S R Houser

Temple University, Philadelphia, Pennsylvania, United States

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Publications (65)387.95 Total impact

  • Mark T Ziolo, Steven R Houser
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    ABSTRACT: Significance: Heart failure (HF) results from poor heart function and is the leading cause of death in Western society. Abnormalities of Ca2+ handling at the level of the ventricular myocyte are largely responsible for much of the poor heart function. Recent Advances: While studies have unraveled numerous mechanisms for the abnormal Ca2+ handling, investigations over the past decade have indicated that much of the contractile dysfunction and adverse remodeling that occurs in HF involves oxidative stress. Critical Issues: Regrettably, anti-oxidant therapy has been an immense disappoint in clinical trials. Thus, redox signaling is being reassessed to elucidate why antioxidants failed to treat HF. Future Directions: A recently identified aspect of redox signaling (specifically the superoxide anion radical) is its interaction with nitric oxide, known as the nitroso-redox balance. There is a large nitroso-redox imbalance with HF and we suggest that correcting this imbalance may be able to restore myocyte contraction and improve heart function.
    Antioxidants & Redox Signaling 05/2014; · 8.20 Impact Factor
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    ABSTRACT: Early-career academic cardiologists currently face unprecedented challenges that threaten a highly valued career path. A team consisting of early career professionals and senior leadership members of American College of Cardiology (ACC) completed this white paper to inform the cardiovascular medicine profession regarding the plight of early career cardiologists and to suggest possible solutions. This paper includes: (1) definition of categories of early career academic cardiologists, (2) general challenges to all categories and specific challenges to each category, (3) obstacles as identified by a survey of current early career members of the ACC, (4) major reasons for the failure of physician-scientists to receive funding from National Institute of Health/National Heart Lung and Blood Institute (NIH/NHLBI) career development grants, (5) potential solutions, and (6) a call to action with specific recommendations.
    Journal of the American College of Cardiology 01/2014; · 14.09 Impact Factor
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    ABSTRACT: During sepsis, acute lung injury (ALI) results from activation of innate immune cells and endothelial cells by endotoxins, leading to systemic inflammation through proinflammatory cytokine overproduction, oxidative stress, and intracellular Ca2+ overload. Despite considerable investigation, the underlying molecular mechanism(s) leading to LPS-induced ALI remain elusive. To determine whether stromal interaction molecule 1-dependent (STIM1-dependent) signaling drives endothelial dysfunction in response to LPS, we investigated oxidative and STIM1 signaling of EC-specific Stim1-knockout mice. Here we report that LPS-mediated Ca2+ oscillations are ablated in ECs deficient in Nox2, Stim1, and type II inositol triphosphate receptor (Itpr2). LPS-induced nuclear factor of activated T cells (NFAT) nuclear accumulation was abrogated by either antioxidant supplementation or Ca2+ chelation. Moreover, ECs lacking either Nox2 or Stim1 failed to trigger store-operated Ca2+ entry (SOCe) and NFAT nuclear accumulation. LPS-induced vascular permeability changes were reduced in EC-specific Stim1-/- mice, despite elevation of systemic cytokine levels. Additionally, inhibition of STIM1 signaling prevented receptor-interacting protein 3-dependent (RIP3-dependent) EC death. Remarkably, BTP2, a small-molecule calcium release-activated calcium (CRAC) channel blocker administered after insult, halted LPS-induced vascular leakage and pulmonary edema. These results indicate that ROS-driven Ca2+ signaling promotes vascular barrier dysfunction and that the SOCe machinery may provide crucial therapeutic targets to limit sepsis-induced ALI.
