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(Circulation Research. 2003;93:e74.)
© 2003 American Heart Association, Inc.

Letter to the Editor

The Janus Faces of iNOS

Imran N. Mungrue, Duncan J. Stewart, Mansoor Husain

The Toronto General and St Michael’s Hospitals, Toronto, Ontario, Canada, mansoor.husain@utoronto.ca

An extract of the first 250 words of the full text is provided, because this article has no abstract.

To the Editor:

Recently, two groups have reported on the phenotype of transgenic mice with cardiac-specific overexpression of the inducible nitric oxide synthase (iNOS). Although both used the -MHC promoter to target iNOS expression, our model used the tetracycline-regulated system (MtTA⁺/iNOS⁺),¹ whereas the other used a nonconditional approach.² Intriguingly, the phenotypes reported varied dramatically, from lethal arrhythmias in our case, to no identifiable abnormality in the second. Additionally, a recent publication from the second group³ includes criticisms of our work that are misleading.

The statement that "iNOS activity in [the nonconditional] model is approximately 100- to 120-fold higher than...in the conditional model" (page 1357)³ is unfounded. A direct comparison between cardiac iNOS activities in the two models is not possible. Heger et al² presented S-ethylisothiourea-sensitive conversion of arginine to citrulline (control: 1.7±3.1 versus transgenic: 697±238 pmolxmin^-1xmg^-1), whereas we measured L-NMMA–sensitive Ca²⁺-independent activity (1 mmol/L EGTA) (0.056±0.05 versus 4.57±1.36 pmolxmin^-1xmg^-1).¹ While both provide measures of iNOS activity, absolute values varied considerably. Although baseline values in the Heger mice were ostensibly 30-fold higher than ours, it is apparent from these^1,2 (and other⁴) reports that basal cardiac iNOS activity in mice is not different from zero. Thus, it is inappropriate to compare directly the reported iNOS activities in these models. Normalizing iNOS activity using control values is invalid, since fold increases based on a denominator that approaches zero is prone to overestimation.

In our view, a more . . . [Full Text of this Article]

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