Naranjan S. Dhalla

University of Manitoba, Winnipeg, Manitoba, Canada

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Publications (694)2107.31 Total impact

  • Yan-Jun Xu · Vijayan Elimban · Naranjan S Dhalla
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    ABSTRACT: The voltage-operated Ca(2+) channels (VOCC), which allow Ca(2+) influx from the extracellular space, are inhibited by anti-hypertensive agents such as verapamil and nifedipine. The Ca(2+) entering from outside into the cell triggers Ca(2+) release from the sarcoplasmic reticulum (SR) stores. To refill the depleted Ca(2+) stores in the SR, another type of Ca(2+) channels in the cell membrane, known as store-operated Ca(2+) channels (SOCC), are activated. These SOCCs are verapamil and nifedipine resistant, but are SKF 96465 (SK) and gadolinium (Gd(3+) ) sensitive. Both SK and Gd(3+) have been shown to reduce [Ca(2+) ]i in the smooth muscle, but their effects on blood pressure have not been reported. Our results demonstrated that both SK and Gd(3+) produced a dose-dependent reduction in blood pressure in rat. The combination of SK and verapamil produced an additive action in lowering the blood pressure. Furthermore, SK, but not Gd(3+) suppressed proliferation of vascular smooth muscle cells in the absence or presence of lysophosphatidic acid (LPA). SK decreased the elevation of [Ca(2+) ]i induced by LPA, endothelin-1 (ET-1) and angiotensin II (Ang II), but did not affect the norepinephrine (NE)-evoked increase in [Ca(2+) ]i . On the other hand, Gd(3+) inhibited the LPA and Ang II induced change in [Ca(2+) ]i , but had no effect on the ET-1 and NE induced increase in [Ca(2+) ]i . The combination of verapamil and SK abolished the LPA- or adenosine-5'-triphosphate (ATP)-induced [Ca(2+) ]i augmentation. These results suggest that SOCC inhibitors, like VOCC blocker, may serve as promising drugs for the treatment of hypertension.
    No preview · Article · Oct 2015 · Journal of Cellular and Molecular Medicine
  • Vineet Goyal · Davinder S. Jassal · Naranjan S. Dhalla
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    ABSTRACT: Sudden cardiac death (SCD) is known to occur in individuals with diverse diseases. Each disease state has a specific etiology and pathophysiology, and is diagnosed and treated differently. Etiologies for SCD include cardiac arrhythmias, coronary artery disease, congenital coronary artery anomalies, hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, dilated cardiomyopathy, and aortic valve stenosis. A potential unifying mechanism of SCD in these diseases involves a massive stimulation of the sympathetic nervous system's stress response and the subsequent elevation of circulating catecholamines. The diagnosis of cardiac diseases that contribute to an increased risk for SCD is accomplished by a combination of different techniques including electrocardiography, echocardiography, magnetic resonance imaging, and invasive cardiac catheterization. Several therapies including anti-arrhythmic drugs, β-blockers, and antiplatelet agents may be used as medical treatment in patients for the prevention of SCD. Invasive therapies including percutaneous angioplasty, coronary artery bypass surgery, and implantable cardioverter-defibrillators are also used in the clinical management of SCD.
