sGCα1 mediates the negative inotropic effects of NO in cardiac myocytes independent of changes in calcium handling
| Autor: | Fumito Ichinose, Sharon M. Cawley, Kenneth D. Bloch, Starsha A. Kolodziej, Peter Brouckaert, Emmanuel S. Buys |
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| Rok vydání: | 2011 |
| Předmět: |
Sarcomeres
Inotrope medicine.medical_specialty Nitric Oxide Synthase Type III Physiology Adrenergic beta-Antagonists Receptors Cytoplasmic and Nuclear chemistry.chemical_element Adrenergic beta-3 Receptor Agonists Calcium Nitric Oxide Nitric oxide Mice chemistry.chemical_compound Soluble Guanylyl Cyclase Physiology (medical) Internal medicine Cyclic GMP-Dependent Protein Kinases medicine Animals Myocyte Myocytes Cardiac Calcium Signaling Mice Knockout Calcium metabolism Receptor Muscarinic M2 biology Immunohistochemistry Myocardial Contraction Cell biology Nitric oxide synthase Endocrinology chemistry Ethanolamines Guanylate Cyclase Receptors Adrenergic beta-3 biology.protein Spermine Signaling and Stress Response Receptors Adrenergic beta-2 Receptors Adrenergic beta-1 Cardiology and Cardiovascular Medicine Soluble guanylyl cyclase Anti-Arrhythmia Agents |
| Zdroj: | American Journal of Physiology-Heart and Circulatory Physiology. 301:H157-H163 |
| ISSN: | 1522-1539 0363-6135 |
| DOI: | 10.1152/ajpheart.01273.2010 |
| Popis: | In the heart, nitric oxide (NO) modulates contractile function; however, the mechanisms responsible for this effect are incompletely understood. NO can elicit effects via a variety of mechanisms including S-nitrosylation and stimulation of cGMP synthesis by soluble guanylate cyclase (sGC). sGC is a heterodimer comprised of a β1- and an α1- or α2-subunit. sGCα1β1 is the predominant isoform in the heart. To characterize the role of sGC in the regulation of cardiac contractile function by NO, we compared left ventricular cardiac myocytes (CM) isolated from adult mice deficient in the sGC α1-subunit (sGCα1−/−) and from wild-type (WT) mice. Sarcomere shortening under basal conditions was less in sGCα1−/− CM than in WT CM. To activate endogenous NO synthesis from NO synthase 3, CM were incubated with the β3-adrenergic receptor (β3-AR) agonist BRL 37344. BRL 37344 decreased cardiac contractility in WT CM but not in sGCα1−/− myocytes. Administration of spermine NONOate, an NO donor compound, did not affect sarcomeric shortening in CM of either genotype; however, in the presence of isoproterenol, addition of spermine NONOate reduced sarcomere shortening in WT but not in sGCα1−/− CM. Neither BRL 37344 nor spermine NONOate altered calcium handling in CM of either genotype. These findings suggest that sGCα1 exerts a positive inotropic effect under basal conditions, as well as mediates the negative inotropic effect of β3-AR signaling. Additionally, our work demonstrates that sGCα1β1 is required for NO to depress β1/β2-AR-stimulated cardiac contractility and that this modulation is independent of changes in calcium handling. |
| Databáze: | OpenAIRE |
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