The activation of endothelin-1 pathway during methionine-induced homocysteinemia mediates endothelial dysfunction in hypertensive individuals.
OBJECTIVE
Endothelin-1 (ET-1) is a key regulator of arterial blood pressure in humans, and homocysteinemia is associated with increased oxidative stress. It is still unclear whether homocysteine-induced oxidative stress is implicated in the regulation of ET-1 expression. We examined the impact of acute homocysteinemia on endothelial function in hypertensive patients and healthy individuals, and the potential role of ET-1.


METHODS
In this double-blind, placebo-controlled study, 39 hypertensive and 49 healthy individuals were randomized to receive high-dose vitamins (2 g vitamin C and 800IU vitamin E) or placebo followed by methionine loading 100 mg/kg body weight. Endothelium-dependent dilation (EDD) and endothelium-independent dilation (EID) of the brachial artery were evaluated by plethysmography, at baseline and 4 h postloading (4 h PML). ET-1 was measured by ELISA, whereas total lipid hydroperoxides (per-ox) levels were measured by a commercially available photometric technique.


RESULTS
Acute, methionine-induced homocysteinemia decreased EDD in all study groups (P < 0.001 for all), whereas vitamins pretreatment failed to prevent this effect, despite the vitamins-induced reduction of peroxidation in the hypertensives group (P < 0.05). On the contrary, methionine loading significantly increased plasma ET-1 levels only in hypertensives (P < 0.05), an effect which was not prevented by antioxidant vitamins (P < 0.05). EID remained unchanged after methionine loading, in all study groups (P = NS for all groups).


CONCLUSIONS
Experimental homocysteinemia rapidly blunts endothelial function in both hypertensive individuals and healthy individuals. The rapid elevation of ET-1 levels observed only in hypertensives, suggests that ET-1 may be the key mediator of homocysteine-induced endothelial dysfunction, independently of oxidative stress.
Tousoulis
Dimitris
D
S Karagiorga 69, Glifada 166 75, Athens, Greece. drtousoulis@hotmail.com
Bouras
George
G
Antoniades
Charalambos
C
Marinou
Kyriakoula
K
Miliou
Antigoni
A
Papageorgiou
Nikos
N
Chatzis
George
G
Tentolouris
Costas
C
Tsioufis
Costas
C
Stefanadis
Christodoulos
C
D000328:Adult; D001205:Ascorbic Acid / Q000008:administration & dosage; D004311:Double-Blind Method; D019332:Endothelin-1 / Q000097:blood / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D005260:Female; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000209:etiology / Q000503:physiopathology*; D006973:Hypertension / Q000097:blood / Q000503:physiopathology*; D008297:Male; D008715:Methionine / Q000008:administration & dosage*; D018384:Oxidative Stress; D015398:Signal Transduction; D014664:Vasodilation / Q000187:drug effects; D014810:Vitamin E / Q000008:administration & dosage
D019332:Endothelin-1; D006710:Homocysteine; D014810:Vitamin E; D008715:Methionine; D001205:Ascorbic Acid