Published online before print May 20, 2002, doi: 10.1161/01.CIR.0000019516.31040.2D
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2002;105:3011.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Cardiac Nitric Oxide Synthase 1 Regulates Basal and ß-Adrenergic Contractility in Murine Ventricular Myocytes
From the University Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford, UK.
Correspondence to Dr Euan Ashley or Dr Barbara Casadei, University Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK. E-mail euan.ashley{at}cardiov.ox.ac.uk or barbara.casadei@cardiov.ox.ac.uk
Background— Evidence indicates that myocardial NO production can modulate contractility, but the source of NO remains uncertain. Here, we investigated the role of a type 1 NO synthase isoform (NOS1), which has been recently localized to the cardiac sarcoplasmic reticulum, in the regulation of basal and ß-adrenergic myocardial contraction.
Methods and Results— Contraction was assessed in left ventricular myocytes isolated from mice with NOS1 gene disruption (NOS1-/- mice) and their littermate controls (NOS1+/+ mice) at 3 stimulation frequencies (1, 3, and 6 Hz) in basal conditions and during ß-adrenergic stimulation with isoproterenol (2 nmol/L). In addition, we examined the effects of acute specific inhibition of NOS1 with vinyl-L-N-5-(1-imino-3-butenyl)-L-ornithine (L-VNIO, 500 µmol/L). NOS1-/- myocytes exhibited greater contraction at all frequencies (percent cell shortening at 6 Hz, 10.7±0.92% in NOS1-/- myocytes versus 7.21±0.8% in NOS1+/+ myocytes; P<0.05) with a flat frequency-contraction relationship. Time to 50% relaxation was increased in NOS1-/- myocytes at all frequencies (at 6 Hz, 26.53±1.4 ms in NOS1-/- myocytes versus 21.27±1.3 ms in NOS1+/+ myocytes; P<0.05). L-VNIO prolonged time to 50% relaxation at all frequencies (at 6 Hz, 21.28±1.7 ms in NOS1+/+ myocytes versus 26.45±1.4 ms in NOS1+/++L-VNIO myocytes; P<0.05) but did not significantly increase basal contraction. However, both NOS1-/- myocytes and NOS1+/+ myocytes treated with L-VNIO showed a greatly enhanced contraction in response to ß-adrenergic stimulation (percent increase in contraction at 6 Hz, 25.2±10.8 in NOS1+/+ myocytes, 68.2±11.2 in NOS1-/- myocytes, and 65.1±13.2 in NOS1+/++L-VNIO myocytes; P<0.05).
Conclusions— NOS1 disruption enhances basal contraction and the inotropic response to ß-adrenergic stimulation in murine ventricular myocytes. These findings indicate that cardiac NOS1-derived NO plays a significant role in the autocrine regulation of myocardial contractility.
Key Words: nitric oxide synthase • myocytes • contractility • receptors, adrenergic, beta
This article has been cited by other articles:
 |
|
 |
|
  X. Loyer, A. M. Gomez, P. Milliez, M. Fernandez-Velasco, P. Vangheluwe, L. Vinet, D. Charue, E. Vaudin, W. Zhang, Y. Sainte-Marie, et al. Cardiomyocyte Overexpression of Neuronal Nitric Oxide Synthase Delays Transition Toward Heart Failure in Response to Pressure Overload by Preserving Calcium Cycling Circulation, June 24, 2008; 117(25): 3187 - 3198. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Wang, M. J. Kohr, C. J. Traynham, D. G. Wheeler, P. M. L. Janssen, and M. T. Ziolo Neuronal nitric oxide synthase signaling within cardiac myocytes targets phospholamban Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1566 - C1575. