Effects of homocysteine on acetylcholine- and adenosine-induced vasodilatation of pancreatic vascular bed in rats.
1. Epidemiological and experimental data have shown that homocysteine may provoke vascular lesions and that moderate homocysteinaemia may constitute an independent risk factor for vascular disease. It is now documented that homocysteine damages human endothelial cells in culture, possibly by producing hydrogen peroxide in an oxygen-dependent reaction. 2. In this study, we have examined the direct effect of this sulphur amino acid on pancreatic vascular resistance. Experiments were performed on the vascular bed of the rat isolated pancreas perfused at constant pressure; thus, any change in pancreatic vascular resistance resulted in a change in the flow rate. D,L-Homocysteine perfused for one hour at three different concentrations (200 microM, 2 mM, 20 mM) did not induce any significant change in the flow rate per se. Homocysteine infusion for 30 min at a concentration of 200 microM or 2 mM abolished the endothelium-dependent vasodilatation induced by acetylcholine (0.05 microM), but did not modify adenosine (1.5 microM)-induced vasodilatation. 3. The effect of D,L-homocysteine (200 microM or 2 mM) cannot be ascribed to a direct antimuscarinic effect since 30 min pretreatment of rat ileum with these concentrations did not significantly change the contractile effect of increasing concentrations of acetylcholine (0.015-15 microM). 4. Preincubation of human umbilical vein endothelial cells with D,L-homocysteine (0.2-5.0 mM) had no significant effect on overall cell number or viability during 18 h of incubation; the endothelial cells exposed to concentrations up to 5 mM exhibited a spindle-shaped, whirled pattern. This pattern was reversed 48 h after the removal of homocysteine. A cytotoxic effect was seen after 18 h incubation in 10 mM D,L-homocysteine. 5. In conclusion, an acute infusion of homocysteine altered acetylcholine endothelium-induced vasodilation, whereas the adenosine vasodilatator effect was insensitive to the deleterious action of homocysteine in vitro.
Quéré
I
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Laboratoire de Pharmacologie (UPRES EA 1677), Faculté de Médecine, Montpellier, France.
Hillaire-Buys
D
D
Brunschwig
C
C
Chapal
J
J
Janbon
C
C
Blayac
J P
JP
Petit
P
P
Loubatières-Mariani
M M
MM
D000109:Acetylcholine / Q000494:pharmacology*; D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D007082:Ileum / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010179:Pancreas / Q000098:blood supply* / Q000187:drug effects; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D014665:Vasodilator Agents; D006710:Homocysteine; D000241:Adenosine; D000109:Acetylcholine