Abstract
Nitric oxide (NO) donors increase heart rate (HR) through a guanylyl cyclase-dependent stimulation of the pacemaker current I(f), without affecting basal I(Ca-L). The activity of I(f)is known to be enhanced by cyclic nucleotides and by an increase in cytosolic Ca(2+). We examined the role of cGMP-dependent signaling pathways and intracellular Ca(2+)stores in mediating the positive chronotropic effect of NO donors. In isolated guinea pig atria, the increase in HR in response to 1-100 micromol/l 3-morpholino-sydnonimine (SIN-1; with superoxide dismutase, n=6) or diethylamine-NO (DEA-NO, n=8) was significantly attenuated by blockers of the cGMP-inhibited phosphodiesterase (PDE3; trequinsin, milrinone or Ro-13-6438, n=22). In addition, the rate response to DEA-NO or sodium nitroprusside (SNP) was significantly reduced following inhibition of PKA (KT5720 or H-89, n=15) but not PKG (KT5728 or Rp-8-pCPT-cGMPs, n=16). Suppression of sarcoplasmic (SR) Ca(2+)release by pretreatment of isolated atria with ryanodine or cyclopiazonic acid (2 micromol/l and 60 micromol/l, n=16) significantly reduced the chronotropic response to 1-100 micromol/l SIN-1 or DEA-NO. Moreover, in isolated guinea pig sinoatrial node cells 5 micromol/l SNP significantly increased diastolic and peak Ca(2+)fluorescence (+13+/-1% and +28+/-1%, n=6, P<0.05). Our findings are consistent with a functionally significant role of cAMP/PKA signaling (via cGMP inhibition of PDE3) and SR Ca(2+)in mediating the positive chronotropic effect of NO donors.
Copyright 2000 Academic Press.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Calcium / metabolism*
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Carbazoles*
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Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
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Cyclic GMP / analogs & derivatives*
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Cyclic GMP / metabolism*
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Cyclic GMP / pharmacology
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Cyclic GMP-Dependent Protein Kinases / antagonists & inhibitors
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Guinea Pigs
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Heart Atria / metabolism
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Heart Rate
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Hydrazines / pharmacology
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Indoles / pharmacology
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Isoquinolines / pharmacology
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Male
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Milrinone / pharmacology
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Models, Biological
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Molsidomine / analogs & derivatives
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Molsidomine / pharmacology
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Nitric Oxide Donors / metabolism*
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Nitric Oxide Donors / pharmacology
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Nitrogen Oxides
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Phosphodiesterase Inhibitors / pharmacology
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Phosphoric Diester Hydrolases / metabolism*
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Platelet Aggregation Inhibitors / pharmacology
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Pyrroles / pharmacology
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Quinazolines / pharmacology
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Ryanodine / pharmacology
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Sarcoplasmic Reticulum / metabolism*
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Signal Transduction
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Spectrometry, Fluorescence
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Sulfonamides*
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Superoxide Dismutase / pharmacology
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Tetrahydroisoquinolines*
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Thionucleotides / pharmacology
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Time Factors
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Vasodilator Agents / pharmacology
Substances
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Carbazoles
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Enzyme Inhibitors
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Hydrazines
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Indoles
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Isoquinolines
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Nitric Oxide Donors
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Nitrogen Oxides
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Phosphodiesterase Inhibitors
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Platelet Aggregation Inhibitors
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Pyrroles
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Quinazolines
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Sulfonamides
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Tetrahydroisoquinolines
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Thionucleotides
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Vasodilator Agents
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Ryanodine
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8-((4-chlorophenyl)thio)cyclic-3',5'-GMP
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KT 5720
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linsidomine
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trequinsin
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1,1-diethyl-2-hydroxy-2-nitrosohydrazine
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quazinone
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Molsidomine
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Superoxide Dismutase
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Cyclic AMP-Dependent Protein Kinases
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Cyclic GMP-Dependent Protein Kinases
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Phosphoric Diester Hydrolases
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Cyclic GMP
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Milrinone
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N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
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Calcium
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cyclopiazonic acid