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. H. Zhang, M. H. Zhang, C. E. Sears, K. Emanuel, C. Redwood, A. El-Armouche, E. G. Kranias, and B. Casadei Reduced Phospholamban Phosphorylation Is Associated With Impaired Relaxation in Left Ventricular Myocytes From Neuronal NO Synthase-Deficient Mice Circ. Res., February 1, 2008; 102(2): 242 - 249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Lim, L. Venetucci, D. A. Eisner, and B. Casadei Does nitric oxide modulate cardiac ryanodine receptor function? Implications for excitation-contraction coupling Cardiovasc Res, January 15, 2008; 77(2): 256 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. W.T. Liu and P. L. Huang Cardiovascular roles of nitric oxide: A review of insights from nitric oxide synthase gene disrupted mice Cardiovasc Res, January 1, 2008; 77(1): 19 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. H. Vandsburger, B. A. French, P. A. Helm, R. J. Roy, C. M. Kramer, A. A. Young, and F. H. Epstein Multi-parameter in vivo cardiac magnetic resonance imaging demonstrates normal perfusion reserve despite severely attenuated {beta}-adrenergic functional response in neuronal nitric oxide synthase knockout mice Eur. Heart J., November 2, 2007; 28(22): 2792 - 2798. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Seddon, A. M. Shah, and B. Casadei Cardiomyocytes as effectors of nitric oxide signalling Cardiovasc Res, July 15, 2007; 75(2): 315 - 326. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.-J. L.H.J. Aarnoudse, C. Newton-Cheh, P. I.W. de Bakker, S. M.J.M. Straus, J. A. Kors, A. Hofman, A. G. Uitterlinden, J. C.M. Witteman, and B. H.C. Stricker Common NOS1AP Variants Are Associated With a Prolonged QTc Interval in the Rotterdam Study Circulation, July 3, 2007; 116(1): 10 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Burkard, A. G. Rokita, S. G. Kaufmann, M. Hallhuber, R. Wu, K. Hu, U. Hofmann, A. Bonz, S. Frantz, E. J. Cartwright, et al. Conditional Neuronal Nitric Oxide Synthase Overexpression Impairs Myocardial Contractility Circ. Res., February 16, 2007; 100(3): e32 - e44. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Oceandy, E. J. Cartwright, M. Emerson, S. Prehar, F. M. Baudoin, M. Zi, N. Alatwi, L. Venetucci, K. Schuh, J. C. Williams, et al. Neuronal Nitric Oxide Synthase Signaling in the Heart Is Regulated by the Sarcolemmal Calcium Pump 4b Circulation, January 30, 2007; 115(4): 483 - 492. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Casadei The emerging role of neuronal nitric oxide synthase in the regulation of myocardial function Exp Physiol, November 1, 2006; 91(6): 943 - 955. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Heaton, M. Lei, D. Li, S. Golding, T. A. Dawson, R. M. Mohan, and D. J. Paterson Remodeling of the Cardiac Pacemaker L-Type Calcium Current and Its {beta}-Adrenergic Responsiveness in Hypertension After Neuronal NO Synthase Gene Transfer Hypertension, September 1, 2006; 48(3): 443 - 452. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Martin, K. Emanuel, C. E. Sears, Y.-H. Zhang, and B. Casadei Are myocardial eNOS and nNOS involved in the {beta}-adrenergic and muscarinic regulation of inotropy? A systematic investigation Cardiovasc Res, April 1, 2006; 70(1): 97 - 106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Godecke On the impact of NO-globin interactions in the cardiovascular system Cardiovasc Res, February 1, 2006; 69(2): 309 - 317. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. K. Chohan, R. B. Singh, N. S. Dhalla, and T. Netticadan L-Arginine administration recovers sarcoplasmic reticulum function in ischemic reperfused hearts by preventing calpain activation Cardiovasc Res, January 1, 2006; 69(1): 152 - 163. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-L. Balligand "La Donna e Mobile...": Is Cardiac Neuronal Nitric Oxide Synthase Such a Disconcerting Enzyme? Circulation, December 13, 2005; 112(24): 3668 - 3671. [Full Text] [PDF]
|
|
|
|
|
|
