© 2000 American Heart Association, Inc.
Integrative Physiology |
Myocardial Glucose Uptake Is Regulated by Nitric Oxide via Endothelial Nitric Oxide Synthase in Langendorff Mouse Heart
From Departments of Physiology (H.T., C.I.T., F.A.R., K.E.L., M.O., G.K., T.H.H.) and Pathology (C.J.S.), New York Medical College, Valhalla, NY; Division of Hypertension and Vascular Research (E.G.S.), Henry Ford Hospital, Detroit, Mich.
Correspondence to Thomas H. Hintze, PhD, Professor, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail Thomas_Hintze{at}nymc.edu
Abstract—Although the role of
nitric oxide (NO) in the modulation of vascular tone has been studied
and well understood, its potential role in the control of myocardial
metabolism is only recently evident. Several lines of
evidence indicate that NO regulates myocardial glucose
metabolism; however, the details and mechanisms responsible
are still unknown. The aim of this study was to further define the role
of NO in the control of myocardial glucose metabolism and
the nitric oxide synthase (NOS) isoform responsible using transgenic
animals lacking endothelial NOS (ecNOS). In the
present study, we examined the regulation of myocardial glucose
uptake using isometrically contracting Langendorff-perfused hearts from
normal mice (C57BL/6J), mice with defects in the expression of ecNOS
[ecNOS (-/-)], and its heterozygote [ecNOS (+/-)], and wild-type
mice [ecNOS (+/+)] (n=6, respectively). In hearts from normal mice,
little myocardial glucose uptake was observed. This myocardial glucose
uptake increased significantly in the presence of
N
-nitro-L-arginine methyl
ester (L-NAME). Similarly, in the hearts from ecNOS (-/-), glucose
uptake was much greater than in normal mice, whereas myocardial glucose
uptake of ecNOS (+/-) and ecNOS (+/+) mice was not different from
normal mice. In addition, myocardial glucose uptake of ecNOS (+/-) and
ecNOS (+/+) mice increased significantly in the presence of L-NAME. At
a workload of 800 g · beats/min, L-NAME increased glucose uptake
from 0.1±0.1 to 3±0.4 µg/min · mg in ecNOS (+/-) mice and
from 0.2±0.1 to 2.7±0.7 µg/min · mg in ecNOS (+/+) mice.
Furthermore, in the hearts from ecNOS (-/-) mice, 8-bromoguanosine
3':5'-cyclic monophosphate (8-Br-cGMP), a cGMP analog or
S-nitroso-N-acetylpenicillamine (SNAP), a
NO donor essentially shut off glucose uptake, and in hearts from ecNOS
(+/-) mice,
1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one
(ODQ), an inhibitor of cGMP, increased the glucose uptake
significantly. These results indicate clearly that cardiac NO
production regulates myocardial glucose uptake via a
cGMP-dependent mechanism and strongly suggest that ecNOS plays a
pivotal role in this regulation. These findings may be important in the
understanding of the pathogenesis of the diseases such as
ischemic heart disease, heart failure, diabetes mellitus,
hypertension, and hypercholesterolemia, in
which NO synthesis is altered and substrate utilization by the
heart changes.
Key Words: cardiac work • mice, knockout • arginine • length-tension
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