Abstract 766: Cardiac MRI Phenotyping of nNOS Knockout Mice In Vivo Demonstrates Attenuated Contractile Response to Dobutamine and Normal Perfusion Reserve
Introduction: NO from nNOS is thought to regulate sarcoplasmic reticulum (SR) calcium release and reuptake during β-adrenergic stimulation. Whether nNOS facilitates or inhibits these processes is controversial. We aimed to determine the role of nNOS on LV size, function, and perfusion using nNOS−/− mice and cardiac MRI (CMR).
Methods: Nine nNOS−/− and 8 wild type (WT) mice aged 8 ± 1 weeks were studied. Multislice cine CMR measured end diastolic and end systolic volume (EDV, ESV), ejection fraction (EF), and LV mass at rest. Myocardial tagging measured circumferential shortening (Ecc), rate of shortening (dEcc/dt), and rate of relaxation (dEcc/dtdiastolic) in 2 mid-ventricular slices at rest and during dobutamine (dob) (40 μg/kg/min). Arterial spin labeling (ASL) assessed perfusion at rest and during vasodilatation.
Results: EDV, ESV, and LV mass were lower in nNOS−/− vs. WT (Table⇓) . With higher HR in nNOS−/−, cardiac index (CI) was similar (Table⇓). Peak Ecc and dEcc/dt, representing contractility, were also similar at rest, which, with reduced EDV, lead to an increased EF in nNOS−/− (Table⇓). With dob, a greater increase in Ecc was seen in WT vs. nNOS−/− (WT : −0.021 ± 0.013 vs. nNOS−/−: −0.004 ± 0.012, p<0.01). Significant increases in dEcc/dt and dEcc/dtdiastolic with dob were also seen in WT but not nNOS−/−. Dob induced similar HR increases (WT : 67 ± 58 vs. nNOS−/−: 68 ± 45, p=NS), and perfusion reserve was similar (Table⇓).
Conclusions: CMR revealed reduced LV size and similar baseline contractility, leading to higher EF in nNOS−/−. The reduced stroke volume coupled with an increased HR in nNOS−/− lead to similar CI as WT. Contractile reserve and relaxation rate with dob were markedly reduced in nNOS−/− despite a normal HR response. Thus, nNOS allows normal systolic and diastolic functional responses to catecholamines, suggesting that it facilitates both SR calcium release and reuptake during β-adrenergic stimulation.