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 intracelluar 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 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) Ca 2+ 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 Ca 2+ fluorescence (+13±1% and +28±1%, n =6, P 2+ in mediating the positive chronotropic effect of NO donors.