The real estate of NOS signaling: location, location, location.

Abstract

HomeCirculation ResearchVol. 92, No. 12The Real Estate of NOS Signaling Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBThe Real Estate of NOS SignalingLocation, Location, Location Mark T. Ziolo and Donald M. Bers Mark T. ZioloMark T. Ziolo From the Department of Physiology, Loyola University Chicago, Maywood, Ill. Search for more papers by this author and Donald M. BersDonald M. Bers From the Department of Physiology, Loyola University Chicago, Maywood, Ill. Search for more papers by this author Originally published27 Jun 2003https://doi.org/10.1161/01.RES.0000080783.34092.AFCirculation Research. 2003;92:1279–1281While sympathetic stimulation of the heart produces chronotropic, inotropic, and lusitropic effects, increased frequency alone causes a positive force-frequency relationship (FFR) and frequency-dependent acceleration of relaxation (FDAR).1 That is, contraction amplitude and relaxation rate are increased with increasing frequency in most species (including humans). The key mechanism involved in the positive FFR is increased sarcoplasmic reticulum (SR) Ca2+ load, due to increased Ca2+ influx and decreased Ca2+ efflux.1,2 Ca2+ influx increases due to more L-type Ca2+ current (ICa) per unit time, while Ca2+ efflux via Na+-Ca2+ exchange (NCX) decreases because the diastolic time is reduced and [Na+]i increases. Enhanced SR Ca2+-pump function causes FDAR and also augments SR Ca2+ loading. Various signaling pathways are involved (eg, CaMKII).3In human heart failure, the FFR reverses (ie, from positive to negative) due to an inability of the SR to increase Ca2+ content.4 This negative FFR is a main contributor to the loss of contractile reserve in the failing heart. Of many pathways that can modify FFR, nitric oxide (NO) signaling is the topic addressed by Khan et al in this issue of Circulation Research.5Nitric Oxide and Cardiac FunctionNO synthase (NOS) produces NO from l-arginine, and cardiac myocytes express all three NOS isoforms.6,7 NOS1 (nNOS) and NOS3 (eNOS) are constitutively expressed and produce low amounts of NO (regulated by [Ca2+-calmodulin]i levels). NOS2 (iNOS) is expressed during inflammatory responses (eg, cytokines, sepsis, heart failure) and continuously produces large amounts of NO (compared with NOS1 and NOS3),7 independent of Ca2+.NO can increase or decrease contractility.8 Many factors modulate NO functional effects: different NO concentrations lead to cGMP-dependent or -independent signaling,9,10 adrenergic state,11 NO species,12 NO effects on targets involved in excitation-contraction coupling (EC coupling) and NOS isoforms.6 These pathways work in concert to determine the net effect of NO. Different NO species (eg, NO· or NO+) activate different pathways. For example, NO· activates cGMP-dependent protein kinase (PKG) and NO+ can have direct effects via nitrosylation, and these can differentially modulate targets (eg, PKG phosphorylation decreases ICa and channel nitrosylation increases ICa).13Recently, Hare’s group provided provocative evidence that the effects of NO (positive or negative) are due to different isoforms of NOS (1 and 3) and their cellular localization.6 NOS1 is localized to the SR and coimmunoprecipitates (Co-IPs) with ryanodine receptors (RyRs), and NOS3 is localized to caveolae and Co-IPs with caveolin-3. Thus, we should envision NO signaling (Figure) as locally controlled (similar to β-adrenergic [β-AR] signaling).14Download figureDownload PowerPointNOS signaling in cardiac myocytes. ATP indicates SR Ca2+-ATPase; NOx, different congeners of NO· (see text for other abbreviations).For NOS2, the situation may differ. Since NOS2 is not localized (cytosolic) and produces