Cardiac inducible nitric oxide synthase negatively modulates
myocardial function in cultured rat myocytes.
Kinugawa, Koh-Ichiro, Osami Kohmoto, Atsushi Yao, Takashi Serizawa,
and Toshiyuki Takahashi.
The Second Department of Internal Medicine, Faculty of Medicine,
University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113, Japan
APStracts 3:0286H, 1996.
Recent work has demonstrated that endotoxin or cytokines induce nitric
oxide synthase (iNOS) in heart or cardiac myocytes. We investigated
the functional significance of iNOS in indo-1-loaded beating myocytes
with regard to intracellular Ca2+ concentration ([Ca2+]i) and cell
contraction. Lipopolysaccharide (LPS, 10 [mu]g/ml) time-dependently
induced iNOS mRNA and protein in cultured neonatal rat cardiac
myocytes. Nitrite concentration in the medium and intracellular
guanosine 3',5'-cyclic monophosphate (cGMP) contents after 24 h
exposure to LPS increased in proportion to the levels of iNOS
induction in these cells. Myocytes treated with both NG-monomethyl-L
-arginine and LPS for 24 h expressed iNOS protein, but nitrites
production was significantly inhibited. Subsequent perfusion with
100-fold molar excess L-arginine of these myocytes elicited decreases
in peak systolic [Ca2+]i (790+/-42 -> 551+/-27 nM, P<0.05),
relative amplitude of cell contraction (100 -> 72.4+/-5.5%,
P<0.05), and spontaneous beating rate (146+/-13 -> 85+/-22
beats/min, P<0.05). Pretreatment with methylene blue or KT5823
inhibited these negative myocardial effects. These results suggest
that LPS induces iNOS in cardiac myocytes, and that the increased
nitric oxide produced by iNOS has cardiac depressant effects through
the activation of cGMP-dependent protein kinase.
Received 16 January 1996; accepted in final form 26 June 1996.
APS Manuscript Number H27-6.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 25 July 1996