© 1999 American Heart Association, Inc.
Original Contributions |
Activation of Distinct cAMP-Dependent and cGMP-Dependent Pathways by Nitric Oxide in Cardiac Myocytes
From the Laboratory of Cardiovascular Science (M.G.V.-P., A.Y., E.G.L., S.J.S.) and Laboratory of Clinical Investigation (J.E.), Intramural Research Program, National Institute on Aging, Gerontology Research Center, Baltimore, Md.
Correspondence to Steven J. Sollott, MD, Laboratory of Cardiovascular Science, Gerontology Research Center, Box 13, Intramural Research Program, National Institute on Aging, 5600 Nathan Shock Dr, Baltimore, MD 21224-6825. E-mail sollotts{at}grc.nia.nih.gov
Abstract—Nitric oxide (NO) donors were recently shown to produce biphasic contractile effects in cardiac tissue, with augmentation at low NO levels and depression at high NO levels. We examined the subcellular mechanisms involved in the opposing effects of NO on cardiac contraction and investigated whether NO modulates contraction exclusively via guanylyl cyclase (GC) activation or whether some contribution occurs via cGMP/PKG-independent mechanisms, in indo 1–loaded adult cardiac myocytes. Whereas a high concentration of the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 100 µmol/L) significantly attenuated contraction amplitude by 24.4±4.5% (without changing the Ca2+ transient or total cAMP), a low concentration of SNAP (1 µmol/L) significantly increased contraction amplitude (38±10%), Ca2+ transient (26±10%), and cAMP levels (from 6.2 to 8.5 pmol/mg of protein). The negative contractile response of 100 µmol/L SNAP was completely abolished in the presence of the specific blocker of PKG KT 5823 (1 µmol/L); the positive contractile response of 1 µmol/L SNAP persisted, despite the presence of the selective inhibitor of GC 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 µmol/L) alone, but was completely abolished in the presence of ODQ plus the specific inhibitory cAMP analog Rp-8-CPT-cAMPS (100 µmol/L), as well as by the NO scavenger oxyhemoglobin. Parallel experiments in cell suspensions showed significant increases in adenylyl cyclase (AC) activity at low concentrations (0.1 to 1 µmol/L) of SNAP (AC, 18% to 20% above basal activity). We conclude that NO can regulate both AC and GC in cardiac myocytes. High levels of NO induce large increases in cGMP and a negative inotropic effect mediated by a PKG-dependent reduction in myofilament responsiveness to Ca2+. Low levels of NO increase cAMP, at least in part, by a novel cGMP-independent activation of AC and induce a positive contractile response.
Key Words: nitric oxide signaling • cGMP • cAMP • contractility • cardiac myocyte
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G. U. Ahmmed, Y. Xu, P. Hong Dong, Z. Zhang, J. Eiserich, and N. Chiamvimonvat Nitric Oxide Modulates Cardiac Na+ Channel via Protein Kinase A and Protein Kinase G Circ. Res., November 23, 2001; 89(11): 1005 - 1013. [Abstract] [Full Text] [PDF]
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F. Brunner, P. Andrew, G. Wolkart, R. Zechner, and B. Mayer Myocardial Contractile Function and Heart Rate in Mice With Myocyte-Specific Overexpression of Endothelial Nitric Oxide Synthase Circulation, December 18, 2001; 104(25): 3097 - 3102. [Abstract] [Full Text] [PDF]
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D. K. Kalra, X. Zhu, M. K. Ramchandani, G. Lawrie, M. J. Reardon, D. Lee-Jackson, W. L. Winters, N. Sivasubramanian, D. L. Mann, and W. A. Zoghbi Increased Myocardial Gene Expression of Tumor Necrosis Factor-{alpha} and Nitric Oxide Synthase-2: A Potential Mechanism for Depressed Myocardial Function in Hibernating Myocardium in Humans Circulation, April 2, 2002; 105(13): 1537 - 1540. [Abstract] [Full Text] [PDF]
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