large amounts of NO, NOS2 signaling is probably less “compartmentalized” and can affect various EC coupling related proteins/processes (eg, ICa, RyRs, and energetics).7,15,16 These effects can contribute to cardiac dysfunction in various diseases where myocyte NOS2 is expressed (eg, rejection of transplanted hearts).17NOS3 seems to depress contractility.6,18 Since NOS3 is localized to caveolae and can inhibit ICa,19,20 it was hypothesized that NO produced by NOS3 selectively regulates ICa, but not RyRs.6 However, since most of the Ca2+ channels thought to be important in EC coupling are at dyadic sarcolemmal-SR junctions, the impact of putative caveolar NOS3-ICa signaling on EC coupling is not completely clear.NOS1 also regulates cardiac myocyte function.5,6,21,22 In NOS1 knockout mice, basal contractility and β-AR responsiveness were depressed.6 Since NOS1 is localized to the SR (and Co-IPs with RyRs), Hare’s group hypothesized that NO produced via NOS1 stimulates RyRs and contractility without altering ICa. Indeed, exogenous NO can directly regulate RyR activity (via nitrosylation) increasing channel open probability,23 although NOS1 was not directly implicated. A complicating aspect here is that RyRs are very closely colocalized with L-type Ca2+ channels, probably 0 to 20 nm apart.1 Given the rapid diffusion of NO, it is difficult to envision how NO can affect RyRs without also altering ICa. Also, using the same NOS1 knockout mice, Casadei’s group21,22 found opposite results (increased basal contractility and β-AR responsiveness) and a flat FFR and increased SR Ca2+ load. Discrepancies between these groups may be technical, such as temperature (37°C versus 22°C), frequency, degree of β-AR stimulation (high versus low),11 or age (or hypertrophic stage) at which animals were studied. Thus, while basal NOS1 activity may be positively inotropic (opposite to NOS3), results are mixed. Even Khan et al5 found little basal change in NOS1 knockout, although negative effects were apparent at higher frequencies.NOS1 and FFRKhan et al5 hypothesized that NOS1 (but not NOS3) would modulate FFR due to its localization to the SR (and the crucial role of SR Ca2+ load in FFR). Indeed, knockout of NOS1 (but not NOS3) did depress FFR and FDAR, and SR Ca2+ load failed to rise at high frequency. The failure of SR Ca2+ load to rise could be due to decreased SR Ca2+ uptake or increased release (or both). The authors favored increased release, because NO can directly activate RyRs23 and NOS1 Co-IPs with RyRs.6 They suggest that oxygen radicals could irreversibly activate RyRs, increasing leak in the NOS1 knockout. However, it is unclear how NOS1 would prevent this. Moreover, the main difference occurs at higher frequency, but at reduced diastolic interval (and comparable SR Ca2+ load), such a diastolic leak should be less influential.Indeed, NO-induced changes in SR Ca2+ load may be equally or more influential than NO effects on RyRs in intact cardiac myocytes,11 as with β-AR stimulation.24 Furthermore, while diastolic RyR leak does increase with frequency, this was secondary to increased SR Ca2+ load25 (which was not observed in NOS1 knockouts).5 We suggest that reduced SR Ca2+ uptake may also be involved in the NOS1 knockout phenotype. This would be consistent with the reported unaltered [Ca2+]i decline despite increase in SERCA2 and decrease in phospholamban (PLB) expression5 (changes that may be compensatory) in the NOS1 knockout mice. That is, the SERCA2a/PLB changes should have accelerated [Ca2+]i decline and increased SR Ca2+ load, but neither was observed. Given that NO can also affect PLB and SERCA2a, the influence of NOS1 on PLB and SERCA2a should be entertained (although NO effects in isolation seem