Role of cGMP-inhibited phosphodiesterase and sarcoplasmic calcium in mediating the increase in basal heart rate with nitric oxide donors

被引:25
作者
Musialek, P [1 ]
Rigg, L
Terrar, DA
Paterson, DJ
Casadei, B
机构
[1] John Radcliffe Hosp, Dept Cardiovasc Med, Oxford OX3 9DU, England
[2] Univ Oxford, Physiol Lab, Oxford OX1 3PT, England
[3] Univ Oxford, Dept Pharmacol, Oxford OX1 3PT, England
基金
英国惠康基金;
关键词
nitric oxide signaling; heart rate; intracellular calcium; sinoatrial node;
D O I
10.1006/jmcc.2000.1216
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Nitric oxide (NO) donors increase heart rate (HR) through a guanylyl cyclase-dependent stimulation of the pacemaker current I-f, without affecting basal 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-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 mu mol/l 3-morpholinosydnonimine (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 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 cells 5 mu mol/l SNP significantly increased diastolic and peak Ca2+ 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 Ca2+ in mediating the positive chronotropic effect of NO donors. (C) 2000 Academic Press.
引用
收藏
页码:1831 / 1840
页数:10
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