Dysfunction of nitric oxide mediation in isolated rat arterioles with methionine diet-induced hyperhomocysteinemia

In humans, increased plasma homocysteine (Hcy) has been shown to be correla ted with occlusive arterial diseases and atherosclerosis. Studies of isolat ed conductance vessels of experimental animals suggest that Hey may interfe re with local vasoregulatory mechanisms, yet the effect of hyperhomocystein emia (HHcy) on the function of microvessels, such as skeletal muscle arteri oles, has not been investigated. Male Wistar rats were divided into 2 group s: control rats (C; plasma Hey, 7.1+/-0.3 mu mol/L; n=25), and rats made HH cy by 1 g/kg body weight daily intake of methionine in the drinking water f or 4 weeks (plasma Hey, 23.6+/-2.9 mu,mol/L; P<0.01. versus C; n=25). First -order arterioles (approximate to 130 mu m in diameter) were isolated from gracilis muscle, cannulated, and pressurized (80 mm Hg, no-flow conditions) . Changes in diameter were observed by videomicroscopy. Arteriolar constric tions to norepinephrine (NE; 3 X 10(-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%). R emoval of the endothelium (-E) augmented NE-induced constrictions only in a rterioles 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 cumula tive doses of acetylcholine (ACh; 10(-8) mol/L) were significantly reduced m arterioles from HHcy rats (C, 64.0+/-5.2%; HHcy) (24.1+/-6.8%). Inhibitio n of nitric oxide (NO) synthesis with NO-nitro-L-arginine (L-NNA; 10(-4) mo l/L) significantly decreased ACh-induced dilations of C arterioles, whereas it did not affect HHcy arterioles. Similar alterations were found in arter iolar dilations to histamine, another known NO-dependent agonist. Endotheli um-independent dilations to the NO donor sodium nitroprusside were not diff erent in arterioles from C and HI-Icy rats, either in the presence or absen ce of L-NNA. Presence of superoxide dismutase and catalase (scavenger of re active oxygen metabolites) did not affect HI-Icy-induced alterations in the ACh response. We conclude that hyperhomocysteinemia reduces rat skeletal m uscle arteriolar dilations in response to ACh and histamine, and enhances c onstrictions to NE, alterations that are likely to be caused by the reduced mediation of these responses by NO. The reduced activity of NO in arteriol es may contribute to the microvascular impairment described in HI-Icy.