to inhibit function).26,27 Nevertheless, depressed Ca2+-pump function in the NOS1 knockout is a possibility. This could also explain the lack of FDAR in NOS1 knockout mice.In addition, “compartmentalization” of NO may be more complex than just localization of NOS isoforms and may involve colocalization of other NO/cGMP signaling molecules (superoxide dismutase, cGMP-specific phosphodiesterase [PDE-V], guanylate cyclase)28,29 along with the SR transporters and ICa.The study by Khan et al5 does implicate NOS1 in modulating cardiac (and SR) function and contributes to our understanding of local NO signaling.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Donald M. Bers, Department of Physiology, Loyola University Chicago, 2160 S First Ave, Maywood, IL 60153. E-mail [email protected] References 1 Bers DM. Excitation-Contraction Coupling and Cardiac Contractile Force. 2nd ed. Dordrecht, Netherlands: Kluwer Academic; 2001.Google Scholar2 Antoons G, Mubagwa K, Nevelsteen I, Sipido KR. Mechanisms underlying the frequency dependence of contraction and [Ca2+] transients in mouse ventricular myocytes. J Physiol. 2002; 543: 889–898.CrossrefMedlineGoogle Scholar3 DeSantiago J, Maier LS, Bers DM. Frequency-dependent acceleration of relaxation in the heart dependents on CaMKII, but not phospholamban. J Mol Cell Cardiol. 2002; 34: 975–984.CrossrefMedlineGoogle Scholar4 Pieske B, Maier LS, Bers DM, Hasenfuss G. Ca2+ handling and sarcoplasmic reticulum Ca2+ content in isolated failing and nonfailing human myocardium. Circ Res. 1999; 85: 38–46.CrossrefMedlineGoogle Scholar5 Khan SA, Skaf MW, Harrison RW, Lee K, Minhas KM, Kumar A, Fradley M, Shoukas AA, Berkowitz DE, Hare JM. Nitric oxide regulation of myocardial contractility and calcium cycling: independent impact of neuronal and endothelial nitric oxide synthases. Circ Res. 2003; 92: 1322–1329.LinkGoogle Scholar6 Barouch LA, Harrison RW, Skaf MW, Rosas GO, Cappola TP, Kobeissi ZA, Hobai IA, Lemmon CA, Burnett AL, O’Rourke B, Rodriguez ER, Huang PL, Lima JAC, Berkowitz DE, Hare JM. Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms. Nature. 2002; 416: 337–340.CrossrefMedlineGoogle Scholar7 Ziolo MT, Harshbarger CH, Roycroft KE, Wahler GM. Myocytes isolated from rejecting transplanted hearts exhibit a nitric oxide mediated reduction in the calcium current. J Mol Cell Cardiol. 2001; 33: 1691–1699.CrossrefMedlineGoogle Scholar8 Shah AM, MacCarthey PA. Paracrine and autocrine effects of nitric oxide on myocardial function. Pharmacol Ther. 2000; 86: 49–86.CrossrefMedlineGoogle Scholar9 Kojda G, Kottenberg K, Nix P, Schlüter D, Piper HM, Noack E. Low increase in cGMP induced by organic nitrates and nitrovasodilators improves contractile response of rat ventricular myocytes. Circ Res. 1996; 78: 91–101.CrossrefMedlineGoogle Scholar10 Villa-Petroff MG, Younes A, Egan J, Lakatta EG, Sollot SJ. Activation of distinct cAMP-dependent and cGMP-dependent pathways by nitric oxide in cardiac myocytes. Circ Res. 1999; 84: 1020–1031.CrossrefMedlineGoogle Scholar11 Ziolo MT, Katoh H, Bers DM. Positive and negative effects of nitric oxide on Ca2+ sparks: influence of β-adrenergic stimulation. Am J Physiol Heart Circ Physiol. 2001; 281: H2295–H2303.CrossrefMedlineGoogle Scholar12 Chesnais JM, Fischmeister R, Mery PF. Positive and negative inotropic effects of NO donors in atrial and ventricular fibres of the frog heart. J Physiol. 1999; 518: 449–461.CrossrefMedlineGoogle Scholar13 Campbell DL, Stamler JS, Strauss HC. Redox modulation of L-type calcium channels in ferret ventricular myocytes. J Gen Physiol. 1996; 108: 277–293.CrossrefMedlineGoogle Scholar14 Bers DM, Ziolo MT. When is cAMP not cAMP? effects of compartmentalization. Circ Res. 2001; 89: 373–375.LinkGoogle Scholar15 Ziolo MT, Katoh H, Bers DM. Expression of inducible NOS depresses calcium release from the sarcoplasmic reticulum in intact ventricular myocytes. Circulation. 