Biomedical subjects

Naranjan S Dhalla

Publications and source records attributed to Naranjan S Dhalla.

At least 19 recordsLinked to original sources

PubMed2006

Role of oxidative stress in alterations of mitochondrial function in ischemic-reperfused hearts.

To study the mechanisms of mitochondrial dysfunction due to ischemia-reperfusion (I/R) injury, rat hearts were subjected to 20 or 30 min of global ischemia followed by 30 min of reperfusion. After recording both left ventricular developed pressure (LVDP) and end-diastolic pressure (LVEDP) to monitor the status of cardiac performance, mitochondria from these hearts were isolated to determine respiratory and oxidative phosphorylation activities. Although hearts subjected to 20 min of ischemia failed to generate LVDP and showed a marked increase in LVEDP, no changes in mitochondrial respiration and phosphorylation were observed. Reperfusion of 20-min ischemic hearts depressed mitochondrial function significantly but recovered LVDP completely and lowered the elevated LVEDP. On the other hand, depressed LVDP and elevated LVEDP in 30-min ischemic hearts were associated with depressions in both mitochondrial respiration and oxidative phosphorylation. Reperfusion of 30-min ischemic hearts elevated LVEDP, attenuated LVDP, and decreased mitochondrial state 3 and uncoupled respiration, respiratory control index, ADP-to-O ratio, as well as oxidative phosphorylation rate. Alterations of cardiac performance and mitochondrial function in I/R hearts were attenuated or prevented by pretreatment with oxyradical scavenging mixture (superoxide dismutase and catalase) or antioxidants [N-acetyl-L-cysteine or N-(2-mercaptopropionyl)-glycine]. Furthermore, alterations in cardiac performance and mitochondrial function due to I/R were simulated by an oxyradical-generating system (xanthine plus xanthine oxidase) and an oxidant (H(2)O(2)) either upon perfusing the heart or upon incubation with mitochondria. These results support the view that oxidative stress plays an important role in inducing changes in cardiac performance and mitochondrial function due to I/R.

Animals↗

PubMed2006

Dependence of changes in beta-adrenoceptor signal transduction on type and stage of cardiac hypertrophy.

To examine whether cardiac hypertrophy is associated with changes in beta-adrenoceptor signal transduction mechanisms, pressure overload (PO) was induced by occlusion of the abdominal aorta and volume overload (VO) by creation of an aortocaval shunt for 4 and 24 wk in rats. After hemodynamic assessment of the animals, the left ventricular (LV) particulate fraction was isolated for measurement of beta(1)-adrenoceptors and adenylyl cyclase activity, and cardiomyocytes were isolated for monitoring of the intracellular Ca(2+) concentration. Although PO and VO produced cardiac hypertrophy and increased LV end-diastolic pressure at 4 wk, cardiac function was increased in animals subjected to PO but remained unaltered in animals subjected to VO. Cardiac hypertrophy and increased LV end-diastolic pressure were associated with depressed cardiac function at 24 wk of PO or VO, but clinical signs of congestive heart failure were evident only in animals subjected to VO. Isoproterenol-induced increases in cardiac function, activation of adenylyl cyclase activity, and increase in intracellular Ca(2+) concentration, as well as beta(1)-adrenoceptor density, were unaltered by PO at 4 wk, augmented by VO at 4 wk, and attenuated by PO and VO at 24 wk. These results suggest that alterations in beta(1)-adrenoceptor signal transduction are dependent on the type and stage of cardiac hypertrophy.

Adenylyl Cyclases↗

PubMed2006

Modification of intracellular calcium concentration in cardiomyocytes by inhibition of sarcolemmal Na+/H+ exchanger.