    The Journal of clinical investigation 01/2013; · 15.39 Impact Factor
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    ABSTRACT: The Ca(2+)-sensing stromal interaction molecule (STIM) proteins are crucial Ca(2+) signal coordinators. Cre-lox technology was used to generate smooth muscle (sm)-targeted STIM1-, STIM2-, and double STIM1/STIM2-knockout (KO) mouse models, which reveal the essential role of STIM proteins in Ca(2+) homeostasis and their crucial role in controlling function, growth, and development of smooth muscle cells (SMCs). Compared to Cre(+/-) littermates, sm-STIM1-KO mice showed high mortality (50% by 30 d) and reduced bodyweight. While sm-STIM2-KO was without detectable phenotype, the STIM1/STIM double-KO was perinatally lethal, revealing an essential role of STIM1 partially rescued by STIM2. Vascular and intestinal smooth muscle tissues from sm-STIM1-KO mice developed abnormally with distended, thinned morphology. While depolarization-induced aortic contraction was unchanged in sm-STIM1-KO mice, α(1)-adrenergic-mediated contraction was 26% reduced, and store-dependent contraction almost eliminated. Neointimal formation induced by carotid artery ligation was suppressed by 54%, and in vitro PDGF-induced proliferation was greatly reduced (79%) in sm-STIM1-KO. Notably, the Ca(2+) store-refilling rate in STIM1-KO SMCs was substantially reduced, and sustained PDGF-induced Ca(2+) entry was abolished. This defective Ca(2+) homeostasis prevents PDGF-induced NFAT activation in both contractile and proliferating SMCs. We conclude that STIM1-regulated Ca(2+) homeostasis is crucial for NFAT-mediated transcriptional control required for induction of SMC proliferation, development, and growth responses to injury.-Mancarella, S., Potireddy, S., Wang, Y., Gao, H., Gandhirajan, K., Autieri, M., Scalia, R., Cheng, Z., Wang, H., Madesh, M., Houser, S. R., Gill, D. L. Targeted STIM deletion impairs calcium homeostasis, NFAT activation, and growth of smooth muscle.
    The FASEB Journal 11/2012; · 5.70 Impact Factor
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    ABSTRACT: Hyperhomocysteinemia (HHcy) accelerates atherosclerosis and increases inflammatory monocytes (MC) in peripheral tissues. However, its causative role in atherosclerosis is not well established and its effect on vascular inflammation has not been studied. The underlying mechanism is unknown. This study examined the causative role of HHcy in atherogenesis and its effect on inflammatory MC differentiation. We generated a novel HHcy and hyperlipidemia mouse model, in which cystathionine β-synthase (CBS) and low-density lipoprotein receptor (LDLr) genes were deficient (Ldlr(-/-) Cbs(-/+)). Severe HHcy (plasma homocysteine (Hcy)=275 μmol/L) was induced by a high methionine diet containing sufficient basal levels of B vitamins. Plasma Hcy levels were lowered to 46 μmol/L from 244 μmol/L by vitamin supplementation, which elevated plasma folate levels. Bone marrow (BM)-derived cells were traced by the transplantation of BM cells from enhanced green fluorescent protein (EGFP) transgenic mice after sublethal irradiation of the recipient. HHcy accelerated atherosclerosis and promoted Ly6C(high) inflammatory MC differentiation of both BM and tissue origins in the aortas and peripheral tissues. It also elevated plasma levels of TNF-α, IL-6, and MCP-1; increased vessel wall MC accumulation; and increased macrophage maturation. Hcy-lowering therapy reversed HHcy-induced lesion formation, plasma cytokine increase, and blood and vessel inflammatory MC (Ly6C(high+middle)) accumulation. Plasma Hcy levels were positively correlated with plasma levels of proinflammatory cytokines. In primary mouse splenocytes, L-Hcy promoted rIFNγ-induced inflammatory MC differentiation, as well as increased TNF-α, IL-6, and superoxide anion production in inflammatory MC subsets. Antioxidants and folic acid reversed L-Hcy-induced inflammatory MC differentiation and oxidative stress in inflammatory MC subsets. HHcy causes vessel wall inflammatory MC differentiation and macrophage maturation of both BM and tissue origins, leading to atherosclerosis via an oxidative stress-related mechanism.
