Role of cGMP-inhibited Phosphodiesterase and Sarcoplasmic Calcium in Mediating the Increase in Basal Heart Rate with Nitric Oxide Donors

• Published in: Journal of molecular and cellular cardiology 2000-10, Vol.32 (10), p.1831-1840
• Main Authors: Musialek, Piotr, Rigg, Lauren, Terrar, Derek A., Paterson, David J., Casadei, Barbara
• Format: Article
• Language: English
• Subjects: Animals; Calcium - metabolism; Carbazoles; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Cyclic GMP - analogs & derivatives; Cyclic GMP - metabolism; Cyclic GMP - pharmacology; Cyclic GMP-Dependent Protein Kinases - antagonists & inhibitors; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Guinea Pigs; Heart Atria - metabolism; Heart Rate; Hydrazines - pharmacology; Indoles - pharmacology; Intracellular calcium; Isoquinolines - pharmacology; Male; Milrinone - pharmacology; Models, Biological; Molsidomine - analogs & derivatives; Molsidomine - pharmacology; Nitric Oxide Donors - metabolism; Nitric Oxide Donors - pharmacology; Nitric oxide signaling; Nitrogen Oxides; Phosphodiesterase Inhibitors - pharmacology; Phosphoric Diester Hydrolases - metabolism; Platelet Aggregation Inhibitors - pharmacology; Pyrroles - pharmacology; Quinazolines - pharmacology; Ryanodine - pharmacology; Sarcoplasmic Reticulum - metabolism; Signal Transduction; Sinoatrial node; Spectrometry, Fluorescence; Sulfonamides; Superoxide Dismutase - pharmacology; Tetrahydroisoquinolines; Thionucleotides - pharmacology; Time Factors; Vasodilator Agents - pharmacology
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1006/jmcc.2000.1216

Nitric oxide (NO) donors increase heart rate (HR) through a guanylyl cyclase-dependent stimulation of the pacemaker current If, without affecting basal ICa-L. The activity of Ifis known to be enhanced by cyclic nucleotides and by an increase in cytosolic Ca2+. We examined the role of cGMP-dependent signaling pathways and intracelluar Ca2+stores in mediating the positive chronotropic effect of NO donors. In isolated guinea pig atria, the increase in HR in response to 1–100 μ mol/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) Ca2+release by pretreatment of isolated atria with ryanodine or cyclopiazonic acid (2 μ mol/l and 60 μ mol/l, n=16) significantly reduced the chronotropic response to 1–100 μ mol/l SIN-1 or DEA-NO. Moreover, in isolated guinea pig sinoatrial node cells 5 μ mol/l SNP significantly increased diastolic and peak Ca2+fluorescence (+13±1% and +28±1%,n =6, P