Although the Na(+)/H(+) exchanger (NHE) is considered to be involved in regulation of intracellular Ca(2+) concentration ([Ca(2+)](i)) through the Na(+)/Ca(2+) exchanger, the exact mechanisms of its participation in Ca(2+) handling by cardiomyocytes are not fully understood. Isolated rat cardiomyocytes were treated with or without agents that are known to modify Ca(2+) movements in cardiomyocytes and exposed to an NHE inhibitor, 5-(N-methyl-N-isobutyl)amiloride (MIA). [Ca(2+)](i) in cardiomyocytes was measured spectrofluorometrically with fura 2-AM in the absence or presence of KCl, a depolarizing agent. MIA increased basal [Ca(2+)](i) and augmented the KCl-induced increase in [Ca(2+)](i) in a concentration-dependent manner. The MIA-induced increase in basal [Ca(2+)](i) was unaffected by extracellular Ca(2+), antagonists of the sarcolemmal (SL) L-type Ca(2+) channel, and inhibitors of the SL Na(+)/Ca(2+) exchanger, SL Ca(2+) pump ATPase and mitochondrial Ca(2+) uptake. However, the MIA-induced increase in basal [Ca(2+)](i) was attenuated by inhibitors of SL Na(+)-K(+)-ATPase and sarcoplasmic reticulum (SR) Ca(2+) transport. On the other hand, the MIA-mediated augmentation of the KCl response was dependent on extracellular Ca(2+) concentration and attenuated by agents that inhibit SL L-type Ca(2+) channels, the SL Na(+)/Ca(2+) exchanger, SL Na(+)-K(+)-ATPase, and SR Ca(2+) release channels and the SR Ca(2+) pump. However, the effect of MIA on the KCl-induced increase in [Ca(2+)](i) remained unaffected by treatment with inhibitors of SL Ca(2+) pump ATPase and mitochondrial Ca(2+) uptake. MIA and a decrease in extracellular pH lowered intracellular pH and increased basal [Ca(2+)](i), whereas a decrease in extracellular pH, in contrast to MIA, depressed the KCl-induced increase in [Ca(2+)](i) in cardiomyocytes. These results suggest that NHE may be involved in regulation of [Ca(2+)](i) and that MIA-induced increases in basal [Ca(2+)](i), as well as augmentation of the KCl-induced increase in [Ca(2+)](i), in cardiomyocytes are regulated differentially.

Adenosine Triphosphatases↗

PubMed2006

MAPK activation and apoptotic alterations in hearts subjected to calcium paradox are attenuated by taurine.

OBJECTIVE: The Ca2+ -paradox is an important phenomenon to study cell injury induced by Ca2+ -overload in myocardium. Although intracellular Ca2+ -overload acts as a trigger and modulator of cell death due to apoptosis under various pathophysiological conditions, the presence of apoptosis in hearts subjected to Ca2+ -paradox has not been demonstrated. Since taurine attenuates the changes in cardiac function due to Ca2+ -paradox, this study investigated the occurrence and mechanisms of apoptosis in Ca2+ -paradoxic hearts treated in the absence and presence of taurine. METHODS: Ca2+ -paradox was induced by perfusing the isolated rat heart with Ca2+ -free medium for 5 min followed by reperfusion with Ca2+ -containing medium for 30 min. Apoptosis related signal transduction mechanisms were determined in Ca2+ -paradoxic hearts perfused with or without 10 mM taurine. RESULTS: Marked alterations in cardiac function and the presence of apoptosis were seen in Ca2+ -paradoxic hearts reperfused for 30 min. Unlike the total protein contents in hearts subjected to Ca2+ -paradox, the contents of phosphorylated p38 mitogen-activated protein kinase (MAPK), extracellular signal regulated kinase (ERK)1, ERK2 and c-jun amino-terminal kinase were increased by 125 +/- 8.6%, 296 +/- 14.3%, 213 +/- 8.5% and 133 +/- 4.2%, respectively vs. control. Caspase-3 and phosphorylated Bcl-2 contents were also increased by 193 +/- 10.2% and 134 +/- 5.0% vs. control whereas phosphorylated Bad and the ratio of Bcl-2/Bad were depressed by 32 +/- 10.8% and 0.23 +/- 0.5% vs. control in Ca2+ -paradoxic hearts. The apoptosis as seen in Ca2+ -paradoxic hearts reperfused for 30 min was not evident in hearts at 10 min Ca2+ -repletion but was similar to hearts subjected to 60 min Ca2+ -repletion. These changes in the apoptotic pathway in cardiomyocytes subjected to Ca2+ -paradox were prevented by taurine. Furthermore, taurine attenuated the KCl- or ATP-induced increase in intracellular concentration of Ca2+ in cardiomyocytes. CONCLUSIONS: This study suggests that cardiac dysfunction due to Ca2+ -paradox may be associated with apoptosis. In addition, the beneficial effects of taurine on cardiac function may be related to the attenuation of changes in MAPK and apoptotic signal transduction mechanisms in Ca2+ -paradoxic hearts.