    Circulation Research 05/2012; 111(1):37-49. · 11.86 Impact Factor
  • Steven R Houser
    Circulation Research 03/2012; 110(7):907-9. · 11.86 Impact Factor
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    ABSTRACT: Necroptosis represents a form of alternative programmed cell death that is dependent on the kinase RIP1. RIP1-dependent necroptotic death manifests as increased reactive oxygen species (ROS) production in mitochondria and is accompanied by loss of ATP biogenesis and eventual dissipation of mitochondrial membrane potential. Here, we show that tumor necrosis factor alpha (TNF-α)-induced necroptosis requires the adaptor proteins FADD and NEMO. FADD was found to mediate formation of the TNF-α-induced pronecrotic RIP1-RIP3 kinase complex, whereas the IκB Kinase (IKK) subunit NEMO appears to function downstream of RIP1-RIP3. Interestingly, loss of RelA potentiated TNF-α-dependent necroptosis, indicating that NEMO regulates necroptosis independently of NF-κB. Using both pharmacologic and genetic approaches, we demonstrate that the overexpression of antioxidants alleviates ROS elevation and necroptosis. Finally, elimination of BAX and BAK or overexpression of Bcl-x(L) protects cells from necroptosis at a later step. These findings provide evidence that mitochondria play an amplifying role in inflammation-induced necroptosis.
    Molecular and cellular biology 07/2011; 31(18):3745-58. · 6.06 Impact Factor
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    Steven R Houser
    Circulation Research 06/2010; 106(11):1672-4. · 11.86 Impact Factor
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    Steven R Houser
    Circulation Research 06/2005; 96(10):1031-2. · 11.86 Impact Factor
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    ABSTRACT: Hearts from non-heart-beating organ donors are not transplanted because of risk of ischemia-reperfusion injury. We tested whether pharmacologic pre-conditioning with adenosine and the Na(+)/H(+) exchanger inhibitor, cariporide, combined with controlled reperfusion, would prevent injury in porcine hearts that had sustained 30 minutes of hypoxia/ischemia in closed-chest animals. Hearts from Yorkshire pigs (100 kg) were studied in 3 groups. Group 1 (control) hearts were surgically removed while beating. Group 2 hearts were harvested from animals made hypoxic by discontinuing mechanical ventilation for 30 minutes. Group 3 hearts were hypoxic as in Group 2, but these animals received adenosine (40 mg) and cariporide (400 mg) 10 minutes before stopping ventilation. Cardiac function in all groups was assessed ex vivo in a working heart apparatus in which pressure and flow measurements were made over 3 hours. Controlled reperfusion in Group 3 hearts used leukocyte-depleted blood perfusate containing free radical scavengers. Myocardial injury was assessed on the basis of perfusate creatine phosphokinase activity and histopathologically determined injury score. Groups 1 and 3 hearts could be resuscitated to perform work equivalently during the entire reperfusion period and showed positive responses to increases in pre-load and norepinephrine. Group 2 hearts could not perform work. After 3 hours, Group 2 hearts showed significantly higher creatine phosphokinase and histopathologic injury scores compared to with Groups 1 and 3, which were not significantly different from each other. Pharmacologic pre-conditioning and controlled reperfusion effectively protect non-beating porcine hearts from injury after 30 minutes of hypoxia/ischemia in situ.
    The Journal of Heart and Lung Transplantation 12/2003; 22(11):1234-44. · 5.11 Impact Factor
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    ABSTRACT: In the failing human heart, altered Ca2+ homeostasis causes contractile dysfunction. Because Ca2+ and Na+ homeostasis are intimately linked through the Na+/Ca2+ exchanger, we compared the regulation of [Na+]i in nonfailing (NF) and failing human myocardium. [Na+]i was measured in SBFI-loaded muscle strips. At slow pacing rates (0.25 Hz, 37 degrees C), isometric force was similar in NF (n=6) and failing (n=12) myocardium (6.4+/-1.2 versus 7.2+/-1.9 mN/mm2), but [Na+]i and diastolic force were greater in failing (22.1+/-2.6 mmol/L and 15.6+/-3.2 mN/mm2) than in NF (15.9+/-3.1 mmol/L and 3.50+/-0.55 mN/mm2; P<0.05) myocardium. In NF hearts, increasing stimulation rates resulted in a parallel increase in force and [Na+]i without changes in diastolic tension. At 2.0 Hz, force increased to 136+/-17% of the basal value (P<0.05), and [Na+]i to 20.5+/-4.2 mmol/L (P<0.05). In contrast, in failing myocardium, force declined to 45+/-3%, whereas [Na+]i increased to 27.4+/-3.2 mmol/L (both P<0.05), in association with significant elevations in diastolic tension. [Na+]i was higher in failing than in NF myocardium at every stimulation rate. [Na+]i predicted in myocytes from Na+ (pipette)-contraction relations was 8.0 mmol/L in NF (n=9) and 12.1 mmol/L in failing (n=57; P<0.05) myocardium at 0.25 Hz. Reverse-mode Na+/Ca2+ exchange induced significant Ca2+ influx in failing but not NF myocytes, compatible with higher [Na+]i in failing myocytes. Na+i homeostasis is altered in failing human myocardium. At slow heart rates, the higher [Na+]i in failing myocardium appears to enhance Ca2+ influx through Na+/Ca2+ exchange and maintain sarcoplasmic reticulum Ca(2+) load and force development. At faster rates, failing myocytes with high [Na+]i cannot further increase sarcoplasmic reticulum Ca2+ load and are prone to diastolic Ca2+ overload.
