Abstract 12386: Cine DENSE and Manganese-enhanced MRI Demonstrate that nNOS, and not eNOS, Plays a Dominant Role in Modulating EC-coupling in the Mouse Heart.
Introduction: Within cardiomyocytes, NO from eNOS and nNOS is thought to modulate L-type calcium channel (LTCC) function and SR calcium cycling, respectively. However, divergent Results from in vitro studies suggest more complex roles. We aimed to elucidate the in vivo roles of eNOS and nNOS in LTCC and contractile function using eNOS−/− and nNOS−/− mice and cardiac MRI.
Methods: Eight wild type (WT), 8 eNOS−/−, and 8 nNOS−/− mice aged 8–12 weeks were studied. Manganese-enhanced MRI measured an in vivo index of LTCC flux (LTCCI) in 2 mid-ventricular short axis slices at baseline (Bsl), during dobutamine (Dob, 5μg/kg·min), and during Dob and carbacholamine (Dob+CCh, CCh = 300μg/kg·min). In WT, LTCCI was also measured with an LTCC inhibitor and with A2a adenosine receptor stimulation. Cine-DENSE MRI measured in vivo circumferential strain (Ecc), as well as systolic (dEcc/dts) and diastolic (dEcc/dtd) strain rates under identical Dob and Dob+CCh conditions. Systolic blood pressure (BP) was measured by tail cuff.
Results: Bsl LTCCI was highest in nNOS−/− mice, but similar among mice with Dob and Dob+CCh (Fig). In WT mice, LTCCI decreased by 50% with an LTCC inhibitor. With A2a stimulation heart rate increased 20% and LTCCI fell 25%, indicating a typical negative LTCCI-frequency relationship. Peak Ecc, representing contraction, was similar in all mice at Bsl, as were dEcc/dts and dEcc/dtd. With Dob, peak Ecc, dEcc/dts, and dEcc/dtd increased in WT and eNOS−/− but not nNOS−/− mice. With Dob+CCh, Ecc, dEcc/dts, and dEcc/dtd were similar to Bsl in all mice. BP was higher in eNOS−/−.
Conclusions: Our results reveal elevated Bsl LTCC function and an attenuated contractile reserve to Dob in nNOS−/− mice. These data suggest a bimodal role for nNOS in inhibiting LTCC function at Bsl and promoting contractility with Dob. In contrast, LTCCI and Ecc were normal in eNOS−/− mice under all conditions. These results suggest that nNOS, not eNOS, plays the dominant role in modulating EC coupling in the heart.
- © 2010 by American Heart Association, Inc.