Adenosine Triphosphate↗

PubMed2006

Norepinephrine-induced changes in gene expression of phospholipase C in cardiomyocytes.

Previously, we have reported that norepinephrine (NE)-mediated cardiac hypertrophy may occur due to stimulation of alpha1-adrenoceptors and phospholipase C (PLC) activity. Since the signal transduction mechanisms involving PLC isozymes in cardiomyocytes are not well established, the present study was conducted to test the hypothesis that stimulation of cardiac PLC activity by NE increases the gene expression for PLC isozymes via a PKC and ERK 1/2-dependent pathway. For this purpose, mRNA levels for PLC beta1, beta3, gamma1, and delta1 isozymes were determined in isolated adult rat cardiomyocytes upon incubation in the absence and presence of NE. The NE-induced increases in PLC isozyme mRNA levels were not only attenuated by prazosin, an inhibitor of alpha1-adrenergic receptor, but also by U73122, an inhibitor of PLC activity. Alterations in NE-induced PLC gene expression by both prazosin and U73122 were associated with inhibition of PLC activity. The inhibition of NE-stimulated PLC gene expression by bisindolylmaleimide, a PKC inhibitor, and PD98059, an ERK1/2 inhibitor, indicated that PKC-MAPK signaling may be involved in this signal transduction pathway. The observed NE-induced changes in gene expression in the presence of different inhibitors were associated with corresponding changes in the protein content. Furthermore, significant increases in mRNA levels and protein contents for all PLC isozymes were found in cardiomyocytes treated with phorbol 12-myristate 13-acetate, a PKC activator. These data indicate that PLC isozymes may regulate their own gene expression through a PKC and ERK 1/2-dependent pathway in a cycle of events associated with the cardiomyocyte hypertrophic response.

Animals↗

PubMed2006

Oxidative stress and redox regulation of phospholipase D in myocardial disease.

Oxidative stress may be viewed as an imbalance between reactive oxygen species (ROS) and oxidant production and the state of glutathione redox buffer and antioxidant defense system. Recently, a new paradigm of redox signaling has emerged whereby ROS and oxidants can function as intracellular signaling molecules, where ROS- and oxidant-induced death signal is converted into a survival signal. It is now known that oxidative stress is involved in cardiac hypertrophy and in the pathogenesis of cardiomyopathies, ischemic heart disease and congestive heart failure. Phospholipase D (PLD) is an important signaling enzyme in mammalian cells, including cardiomyocytes. PLD catalyzes the hydrolysis of phosphatidylcholine to produce phosphatidic acid (PA). Two mammalian PLD isozymes, PLD1 and PLD2 have been identified, characterized and cloned. The importance of PA in heart function is evident from its ability to stimulate cardiac sarcolemmal membrane and sarcoplasmic reticular Ca2+-related transport systems and to increase the intracellular concentration of free Ca2+ in adult cardiomyocytes and augment cardiac contractile activity of the normal heart. In addition, PA is also considered an important signal transducer in cardiac hypertrophy. Accordingly, this review discusses a role for redox signaling mediated via PLD in ischemic preconditioning and examines how oxidative stress affects PLD in normal hearts and during different myocardial diseases. In addition, the review provides a comparative account on the regulation of PLD activities in vascular smooth muscle cells under conditions of oxidative stress.