    No preview · Article · Sep 2015 · Canadian Journal of Physiology and Pharmacology
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    ABSTRACT: This study was undertaken to examine if conjugated linoleic acid (CLA) isomers c9,t11 and t10,c12, provide protection against cardiac dysfunction in diabetic male and female rats. Diabetes was induced by an intravenous injection of streptozotocin (65 mg/kg body weight) in male and female rats. Four wks after the induction of diabetes, the animals were treated daily for 4 wks with or without 0.5% of each CLA isomer by oral gavage. Eight wks diabetes was associated wiThelevated levels of plasma total cholesterol, HDL-cholesterol, triglycerides and glucose as well as depressed rate of cardiac relaxation (-dP/dt) in both male and female animals. However, unlike females, male diabetic rats showed an increase in heart weight: body weight ratio and decreased rates of cardiac contraction (+dP/dt) and fractional shortening (FS). Both CLA isomers improved the lipid profile in male diabetic rats, whereas only CLA c9,t11 isomer improved the lipid profile in females. CLA intervention did not affect blood glucose levels in male or female diabetic animals. While CLA c9,t11 isomer improved ± dP/dt in the male rats, a deterioration of +dP/dt and-dP/dt in the female diabetic rats was observed. Although FS was normalized by both CLA isomers in males, CLA t10,c12 isomer depressed FS in the female diabetic rats. CLA treatment normalized GLUT 4 gene expression levels, but markedly increased insulin receptor gene expression in the heart of male diabetic rats. These data suggest that, unlike females, improved myocardial function in male diabetic rats in response to CLA may be related to a favorable shift in myocardial energetics. © 2015, International Journal of Diabetes and Metabolism. All rights reserved.
    No preview · Article · Apr 2015
  • Paramjit S Tappia · Naranjan S Dhalla
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    ABSTRACT: Although diabetic cardiomyopathy is associated with heart dysfunction and disturbance in cardiac sarcolemmal membrane phospholipid composition, the role of the different phospholipases and their related signaling mechanisms to altered function of the heart in diabetes is not completely understood. Thus, understanding the pathophysiology of cardiovascular abnormalities in diabetes, as well as identifying defects in various components of the phospholipid signaling pathways, that could serve as therapeutic targets, is warranted. Accordingly, this review provides an outline of the role of and the mechanisms for the defects in phospholipase A2, C and D-mediated signal transduction in the diabetic heart. In addition, the potential of different phospholipases as targets for drug development for the prevention/treatment of heart disease in diabetes is discussed.
    No preview · Article · Dec 2014 · Indian journal of biochemistry & biophysics
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    ABSTRACT: Background: Diabetes is associated with myocardial electrical instability and prolongation of action potential duration that result in disturbances in the rhythm of the heart. Th is study was undertaken to examine the role of circulating catecholamines in abnormal cardiac rhythm and contractility during diff erent stages of diabetes. Diabetes was induced in male Sprague-Dawley rats with streptozotocin (STZ; 65 mg/kg, i.v.). Epinephrine (4-128 μg/kg, i.v.) -induced arrhythmias and plasma levels of epinephrine (Epi) and norepinephrine (NE) were determined in control, 4- and 8-wk diabetic animals. Echocardiography was used to assess cardiac remodeling and contractile function. Although diabetes induced cardiac dysfunction, there were no significant differences in cardiac output, ejection fraction, left ventricle (LV) dimensions, LV fractional shortening between the 4- and 8-wk diabetic animals. Th e electrocardiogram of both diabetic groups showed deep S wave as well as changes in T wave and ST segment. In addition, prolongation of the RR interval in the 4- and 8-wk diabetic animals was seen, while prolongation of the QT and PR intervals were only seen in the 8-wk diabetic animals. Th e severity of Epi-induced ventricular arrhythmias, as assessed by arrhythmia score, was significantly lower in the 8-wk diabetic rats, as compared to the 4-wk diabetic animals. Circulating Epi levels were significantly decreased in the 8-wk diabetic rats, whereas NE levels were increased in the 4-wk diabetic rats. Th e sensitivity of the diabetic heart to catecholamine- triggered arrhythmias may be dependent on circulating Epi rather than NE and thus it can be proposed that the increased incidence of sudden cardiac death in diabetics may not be associated with response to catecholamines.
