title: Role of cGMP-inhibited phosphodiesterase and sarcoplasmic calcium in mediating the increase in basal heart rate with nitric oxide donors.
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.
authors.affiliation: Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford, UK. piotr.musialek@clinical-medicine.ox.ac.uk
authors.forename: P
authors.initials: P
authors.lastname: Musialek
authors.forename: L
authors.initials: L
authors.lastname: Rigg
authors.forename: D A
authors.initials: DA
authors.lastname: Terrar
authors.forename: D J
authors.initials: DJ
authors.lastname: Paterson
authors.forename: B
authors.initials: B
authors.lastname: Casadei
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002227:Carbazoles; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000378:metabolism; D006339:Heart Rate; D006834:Hydrazines / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D020105:Milrinone / Q000494:pharmacology; D008954:Models, Biological; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000378:metabolism* / Q000494:pharmacology; D009589:Nitrogen Oxides; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D012433:Ryanodine / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D015398:Signal Transduction; D013050:Spectrometry, Fluorescence; D013449:Sulfonamides; D013482:Superoxide Dismutase / Q000494:pharmacology; D044005:Tetrahydroisoquinolines; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D002227:Carbazoles; D004791:Enzyme Inhibitors; D006834:Hydrazines; D007211:Indoles; D007546:Isoquinolines; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011758:Pyrroles; D011799:Quinazolines; D013449:Sulfonamides; D044005:Tetrahydroisoquinolines; D013873:Thionucleotides; D014665:Vasodilator Agents; D012433:Ryanodine; C055656:8-((4-chlorophenyl)thio)cyclic-3',5'-GMP; C057416:KT 5720; C002385:linsidomine; C035964:trequinsin; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; C040850:quazinone; D008981:Molsidomine; D013482:Superoxide Dismutase; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP; D020105:Milrinone; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D002118:Calcium; C000543:cyclopiazonic acid