Short and long term effects of cytokines on neonatal cardiac
myocyte calcium transients and adenylate cyclase activity.
Bick, Roger J., Jing-Piin Liao, Timothy W. King, Anne Lemaistre,
Jeanie B. McMillin, and L. Maximilian Buja.
The Department of Pathology and Laboratory Medicine, The University
of Texas Health Science Center at Houston, Houston, Texas 77030
APStracts 3:0500H, 1996.
This study investigates the hypothesis that inflammatory cytokines,
interleukin 1-alpha (IL-1[alpha]), interleukin 1-beta (IL-1[beta])
and tumor necrosis factor (TNF), influence cardiac function by
affecting calcium homeostasis and that this effect is mediated by the
beta adrenergic/adenylate cyclase system. After 4 days in culture,
neonatal rat ventricular myocytes are treated with cytokines
(10ng/ml) for short (2hr) or longer (18hr) times. Myocyte calcium,
contractility and adenylate cyclase are measured under each
condition. Anticipated stepwise increases in adenylate cyclase and
intracellular calcium are seen in controls (-cytokines) with 10-7M
isoproterenol, 10-7M isoproterenol + 0.1mM GTP and 10-9M forskolin.
Cells in the presence of cytokine for 2 hrs, show increased basal
calcium levels but no changes in adenylate cyclase activities, and
isoproterenol fails to elevate adenylate cyclase or affect
contractile shortening. Following long-term treatment with IL-1[beta]
or TNF, but not IL-1[alpha], the significantly elevated levels of
basal systolic calcium remain, and isoproterenol increases adenylate
cyclase activity, unlike after short exposure. Forskolin maximally
activates adenylate cyclase following both short and long-term
incubation, but the step-wise increase in activity is blunted
following prolonged exposure. Thus, short term cytokine treatment
blocks the adrenergic receptor-mediated increases in c-AMP,
dissociating adenylate cyclase activation from cytokine-mediated
increases in cell calcium, whereas longer treatment apparently
produces direct affects on adenylate cyclase. Time-dependent
differences in contractile response are seen with IL-1[alpha] at 2
hours, and TNF at 18 hours, inferring that myofibrillar
responsiveness to increased cytoplasmic calcium is dependent both on
cytokine species and exposure time.
Received 29 March 1996; accepted in final form 16 October 1996.
APS Manuscript Number H297-6.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 31 December 1996