    Preview · Article · Jun 2014 · Serbian Journal of Experimental and Clinical Research
  • Paramjit S. Tappia · Naranjan S. Dhalla
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    ABSTRACT: Phospholipase D (PLD) produces phosphatidic acid, which is converted to diacylglycerol (DAG) by phosphatidate phosphohydrolase (PAP). Since both these lipid signaling molecules regulate Ca2+-movements, they also influence cardiac contractile function. In this article, we discuss the importance of PLD in relation to the production of lipid signaling molecules and regulation of cardiac function under various pathophysiological conditions such as ischemic heart disease, diabetic cardiomyopathy, and congestive heart failure. In fact, marked alterations in PLD activities have been reported to occur in ischemic heart, diabetic heart, and failing heart. While the mechanisms of changes in PLD activities in heart disease may be of complex nature, oxidative stress seems to play a critical role in the activation of PLD. From the evidence provided it is suggested that impairment in this phospholipid signal transduction pathway results in cardiac dysfunction during the development of different myocardial diseases.
    No preview · Article · Jan 2014
  • Andrea Babick · Vijayan Elimban · Shelley Zieroth · Naranjan S Dhalla
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    ABSTRACT: In order to examine the reversibility of heart failure due to myocardial infarction (MI) by β-adrenoceptor blockade, 12 wks infarcted rats were treated with or without metoprolol (50 mg/kg/day) for 8 wks. The depressed left ventricular (LV) systolic pressure, positive and negative rates of changes in pressure development, ejection fraction, fractional shortening and cardiac output, as well as increased LV end-diastolic pressure in 20 wks MI animals were partially reversed by metoprolol. MI-induced decreases in septum (systolic) thickness as well as increase in LV posterior wall thickness and LV internal diameter were partially or fully reversible by metoprolol. Treatment of MI animals with metoprolol partially reversed the elevated levels of plasma norepinephrine and dopamine without affecting the elevated levels of epinephrine. Although sarcoplasmic reticular (SR) Ca(2+) -uptake, as well as protein content for SR Ca(2+) -pump and phospholamban, were reduced in the infarcted hearts; these changes were partially reversible with metoprolol. Depressed myofibrillar Ca(2+) -stimulated ATPase activity, as well as mRNA levels for SR Ca(2+) -pump, phospholamban and α-myosin heavy chain, were unaffected whereas increased mRNA level for β-myosin heavy chain was partially reversed by metoprolol. The results suggest that partial improvement of cardiac performance by β-adrenoceptor blockade at advanced stages of heart failure may be due to partial reversal of changes in SR Ca(2+) -pump function whereas partial to complete reverse cardiac remodeling may be due to partial reduction in the elevated levels of plasma catecholamines. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
    No preview · Article · Oct 2013 · Journal of Cellular Physiology
  • Paramjit S Tappia · Yan-Jun Xu · Naranjan S Dhalla
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    ABSTRACT: Although synthetic chemicals and pharmacological agents are being used for the treatment of cardiovascular disease in the western world, there now appears to be a cultural and philosophical shift toward Eastern Medicine and many patients are increasingly using alternative approaches for prevention and therapeutic purposes. This brief review summarizes the experimental and clinical evidence of some functional foods, herbal products and medicinal plants for improving plasma HDL cholesterol, LDL cholesterol, triglycerides and glucose levels, as well as reducing oxidative stress. In addition, the potential of acupuncture and Yogic meditation are discussed as emerging approaches for reducing cardiovascular disease risk factors. The available evidence indicates that several functional foods, herbal products and medicinal plants exert lipid-lowering and hypoglycemic actions, as well as exhibit antioxidant properties; however, a great deal of research work and extensive clinical trials are needed to establish their use in medical practice.
    No preview · Article · Jun 2013 · Clinical Lipidology
  • Adriana Adameova · Naranjan S Dhalla
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    ABSTRACT: Although heart disease due to diabetes is mainly associated with complications of the large vessels, microvascular abnormalities are also considered to be involved in altering cardiac structure and function. Three major defects, such as endothelial dysfunction, alteration in the production/release of hormones, and shift in metabolism of smooth muscle cells, have been suggested to produce damage to the small arteries and capillaries (microangiopathy) due to hyperglycemia, and promote the development of diabetic cardiomyopathy. These factors may either act alone or in combination to produce oxidative stress as well as changes in cellular signaling and gene transcription, which in turn cause vasoconstriction and structural remodeling of the coronary vessels. Such alterations in microvasculature produce hypoperfusion of the myocardium and thereby lower the energy status resulting in changes in Ca2+-handling, apoptosis, and decreased cardiac contractile force. This article discusses diabetes-induced mechanisms of microvascular damage leading to cardiac dysfunction that is characterized by myocardial dilatation, cardiac hypertrophy as well as early diastolic and late systolic defects. Metabolic defects and changes in neurohumoral system due to diabetes, which promote disturbances in vascular homeostasis, are highlighted. In addition, increase in the vulnerability of the diabetic heart to the development of heart failure and the signaling pathways integrating nuclear factor κB and protein kinase C in diabetic cardiomyopathy are also described for comparison.
