Dose-dependent effects of a selective phosphodiesterase-5-inhibitor on endothelial dysfunction induced by peroxynitrite in rat aorta.
Reactive oxygen species, such as peroxynitrite, induce oxidative stress and DNA injury leading to endothelial dysfunction. It has been proposed, that elevated intracellular cyclic GMP (cGMP)-levels may contribute to an effective cytoprotection against nitro-oxidative stress. We investigated the dose-dependent effects of vardenafil, an inhibitor of phosphodiesterase-5, on endothelial dysfunction induced by peroxynitrite. In organ bath experiments, we investigated the endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside, SNP) vasorelaxation of isolated aortic rings of rats. Endothelial dysfunction was induced by peroxynitrite. In the treatment groups, rats received low doses (0.01-5 microg/kg) or high doses (5-300 microg/kg) of vardenafil. DNA strand breaks were assessed by the TUNEL method. Immunohistochemical analysis was performed for cGMP and nitrotyrosine. Exposure to peroxynitrite resulted in an impairment of endothelium-dependent vasorelaxation of aortic rings. Pre-treatment with lower doses of vardenafil led to an improvement of endothelial function as reflected by the higher maximal vasorelaxation (R(max)) to acetylcholine. Interestingly, at higher doses, R(max) to acetylcholine was attenuated leading to U-shaped dose-response curves. The endothelium-independent vasorelaxation to SNP under peroxynitrite stress showed a significant left-shift of the SNP concentration-response curves in the vardenafil groups without any alterations of the R(max). Vardenafil-pre-treatment significantly reduced DNA-breakage, reduced nitrosative stress, and increased cGMP score in the aortic wall. Our working hypothesis is that improvement of endothelial function could be mainly due to the cytoprotection of endothelium by vardenafil. This work supports the view that acute PDE5-inhibition might be advantageous in the treatment of endothelial dysfunction induced by disturbed NO-cGMP pathway due to nitro-oxidative stress.
Korkmaz
Sevil
S
Department of Cardiac Surgery, University of Heidelberg, 2. OG. INF 326., 69120 Heidelberg, Germany. korkmaz_sevil@hotmail.com
Radovits
Tamás
T
Barnucz
Eniko
E
Neugebauer
Philipp
P
Arif
Rawa
R
Hirschberg
Kristóf
K
Loganathan
Sivakkanan
S
Seidel
Beatrice
B
Karck
Matthias
M
Szabó
Gábor
G
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000378:metabolism* / Q000494:pharmacology; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D000069058:Vardenafil Dihydrochloride; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D007093:Imidazoles; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D017382:Reactive Oxygen Species; D013450:Sulfones; D014227:Triazines; D014665:Vasodilator Agents; D030421:Peroxynitrous Acid; D009599:Nitroprusside; D000069058:Vardenafil Dihydrochloride; D006152:Cyclic GMP; D000109:Acetylcholine