Submitted on August 14, 2006
Accepted on October 24, 2006
Acute and conditioned hypoxic tolerance augmented by endothelial nitric oxide synthase inhibition in mice
Michael Y. Song1, Charles F. Zwemer2, Steven E Whitesall3, and Louis G D'Alecy4*
1 College of Literature, Science and the Arts, University of Michigan Medical School, Ann Arbor, Michigan, United States
2 Biology, Dickinson College, Carlisle, Pennsylvania, United States
3 Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States
4 Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States; Department of Surgery, William Beaumont Hospital, Royal Oak, Michigan, United States
* To whom correspondence should be addressed. E-mail: lgdalecy{at}umich.edu.
To identify a possible role for nitric oxide (NO) in acute hypoxic tolerance (HT) we measured hypoxic survival time (HST), hypoxic conditioning effect (HC), and survival following hypoxic conditioning while blocking or mimicking the action of nitric oxide synthase (NOS). To inhibit NOS, CD-1 mice were given supplemental endogenous NOS inhibitor asymmetrical dimethylarginine (ADMA) or a synthetic NOS inhibitor omega N-nitro-L-arginine (LNNA), both of which non-selectively inhibit three of the isoforms of NOS (iNOS, nNOS, and eNOS). ADMA (10 mg/kg, IP) or saline vehicle was given five minutes prior to HST testing. LNNA was given orally at 1 g/L in drinking water with tap water as the control for 48 hours prior to testing. Both ADMA and LNNA significantly increased HST and augmented the HC effect on HST. Neither the nNOS selective inhibitor 7-nitroindazole (7-NI) nor the iNOS selective inhibitor N-[[3-(aminomethyl)phenyl]methyl]-enthanimidamide (1400W) had a statistically significant effect on HST or HT. The NO donor, 3-morpholinosydnoeimine (SIN-1), when given alone did not significantly decrease HT, but did mitigate the increased HT effect of LNNA. These data confirm acute hypoxic conditioning increases HT and that NOS inhibition by endogenous (ADMA) and a synthetic NOS inhibitor (LNNA) further increases HT while iNOS and nNOS inhibition does not, suggesting that it is the inhibition of eNOS that mediates enhanced in HT.