    No preview · Article · Mar 2013 · Heart Failure Reviews
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    ABSTRACT: Diabetic cardiomyopathy is not only associated with heart failure but there also occurs a loss of the positive inotropic effect of different agents. It is now becoming clear that cardiac dysfunction in chronic diabetes is intimately involved with Ca(2+)-handling abnormalities, metabolic defects and impaired sensitivity of myofibrils to Ca(2+) in cardiomyocytes. On the other hand, loss of the inotropic effect in diabetic myocardium is elicited by changes in signal transduction mechanisms involving hormone receptors and depressions in phosphorylation of various membrane proteins. Ca(2+)-handling abnormalities in the diabetic heart occur mainly due to defects in sarcolemmal Na(+)-K(+) ATPase, Na(+)-Ca(2+) exchange, Na(+)-H(+) exchange, Ca(2+)-channels and Ca(2+)-pump activities as well as changes in sarcoplasmic reticular Ca(2+)-uptake and Ca(2+)-release processes; these alterations may lead to the occurrence of intracellular Ca(2+) overload. Metabolic defects due to insulin deficiency or ineffectiveness as well as hormone imbalance in diabetes are primarily associated with a shift in substrate utilization and changes in the oxidation of fatty acids in cardiomyocytes. Mitochondria initially seem to play an adaptive role in serving as a Ca(2+) sink, but the excessive utilization of long-chain fatty acids for a prolonged period results in the generation of oxidative stress and impairment of their function in the diabetic heart. In view of the activation of sympathetic nervous system and renin-angiotensin system as well as platelet aggregation, endothelial dysfunction and generation of oxidative stress in diabetes and blockade of their effects have been shown to attenuate subcellular remodeling, metabolic derangements and signal transduction abnormalities in the diabetic heart. On the basis of these observations, it is suggested that oxidative stress and subcellular remodeling due to hormonal imbalance and metabolic defects play a critical role in the genesis of heart failure during the development of diabetic cardiomyopathy.
    No preview · Article · Feb 2013 · Heart Failure Reviews
  • Yan-Jun Xu · Paramjit S Tappia · Nirankar S Neki · Naranjan S Dhalla
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    ABSTRACT: Oxidative stress is considered to play an important role in the pathogenesis of diabetes-induced cardiovascular disease (CVD), which is invariably associated with abnormal blood lipid profile, insulin resistance and metabolic syndrome. Stress, smoking, high saturated fat intake as well as low fruit and vegetable intakes have been shown to increase oxidative stress and hyperlipidemia, which increase the predisposition of diabetic subjects to atherosclerosis, stroke and coronary heart disease. The oxidation of low-density lipoprotein by oxidative stress is essential for the development of atherosclerosis, and the reduction in oxidative stress as well as blood glucose and cholesterol is considered critical for the prevention of diabetes-induced CVD. Although epidemiological studies have demonstrated that vitamin C and vitamin E decrease the incidence of coronary heart disease, different clinical trials have failed to support the beneficial effect of these antioxidants. Nonetheless, it has been suggested that natural forms of these vitamins may be more efficacious than synthetic vitamins, and this may explain the inconsistencies in results. Antioxidants, N-acetyl-L-cysteine and resveratrol, have also been shown to attenuate the diabetes-induced cardiovascular complications. It has been indicated that the antioxidant therapy may be effective in a prevention strategy rather than as a treatment for CVD. The evidence presented here supports the view that cardiovascular complications in diabetes may be induced by oxidative stress and appropriate antioxidant therapy may be promising for attenuating the progression of diabetes-induced CVD.
