Hyperhomocysteinemia evoked by folate depletion: effects on coronary and carotid arterial function.
High circulating concentrations of homocysteine (ie, hyperhomocysteinemia [Hhcy]) impair the vascular function of peripheral conduit arteries and arterioles perfusing splanchnic and skeletal muscle regions. The effects of HHcy on coronary resistance vessel function and other indexes of vascular function, ie, arterial permeability and stiffening, are unclear. We tested the hypotheses that HHcy impairs coronary resistance vessel reactivity; increases carotid arterial permeability; and initiates arterial stiffening. Male rats that consumed folate-replete (CON, n=44) or folate-deplete (HHcy, n=48) chow for 4 to 5 weeks had total plasma homocysteine concentrations of 7+/-2 or 58+/-4 micromol/L, respectively. Maximal acetylcholine-evoked relaxation (approximately 40% vs approximately 60%) and tension development from baseline in response to nitric oxide synthase inhibition (approximately 20% vs approximately 40%) were lower (both P<0.05) in coronary resistance vessels (approximately 120 microm, internal diameter) isolated from HHcy versus CON animals, respectively, whereas sodium nitroprusside-evoked relaxation and contractile responses to serotonin and potassium chloride were similar between groups. Permeability to 4400 MW and 65 000 MW fluorescently labeled (TRITC) dextran reference macromolecules (quantitative fluorescence microscopy) was approximately 44% and approximately 24% greater (P<0.05), respectively, in carotid arteries from HHcy versus CON rats. Maximal strain, evaluated by using a vessel elastigraph, was less ( approximately 32% vs 42%, P<0.05) in carotid arterial segments from HHcy versus CON animals, respectively. Finally, estimates of oxidative (copper-zinc+manganese superoxide dismutase activity) and glycoxidative (pentosidine) stress were elevated (P<0.05) in arterial tissue from HHcy versus CON rats. These findings suggest that moderately severe HHcy evoked by folate-depletion impairs endothelium-dependent relaxation of coronary resistance vessels, increases carotid arterial permeability, and initiates arterial stiffening. HHcy may produce these effects by a mechanism associated with increased oxidative and glycoxidative stress.
Symons
J David
JD
College of Health, University of Utah, Salt Lake City, Utah 84112, USA. j.david.symons@hsc.utah.edu
Mullick
Adam E
AE
Ensunsa
Jodi L
JL
Ma
Amy A
AA
Rutledge
John C
JC
D000818:Animals; D002199:Capillary Permeability / Q000502:physiology; D002339:Carotid Arteries / Q000503:physiopathology*; D003331:Coronary Vessels / Q000503:physiopathology*; D004032:Diet; D004548:Elasticity; D005492:Folic Acid / Q000378:metabolism; D005494:Folic Acid Deficiency / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D017127:Glycation End Products, Advanced / Q000097:blood; D020138:Hyperhomocysteinemia / Q000097:blood / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014655:Vascular Resistance / Q000502:physiology
D017127:Glycation End Products, Advanced; D005492:Folic Acid