2001; 104: 2961–2966.CrossrefMedlineGoogle Scholar16 Keira N, Tatsumi T, Matoba S, Shiraishi J, Yamanaka S, Akashi K, Kobara M, Asayama J, Fushiki S, Fliss H, Nakagawa M. Lethal effect of cytokine-induced nitric oxide and peroxynitrite on cultured rat cardiac myocytes. J Mol Cell Cardiol. 2002; 34: 583–596.CrossrefMedlineGoogle Scholar17 Ziolo MT, Dollinger SJ, Wahler GM. Myocytes isolated from rejecting transplanted hearts exhibit reduced basal shortening which is reversible by aminoguanidine. J Mol Cell Cardiol. 1998; 30: 1009–1017.CrossrefMedlineGoogle Scholar18 Brunner F, Andrew P, Wölkart G, Zechner R, Mayer B. Myocardial contractile function and heart rate in mice with myocyte-specific overexpression of endothelial nitric oxide synthase. Circulation. 2001; 104: 3097–3102.CrossrefMedlineGoogle Scholar19 Gallo MP, Ghigo D, Bosia A, Alloatti G, Costamagna C, Penna C, Levi RC. Modulation of guinea-pig cardiac L-type calcium current by nitric oxide synthase inhibitors. J Physiol. 1998; 506: 639–651.CrossrefMedlineGoogle Scholar20 Matsumoto S, Takahashi T, Ikeda M, Nishikawa T, Yoshida S, Kawase T. Effects of NG-monomethyl-l-arginine on Ca2+ current and nitric-oxide synthase in rat ventricular myocytes. J Pharmacol Exp Ther. 2000; 294: 216–233.MedlineGoogle Scholar21 Ashley EA, Sears CE, Bryant SM, Watkins HC, Casadei B. Cardiac nitric oxide synthase 1 regulates basal and β-adrenergic contractility in murine ventricular myocytes. Circulation. 2002; 105: 3011–3016.LinkGoogle Scholar22 Sears CE, Bryant SM, Ashley EA, Lygate CA, Rakovic S, Wallis HL, Neubauer S, Terrar DA, Casadei B. Cardiac neuronal nitric oxide synthase isoform regulates myocardiac contraction and calcium handling. Circ Res. 2003; 92: e52–e59.LinkGoogle Scholar23 Xu L, Eu JP, Meissner G, Stamler JS. Activation of the cardiac calcium release channel (ryanodine receptor) by poly-S-nitrosylation. Science. 1998; 279: 234–237.CrossrefMedlineGoogle Scholar24 Li Y, Kranias EG, Mignery GA, Bers DM. Protein kinase A phosphorylation of the ryanodine receptor does not affect calcium sparks in mouse ventricular myocytes. Circ Res. 2002; 90: 309–316.CrossrefMedlineGoogle Scholar25 Shannon TR, Ginsburg KS, Bers DM. Quantitative assessment of the SR Ca2+ leak-load relationship. Circ Res. 2002; 91: 594–600.LinkGoogle Scholar26 Stojanovic MO, Ziolo MT, Wahler GM, Wolska BM. Anti-adrenergic effects of nitric oxide donor SIN-1 in rat cardiac myocytes. Am J Physiol Cell Physiol. 2001; 281: C342–C349.CrossrefMedlineGoogle Scholar27 Viner RI, Ferrington DA, Williams TD, Bigelow DJ, Schoneich C. Protein modification during biological aging: selective tyrosine nitration of the SERCA2a isoform of the sarcoplasmic reticulum Ca2+-ATPase in skeletal muscle. Biochem J. 1999; 340: 657–669.CrossrefMedlineGoogle Scholar28 Ziolo MT, Lewandowski SJ, Smith JM, Romano FD, Wahler GM. Inhibition of cyclic GMP hydrolysis with zaprinast reduces basal and cAMP-elevated L-type calcium current in guinea pig ventricular myocytes. Br J Pharmacol. 2003; 138: 986–994.CrossrefMedlineGoogle Scholar29 Brahmajothi MV, Campbell DL. Heterogenous basal expression of nitric oxide synthase and superoxide dismutase isoforms in mammalian heart: implications for mechanisms governing indirect and direct nitric oxide-related effects. Circ Res. 1999; 85: 575–587.