    No preview · Article · Feb 2013 · Heart Failure Reviews
  • Harjot K Saini-Chohan · Larry Hryshko · Yan-Jun Xu · Naranjan S Dhalla
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    ABSTRACT: We examined the role of redox-sensitive signal transduction mechanisms in modifying the changes in [Ca(2+)](i) produced by ouabain upon incubating adult rat cardiomyocytes with antioxidants or inhibitors of different protein kinases and monitoring alterations in fura-2 fluorescence. Ouabain increased basal [Ca(2+)](i), augmented the KCl-induced increase in [Ca(2+)](i), and promoted oxyradical production in cardiomyocytes. These actions of ouabain were attenuated by an oxyradical scavenging mixture (superoxide dismutase plus catalase), and the antioxidants (N-acetyl-l-cysteine and N-(2-mercaptoproprionyl)glycine). An inhibitor of MAP kinase (PD98059) depressed the ouabain-induced increase in [Ca(2+)], whereas inhibitors of tyrosine kinase (tyrphostin and genistein) and PI3 kinase (Wortmannin and LV294002) enhanced the ouabain-induced increase in [Ca(2+)](i). Inhibitors of protein kinase C (calphostin and bisindolylmalaimide) augmented the ouabain-induced increase in [Ca(2+)](i), whereas stimulation of protein kinase C by a phorbol ester (phorbol 12-myristate 13-acetate) depressed the action of ouabain. These results suggest that ouabain-induced inhibition of Na (+)-K(+) ATPase may alter the redox status of cardiomyocytes through the production of oxyradicals, and increase the activities of various protein kinases. Thus, these redox-sensitive signal transduction mechanisms involving different protein kinases may modify Ca(2+)-handling sites in cardiomyocytes and determine the magnitude of net increase in [Ca(2+)](i) in response to ouabain.
    No preview · Article · Feb 2013 · Canadian Journal of Physiology and Pharmacology
  • Naranjan S Dhalla · Satoshi Takeda · Vijayan Elimban
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    ABSTRACT: Abstract Although vitamin B6 and its metabolite, pyridoxal 5'-phosphate (PLP), have been shown to exert beneficial effects in ischemic heart disease, the mechanisms of their action are not fully understood. Some studies have shown that ventricular arrhythmias and mortality upon the occlusion of coronary artery were attenuated by pretreatment of animals with PLP. Furthermore, ischemia-reperfusion-induced abnormalities in cardiac performance and defects in sarcoplasmic reticular Ca2+-transport activities were decreased by PLP. The increase in cardiac contractile activity of isolated heart by ATP was reduced by PLP, unlike propranolol, whereas that by isoproterenol was not depressed by PLP. ATP-induced increase in [Ca2+]i, unlike KCl-induced increase in [Ca2+]i in cardiomyocytes was depressed by PLP. Both high- and low-affinity sites for ATP binding in sarcolemmal membranes were also decreased by PLP. These observations support the view that PLP may produce cardioprotective effects in ischemic heart disease by attenuating the occurrence of intracellular Ca2+ overload due to the blockade of purinergic receptors.
    No preview · Article · Jan 2013 · Clinical Chemistry and Laboratory Medicine
  • Dustin Scott Kehler · Naranjan S. Dhalla · Todd A. Duhamel
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    ABSTRACT: Angiogenesis refers to the growth of new capillaries from a pre-existing capillary bed which can occur during normal physiological and pathological conditions by sprouting and non-sprouting processes, which are activated by different stimuli. Various studies have demonstrated that exercise increases the expression of several growth factors for both sprouting and non-sprouting angiogenesis, including vascular endothelial growth factor and other cytokines in skeletal and cardiac muscle, which are associated with an increase in the number of capillaries in the heart and skeletal muscle. Exercise is known to stimulate the release of several pro- and anti-angiogenic proteins and transcription factors and it appears that hypoxia and/or ischemia play a major role in the growth and expansion of new capillaries and has also been suggested that mechanical forces, such as shear stress or muscle overload, stimulate exercise-induced angiogenesis. More importantly, an in-depth understanding of the factors that influence exercise-induced angiogenesis may contribute to the development of potential therapeutic strategies for the treatment of different diseases including hypertension and ischemic heart disease.
