an acute overload, which are related to a defective increase in myocardial perfusion. [source] Cardiac Overexpression of Alcohol Dehydrogenase Exacerbates Cardiac Contractile Dysfunction, Lipid Peroxidation, and Protein Damage After Chronic Ethanol IngestionALCOHOLISM, Issue 7 2003Kadon K. Hintz Background: Alcoholic cardiomyopathy is manifested as ventricular dysfunction, although its specific toxic mechanism remains obscure. This study was designed to examine the impact of enhanced acetaldehyde exposure on cardiac function via cardiac-specific overexpression of alcohol dehydrogenase (ADH) after alcohol intake. Methods: ADH transgenic and wild-type FVB mice were placed on a 4% alcohol or control diet for 8 weeks. Mechanical and intracellular Ca2+ properties were evaluated in cardiac myocytes. Levels of acetaldehyde, lipid peroxidation, and protein carbonyl formation were determined. Results: FVB and ADH mice consuming ethanol exhibited elevated blood ethanol/acetaldehyde, cardiac acetaldehyde, and cardiac hypertrophy compared with non-ethanol-consuming mice. However, the levels of cardiac acetaldehyde and hypertrophy were significantly greater in ADH ethanol-fed mice than FVB ethanol-fed mice. ADH transgene itself did not affect mechanical and intracellular Ca2+ properties with the exception of reduced resting intracellular Ca2+ and Ca2+ re-sequestration at low pace frequency. Myocytes from ethanol-fed mice showed significantly depressed peak shortening, velocity of shortening/relengthening, rise of intracellular Ca2+ transients, and sarco(endo)plasmic reticulum Ca2+ load associated with similar duration of shortening/relengthening compared with myocytes from control mice. Strikingly, the ethanol-induced mechanical and intracellular Ca2+ defects were exacerbated in ADH myocytes compared with the FVB group except velocity of shortening/relengthening. The lipid peroxidation end products malondialdehyde and protein carbonyl formation were significantly elevated in both livers and hearts after chronic ethanol consumption, with the cardiac lipid and protein damage being exaggerated by ADH transgene. Conclusion: These data suggest that increased cardiac acetaldehyde exposure due to ADH transgene may play an important role in cardiac contractile dysfunctions associated with lipid and protein damage after alcohol intake. [source] | |||||||||||||