Key result
iNOS deletion enhances beta-adrenergic cardiac responsiveness without preventing renovascular hypertension or hypertrophy.
Why the study?
Does deletion of iNOS preserve cardiac function or prevent hypertrophy in mice with 2-kidney, 1-clip hypertension?
Does deletion of iNOS preserve cardiac function or prevent hypertrophy in mice with 2-kidney, 1-clip hypertension?
Genetic deletion of iNOS in mice with renovascular hypertension preserves cardiac function by reducing oxidative stress, without affecting blood pressure or cardiac hypertrophy.
iNOS deletion may preserve beta-adrenergic responses in murine renovascular hypertension; leaves open any role in human hypertensive heart disease.
Inducible NO synthase (iNOS) has been implicated in the pathogenesis of hypertension and target organ damage. We hypothesized that induction of iNOS contributes to left ventricular (LV) hypertrophy and dysfunction in mice with 2-kidney, 1-clip hypertension. Deletion of iNOS diminishes oxidative stress, thereby attenuating LV hypertrophy and enhancing cardiac performance. 2-Kidney, 1-clip hypertension was induced in mice lacking iNOS and wild-type controls (C57BL/6J). Sham-clipped mice served as controls. Systolic blood pressure was measured weekly by tail cuff. Left ventricular ejection fraction (by echocardiography) and cardiac response (maximum and minimum dP/dt, as well as an indicator of isovolumic contraction) to isoproterenol (50 ng per mouse, i.v.) were studied at the end of the experiment. 4-Hydroxy-2-nonenal (a byproduct of lipid peroxidation and an indicator of oxidative stress) was measured by immunohistochemical staining. gp91(phox), endothelial NO synthase, and iNOS protein expression were determined by Western blot. We found that systolic blood pressure, LV weight, myocyte cross-sectional area, interstitial collagen fraction, ejection fraction, and cardiac response to isoproterenol did not differ between strains with sham clipping. 2-Kidney, 1-clip hypertension increased systolic blood pressure, LV weight, myocyte cross-sectional area, and interstitial collagen fraction similarly in both strains. However, in mice lacking iNOS, maximum and minimum dP/dt, as well as an indicator of isovolumic contraction, markedly increased in response to isoproterenol, associated with decreased cardiac 4-hydroxy-2-nonenal expression and urinary nitrate/nitrite. We concluded that deletion of iNOS does not seem to play a significant role in preventing 2-kidney, 1-clip hypertension-induced hypertension and cardiac hypertrophy; however, it does enhance preservation of cardiac function, probably because of a reduction of iNOS-induced oxidative stress.
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Sun et al. (2008) studied 2-Kidney, 1-clip hypertension. iNOS gene deletion vs. Wild-type (C57BL/6J) was evaluated on Systolic blood pressure, left ventricular hypertrophy, and cardiac contractile/relaxation responses to isoproterenol. Deletion of iNOS in mice with 2-kidney, 1-clip hypertension did not prevent hypertension or cardiac hypertrophy but enhanced cardiac contractile and relaxation responses to isoproterenol by reducing oxidative stress.
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