Activation of Distinct cAMP-Dependent and cGMP-Dependent Pathways by Nitric Oxide in Cardiac Myocytes

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 N...

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Published in:Circulation research 1999-05, Vol.84 (9), p.1020-1031
Main Authors: Vila-Petroff, Martin G, Younes, Antoine, Egan, Josephine, Lakatta, Edward G, Sollott, Steven J
Format: Article
Language:English
Subjects:
Actin Cytoskeleton - drug effects
Actin Cytoskeleton - physiology
Adenylyl Cyclases - metabolism
Animals
Biological and medical sciences
Calcium - metabolism
Calcium - physiology
Cyclic AMP - metabolism
Cyclic AMP - physiology
Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors
Cyclic GMP - metabolism
Cyclic GMP - physiology
Enzyme Inhibitors - pharmacology
Fundamental and applied biological sciences. Psychology
Guanylate Cyclase - antagonists & inhibitors
Heart
Intracellular Membranes - metabolism
Myocardial Contraction - drug effects
Myocardium - cytology
Myocardium - metabolism
Nitric Oxide - physiology
Osmolar Concentration
Penicillamine - analogs & derivatives
Penicillamine - pharmacology
Rats
Rats, Sprague-Dawley
S-Nitroso-N-Acetylpenicillamine
Vertebrates: cardiovascular system
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Summary: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 [micro sign]mol/L) significantly attenuated contraction amplitude by 24.4 +/- 4.5% (without changing the Ca transient or total cAMP), a low concentration of SNAP (1 [micro sign]mol/L) significantly increased contraction amplitude (38 +/- 10%), Ca transient (26 +/- 10%), and cAMP levels (from 6.2 to 8.5 pmol/mg of protein). The negative contractile response of 100 [micro sign]mol/L SNAP was completely abolished in the presence of the specific blocker of PKG KT 5823 (1 [micro sign]mol/L); the positive contractile response of 1 [micro sign]mol/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 [micro sign]mol/L) alone, but was completely abolished in the presence of ODQ plus the specific inhibitory cAMP analog Rp-8-CPT-cAMPS (100 [micro sign]mol/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 [micro sign]mol/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 Ca. Low levels of NO increase cAMP, at least in part, by a novel cGMP-independent activation of AC and induce a positive contractile response. (Circ Res. 1999;84:1020-1031.)
ISSN:0009-7330
1524-4571
DOI:10.1161/01.res.84.9.1020