D. Dawson, C. A. Lygate, M.-H. Zhang, K. Hulbert, S. Neubauer, and B. Casadei nNOS Gene Deletion Exacerbates Pathological Left Ventricular Remodeling and Functional Deterioration After Myocardial Infarction Circulation, December 13, 2005; 112(24): 3729 - 3737. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Khan, K. Lee, K. M. Minhas, D. R. Gonzalez, S. V. Y. Raju, A. D. Tejani, D. Li, D. E. Berkowitz, and J. M. Hare From the Cover: Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation-contraction coupling PNAS, November 9, 2004; 101(45): 15944 - 15948. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. B. Massion, C. Dessy, F. Desjardins, M. Pelat, X. Havaux, C. Belge, P. Moulin, Y. Guiot, O. Feron, S. Janssens, et al. Cardiomyocyte-Restricted Overexpression of Endothelial Nitric Oxide Synthase (NOS3) Attenuates {beta}-Adrenergic Stimulation and Reinforces Vagal Inhibition of Cardiac Contraction Circulation, October 26, 2004; 110(17): 2666 - 2672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Bendall, T. Damy, P. Ratajczak, X. Loyer, V. Monceau, I. Marty, P. Milliez, E. Robidel, F. Marotte, J.-L. Samuel, et al. Role of Myocardial Neuronal Nitric Oxide Synthase-Derived Nitric Oxide in {beta}-Adrenergic Hyporesponsiveness After Myocardial Infarction-Induced Heart Failure in Rat Circulation, October 19, 2004; 110(16): 2368 - 2375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Lei, S. A. Jones, J. Liu, M. K. Lancaster, S. S.-M. Fung, H. Dobrzynski, P. Camelliti, S. K. G. Maier, D. Noble, and M. R. Boyett Requirement of neuronal- and cardiac-type sodium channels for murine sinoatrial node pacemaking J. Physiol., September 15, 2004; 559(3): 835 - 848. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J. F. Danson, K. S. Mankia, S. Golding, T. Dawson, L. Everatt, S. Cai, K. M. Channon, and D. J. Paterson Impaired regulation of neuronal nitric oxide synthase and heart rate during exercise in mice lacking one nNOS allele J. Physiol., August 1, 2004; 558(3): 963 - 974. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Janssens, P. Pokreisz, L. Schoonjans, M. Pellens, P. Vermeersch, M. Tjwa, P. Jans, M. Scherrer-Crosbie, M. H. Picard, Z. Szelid, et al. Cardiomyocyte-Specific Overexpression of Nitric Oxide Synthase 3 Improves Left Ventricular Performance and Reduces Compensatory Hypertrophy After Myocardial Infarction Circ. Res., May 14, 2004; 94(9): 1256 - 1262. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Chen, J. Petranka, K. Yamamura, R. E. London, C. Steenbergen, and E. Murphy Gender differences in sarcoplasmic reticulum calcium loading after isoproterenol Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2657 - H2662. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Dobson, J. Fray, J. L. Leonard, and R. E. Pratt Molecular mechanisms of reduced {beta}-adrenergic signaling in the aged heart as revealed by genomic profiling Physiol Genomics, October 17, 2003; 15(2): 142 - 147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.B. Massion, O. Feron, C. Dessy, and J.-L. Balligand Nitric Oxide and Cardiac Function: Ten Years After, and Continuing Circ. Res., September 5, 2003; 93(5): 388 - 398. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. Ziolo and D. M. Bers The Real Estate of NOS Signaling: Location, Location, Location Circ. Res., June 27, 2003; 92(12): 1279 - 1281. [Full Text] [PDF]
|
|
|
|
|
|
S. A. Khan, M. W. Skaf, R. W. Harrison, K. Lee, K. M. Minhas, A. Kumar, M. Fradley, A. A. Shoukas, D. E. Berkowitz, and J. M. Hare Nitric Oxide Regulation of Myocardial Contractility and Calcium Cycling: Independent Impact of Neuronal and Endothelial Nitric Oxide Synthases Circ. Res., June 27, 2003; 92(12): 1322 - 1329. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Ortiz and J. L. Garvin Cardiovascular and renal control in NOS-deficient mouse models Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2003; 284(3): R628 - R638. [Abstract] [Full Text] [PDF]
|
|