Physiological concentration of nitric oxide induces positive inotropic effects through cGMP pathway in isolated rat ventricular myocytes.
We used authentic NO or NO from NO donors to show that the physiological levels of NO (<1 microM) induce a positive inotropic effect and demonstrated that the effect is evoked through a cGMP-dependent pathway. In isolated rat ventricular myocytes, authentic NO at 588 nM increased both cell shortening and the intracellular Ca(2+) ([Ca(2+)]i) transient (133 and 117%, respectively; p < 0.05 vs. baseline), and 0.16-1.7 microM NO elicited reproducible dose-dependent increases in cell shortening. NOC18 (0.1 mM: actual NO concentration 673 nM) or SNAP (0.1 mM: actual NO concentration 285 nM) showed similar effects (shortening 215% and [Ca(2+)]i transient 160% increases, and shortening 148% and [Ca(2+)]i transient 117% increases, respectively). The NO-induced increases in cell shortening and the [Ca(2+)]i transient were inhibited by an inhibitor of soluble guanylate cyclase (ODQ, 30 microM) or by an inhibitor of cAMP-dependent protein kinase (KT5720, 0.1 microM). In the presence of an inhibitor of cGMP-inhibited cAMP-phosphodiesterase (milrinone, 10 microM), NO failed to increase both cell shortening and the [Ca(2+)]i transient. These results suggest that physiological levels of NO induce positive inotropy through a cGMP-dependent pathway.
Hirota
Y
Y
Department of Physiology, School of Medicine, Tokai University, Isehara, 259-1193, Japan.
Ishida
H
H
Genka
C
C
Obama
R
R
Matsuyama
S
S
Nakazawa
H
H
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D018929:Cell Culture Techniques; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000166:cytology*; D009569:Nitric Oxide / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016276:Ventricular Function
D009569:Nitric Oxide; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D006152:Cyclic GMP