Homocysteine attenuates hemodynamic responses to nitric oxide in vivo.
Homocysteine is a significant but modifiable risk factor for vascular diseases. While several pathological processes may be involved, homocysteine can cause significant endothelial impairment and compromise vascular NO bioactivity. In the present study, we aimed to assess effects of homocysteine on NO-mediated hemodynamic responses in vivo. We created an acute hyperhomocysteinemia model (plasma homocysteine of 65-276 micromol/l) by continuous venous infusion of D,L-homocysteine to anaesthetized Sprague-Dawley rats. Vasodilators including NO donors: S-nitrosohomocysteine (SNOHcy), S-nitrosocysteine (SNOCys) and sodium nitroprusside (SNP), the endothelial NO synthase (eNOS) activator: acetylcholine (ACh), and calcium channel blocker: verapamil and nicardipine, were administered by one bolus injection to the homocysteinemic rats. While homocysteine infusion produced no change in the mean femoral arterial blood pressure, each of these vasodilators led to a rapid and substantial dose-dependent fall in blood pressure. Concurrent homocysteine infusion, however, attenuated the blood pressure lowering effects induced by NO donors (P<0.01), but not by the calcium channel blockers. Homocysteine inhibited not only the endothelial-derived NO as stimulated by ACh, but also the bioactivity of exogenously supplied NO by SNOHcy, SNOCys and SNP. Our findings indicate that homocysteine may have an effect on NO bioproduction and bioavailability. Vasodilating efficacy of commonly used NO donors such as nitroglycerine may be seriously compromised by hyperhomocysteinemia, which is common among ischemic heart disease patients.
Fu
Wei Yu
WY
Department of Medicine, Prince Henry/Prince of Wales Hospitals and Center for Thrombosis and Vascular Biology, University of New South Wales, Sydney, Australia.
Dudman
Nicholas P B
NP
Perry
Michael A
MA
Wang
Xing Li
XL
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005263:Femoral Artery; D006710:Homocysteine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology*; D008297:Male; D009529:Nicardipine / Q000494:pharmacology; D009569:Nitric Oxide / Q000008:administration & dosage / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D026403:S-Nitrosothiols / Q000494:pharmacology; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D026403:S-Nitrosothiols; D014665:Vasodilator Agents; D006710:Homocysteine; C079202:S-nitrosohomocysteine; D009599:Nitroprusside; D009569:Nitric Oxide; C021315:S-nitrosocysteine; D014700:Verapamil; D009529:Nicardipine; D003545:Cysteine; D000109:Acetylcholine