Abstract
In septic shock excessive nitric oxide and superoxide are produced, thus generating peroxynitrite. This study investigates whether and how intravasal peroxynitrite causes lung dysfunction. To generate peroxynitrite, isolated and ventilated rat lungs were perfused blood-free in a pressure-constant, recirculating mode with hypoxanthine/xanthine oxidase plus sodium nitroprusside. Airway and vascular resistance, and release of thromboxane A2, prostacyclin, and endothelin-1 were assessed over 200 min. Peroxynitrite generation, as demonstrated by oxidation of the marker 2′,7′-dichlorodihydrofluorescein diacetate, caused broncho- and vasoconstriction starting after 100 min. Both reactants alone, i.e., NO⋅ or O⨪2, had no effect. The thromboxane A2/prostaglandin H2 receptor antagonist BM13.177 did not affect peroxynitrite-induced broncho- and vasoconstriction. Combined endothelinA/B(ETA/B) receptor antagonism (BQ123 plus BQ788) prevented broncho- and vasoconstriction more effectively than the ETAreceptor antagonist BQ123 alone. In tissue from lungs exposed to peroxynitrite, significantly increased amounts of endothelin-1 were detected. This study identifies endothelin-1 rather than prostanoids as a distal mediator induced by the reaction product of superoxide and nitric oxide, i.e., peroxynitrite. It is concluded that 1) endothelin-1 is a causal mediator of peroxynitrite-induced acute rat lung injury, and 2) peroxynitrite-induced broncho- and vasoconstriction are mediated by both ETA and ETB receptors.
Footnotes
-
Send reprint requests to: Dr. Albrecht Wendel, Biochemical Pharmacology, University of Konstanz, D-78457 Konstanz, Box M668, Germany. E-mail: Albrecht.Wendel{at}uni-konstanz.de
-
The study was supported by Grant We 686/18 of the Deutsche Forschungsgemeinschaft to the research group “Endogenous tissue injury: Mechanisms of autodestruction”.
- Abbreviations:
- ARDS
- acute respiratory distress syndrome
- NO
- nitric oxide
- O⨪2
- superoxide anion
- PGI2
- prostacyclin
- ET
- endothelin
- ETA/B
- endothelinA/B receptor
- TXA2
- thromboxane A2
- PGH2
- prostaglandin H2
- XO
- xanthine oxidase
- DCHF
- 2′,7′-dichlorodihydrofluorescein diacetate
- EIA
- enzyme immunoassay
- TXB2
- thromboxane B2
- RL
- airway resistance
- RV
- vascular resistance
- PBS
- phosphate-buffered saline
- SNP
- sodium nitroprusside
- HX
- hypoxanthine
- COX 1/2
- cyclooxygenase 1/2
- Received October 16, 2000.
- Accepted December 26, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|