    No preview · Chapter · Jan 2013
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    ABSTRACT: This study was undertaken to examine the effects of dietary supplementation of cysteine and taurine in rats with diabetes induced with streptozotocin (STZ, 65 mg/kg body weight). Experimental animals were treated orally (by gavage) with cysteine (200 mg/kg) and taurine (400 mg/kg), alone or in combination, daily for 8 wks. In one group, rats were also pretreated 3 wks before the induction of diabetes (prevention arm) whereas in the other, the treatment was started 3 days after the induction of diabetes (reversal arm). Diabetes increased heart weight/body weight (HW/BW) ratio, plasma glucose, triglyceride and cholesterol levels as well as depressed heart rate (HR), blood pressure, left ventricular systolic pressure (LVSP), rate of contraction (+dP/dt), rate of relaxation (-dP/dt), fractional shortening (FS) and cardiac output (CO). The left ventricular internal diameter in systole (LViDs) was increased whereas that in diastole (LViDd) was decreased. In the prevention arm, treatment of the diabetic animals with cysteine or taurine decreased HW/BW ratio and improved HR, FS, +dP/dt and -dP/dt, as well as normalized LViDs, without altering the increase in glucose level. Cysteine decreased plasma triglyceride and cholesterol levels and improved LVSP whereas CO was improved by taurine. In the reversal arm, cysteine alone or with taurine did not correct the changes in hemodynamic parameters, FS and plasma triglycerides. Diabetes-induced cardiac dysfunction and increases in plasma triglycerides can be prevented, but not reversed, by dietary cysteine alone or in combination with taurine.
    No preview · Article · Dec 2012 · Physiological research / Academia Scientiarum Bohemoslovaca
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    Alison L Müller · Darren Freed · Naranjan S Dhalla
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    ABSTRACT: Previous studies have shown that ischemia-reperfusion (I/R) injury is associated with cardiac dysfunction and changes in sarcolemmal Na(+)-K(+) ATPase subunits and activity. This study was undertaken to evaluate the role of proteases in these alterations by subjecting rat hearts to different times of global ischemia, as well as reperfusion after 45 min of ischemia. Decreases in Na(+)-K(+) ATPase activity at 30 to 60 min of global ischemia were accompanied by augmented activities of both calpain and matrix metalloproteinases (MMPs) and depressed protein content of β-1 and β-2 subunits, without changes in α-1 and α-2 subunits of the enzyme. In comparison to control values, the activities of both calpain and MMP-2 were increased whereas the activity and protein content for all subunits of Na(+)-K(+) ATPase were decreased upon reperfusion for 5 to 40 min except that α-1 and α-2 subunit content was not depressed in 5 min I/R hearts. MDL28170, a calpain inhibitor, was more effective in attenuating the I/R-induced alterations in cardiac contracture, Na(+)-K(+)-ATPase activity and α-2 subunit than doxycycline, an MMP inhibitor. Incubation of control SL preparation with calpain, unlike MMP-2, depressed Na(+)-K(+) ATPase activity and decreased α-1, α-2 and β-2 subunits without changes in the β-1 subunit. These results support the view that activation of both calpain and MMP-2 are involved in depressing Na(+)-K(+) ATPase activity and degradation of its subunits directly or indirectly in hearts subjected to I/R injury.