    Circulation 07/2002; 106(4):447-53. · 15.20 Impact Factor
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    ABSTRACT: The present study was designed to determine whether myocardial atrophy is necessarily associated with changes in cardiac contractility. Myocardial unloading of normal hearts was produced via heterotopic transplantation in rats. Contractions of isolated myocytes (1.2 mM Ca2+; 37 degrees C) were assessed during field stimulation (0.5, 1.0, and 2.0 Hz), and papillary muscle contractions were assessed during direct stimulation (2.0 mM Ca2+; 37 degrees C; 0.5 Hz). Hemodynamic unloading was associated with a 41% decrease in median myocyte volume and proportional decreases in myocyte length and width. Nevertheless, atrophic myocytes had normal fractional shortening, time to peak contraction, and relaxation times. Despite decreases in absolute maximal force generation (F(max)), there were no differences in F(max)/ area in papillary muscles isolated from unloaded transplanted hearts. Therefore, atrophic remodeling after unloading is associated with intact contractile function in isolated myocytes and papillary muscles when contractile indexes are normalized to account for reductions in cell length and cross-sectional area, respectively. Nevertheless, in the absence of compensatory increases in contractile function, reductions in myocardial mass will lead to impaired overall work capacity.
    AJP Heart and Circulatory Physiology 10/2001; 281(3):H1131-6. · 4.01 Impact Factor
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    ABSTRACT: Recognizing that mechanical circulatory support with a left ventricular assist device (LVAD) induces changes in myocardial structure and contractile function, we examined whether there are changes in ventricular conduction and/or repolarization among failing human hearts after LVAD implantation. We examined 12-lead electrocardiograms before surgery, immediately after LVAD placement, and at a delayed (>1 week) postoperative time point in 23 patients who were receiving LVAD support for refractory heart failure. The immediate effects of hemodynamic unloading via LVAD placement included a decrease in QRS duration from 117+/-6 to 103+/-6 ms (P<0.01), an increase in absolute QT duration from 359+/-6 to 378+/-8 ms (P<0.05), and an increase in the heart rate-corrected QT interval (QTc) from 379+/-10 to 504+/-11 ms (P<0.01). None of these immediate changes were observed among 22 patients undergoing routine coronary artery bypass grafting. With sustained cardiac unloading via LVAD support, there was a marked decrease in the QTc from 504+/-11 to 445+/-9 ms (P<0.001). Studies in isolated cardiac myocytes, obtained at the time of transplantation, confirmed that delayed decreases in heart rate-adjusted QTc were the result of decreases in action potential duration after LVAD support. Acute electrocardiogram responses to LVAD placement demonstrate the dependence of QRS and QT duration on load in the failing human heart. Delayed decreases in QTc and action potential duration reflect reversal of electrophysiologic remodeling in the failing heart. Shortening of the action potential duration likely contributes to the improved cellular contractile performance observed after sustained LVAD support.
