SUPEROXIDE-DEPENDENT CEREBROVASCULAR EFFECTS OF HOMOCYSTEINE

Recent evidence indicates that elevated plasma levels of homocysteine are a risk factor for ischemic cerebrovascular diseases. However, litt le is known about cerebrovascular effects of homocysteine. Homocystein e could impair cerebrovascular function by metal-catalyzed production of activated oxygen species. We studied whether homocysteine, in the p resence of Cu2+, alters reactivity of cerebral circulation and, if so, whether this effect depends on O-2(-) generation. In halothane-anesth etized rats the parietal cortex was exposed and superfused with Ringer solution. Cerebrocortical blood flow (CBF) was monitored by a laser-D oppler probe. With Ringer solution superfusion, CBF increased with hyp ercapnia (+134 +/- 7%; Pco(2) = 50-60 mmHg) and topical application of 10 mu M ACh (+35 +/- 3%), the NO donor S-nitroso-N-acetylpenicillamin e (SNAP, 500 mu M; +66 +/- 6%), or 1 mM papaverine (+100 +/- 6%; n = 5 ). Superfusion with 40 mu M Cu2+ alone did not perturb resting CBF or responses to hypercapnia, ACh, SNAP, or papaverine (P > 0.05, n = 5). However, superfusion of homocysteine-Cu2+ reduced resting CBF (-28 +/- 4%) and attenuated (P < 0.05) responses to hypercapnia (-31 +/- 9%), ACh (-73 +/- 6%), or SNAP (-48 +/- 4%), but not papaverine. The effect was observed only at 1 mM homocysteine. Cerebrovascular effects of ho mocysteine-Cu2+ were prevented by coadministration of superoxide dismu tase (SOD; 1,000 U/ml; n = 5). SOD alone did not affect resting CBF or CBF reactivity (n = 5). The observation that homocysteine-Cu2+ attenu ates the response to hypercapnia, ACh, and SNAP, but not the NO-indepe ndent vasodilator papaverine, suggests that homocysteine-Cu2+ selectiv ely impairs NO-related cerebrovascular responses. The fact that SOD pr events such impairment indicates that the effect of homocysteine is O- 2(-) dependent. The data support the conclusion that O-2(-), generated by the reaction of homocysteine with CU2+, inhibits NO-related cerebr ovascular responses by scavenging NO, perhaps through peroxynitrite fo rmation. O-2(-)-mediated scavenging of NO might be one of the mechanis ms by which hyperhomocysteinemia predisposes to cerebrovascular diseas es.