Activation of distinct cAMP-dependent and cGMP-dependent pathways by nitric oxide in cardiac myocytes

Martin G. Vila-Petroff, Antoine Younes, Josephine Egan, Edward G. Lakatta, Steven J. Sollott

Research output: Contribution to journalArticlepeer-review

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 (1μmol/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 1μmol/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.

Original languageEnglish (US)
Pages (from-to)1020-1031
Number of pages12
JournalCirculation research
Volume84
Issue number9
DOIs
StatePublished - May 14 1999
Externally publishedYes

Keywords

  • CAMP
  • CGMP
  • Cardiac myocyte
  • Contractility
  • Nitric oxide signaling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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