Homocysteine-induced changes in vascular reactivity of guinea-pig pulmonary arteries: role of the oxidative stress and poly (ADP-ribose) polymerase activation.
This study was aimed to examine the effects of homocysteine (Hcy) on vascular responsiveness of guinea-pig isolated pulmonary arteries and to investigate possible underlying mechanisms. In order to evaluate vascular reactivity, isometric tension studies were performed in response to potassium chloride (KCl), phenylephrine (Phe), acetylcholine (ACh), and sodium nitroprusside (SNP). Incubation of pulmonary artery rings with Hcy (10(-3)M, 180min) resulted in significant inhibition of response to ACh (an endothelium-dependent vasodilator)(E(max): 55.3+/-6.7 vs. 13.1+/-2.0(*), P<0.05) while SNP (an endothelium-independent vasodilator)-induced relaxation was not changed significantly. Furthermore, Hcy enhanced KCl- and Phe-induced contraction of pulmonary artery rings (E(max): 1568+/-81 vs. 2101+/-145(*)mg for KCl and 1081+/-101 vs. 1544+/-117(*)mg for Phe, P<0.05). Pulmonary artery ring contractions induced by stepwise addition to Ca(2+) to high KCl solution with no Ca(2+) were also significantly augmented by Hcy incubation (E(max): 1750+/-121 vs. 2295+/-134(*)mg, P<0.05). To investigate mechanisms of Hcy action, additional sets of experiments involving rings incubation with Hcy alone or with addition of Tiron (an intracellular superoxide anion scavenger, 10(-2)M), PJ34 (an inhibitor of polyADP-ribose polymerase, 3x10(-6)M), and combination of two antioxidant enzymes superoxide dismutase (SOD, 100U/ml) and catalase (CAT, 120U/ml) for 180min. The findings of our study clearly show that all these co-treatments significantly prevented the development of endothelial dysfunction induced by Hcy. Furthermore, the effect of Hcy on KCl- and Phe-induced contraction was significantly inhibited by the concomitant incubation with either SOD plus CAT, Tiron or PJ34. This study demonstrates that Hcy causes a significant alteration in vascular reactivity of pulmonary arteries, and this alteration seems to be via oxidative stress in pulmonary artery endothelium with subsequent DNA damage and activation of poly(ADP-ribose) polymerase (PARP) pathway.
Tasatargil
Arda
A
Faculty of Medicine, Department of Pharmacology, Akdeniz University, 07070, Antalya, Turkey. ardatas@akdeniz.edu.tr
Sadan
Gulay
G
Karasu
Edibe
E
D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002122:Calcium Chloride / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016166:Free Radical Scavengers / Q000494:pharmacology; D006168:Guinea Pigs; D006710:Homocysteine / Q000494:pharmacology; D006711:Homocystine / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010616:Phenanthrenes / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D013482:Superoxide Dismutase / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D000975:Antioxidants; D016166:Free Radical Scavengers; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D006710:Homocysteine; D009599:Nitroprusside; D010656:Phenylephrine; D006711:Homocystine; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D011189:Potassium Chloride; D002374:Catalase; D013482:Superoxide Dismutase; D011065:Poly(ADP-ribose) Polymerases; D002122:Calcium Chloride; D000109:Acetylcholine