Animals↗

PubMed2006

Angiogenesis--a new target for future therapy.

Development of blood vessels from in situ differentiating endothelial cells (EC) is called vasculogenesis, whereas sprouting of new blood vessels from the pre-existing ones is termed angiogenesis or neovascularisation. Angiogenesis, the growth of new blood vessels, is essential during tissue repair, foetal development, and female reproductive cycle. In contrast, uncontrolled angiogenesis promotes tumor and retinopathies, while inadequate angiogenesis can lead to coronary artery disease. A balance between pro-angiogenic and anti-angiogenic growth factors and cytokines tightly controls angiogenesis. With the identification of several proangiogenic molecules such as the vascular endothelial cell growth factor (VEGF), the fibroblast growth factors (FGFs), and the angiopoietins, and the recent description of specific inhibitors of angiogenesis such as platelet factor-4, angiostatin, endostatin, and vasostatin, it is recognized that therapeutic interference with vasculature formation offers a tool for clinical applications in various pathologies. Inhibition of angiogenesis can prevent diseases such as cancer, diabetic nephropathy, arthritis, psoriasis, whereas stimulation of angiogenesis is beneficial in the treatment of coronary artery disease (CAD), cardiac failure, tissue injury, etc. One of the most specific and critical regulators of angiogenesis is vascular endothelial growth factor (VEGF), which regulates endothelial proliferation, permeability, and survival. Substantial evidence also implicates VEGF as an angiogenic mediator in tumors and intraocular neovascular syndromes, and numerous clinical trials are presently testing the hypothesis that inhibition of VEGF may have therapeutic value.

Adiponectin↗

PubMed2006

Inhibition of phospholipase C-gamma 1 augments the decrease in cardiomyocyte viability by H2O2.

The present study was conducted to examine the role of a major cardiac phospholipase C (PLC) isozyme, PLC-gamma 1, in cardiomyocytes during oxidative stress. Left ventricular cardiomyocytes were isolated by collagenase digestion from adult male Sprague-Dawley rats (250-300 g) and treated with 20, 50, and 100 microM H2O2 for 15 min. A concentration-dependent (up to 50 microM) increase in the mRNA level and membrane protein content of PLC-gamma 1 was observed with H2O2 treatment. Furthermore, PLC-gamma 1 was activated in response to H2O2, as revealed by an increase in the phosphorylation of its tyrosine residues. There was a marked increase in the phosphorylation of the antiapoptotic protein Bcl-2 by H2O2; this change was attenuated by a PLC inhibitor, U-73122. Although both protein kinase C (PKC)-delta and -epsilon protein contents were increased in the cardiomyocyte membrane fraction in response to H2O2, PKC-epsilon activation, unlike PKC-delta, was attenuated by U-73122 (2 microM). Inhibition of PKC-epsilon with inhibitory peptide (0.1 microM) prevented Bcl-2 phosphorylation. Moreover, different concentrations (0.05, 0.1, and 0.2 microM) of this peptide augmented the decrease in cardiomyocyte viability in response to H2O2. In addition, a decrease in cardiomyocyte viability, as assessed by trypan blue exclusion, due to H2O2 was also seen when cells were pretreated with U-73122 and was as a result of increased apoptosis. It is therefore suggested that PLC-gamma 1 may play a role in cardiomyocyte survival during oxidative stress via PKC-epsilon and phosphorylation of Bcl-2.

Animals↗

PubMed2006

Myofibrillar remodeling in cardiac hypertrophy, heart failure and cardiomyopathies.

