© 1999 American Heart Association, Inc.
Vascular Biology |
Dysfunction of Nitric Oxide Mediation in Isolated Rat Arterioles With Methionine Diet–Induced Hyperhomocysteinemia
From the Department of Pathophysiology, Semmelweis University of Medicine, H-1445, Budapest, Hungary and Department of Physiology, New York Medical College, Valhalla, New York 10595.
Correspondence to Akos Koller, MD, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail akos koller{at}nymc.edukoller@nymc.edu
Abstract—In humans, increased
plasma homocysteine (Hcy) has been shown to be correlated with
occlusive arterial diseases and
atherosclerosis. Studies of isolated conductance
vessels of experimental animals suggest that Hcy may interfere with
local vasoregulatory mechanisms, yet the effect of hyperhomocysteinemia
(HHcy) on the function of microvessels, such as skeletal muscle
arterioles, has not been investigated. Male Wistar rats were divided
into 2 groups: control rats (C; plasma Hcy, 7.1±0.3 µmol/L; n=25),
and rats made HHcy by 1 g/kg body weight daily intake of methionine in
the drinking water for 4 weeks (plasma Hcy, 23.6±2.9 µmol/L;
P<0.01 versus C; n=25). First-order arterioles
(
130 µm in diameter) were isolated from gracilis muscle,
cannulated, and pressurized (80 mm Hg, no-flow conditions).
Changes in diameter were observed by videomicroscopy. Arteriolar
constrictions to norepinephrine (NE; 3x10-7
mol/L) were significantly (P<0.01) greater in HHcy
compared with C rats (C, 37.7±4.9%; HHcy, 59.5±5.2%). Removal of
the endothelium (-E) augmented NE-induced constrictions
only in arterioles from C rats, whereas it had no effect on responses
of arterioles from HHcy rats (C-E, 55.9±6.9%; HHcy-E,
56.5±7.0%). Dilations to cumulative doses of acetylcholine (ACh;
10-8 mol/L) were significantly reduced in arterioles from
HHcy rats (C, 64.0±5.2%; HHcy, 24.1±6.8%). Inhibition of nitric
oxide (NO) synthesis with N
-nitro-L-arginine
(L-NNA; 10-4 mol/L) significantly decreased ACh-induced
dilations of C arterioles, whereas it did not affect HHcy arterioles.
Similar alterations were found in arteriolar dilations to histamine,
another known NO-dependent agonist.
Endothelium-independent dilations to the NO donor
sodium nitroprusside were not different in arterioles from C and HHcy
rats, either in the presence or absence of L-NNA. Presence of
superoxide dismutase and catalase (scavenger of reactive oxygen
metabolites) did not affect HHcy-induced alterations in the ACh
response. We conclude that hyperhomocysteinemia reduces rat skeletal
muscle arteriolar dilations in response to ACh and histamine, and
enhances constrictions to NE, alterations that are likely to be caused
by the reduced mediation of these responses by NO. The reduced activity
of NO in arterioles may contribute to the microvascular impairment
described in HHcy.
Key Words: homocysteinemia • microcirculation • acetylcholine • norepinephrine • histamine • nitric oxide
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