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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.

Original publication




Journal article


J Mol Cell Cardiol

Publication Date





1831 - 1840


Animals, Calcium, Carbazoles, Cyclic AMP-Dependent Protein Kinases, Cyclic GMP, Cyclic GMP-Dependent Protein Kinases, Dose-Response Relationship, Drug, Enzyme Inhibitors, Guinea Pigs, Heart Atria, Heart Rate, Hydrazines, Indoles, Isoquinolines, Male, Milrinone, Models, Biological, Molsidomine, Nitric Oxide Donors, Nitrogen Oxides, Phosphodiesterase Inhibitors, Phosphoric Diester Hydrolases, Platelet Aggregation Inhibitors, Pyrroles, Quinazolines, Ryanodine, Sarcoplasmic Reticulum, Signal Transduction, Spectrometry, Fluorescence, Sulfonamides, Superoxide Dismutase, Tetrahydroisoquinolines, Thionucleotides, Time Factors, Vasodilator Agents