    Full-text · Article · Dec 2012 · Journal of Applied Physiology
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    ABSTRACT: This study tested the reversal of subcellular remodeling in heart failure due to myocardial infarction (MI) upon treatment with losartan, an angiotensin II receptor antagonist. Twelve wks after inducing MI, rats were treated with or without losartan (20 mg/kg; daily) for 8 wks and assessed for cardiac function, cardiac remodeling, subcellular alterations and plasma catecholamines. Cardiac hypertrophy and lung congestion in 20 wks MI-induced heart failure were associated with increases in plasma catecholamine levels. Hemodynamic examination revealed depressed cardiac function whereas echocardiographic analysis showed impaired cardiac performance and marked increases in left ventricle wall thickness and chamber dilatation at 20 wks of inducing MI. These changes in cardiac function, cardiac remodeling and plasma dopamine levels in heart failure were partially or fully reversed by losartan. Sarcoplasmic reticular (SR) Ca(2+) -pump activity and protein expression, protein and gene expression for phospholamban, as well as myofibrillar (MF) Ca(2+) -stimulated ATPase activity and α-myosin heavy chain mRNA levels were depressed whereas β-myosin heavy chain expression was increased in failing hearts; these alterations were partially reversed by losartan. Although SR Ca(2+) -release activity and mRNA levels for SR Ca(2+) -pump were decreased in failing heart, these changes were not reversed upon losartan treatment; no changes in mRNA levels for SR Ca(2+) -release channels were observed in untreated or treated heart failure. These results suggest that partial improvement of cardiac performance in heart failure due to MI by losartan treatment is associated with partial reversal of cardiac remodeling as well as partial recovery of SR and MF functions. © 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
    Preview · Article · Sep 2012 · Journal of Cellular and Molecular Medicine
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    Naranjan S Dhalla · Shashanka Rangi · Shelley Zieroth · Yan-Jun Xu
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    ABSTRACT: Although diabetes due to insulin deficiency or insulin resistance is a major cause of heart disease, the pathogenesis of cardiac dysfunction during the development of diabetic cardiomyopathy is not fully understood. Varying degrees of defects in subcellular organelles, such as sarcolemma, mitochondria, sarcoplasmic reticulum, myofibrils and extracellular matrix have been observed in the diabetic heart. These subcellular abnormalities in chronic diabetes become evident with the occurrence of hormonal imbalance, metabolic defects, oxidative stress and intracellular Ca(2+) overload. During the initial stages of diabetes, hormonal imbalances, including elevated plasma levels of catecholamines and angiotensin II, as well as metabolic defects, appear to favour the development of oxidative stress; these changes lead to subcellular defects in the myocardium. Reductions in sarcoplasmic reticular Ca(2+) pump and Ca(2+) release channel function are associated with cardiac dysfunction, whereas alterations in sarcolemmal Na(+)/Ca(2+) exchanger and Na(+)/K(+) ATPase activities contribute to intracellular Ca(2+) overload at late stages of diabetes. The continued accumulation of Ca(2+) in mitochondria produces Ca(2+) overload in these organelles, and this change induces impairment of energy production and depletion of energy stores as well as further promotion of oxidative stress in chronic diabetes. Generation of oxyradicals due to impaired electron transport results in the opening of mitochondrial pores, leakage of toxic proteins and myocardial cell damage in diabetes. These observations support the view that alterations in sarcoplasmic reticular and mitochondrial functions produce intracellular Ca(2+) overload and depletion of energy stores and, thus, play an important role in the development of cardiac dysfunction in diabetic cardiomyopathy.
    Preview · Article · Sep 2012 · Experimental and clinical cardiology
  • Paramjit S Tappia · Naranjan S Dhalla
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    ABSTRACT: Clinicians and health professionals are increasingly becoming aware of different health needs of men and women. Differences in gender and corresponding sex hormones result in disparities in risk and protection of cardiovascular disease as men develop cardiovascular disease at an earlier age while women are affected at older ages. Myocardial adaptation and lipid metabolism, including plasma levels of cholesterol and triglycerides, are different in men and women. Gender differences in optimal treatment and secondary prevention measures in patients with coronary heart disease are also evident. This report addresses some of the issues relating to gender differences in the risk, clinical manifestation and management of as well as response to therapy, with particular attention given to changes in plasma HDL-cholesterol, LDL-cholesterol and triglyceride levels. Understanding these differences in lipid control will help to improve the diagnosis of cardiovascular disease and provide information for therapeutic or preventive strategies that may be specifically designed for men and women.