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Akolkar G, Malik A, Bagchi A, Singla D, Khaper N and Singal P (2023) Role of Nitric Oxide Synthases in Doxorubicin-Induced Cardiomyopathy Nitric Oxide: From Research to Therapeutics, 10.1007/978-3-031-24778-1_7, (127-145), . Podoksenov Y, Kamenshchikov N and Mandel I (2019) Nitric oxide application for myocardial protection in coronary artery disease, Anesteziologiya i Reanimatologiya, 10.17116/anaesthesiology201902134:2, (34), . Gabrielová E, Bartošíková L, Nečas J and Modrianský M (2019) Cardioprotective effect of 2,3-dehydrosilybin preconditioning in isolated rat heart, Fitoterapia, 10.1016/j.fitote.2018.10.028, 132, (12-21), Online publication date: 1-Jan-2019. Cannavo A and Koch W (2018) GRK2 as negative modulator of NO bioavailability: Implications for cardiovascular disease, Cellular Signalling, 10.1016/j.cellsig.2017.01.014, 41, (33-40), Online publication date: 1-Jan-2018. Akolkar G, Bagchi A, Ayyappan P, Jassal D and Singal P (2017) Doxorubicin-induced nitrosative stress is mitigated by vitamin C via the modulation of nitric oxide synthases, American Journal of Physiology-Cell Physiology, 10.1152/ajpcell.00356.2016, 312:4, (C418-C427), Online publication date: 1-Apr-2017. Neri M, Riezzo I, Pascale N, Pomara C and Turillazzi E (2017) Ischemia/Reperfusion Injury following Acute Myocardial Infarction: A Critical Issue for Clinicians and Forensic Pathologists, Mediators of Inflammation, 10.1155/2017/7018393, 2017, (1-14), . Seehase M, Houthuizen P, Collins J, Zimmermann L and Kramer B (2016) Propofol administration to the fetal–maternal unit reduces cardiac oxidative stress in preterm lambs subjected to prenatal asphyxia and cardiac arrest, Pediatric Research, 10.1038/pr.2016.10, 79:5, (748-753), Online publication date: 1-May-2016. Arcaro A, Pirozzi F, Angelini A, Chimenti C, Crotti L, Giordano C, Mancardi D, Torella D and Tocchetti C (2016) Novel Perspectives in Redox Biology and Pathophysiology of Failing Myocytes: Modulation of the Intramyocardial Redox Milieu for Therapeutic Interventions—A Review Article from the Working Group of Cardiac Cell Biology, Italian Society of Cardiology, Oxidative Medicine and Cellular Longevity, 10.1155/2016/6353469, 2016, (1-13), . Roof S, Ho H, Little S, Ostler J, Brundage E, Periasamy M, Villamena F, Györke S, Biesiadecki B, Heymes C, Houser S, Davis J and Ziolo M (2015) Obligatory role of neuronal nitric oxide synthase in the heart's antioxidant adaptation with exercise, Journal of Molecular and Cellular Cardiology, 10.1016/j.yjmcc.2015.01.003, 81, (54-61), Online publication date: 1-Apr-2015. Ziolo M and Houser S (2014) Abnormal Ca 2+ Cycling in Failing Ventricular Myocytes: Role of NOS1-Mediated Nitroso-Redox Balance , Antioxidants & Redox Signaling, 10.1089/ars.2014.5873, 21:14, (2044-2059), Online publication date: 10-Nov-2014. Lu Y, Akinwumi B, Shao Z and Anderson H (2014) Ligand Activation of Cannabinoid Receptors Attenuates Hypertrophy of Neonatal Rat Cardiomyocytes, Journal of Cardiovascular Pharmacology, 10.1097/FJC.0000000000000134, 64:5, (420-430), Online publication date: 1-Nov-2014. Soetkamp D, Nguyen T, Menazza S, Hirschhäuser C, Hendgen-Cotta U, Rassaf T, Schlüter K, Boengler K, Murphy E and Schulz R (2014) S-nitrosation of mitochondrial connexin 43 regulates mitochondrial function, Basic Research in Cardiology, 10.1007/s00395-014-0433-x, 109:5, Online publication date: 1-Sep-2014. Tang L, Wang H and Ziolo M (2014) Targeting NOS as a therapeutic approach for heart failure, Pharmacology & Therapeutics, 10.1016/j.pharmthera.2013.12.013, 142:3, (306-315), Online publication date: 1-Jun-2014. Zaobornyj T and Valdez L (2014) Heart Mitochondrial Nitric Oxide Synthase Nitric Oxide, 10.1016/B978-0-12-800254-4.00003-9, (29-58), . Sambol J, Deitch E, Takimoto K, Dosi G and Yatani A (2013) Cellular basis of burn-induced cardiac dysfunction and prevention by mesenteric lymph duct ligation, Journal of Surgical Research, 10.1016/j.jss.2013.01.065, 