nNOS Gene Deletion Exacerbates Pathological Left Ventricular Remodeling and Functional Deterioration After Myocardial Infarction

D. Dawson
2005 Circulation  
Background-The neuronal isoform of nitric oxide synthase (nNOS) has been implicated in the regulation of basal and ␤-adrenergic inotropy in normal and chronically infarcted hearts. Furthermore, myocardial nNOS expression and activity increase in failing hearts, raising the possibility that nNOS may influence left ventricular (LV) remodeling progression and functional deterioration after myocardial infarction (MI) Methods and Results-We compared LV remodeling at 1, 4, and 8 weeks after MI in
more » ... -knockout mice (nNOS -/-) and their wild-type (WT) littermates matched for infarct size by using a highly accurate 3-dimensional echocardiographic technique. Basal LV hemodynamics and the inotropic response to dobutamine infusion (4 and 16 ng · g Ϫ1 · min Ϫ1 ) were also evaluated 8 weeks after MI. Sham-operated nNOS -/mice showed enhanced basal LV contractility (PϽ0.03 versus WT, as evaluated by preload-recruitable stroke work) but an attenuated inotropic response to dobutamine infusion (PϽ0.01 versus WT). Both basal and ␤-adrenergic LV relaxations were significantly impaired in nNOS -/mice. Survival after MI did not differ between groups. However, nNOS -/mice developed a faster and more severe LV dilation compared with WT mice (PϽ0.05 for both end-systolic and end-diastolic volume indices). WT mice maintained a positive inotropic response to dobutamine 8 weeks after MI. In contrast, infarcted nNOS -/mice responded to dobutamine with a dramatic fall in LV contractility (PϽ0.01 for preload-recruitable stroke work). Conclusions-nNOS plays a crucial role in preventing adverse LV remodeling and maintaining myocardial ␤-adrenergic reserve after MI. Taken together, our findings suggest that upregulation of myocardial nNOS in infarcted hearts may be an important adaptive mechanism. (Circulation. 2005;112:3729-3737.)
doi:10.1161/circulationaha.105.539437 pmid:16344403 fatcat:dnpidhtswrenbar7rnucmvpuda