Nitric oxide-cGMP pathway is involved in endotoxin-induced contractile dysfunction in rat hearts.
The mechanisms by which endotoxemia causes cardiac depression have not been fully elucidated. The present study examined the involvement of nitric oxide (NO) in this pathology. Rats were infused with lipopolysaccharide (LPS) or saline, and the plasma and myocardial NO(2)(-) and NO(3)(-) (NOx) concentrations were measured before or 3, 6, and 24 h after treatment. The hearts were then immediately isolated and mounted in a Langendorff apparatus, and left ventricular developed pressure (LVDP) was determined before biochemical analysis of the myocardium. LPS injection effected the expression of inducible NO synthase (iNOS) in the myocardium, a marked increase in plasma and myocardial NOx levels, and a significant decline in LVDP compared with saline controls. The LPS-induced NO production and concomitant cardiac depression were most pronounced 6 h after LPS injection and were accompanied by a significant increase in myocardial cGMP content. Myocardial ATP levels were not significantly altered after LPS injection. Significant negative correlation was observed between LVDP and myocardial cGMP content, as well as between LVDP and plasma NOx levels. Aminoguanidine, an inhibitor of iNOS, significantly attenuated the LPS-induced NOx production and contractile dysfunction. Furthermore, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanylate cyclase, significantly decreased myocardial cGMP content and attenuated the contractile depression, although aminoguanidine or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one was not able to completely reverse myocardial dysfunction. Our data suggest that endotoxin-induced contractile dysfunction in rat hearts is associated with NO production by myocardial iNOS and a concomitant increase in myocardial cGMP.
Tatsumi
Tetsuya
T
Second Department of Medicine, Kyoto Prefectural University of Medicine, Japan. tatsumi@koto.kpu-m.ac.jp
Keira
Natsuya
N
Akashi
Kazuko
K
Kobara
Miyuki
M
Matoba
Satoaki
S
Shiraishi
Jun
J
Yamanaka
Satoshi
S
Mano
Akiko
A
Takeda
Mitsuo
M
Nishikawa
Susumu
S
Asayama
Jun
J
Fliss
Henry
H
Nakagawa
Masao
M
D000818:Animals; D006152:Cyclic GMP / Q000502:physiology*; D004731:Endotoxins / Q000633:toxicity*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology
D004731:Endotoxins; D009569:Nitric Oxide; D006152:Cyclic GMP