P. Musialek et al., Role of cGMP-inhibited phosphodiesterase and sarcoplasmic calcium in mediating the increase in basal heart rate with nitric oxide donors, J MOL CEL C, 32(10), 2000, pp. 1831-1840
Nitric oxide (NO) donors increase heart rate (HR) through a guanylyl cyclas
e-dependent stimulation of the pacemaker current I-f, without affecting bas
al ICa-L. The activity of I-f is known to be enhanced by cyclic nucleotides
and by an increase in cytosolic Ca2+. We examined the role of cGMP-depende
nt signaling pathways and intracelluar Ca2+ stores in mediating the positiv
e chronotropic effect of NO donors. In isolated guinea pig atria, the incre
ase in HR in response to 1-100 mu mol/l 3-morpholinosydnonimine (SIN-1: wit
h superoxide dismutase, n=6) or diethylamine-NO (DEA-NO, n=8) was significa
ntly 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 mu mol/l and 60
mu mol/l, n=16) significantly reduced the chronotropic response to 1-100 mu
mol/l SIN-1 or DEA-NO. Moreover, in isolated guinea pig sinoatrial node ce
lls 5 mu mol/l SNP significantly increased diastolic and peak Ca2+ fluoresc
ence (+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 inhibi
tion of PDE3) and SR Ca2+ in mediating the positive chronotropic effect of
NO donors. (C) 2000 Academic Press.