BACKGROUND: A wide variety of pathological conditions have been shown to result in cardiac remodelling and myocardial dysfunction. However, the mechanisms of transition from adaptive to maladaptive alterations, as well as those for changes in cardiac performance leading to heart failure, are poorly understood. OBSERVATIONS: Extensive studies have revealed a broad spectrum of progressive changes in subcellular structures and function, as well as in signal transduction and metabolism in the heart, among different cardiovascular disorders. The present review is focused on identifying the alterations in molecular and biochemical structure of myofibrils (myofibrillar remodelling) in hypertrophied and failing myocardium in different types of heart diseases. Numerous changes at the level of gene expression for both contractile and regulatory proteins have already been reported in failing hearts and heart diseases; these changes are potential precursors for heart failure such as cardiac hypertrophy and cardiomyopathies. Myofibrillar remodelling, as a consequence of proteolysis, oxidation, and phosphorylation of some functional groups in both contractile and regulatory proteins in hearts failing due to different etiologies, has also been described. CONCLUSIONS: Although myofibrillar remodelling appears to be associated with cardiac dysfunction, alterations in both contractile and regulatory proteins are dependent on the type and stage of heart disease.

Cardiomegaly↗

PubMed2006

Expression of protein kinase C isoforms in cardiac hypertrophy and heart failure due to volume overload.

The present study determined whether changes in the activity and isoforms of protein kinase C (PKC) are associated with cardiac hypertrophy and heart failure owing to volume overload induced by aortocaval shunt (AVS) in rats. A significant increase in Ca2+-dependent and Ca2+-independent PKC activities in the homogenate and particulate fractions, unlike the cystolic fraction, of the hypertrophied left ventricle (LV) were evident at 2 and 4 weeks after inducing the AVS. This increase coincided with increases in PKC-alpha and PKC-zeta contents at 2 week and increases in PKC-alpha, PKC-beta1, PKC-beta2, and PKC-zeta contents at 4 weeks in the hypertrophied LV. By 8 and 16 weeks of AVS, PKC activity and content were unchanged in the failing LV. On the other hand, no increase in the PKC activity or isoform content in the hypertrophied right ventricle (RV) was observed during the 16 weeks of AVS. The content of G alpha q was increased in the LV at 2 weeks but then decreased at 16 weeks, whereas G alpha q content was increased in RV at 2 and 4 weeks. Our data suggest that an increase in PKC isoform content neither plays an important role during the development of cardiac hypertrophy nor participates in the phase leading to heart failure owing to volume overload.

Animals↗

PubMed2006

Differential changes in beta-adrenoceptor signal transduction in left and right ventricles of infarcted rats.

Although different experimental and clinical studies have revealed varying degrees of defects in beta-adrenoceptors (beta-ARs) during the development of heart failure, the mechanisms for differences in beta-AR signal transduction between the left (LV) and right ventricle (RV) are not understood. Because biochemical alterations in the myocardium depend on the stage of heart disease, this study was undertaken to assess the status of beta-ARs in the LV and RV at different stages of heart failure. Myocardial infarction was induced in rats by occluding the left coronary artery for 8 and 24 weeks. The beta-AR signal transduction was monitored by measuring beta1-AR density, the isoproterenol-induced positive inotropic effect, the increase in [Ca2+]i in cardiomyocytes, and the activation of adenylyl cyclase. The beta-AR signal transduction parameters in the 8- and 24-week failing LV were depressed, whereas the RV showed upregulation at 8 weeks and downregulation at 24 weeks of these mechanisms. These results suggest that beta-AR-mediated signal transduction in the LV and RV are differentially regulated and are dependent upon the stage of development of congestive heart failure due to myocardial infarction.

Adenylyl Cyclases↗

PubMed2006

Subcellular remodeling as a viable target for the treatment of congestive heart failure.

