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
相关论文
共 49 条
[31]  
MUSIALEK P, 1999, THESIS U OXFORD OXFO
[32]  
MUSIALEK P, 2000, J PHYSL LOND P, V253, P267
[33]   THE ABILITY OF DENBUFYLLINE TO INHIBIT CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE AND ITS AFFINITY FOR ADENOSINE RECEPTORS AND THE ADENOSINE RE-UPTAKE SITE [J].
NICHOLSON, CD ;
JACKMAN, SA ;
WILKE, R .
BRITISH JOURNAL OF PHARMACOLOGY, 1989, 97 (03) :889-897
[34]   Mechanical transduction of nitric oxide synthesis in the beating heart [J].
Pinsky, DJ ;
Patton, S ;
Mesaros, S ;
Brovkovych, V ;
Kubaszewski, E ;
Grunfeld, S ;
Malinski, T .
CIRCULATION RESEARCH, 1997, 81 (03) :372-379
[35]   Possible role of calcium release from the sarcoplasmic reticulum in pacemaking in guinea-pig sino-atrial node [J].
Rigg, L ;
Terrar, DA .
EXPERIMENTAL PHYSIOLOGY, 1996, 81 (05) :877-880
[36]   Elevated blood pressures in mice lacking endothelial nitric oxide synthase [J].
Shesely, EG ;
Maeda, N ;
Kim, HS ;
Desai, KM ;
Krege, JH ;
Laubach, VE ;
Sherman, PA ;
Sessa, WC ;
Smithies, O .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (23) :13176-13181
[37]   CYTOSOLIC AND SARCOPLASMIC RETICULUM-ASSOCIATED LOW KM, CGMP-INHIBITED CAMP PHOSPHODIESTERASE IN MAMMALIAN MYOCARDIUM [J].
SMITH, CJ ;
KRALL, J ;
MANGANIELLO, VC ;
MOVSESIAN, MA .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1993, 190 (02) :516-521
[38]   SIMULTANEOUS MEASUREMENT OF CA-2+, CONTRACTION, AND POTENTIAL IN CARDIAC MYOCYTES [J].
SPURGEON, HA ;
STERN, MD ;
BAARTZ, G ;
RAFFAELI, S ;
HANSFORD, RG ;
TALO, A ;
LAKATTA, EG ;
CAPOGROSSI, MC .
AMERICAN JOURNAL OF PHYSIOLOGY, 1990, 258 (02) :H574-H586
[39]  
Stoclet J.C., 1995, Exp. Opin. Invest. Drugs, V4, P1081, DOI DOI 10.1517/13543784.4.11.1081
[40]   Nitric oxide activates skeletal and cardiac ryanodine receptors [J].
Stoyanovsky, D ;
Murphy, T ;
Anno, PR ;
Kim, YM ;
Salama, G .
CELL CALCIUM, 1997, 21 (01) :19-29