Superoxide-dependent cerebrovascular effects of homocysteine.
Recent evidence indicates that elevated plasma levels of homocysteine are a risk factor for ischemic cerebrovascular diseases. However, little is known about cerebrovascular effects of homocysteine. Homocysteine could impair cerebrovascular function by metal-catalyzed production of activated oxygen species. We studied whether homocysteine, in the presence of Cu2+, alters reactivity of cerebral circulation and, if so, whether this effect depends on O-2 generation. In halothane-anesthetized rats the parietal cortex was exposed and superfused with Ringer solution. Cerebrocortical blood flow (CBF) was monitored by a laser-Doppler probe. With Ringer solution superfusion, CBF increased with hypercapnia (+134 +/- 7%; PCO2 = 50-60 mmHg) and topical application of 10 microM ACh (+35 +/- 3%), the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 500 microM; +66 +/- 6%), or 1 mM papaverine (+100 +/- 6%; n = 5). Superfusion with 40 microM 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 homocysteine-Cu2+ were prevented by coadministration of superoxide dismutase (SOD; 1,000 U/ml; n = 5). SOD alone did not affect resting CBF or CBF reactivity (n = 5). The observation that homocysteine-Cu2+ attenuates the response to hypercapnia, ACh, and SNAP, but not the NO-independent vasodilator papaverine, suggests that homocysteine-Cu2+ selectively impairs NO-related cerebrovascular responses. The fact that SOD prevents 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 cerebrovascular responses by scavenging NO, perhaps through peroxynitrite formation. O-2-mediated scavenging of NO might be one of the mechanisms by which hyperhomocysteinemia predisposes to cerebrovascular diseases.
Zhang
F
F
Laboratory of Cerebrovascular Biology and Stroke, Department of Neurology, University of Minnesota Medical School, Minnesota 55455, USA.
Slungaard
A
A
Vercellotti
G M
GM
Iadecola
C
C
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000201:enzymology; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D006710:Homocysteine / Q000494:pharmacology*; D006935:Hypercapnia / Q000503:physiopathology; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D010208:Papaverine / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026423:S-Nitroso-N-Acetylpenicillamine; D013481:Superoxides / Q000378:metabolism* / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D014665:Vasodilator Agents; D006710:Homocysteine; D013481:Superoxides; D026423:S-Nitroso-N-Acetylpenicillamine; D010208:Papaverine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D010396:Penicillamine; D000109:Acetylcholine