It is now well known that congestive heart failure (CHF) is invariably associated with cardiac hypertrophy, and changes in the shape and size of cardiomyocytes (cardiac remodeling) are considered to explain cardiac dysfunction in CHF. However, the mechanisms responsible for the transition of cardiac hypertrophy to heart failure are poorly understood. Several lines of evidence both from various experimental models of CHF and from patients with different types of CHF have indicated that the functions of different subcellular organelles such as extracellular matrix, sarcolemma, sarcoplasmic reticulum, myofibrils, mitochondria, and nucleus are defective. Subcellular abnormalities for protein contents, gene expression, and enzyme activities in the failing heart become evident as a consequence of prolonged hormonal imbalance, metabolic derangements, and cation maldistribution. In particular, the occurrence of oxidative stress, development of intracellular Ca2+ overload, activation of proteases and phospholipases, and alterations in cardiac gene expression result in changes in the biochemical composition, molecular structure, and function of different subcellular organelles (subcellular remodeling). Not only does subcellular remodeling appear to be intimately involved in the transition of cardiac hypertrophy to heart failure, the mismatching of the function of different subcellular organelles leads to the development of cardiac dysfunction. Although blockade of the renin-angiotensin system, sympathetic nervous system, and various other hormonal actions have been reported to produce beneficial effects on cardiac remodeling and heart dysfunction in CHF, the actions of various cardiac drugs on subcellular remodeling have not been examined extensively. Some recent studies have indicated that both the angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists attenuate changes in sarcolemma, sarcoplasmic reticulum, and myofibril enzyme activities, protein contents, and gene expression, and partly improve cardiac function in the failing hearts. It is suggested that subcellular remodeling is an excellent target for the development of improved drug therapy for CHF. Furthermore, extensive studies should investigate the effects of different agents individually or in combination on reverse subcellular remodeling, cardiac remodeling, and cardiac dysfunction in various experimental models of CHF.

Animals↗

PubMed2006

Blockade of the renin-angiotensin system attenuates sarcolemma and sarcoplasmic reticulum remodeling in chronic diabetes.

Although the defects in the sarcolemma (SL) and sarcoplasmic reticulum (SR) membranes are known to be associated with cardiac dysfunction in chronic diabetes, very little information regarding the mechanisms of these membrane abnormalities is available in the literature. For this reason, rats were treated daily for 8 weeks with and without enalapril, an angiotensin-converting enzyme inhibitor, or losartan, an angiotensin receptor antagonist, 3 days after inducing diabetes with an injection of streptozocin. Treatment of diabetic animals with both enalapril and losartan attenuated alterations in cardiac function and the left ventricular redox potential without any changes in the increased plasma glucose or reduced plasma insulin levels. The SL Na+-K+ ATPase, Ca2+ pump, Na+-dependent Ca2+-uptake, Ca2+-channel density, and low-affinity Ca2+-binding activities were depressed whereas Ca2+ ecto-ATPase activity was increased in the diabetic heart. Furthermore, the SR Ca2+-release and Ca2+-pump activities in the diabetic hearts were decreased without any changes in the Mg2+-ATPase activity. These alterations in SL and SR membranes in diabetic animals were partly prevented by treatments with enalapril and losartan. The results suggest that the activation of the renin-angiotensin system plays an important role in diabetes-induced changes in SL and SR membranes as well as cardiac function.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2005

Mechanisms of lysophosphatidic acid-induced increase in intracellular calcium in vascular smooth muscle cells.