183:2, (678-685), Online publication date: 1-Aug-2013. Roof S, Tang L, Ostler J, Periasamy M, Györke S, Billman G and Ziolo M (2013) Neuronal nitric oxide synthase is indispensable for the cardiac adaptive effects of exercise, Basic Research in Cardiology, 10.1007/s00395-013-0332-6, 108:2, Online publication date: 1-Mar-2013. Zaobornyj T and Ghafourifar P (2012) Strategic localization of heart mitochondrial NOS: a review of the evidence, American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.00674.2011, 303:11, (H1283-H1293), Online publication date: 1-Dec-2012. Wang H, Bonilla I, Huang X, He Q, Kohr M, Carnes C and Ziolo M (2012) Prolonged Action Potential and After depolarizations Are Not due to Changes in Potassium Currents in NOS3 Knockout Ventricular Myocytes, Journal of Signal Transduction, 10.1155/2012/645721, 2012, (1-8), Online publication date: 28-Aug-2012. Villamena F, Das A and Nash K (2012) Potential implication of the chemical properties and bioactivity of nitrone spin traps for therapeutics, Future Medicinal Chemistry, 10.4155/fmc.12.74, 4:9, (1171-1207), Online publication date: 1-Jun-2012. Fernandes Jr. C and de Assuncao M (2012) Myocardial Dysfunction in Sepsis: A Large, Unsolved Puzzle, Critical Care Research and Practice, 10.1155/2012/896430, 2012, (1-9), . Vandsburger M, French B, Kramer C, Zhong X and Epstein F (2012) Displacement-encoded and manganese-enhanced cardiac MRI reveal that nNOS, not eNOS, plays a dominant role in modulating contraction and calcium influx in the mammalian heart, American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.00705.2011, 302:2, (H412-H419), Online publication date: 1-Jan-2012. Opie L and Hasenfuss G (2012) Mechanisms of Cardiac Contraction and Relaxation Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 10.1016/B978-1-4377-0398-6.00024-X, (459-486), . Weerateerangkul P, Chattipakorn S and Chattipakorn N (2011) Roles of the nitric oxide signaling pathway in cardiac ischemic preconditioning against myocardial ischemia-reperfusion injury, Medical Science Monitor, 10.12659/MSM.881385, 17:2, (RA44-RA52), . Filice E, Angelone T, De Francesco E, Pellegrino D, Maggiolini M and Cerra M Crucial Role of Phospholamban Phosphorylation and S-Nitrosylation in the Negative Lusitropism Induced by 17β-estradiol in the Male Rat Heart, Cellular Physiology and Biochemistry, 10.1159/000331712, 28:1, (41-52) Le Douairon Lahaye S, Rebillard A, Zguira M, Malardé L, Saïag B, Gratas-Delamarche A, Carré F and Bekono F (2010) Effects of exercise training combined with insulin treatment on cardiac NOS1 signaling pathways in type 1 diabetic rats, Molecular and Cellular Biochemistry, 10.1007/s11010-010-0611-6, 347:1-2, (53-62), Online publication date: 1-Jan-2011. Balligand J, Feron O and Dessy C (2009) eNOS Activation by Physical Forces: From Short-Term Regulation of Contraction to Chronic Remodeling of Cardiovascular Tissues, Physiological Reviews, 10.1152/physrev.00042.2007, 89:2, (481-534), Online publication date: 1-Apr-2009. Strijdom H, Friedrich S, Hattingh S, Chamane N and Lochner A (2008) Hypoxia-induced regulation of nitric oxide synthase in cardiac endothelial cells and myocytes and the role of the PI3-K/PKB pathway, Molecular and Cellular Biochemistry, 10.1007/s11010-008-9906-2, 321:1-2, (23-35), Online publication date: 1-Jan-2009. Ziolo M, Kohr M and Wang H (2008) Nitric oxide signaling and the regulation of myocardial function, Journal of Molecular and Cellular Cardiology, 10.1016/j.yjmcc.2008.07.015, 45:5, (625-632), Online publication date: 1-Nov-2008. Kohr M, Wang H, Wheeler D, Velayutham M, Zweier J and Ziolo M (2008) Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state, Free Radical Biology and Medicine, 10.1016/j.freeradbiomed.2008.03.019, 