Homocysteine reduces smooth muscle [Ca2+](i) and constrictor responses of isolated arterioles

Chronic elevation of plasma homocysteine concentration has been shown to be associated with impaired vascular function. The acute direct effect of hom ocysteine on the tone and vasoactive responses of arterioles and the possib le underlying mechanisms, however, have not yet been elucidated. Thus arter ioles were isolated from gracilis muscle of rats (d: similar to 130 mum) an d their diameter was measured by videomicroscopy. Homocysteine(10(-6)-10(-4 ) M) elicited dose-dependent dilation of arterioles (maximum: 44 +/- 6% at 10(-4) M). The dilation was not affected by the presence of the nitric oxid e synthase inhibitor N-omega-nitro-L-arginine methyl ester or by removal of the endothelium, or the free radical scavenger catalase and superoxide dis mutase, or the K+ channel inhibitors glibenclamide, 4-aminopyridine, or tet raethyl ammonium. Incubation of vessels with homocysteine (10(-4) M, 20 min ) did not affect dilations to acetylcholine or sodium nitroprusside, wherea s it significantly decreased constrictions to norepinephrine (at 10(-6) M; control: 57 +/- 7%, homocysteine: 21 +/- 5%) and to the thromboxane A(2) an alogue U46619 (at 10(-8) M; control: 44 +/- 3%. homocysteine: 20 +/- 4%). H omocysteine (10(-4) M), similar to the voltage-operated Ca2+ channel inhibi tor nitrendipine (10(-8) M), significantly decreased the arteriolar smooth muscle [Ca2+](i) as assessed by changes in the fura-2 ratiometric signal (R -Ca, -6 +/- 1% and -24 +/- 3%, respectively). These data suggest that in is olated arterioles homocysteine decreases pressure-induced tone and response s to vasoconstrictor agents, likely by altering Ca2+ signaling of arteriola r smooth muscle.