Although lysophosphatidic acid (LPA) is known to cause an increase in intracellular Ca2+ concentration ([Ca2+]i) in vascular smooth muscle cells (VSMCs), the mechanisms of [Ca2+]i mobilization by LPA are not fully understood. In the present study, the effect of LPA on [Ca2+]i mobilization in cultured A10 VSMCs was examined by Fura-2 fluorescence technique. The expression of LPA receptors was studied by immunostaining. LPA was observed to increase [Ca2+]i in a concentration-dependent manner; this increase was dependent on the concentration of extracellular Ca2+. Both sarcolemmal (SL) Na(+)-Ca2+ exchange inhibitors (amiloride, Ni2+ and KB-R7943) and Na(+)-H+ exchange inhibitor (MIA) as well as SL store-operated Ca2+ channel (SOC) antagonists (SK&F 96365, tyrphostin A9 and gadolinium), unlike SL Ca2+ channel antagonists (verapamil and diltiazem), inhibited the LPA-induced increase in [Ca2+]i. In addition, sarcoplasmic reticulum (SR) Ca2+ channel blocker (ryanodine), SR Ca2+ channel opener (caffeine), SR Ca2+ pump ATPase inhibitor (thapsigargin) and inositol 1,4,5-trisphosphate (InsP3) receptor antagonists (xestospongin and 2-aminoethoxydiphenyl borate) were found to inhibit the LPA-induced Ca2+ mobilization. Furthermore, phospholipase C (PLC) inhibitor (U 73122) and protein kinase C (PKC) activator (phorbol 12-myristate 13-acetate) attenuated the LPA-induced increase in [Ca2+]i. These results indicate that Ca2+ mobilization by LPA involves extracellular Ca2+ entry through SL Na(+)-Ca2+ exchanger, Na(+)-H+ exchanger and SL SOCs. In addition, ryanodine-sensitive and InsP(3)-sensitive intracellular Ca2+ pools may be associated with the LPA-induced increase in [Ca2+]i. Furthermore, the LPA-induced [Ca2+]i mobilization in VSMCs seems to be due to the activation of both PLC and PKC.

Animals↗

PubMed2005

Involvement of Na+/Ca2+ exchanger in catecholamine-induced increase in intracellular calcium in cardiomyocytes.

Although sarcolemmal (SL) Na+/Ca2+ exchanger is known to regulate the intracellular Ca2+ concentration ([Ca2+]i), its involvement in catecholamine-induced increase in [Ca2+]i is not fully understood. To gain some information in this regard, isolated rat cardiomyocytes were treated with different agents, which are known to modify Ca2+ movements, in the absence or presence of a beta-adrenoceptor agonist, isoproterenol, and [Ca2+]i in cardiomyocytes was determined spectrofluorometrically with fura-2 AM. Treatment with isoproterenol did not alter [Ca2+]i in quiescent cardiomyocytes, whereas the ATP (purinergic receptor agonist)-induced increase in [Ca2+]i was significantly potentiated by isoproterenol. Unlike ryanodine and cyclopiazonic acid, which affect the sarcoplasmic reticulum function, SL L-type Ca2+ channel blockers verapamil and diltiazem, as well as a SL Ca2+-pump inhibitor, vanadate, caused a significant depression in the isoproterenol-induced increase in [Ca2+]i. The SL Na+/Ca2+ exchange blockers amiloride, Ni2+, and KB-R7943 also attenuated the isoproterenol-mediated increase in [Ca2+]i. Combination of KB-R7943 and verapamil showed additive inhibitory effects on the isoproterenol-induced increase in [Ca2+]i. The isoproterenol-induced increase in [Ca2+]i in KCl-depolarized cardiomyocytes was augmented by low Na+; this augmentation was significantly depressed by treatment with KB-R7943. The positive inotropic action of isoproterenol in isolated hearts was also reduced by KB-R7943. These data suggest that in addition to SL L-type Ca2+ channels, SL Na+/Ca2+ exchanger seems to play an important role in catecholamine-induced increase in [Ca2+]i in cardiomyocytes.

Adenosine Triphosphate↗

PubMed2005

L-arginine administration recovers sarcoplasmic reticulum function in ischemic reperfused hearts by preventing calpain activation.

