Control of myocardial oxygen consumption in transgenic mice overexpressing vascular eNOS

1 Department of Physiology, New York Medical College, Valhalla, New York 10595; 2 Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932; and 3 Department of Cell Biology and Genetics and 4 Department of Vascular Surgery,...

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Published in:American journal of physiology. Heart and circulatory physiology 2004-11, Vol.287 (5), p.H2115-H2121
Main Authors: Walsh, E. K, Huang, H, Wang, Z, Williams, J, de Crom, R, van Haperen, R, Thompson, C. I, Lefer, D. J, Hintze, T. H
Format: Article
Language:English
Subjects:
Animals
Blood Pressure
Blotting, Western
Bradykinin - administration & dosage
Bradykinin - pharmacology
Carbachol - administration & dosage
Carbachol - pharmacology
Colforsin - administration & dosage
Colforsin - pharmacology
Dose-Response Relationship, Drug
Echocardiography
Female
Hemodynamics
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Myocardium - enzymology
Myocardium - metabolism
Nitric Oxide Synthase - metabolism
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III
Oxygen Consumption - drug effects
S-Nitroso-N-Acetylpenicillamine - administration & dosage
S-Nitroso-N-Acetylpenicillamine - pharmacology
Sex Characteristics
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Summary:1 Department of Physiology, New York Medical College, Valhalla, New York 10595; 2 Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932; and 3 Department of Cell Biology and Genetics and 4 Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam 3000 DR, The Netherlands Submitted 16 March 2004 ; accepted in final form 13 July 2004 Our objective was to investigate the potential role of selective endothelial nitric oxide (NO) synthase (eNOS) overexpression in coronary blood vessels in the control of myocardial oxygen consumption (MV O 2 ). Transgenic (Tg) eNOS-overexpressing mice (eNOS Tg) ( n = 22) and wild-type (WT) mice ( n = 24) were studied. Western blot analysis indicated greater than sixfold increase of eNOS in cardiac tissue. Echocardiography in awake mice indicated no difference in cardiac function between WT and eNOS Tg; however, systolic pressure in eNOS Tg mice decreased significantly (126 ± 2.3 to 109 ± 2.3 mmHg; P < 0.05), whereas heart rate (HR) was not different. Total peripheral resistance (TPR) was also decreased (9.8 ± 0.8 to 7.6 ± 0.4 4 mmHg·ml –1 ·min; P < 0.05) in eNOS Tg. Furthermore, female eNOS Tg mice showed even lower TPR (7.2 ± 0.4 mmHg·ml –1 ·min) compared with male eNOS mice (8.6 ± 0.5, mmHg·ml·min –1 ; P < 0.05). Left ventricular slices were isolated from WT and eNOS Tg mice. With the use of a Clark-type oxygen electrode in an airtight bath, MV O 2 was determined as the percent decrease during increasing doses (10 –10 to 10 –4 mol/l) of bradykinin (BK), carbachol (CCh), forskolin (10 –12 to 10 –6 mol/l), or S -nitroso- N -acetyl penicillamine (SNAP; 10 –7 to 10 –4 mol/l). Baseline MV O 2 was not different between WT (181 ± 13 nmol·g –1 ·min –1 ) and eNOS Tg (188 ± 14 nmol·g –1 ·min –1 ). BK decreased MV O 2 (10 –4 mol/l) in WT by 17% ± 1.1 and 33% ± 2.7 in eNOS Tg ( P < 0.05). CCh also decreased MV O 2 , 10 –4 mol/l, in WT by 20% ± 1.7 and 31% ± 2.0 in eNOS Tg ( P < 0.05). Forskolin (10 –6 mol/l) or SNAP (10 –4 mol/l) also decreased MV O 2 in WT by 24% ± 2.8 and 36% ± 1.8 versus eNOS 31% ± 1.8 and 37% ± 3.5, respectively. N -nitro- L -arginine methyl ester (10 –3 mol/l) inhibited the MV O 2 reduction to BK, CCh, and forskolin by a similar degree ( P < 0.05), but not to SNAP. Thus selective overexpression of eNOS in cardiac blood vessels in mice enhances the control of MV O 2 by eNOS-derived NO. forskolin; nitric oxide Address for
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.00267.2004