45:1, (73-80), Online publication date: 1-Jul-2008. Wang H, Kohr M, Traynham C, Wheeler D, Janssen P and Ziolo M (2008) Neuronal nitric oxide synthase signaling within cardiac myocytes targets phospholamban, American Journal of Physiology-Cell Physiology, 10.1152/ajpcell.00367.2007, 294:6, (C1566-C1575), Online publication date: 1-Jun-2008. Feldman D, Elton T, Sun B, Martin M and Ziolo M (2008) Mechanisms of Disease: detrimental adrenergic signaling in acute decompensated heart failure, Nature Clinical Practice Cardiovascular Medicine, 10.1038/ncpcardio1127, 5:4, (208-218), Online publication date: 1-Apr-2008. Wang H, Kohr M, Wheeler D and Ziolo M (2008) Endothelial nitric oxide synthase decreases β-adrenergic responsiveness via inhibition of the L-type Ca 2+ current , American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.01249.2007, 294:3, (H1473-H1480), Online publication date: 1-Mar-2008. Radin M, Holycross B, Hoepf T and McCune S (2009) Salt-Induced Cardiac Hypertrophy Is Independent of Blood Pressure and Endothelin in Obese, Heart Failure-Prone SHHF Rats, Clinical and Experimental Hypertension, 10.1080/10641960802251917, 30:7, (541-552), Online publication date: 1-Jan-2008. Vandsburger M, French B, Helm P, Roy R, Kramer C, Young A and Epstein F (2007) Multi-parameter in vivo cardiac magnetic resonance imaging demonstrates normal perfusion reserve despite severely attenuated β-adrenergic functional response in neuronal nitric oxide synthase knockout mice, European Heart Journal, 10.1093/eurheartj/ehm241, 28:22, (2792-2798), Online publication date: 1-Nov-2007., Online publication date: 1-Nov-2007. Harpster M, Bandyopadhyay S, Thomas D, Ivanov P, Keele J, Pineguina N, Gao B, Amarendran V, Gomelsky M, McCormick R and Stayton M (2006) Earliest changes in the left ventricular transcriptome post-myocardial infarction, Mammalian Genome, 10.1007/s00335-005-0120-1, 17:7, (701-715), Online publication date: 1-Jul-2006. Sun J, Picht E, Ginsburg K, Bers D, Steenbergen C and Murphy E (2006) Hypercontractile Female Hearts Exhibit Increased S-Nitrosylation of the L-Type Ca2+ Channel α1 Subunit and Reduced Ischemia/Reperfusion Injury, Circulation Research, 98:3, (403-411), Online publication date: 17-Feb-2006. Schulz R, Rassaf T, Massion P, Kelm M and Balligand J (2005) Recent advances in the understanding of the role of nitric oxide in cardiovascular homeostasis, Pharmacology & Therapeutics, 10.1016/j.pharmthera.2005.04.005, 108:3, (225-256), Online publication date: 1-Dec-2005. Massion P, Pelat M, Belge C and Balligand J (2005) Regulation of the mammalian heart function by nitric oxide, Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 10.1016/j.cbpb.2005.05.048, 142:2, (144-150), Online publication date: 1-Oct-2005. Khan S, Lee K, Minhas K, Gonzalez D, Raju S, Tejani A, Li D, Berkowitz D and Hare J (2004) Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation-contraction coupling, Proceedings of the National Academy of Sciences, 10.1073/pnas.0404136101, 101:45, (15944-15948), Online publication date: 9-Nov-2004. Kempf T and Wollert K (2004) Nitric oxide and the enigma of cardiac hypertrophy, BioEssays, 10.1002/bies.20049, 26:6, (608-615), Online publication date: 1-Jun-2004. Ziolo M, Maier L, Piacentino V, Bossuyt J, Houser S and Bers D (2004) Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca2+ Transients, Circulation, 109:15, (1886-1891), Online publication date: 20-Apr-2004. June 27, 2003Vol 92, Issue 12 Advertisement Article InformationMetrics https://doi.org/10.1161/01.RES.0000080783.34092.AFPMID: 12829613 Originally publishedJune 27, 2003 KeywordsL-type Ca2+ currentcardiac myocytecompartmentalizationryanodine receptornitric oxide synthasePDF download Advertisement