    Circulation 10/2001; 104(11):1241-7. · 15.20 Impact Factor
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    ABSTRACT: Alterations in Ca(2+)-handling proteins are thought to underlie the deranged Ca(2+) transients that contribute to deterioration of cardiac function in congestive heart failure (CHF). Clinical trials in CHF patients have shown that treatment with beta-adrenergic receptor antagonists (betaB) improves cardiac performance. The present study determined whether the abundance of Ca(2+)-handling proteins is different in failing hearts from patients treated or untreated with beta B. Ca(2+) regulatory protein abundance was compared in LV myocardium of 10 nonfailing hearts (NF group) and 44 failing hearts (CHF group) removed at transplantation. Analysis was performed in betaB-treated (betaB-CHF) and non-betaB treated (non-betaB-CHF) patients and in 4 subgroups: ischemic cardiomyopathy (ICM, n=10), nonischemic dilated cardiomyopathy (DCM, n=10), ICM with betaB therapy (betaB-ICM, n=12), and DCM with betaB therapy (betaB-DCM, n=12). Sarcoplasmic reticulum Ca(2+) ATPase, phospholamban, and Na(+)-Ca(2+) exchanger protein abundance were determined by use of Western blot analysis. Ca(2+) transients were measured with fluo-3. Sarcoplasmic reticulum Ca(2+) ATPase was significantly less abundant whereas phospholamban and Na(+)-Ca(2+) exchanger were not significantly altered in non-betaB-CHF versus NF. Sarcoplasmic reticulum Ca(2+) ATPase in the betaB-ICM and betaB-DCM was greater than in non-betaB-CHF and were not different than in NF. Ca(2+) transients in non-betaB-CHF myocytes had significantly smaller peaks and were prolonged versus NF myocytes. Ca(2+) transients from betaB-CHF myocytes had shorter durations than in betaB-CHF myocytes. betaB treatment in CHF patients can normalize the abundance of myocyte Ca(2+) regulatory proteins and improve Ca(2+)-handling.
    Circulation 09/2001; 104(9):1012-8. · 15.20 Impact Factor
  • S R Houser
    Cardiovascular Research 03/2001; 49(2):253-6. · 5.81 Impact Factor
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    S R Houser
    Circulation Research 11/2000; 87(9):725-7. · 11.86 Impact Factor
  • S R Houser, V Piacentino, J Weisser
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    ABSTRACT: Progressive deterioration of cardiac contractility is a central feature of congestive heart failure (CHF) in humans. In this report we review those studies that have addressed the idea that alterations of intracellular calcium (Ca(2+)) regulation is primarily responsible for the depressed contractility of the failing heart. The review points out that Ca(2+)transients and contraction are similar in non-failing and failing myocytes at very slow frequencies of stimulation (and other low stress environments). Faster pacing rates, high Ca(2+)and beta-adrenergic stimulation reveal large reductions in contractile reserve in failing myocytes. The underlying cellular basis of these defects is then considered. Studies showing changes in the abundance of L-type Ca(2+)channels, Ca(2+)transport proteins [sarcoplasmic reticulum Ca(2+)ATPase (SERCA2), phospholamban (PLB), Na(+)/Ca(2+) exchanger (NCX)] and Ca(2+) release channels (RYR) in excitation-contraction coupling and Ca(2+)release and uptake by the sarcoplasmic reticulum (SR) are reviewed. These observations support our hypotheses that (i) defective Ca(2+)regulation involves multiple molecules and processes, not one molecule, (ii) the initiation and progression of CHF inolves defective Ca(2+)regulation, and (iii) prevention or correction of Ca(2+)regulatory defects in the early stages of cardiac diseases can delay or prevent the onset of CHF.
    Journal of Molecular and Cellular Cardiology 10/2000; 32(9):1595-607. · 5.15 Impact Factor
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    ABSTRACT: Reduced peak systolic Ca2+ and slow decay of the Ca2+ transient are common features of the end-stage failing human ventricular myocyte and are thought to underlie abnormal ventricular contractility in congestive heart failure (CHF). Individual changes in the expression or activity of Ca2+ transport proteins of the sarcoplasmic reticulum (SR Ca2+ ATPase, SERCa) or the sarcolemmal (sodium-calcium exchanger, NCX) have not always been observed in CHF and cannot per se consistently explain these Ca2+ transient defects. We review recent data that suggests that the normal balance of transport activities of SERCa and NCX is deranged in failing human myocytes. We hypothesize that an increase in the NCX/SERCa transport capacity in failing myocytes can explain the abnormal Ca2+ homeostasis of the failing human ventricular myocyte.
