© 1998 American Heart Association, Inc.
Original Contributions |
Coronary Hemodynamics in Endothelial NO Synthase Knockout Mice
From the Institut für Herz- und Kreislaufphysiologie (A.G., U.K.M.D., S.G., J.S.), Institut für experimentelle Anästhesiologie (Z.D.), Biologisch-Medizinisches Forschungszentrum (J.H., J.S.), and Institut für Neuroanatomie (H.-J.B.), Heinrich-Heine-Universität Düsseldorf, Germany.
Correspondence to Dr A. Gödecke, Institut für Herz- und Kreislaufphysiologie, Heinrich-Heine-Universität Düsseldorf, Universitätsstr 1, Postfach 10 10 07, 40001 Düsseldorf, Germany. E-mail axel{at}herzkreis.uni-duesseldorf.de
Abstract—For the specific
analysis of endothelial NO synthase (eNOS)
function in the coronary vasculature, we generated a mouse
homozygous for a defective eNOS gene (eNOS-/-). Western blot as well
as immunohistochemical staining revealed the absence of eNOS protein in
eNOS-/- mice. Aortic endothelial cells derived from
eNOS-/- mice displayed only background levels of NOx
formation compared with wild-type (WT) cells (88 versus 1990 pmol
NOx · h-1/mg protein-1).
eNOS-/- mice were hypertensive (mean arterial pressure,
135±15 versus 107±8 mm Hg in WT) without the development of
cardiac hypertrophy. Coronary
hemodynamics, analyzed in Langendorff-perfused
hearts, showed no differences either in basal coronary flow or
in maximal and repayment flow of reactive hyperemia. Acute NOS
inhibition with
N
-nitro-L-arginine methyl
ester (L-NAME) in WT hearts substantially reduced basal flow and
reactive hyperemia. The coronary response to
acetylcholine (ACh) (500 nmol/L) was biphasic: An initial
vasoconstriction (flow, -35%) in WT hearts was followed by sustained
vasodilation (+190%). L-NAME significantly reduced vasodilation in WT
hearts (+125%) but did not alter the initial vasoconstriction. In
eNOS-/- hearts, the initial vasoconstriction was augmented (-70%),
whereas the ACh-induced vasodilation was not affected. Inhibition of
cyclooxygenase with diclofenac converted the
ACh-induced vasodilation into vasoconstriction (-49% decrease of
basal flow). This effect was even more pronounced in eNOS-/- hearts
(-71%). Our results demonstrate that (1) acute inhibition of eNOS
reveals a role for NO in setting the basal coronary vascular
tone as well as participation in reactive hyperemia and the
response to ACh; (2) chronic inhibition of NO formation in eNOS-/-
mutant mice induces no changes in basal coronary flow and
reactive hyperemia, suggesting the activation of important
compensatory mechanisms; and (3) prostaglandins are the
main mediators of the ACh-induced vasodilation in both WT and
eNOS-/- mice.
Key Words: heart • gene targeting • reactive hyperemia • coronary flow • blood pressure
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