OBJECTIVE: Earlier studies have shown that impaired cardiac contractility in ischemia reperfusion (IR) is associated with alterations in sarcoplasmic reticulum (SR) function. Impaired release of nitric oxide (NO) has been reported during IR, while administration of NO donors, such as L-arginine (LA), has been shown to improve cardiac performance in IR hearts. We therefore investigated the mechanisms underlying the recovery of contractile function in IR hearts treated with LA. METHODS: Isolated rat hearts subjected to 30 min of global ischemia were reperfused for 60 min. The effects of LA on cardiac performance, SR function and its regulation were examined. RESULTS: IR-induced impairment in cardiac performance was associated with a reduction in SR function and its regulation. IR caused an increase in calpain activity and a decrease in the sarcolemmal and SR nitric oxide synthase (NOS) isoform protein content as well as cytosolic NO levels. Administration of LA prevented contractile dysfunction in IR hearts, which was associated with a recovery of SR function and SR regulation by protein phosphorylation. This was consistent with a recovery in protein levels of major SR Ca2+-cycling and Ca2+-regulatory proteins. LA treatment attenuated an increase in calpain activity, possibly by nitrosylation of calpain, and increased cytosolic NO levels and SR NOS protein content in IR hearts. DISCUSSION: These results suggest that LA administration improved cardiac contractility by preventing alterations in SR Ca2+ handling and calpain activation in IR hearts.

Animals↗

PubMed2005

Phospholipid profile of developing heart of rats exposed to low-protein diet in pregnancy.

Although the myocardial phospholipid and fatty acid content have profound effects on the heart function, very little information is available on the effects of restricted maternal protein intake during pregnancy on the phospholipid profile and fatty acid content of the developing heart. The present study was therefore undertaken to examine the effect of pregnant dams fed diets containing either 180 (normal) or 90 (low) g/kg casein diet for 2 wk before mating and throughout pregnancy on myocardial phospholipid and fatty acid content of male offspring. Whereas no changes in phosphatidylcholine and phosphatidylethanolamine were detected, increases in lysophosphatidylcholine, phosphatidylserine, and sphingomyelin were seen in the hearts of offspring in the low-protein (LP) group. Analysis of cardiac fatty acids revealed that although the saturated fatty acid (myristate, palmitate, and stearate) levels were significantly reduced, the unsaturated fatty acid (linoleate, arachidonate, and decosahexanoate) levels were significantly increased in the developing heart in the LP group. Furthermore, assessment of nuclear transcription factors involved in regulation of cardiac metabolism revealed a decrease in myocyte enhancer factor-2C mRNA levels in the LP group, whereas an increase in the mRNA amount of peroxisome proliferator-activated receptor-alpha was observed in this group. These results demonstrate that maternal LP diet can induce changes in the phospholipid profile and fatty acid content of the developing heart, which may have implications for metabolism of the neonatal heart.

Animals↗

PubMed2005

Modification of alterations in cardiac function and sarcoplasmic reticulum by vanadate in ischemic-reperfused rat hearts.

To study the cardioprotective effects of vanadate on ischemia-reperfusion (I/R) injury, isolated rat hearts perfused at constant flow were subjected to global ischemia for 30 min followed by reperfusion for 30 min. In this experimental model, I/R markedly decreased ventricular developed pressure and increased end-diastolic pressure. Pretreatment of hearts with 4 microM vanadate attenuated I/R-induced cardiac dysfunction. The reduction in sarcoplasmic reticulum (SR) Ca2+ uptake and Ca2+ release, as well as SR protein contents for Ca2+-pump ATPase and Ca2+-release channel, was also prevented by vanadate. Pretreatment of hearts with an antioxidant mixture containing superoxide dismutase + catalase exerted effects similar to those of vanadate in I/R hearts. Postischemic treatment of hearts with vanadate or superoxide dismutase + catalase also had beneficial effects on I/R-induced changes in cardiac performance and SR function. Alterations in cardiac function and SR Ca2+ transport due to an oxyradical-generating system (xanthine + xanthine oxidase) or an oxidant (H2O2) were attenuated by treatment with vanadate. These results suggest that vanadate may exert beneficial effects on cardiac performance and SR function in I/R hearts because of its antioxidant action.

Animals↗