    No preview · Article · Aug 2012 · Clinical Lipidology
  • Melissa R Dent · Paramjit S Tappia · Naranjan S Dhalla
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    ABSTRACT: This study was undertaken to determine gender related changes in different components of β-adrenoceptor (β-AR) system in response to arteriovenous fistula (AV-shunt), which is known to produce heart failure due to volume overload. AV-shunt was induced in male and female rats for 16 weeks by the needle technique; ovariectomized (OVX) rats treated with or without estrogen were also used. Although AV-shunt for 16 weeks produced cardiac hypertrophy in both sexes, male animals showed cardiac dysfunction whereas cardiac performance was maintained in females. Both β(1) -AR and β(2) -AR protein content and mRNA levels were decreased in male and increased in female hearts post-AV-shunt. The basal adenylyl cyclase (AC) activity was lower in the female heart; however, AC protein content and the increase in epinephrine (EPi)-stimulated AC activity were greater in the female AV-shunt group as compared to males. While AC V/VI and β-arrestin 2 mRNA levels were decreased in males, mRNA level for GRK2 was increased in females post-AV-shunt. In contrast to intact females, AV-shunt OVX animals showed depressed cardiac function, decreased β(1) -AR, β(2) -AR, and AC protein content, as well as reduced EPi-stimulated AC activity. Treatment of OVX rats with 17-β estradiol attenuated the AV-shunt induced changes in β-AR and AC protein content as well as cardiac dysfunction. These results reveal that β-AR signal transduction system in response to AV-shunt is downregulated in males and upregulated in females. Furthermore, estrogen appears to play an important role in the upregulation of β-AR mechanisms and the maintenance of cardiac function in AV-shunt females.
    No preview · Article · Aug 2012 · Journal of Cellular Physiology

Publication Stats

15k Citations
2,107.31 Total Impact Points


  • 1970-2015
    • University of Manitoba
      • • Department of Physiology
      • • Faculty of Medicine
      Winnipeg, Manitoba, Canada
  • 1987-2013
    • St. Boniface Hospital Research
      • Institute of Cardiovascular Sciences
      Winnipeg, Manitoba, Canada
  • 2007
    • Texas A&M University - Kingsville
      NQI, Texas, United States
    • University of Virginia
      • Department of Medicine
      Charlottesville, Virginia, United States
  • 2005-2007
    • Ankara University
      • • Faculty of Pharmacy
      • • Department of Biophysics
      Engüri, Ankara, Turkey
  • 2006
    • University of Alberta
      • Department of Agricultural, Food, and Nutritional Science
      Edmonton, Alberta, Canada
  • 2003
    • The Jikei University School of Medicine
      Edo, Tokyo, Japan
  • 1975-2003
    • Hôpital St-Boniface Hospital
      Winnipeg, Manitoba, Canada
  • 2002
    • University Hospital Motol
      Praha, Praha, Czech Republic
    • The Police Academy of the Czech Republic in Prague
      Praha, Praha, Czech Republic
  • 2001
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 1977-2001
    • The University of Winnipeg
      Winnipeg, Manitoba, Canada
  • 1999
    • Academy of Sciences of the Czech Republic
      • Fyziologický ústav
      Praha, Hlavni mesto Praha, Czech Republic
  • 1991
    • Tokoha University
      • Department of Internal Medicine II
      Hamamatu, Shizuoka, Japan
    • University of Tartu
      Dorpat, Tartu County, Estonia
  • 1973
    • University of British Columbia - Vancouver
      • Faculty of Medicine
      Vancouver, British Columbia, Canada
  • 1972
    • Washington University in St. Louis
      San Luis, Missouri, United States