© 1996 American Heart Association, Inc.
Articles |
Role of Poly-ADP Ribosyltransferase Activation in the Vascular Contractile and Energetic Failure Elicited by Exogenous and Endogenous Nitric Oxide and Peroxynitrite
From the Children's Hospital Medical Center, Division of Critical Care, Cincinnati, Ohio.
Correspondence to Dr Csaba Szabó, Children's Hospital Medical Center, Division of Critical Care, 3333 Burnet Ave, Cincinnati, OH 45229.
Abstract Stimulation of vascular smooth muscle with bacterial
lipopolysaccharide (LPS) and proinflammatory
cytokines induces the expression of a distinct isoform of NO
synthase (inducible NOS [iNOS]) contributing to the suppression of
vascular contractility. We have obtained evidence of
the involvement of an indirect pathway triggered by NO and its reaction
product peroxynitrite (ONOO-) through the
activation of the nuclear enzyme poly-ADP ribosyltransferase (PARS) in
the pathogenesis of cellular energetic and contractile failure in
vascular smooth muscle. Exposure of vascular smooth muscle cells caused
DNA strand breaks, activation of PARS, depletion of
NAD+, and inhibition of mitochondrial respiration.
The NAD+ depletion and inhibition of mitochondrial
respiration were reduced by pharmacological inhibition of PARS.
Stimulation of vascular smooth muscle cells with LPS and interferon
gamma (IFN-
) triggered the production of superoxide anion
over 3 to 48 hours and NO and ONOO- over 24 to 48
hours and resulted in significant DNA strand breakage. The decrease in
mitochondrial respiration in response to LPS and IFN- stimulation
was inhibited by the ONOO- scavenger uric acid (100
µmol/L) and by inhibitors of iNOS. The PARS
inhibitors 3-aminobenzamide (1 mmol/L), nicotinamide
(1 mmol/L), and PD 128763 (100 µmol/L) inhibited the reduction in
cellular NAD+ and ATP and the suppression of mitochondrial
respiration in response to LPS and IFN- stimulation.
Administration of 3-aminobenzamide also reduced PARS activation and
vascular hyporeactivity of rat thoracic aortas exposed to
ONOO- (300 µmol/L to 1.5 mmol/L) in vitro.
3-Aminobenzamide (10 mg/kg IP) preserved the ex vivo
contractility of aortas obtained from endotoxic rats
and improved survival in lethal murine endotoxic shock. These data
suggest that PARS activation due to iNOS induction (1) is involved in
the energetic depletion of vascular smooth muscle cells that express
iNOS and (2) contributes to the pathogenesis of vascular energetic and
contractile failure in endotoxic shock. Inhibition of PARS may be a
novel concept of therapeutic potential in shock.
Key Words: septic shock • contraction • inflammation • endotoxin • hyporeactivity
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