Endogenous nitric oxide mechanisms mediate the stretch dependence of Ca2+ release in cardiomyocytes

M G Petroff; S H Kim; S Pepe; C Dessy; E Marbán; J L Balligand; S J Sollott

doi:10.1038/ncb1001-867

Endogenous nitric oxide mechanisms mediate the stretch dependence of Ca2+ release in cardiomyocytes

Nat Cell Biol. 2001 Oct;3(10):867-73. doi: 10.1038/ncb1001-867.

Authors

M G Petroff¹, S H Kim, S Pepe, C Dessy, E Marbán, J L Balligand, S J Sollott

Affiliation

¹ Laboratory of Cardiovascular Science, Gerontology Research Center, Intramural Research Program, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, Maryland 21224-6825, USA.

PMID: 11584267
DOI: 10.1038/ncb1001-867

Abstract

Stretching of cardiac muscle modulates contraction through the enhancement of the Ca2+ transient, but how this occurs is still not known. We found that stretching of myocytes modulates the elementary Ca2+ release process from ryanodine-receptor Ca2+-release channels (RyRCs), Ca2+ sparks and the electrically stimulated Ca2+ transient. Stretching induces PtdIns-3-OH kinase (PI(3)K)-dependent phosphorylation of both Akt and the endothelial isoform of nitric oxide synthase (NOS), nitric oxide (NO) production, and a proportionate increase in Ca2+-spark frequency that is abolished by inhibiting NOS and PI(3)K. Exogenously generated NO reversibly increases Ca2+-spark frequency without cell stretching. We propose that myocyte NO produced by activation of the PI(3)K-Akt-endothelial NOS axis acts as a second messenger of stretch by enhancing RyRC activity, contributing to myocardial contractile activation.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Animals
Calcium / metabolism*
Calcium Signaling / physiology*
Electric Stimulation
Enzyme Inhibitors / pharmacology
Fluorescent Dyes / metabolism
Male
Myocardial Contraction / drug effects
Myocardial Contraction / physiology*
Myocardium / cytology
Myocardium / metabolism*
NG-Nitroarginine Methyl Ester / pharmacology
Nitric Oxide / metabolism*
Nitric Oxide Synthase / genetics
Nitric Oxide Synthase / metabolism
Nitric Oxide Synthase Type III
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors
Phosphorylation
Protein Serine-Threonine Kinases*
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-akt
Rats
Rats, Sprague-Dawley
S-Nitroso-N-Acetylpenicillamine / pharmacology
Spectrometry, Fluorescence

Substances

Enzyme Inhibitors
Fluorescent Dyes
Phosphoinositide-3 Kinase Inhibitors
Proto-Oncogene Proteins
Nitric Oxide
S-Nitroso-N-Acetylpenicillamine
Nitric Oxide Synthase
Nitric Oxide Synthase Type III
Nos3 protein, rat
Akt1 protein, rat
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt
Calcium
NG-Nitroarginine Methyl Ester