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Departments of 1 Physiology and 2 Pathology, New York Medical College, Valhalla, New York 10595; and 3 Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, Michigan 48202
The mechanisms that
account for acetylcholine (ACh)-induced responses of skeletal muscle
arterioles of mice lacking endothelial nitric oxide (NO) synthase
(eNOS-KO) were investigated. Isolated, cannulated, and pressurized
arterioles of gracilis muscle from male eNOS-KO (74.1 ± 2.3 µm) and
wild-type (WT, 87.2 ± 2.1 µm) mice developed spontaneous tone
accounting for 63 and 61% of their passive diameter (116.8 ± 3.4 vs.
143.2 ± 2.8 µm, respectively) and dilated dose-dependently to ACh
(10
9-107
M). These dilations were significantly smaller in vessels of eNOS-KO
compared with WT mice (29.2 ± 2.0 µm vs. 46.3 ± 2.1 µm, at
maximum concentration) but responses to the NO donor, sodium nitrite
(NaNO2, 106-3 × 105 M), were comparable in the vessels
of the two strains.
NG-nitro-L-arginine
(L-NNA, 104 M), an inhibitor
of eNOS, inhibited ACh-induced dilations by 60-90% in arterioles
of WT mice but did not affect responses in those of eNOS-KO mice. In
arterioles of eNOS-KO mice, dilations to ACh were not affected by
indomethacin but were essentially abolished by inhibitors of cytochrome
P-450, clotrimazole (CTZ, 2 × 106 M) or miconazole (MCZ, 2 × 106 M), as well as by either high
K+ (40 mM) or iberiotoxin
[107 M, a blocker of
Ca2+-dependent K+ channels (KCa
channels)]. On the other hand, in WT arterioles CTZ
or MCZ inhibited ACh-induced dilations only by ~10% and only in the
presence of L-NNA. These results indicate that in
arterioles of eNOS-KO mice, endothelium-derived hyperpolarizing factor
(EDHF), synthesized via cytochrome P-450, accounts entirely for
the mediation of ACh-induced dilation via an increase in
KCa-channel activity. In contrast, in arterioles of WT
mice, endothelium-derived NO predominantly mediates ACh-induced
dilation in which participation of EDHF becomes apparent only after
inhibition of NO synthesis.
nitric oxide; endothelium; cytochrome P-450; potassium channels; arteriolar smooth muscle
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