    Trends in Cardiovascular Medicine 05/2000; 10(3):101-7. · 1.47 Impact Factor
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    ABSTRACT: 1. Direct voltage-gated (voltage-dependent Ca2+ release, VDCR) and Ca2+ influx-gated (Ca2+-induced Ca2+ release, CICR) sarcoplasmic reticulum (SR) Ca2+ release were studied in feline ventricular myocytes. The voltage-contraction relationship predicted by the VDCR hypothesis is sigmoidal with large contractions at potentials near the Ca2+ equilibrium potential (ECa). The relationship predicted by the CICR hypothesis is bell-shaped with no contraction at ECa. 2. The voltage dependence of contraction was measured in ventricular myocytes at physiological temperature (37 C), resting membrane potential and physiological [K+]. Experiments were performed with cyclic adenosine 3',5'-monophosphate (cAMP) in the pipette or in the presence of the beta-adrenergic agonist isoproterenol (isoprenaline; ISO). 3. The voltage-contraction relationship was bell-shaped in Na+-free solutions (to eliminate the Na+ current and Na+-Ca2+ exchange, NCX) but the relationship was broader than the L-type Ca2+ current (ICa,L)-voltage relationship. 4. Contractions induced with voltage steps from normal resting potentials to -40 mV are thought to represent VDCR rather than CICR. We found that cAMP and ISO shifted the voltage dependence of ICa,L activation to more negative potentials so that ICa,L was always present with steps to -40 mV. ICa,L at -40 mV inactivated when the holding potential was decreased (VŁ = -57.8 +/- 0.49 mV). 5. ISO increased inward current, SR Ca2+ load and contraction in physiological [Na+] and a broad bell-shaped voltage-contraction relationship was observed. Inhibition of reverse-mode NCX, decreasing ICa,L and decreasing SR Ca2+ loading all decreased contractions at strongly positive potentials near ECa. 6. The voltage-contraction relationship in 200 microM cadmium (Cd2+) was bell-shaped, supporting a role of ICa,L rather than VDCR. 7. All results could be accounted for by the CICR hypothesis, and many results exclude the VDCR hypothesis.
    The Journal of Physiology 04/2000; 523 Pt 3:533-48. · 4.38 Impact Factor
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    ABSTRACT: Defects in myocyte contraction and relaxation are key features of human heart failure. Sodium/calcium exchanger-mediated contribution to contraction and relaxation were separated from other mechanisms [L-type calcium current, sarco(endo)plasmic reticulum (SR) Ca(2+)-ATPase] based on voltage, temperature, and selective blockers. Rod-shaped left ventricular myocytes were isolated from failed human explants (n = 29) via perfusion with collagenase-containing Krebs solution. Action potentials using perforated patch and contractions using an edge detector were recorded at 0.5-1.5 Hz in Tyrode solution at 25 degrees C and 37 degrees C. Contraction duration was dependent on action potential (AP) duration at 37 degrees C but not at 25 degrees C, suggesting the role of the exchanger in relaxation and linking myocyte relaxation to the repolarization phase of the AP. Voltage-clamp experiments from -50 to +10 mV for 1,500 ms in Tyrode or Na(+)- and K(+)-free solutions after conditioning pulses triggered biphasic contractions that included a rapid SR-mediated component and a slower voltage-dependent exchanger-mediated component. We used thapsigargin to block the SR, which eliminated the rapid component, and we used an exchanger blocker, Kanebo 7943, which eliminated the slow component. The exchanger was shown to contribute to contraction through reverse-mode exchange, as well as to play a key role in relaxation of human ventricular myocytes.
    The American journal of physiology 09/1999; 277(2 Pt 2):H714-24. · 3.28 Impact Factor

Publication Stats

2k Citations
387.95 Total Impact Points

Institutions

  • 1983–2014
    • Temple University
      • • Independence Blue Cross Cardiovascular Research Center (CVRC)
      • • Department of Physiology
      • • Department of Medicine
      Philadelphia, Pennsylvania, United States
  • 2002
    • Universitätsmedizin Göttingen
      • Department of Cardiology and Pneumology
      Göttingen, Lower Saxony, Germany
  • 1987–1988
    • National Institute on Aging
      • Laboratory of Cardiovascular Science (LCS)
      Baltimore, MD, United States