Oxidative stress and TGFbeta in kidney-transplanted patients with cyclosporin-induced hypertension. Effect of carvedilol and nifedipine.
Cyclosporin is a powerful stimulator of oxidative stress signaling, leading to TGFbeta production, NO degradation, endothelial dysfunction, hypertension and post-transplant nephropathy. Carvedilol, alpha1-beta-blocker with strong antioxidant activity, may interfere with this chain of events. Therefore, we measured monocyte ecNOS, TGFbeta and heme oxygenase-1 (HO-1) mRNA level and plasma nitrite/nitrate, 3-nitrotyrosine, an estimate of peroxynitrite, and total plasma antioxidant power in kidney-transplanted patients with post-transplant hypertension, before and after treatment with carvedilol, 25 - 50 mg o.d. orally for 4 months (n = 15). The dihydropyridine calcium channel blocker nifedipine (n = 10) was used as comparator antihypertensive drug. Blood pressure fell to a similar extent with both drugs. Carvedilol increased plasma antioxidant power and HO-1 mRNA and reduced 3-nitrotyrosine and TGFbeta mRNA levels, while the same was not observed with nifedipine. Monocyte ec NOS mRNA levels and plasma nitrite/nitrate were higher in the patients than in a normotensive healthy control group and were unaffected by either treatment. In conclusion, carvedilol reduces the oxidative stress and corrects the altered cellular signaling mediated by oxidative stress in CsA-induced post-transplant hypertension. Therefore, it may prevent long-term complications, such as endothelial dysfunction, fibrogenesis and post-transplant nephropathy by decreasing NO degradation and production of TGFbeta, a key fibrogenic cytokine, and by activating HO-1 production.
Calò
L
L
renzcalo@unipd.it
Giacon
B
B
Davis
P A
PA
Pagnin
E
E
Piccin
A
A
Riegler
P
P
Huber
W
W
Antonello
A
A
Semplicini
A
A
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000328:Adult; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002227:Carbazoles / Q000627:therapeutic use*; D000077261:Carvedilol; D016572:Cyclosporine / Q000009:adverse effects*; D004341:Drug Evaluation; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000097:blood / Q000187:drug effects; D051547:Heme Oxygenase-1; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D016030:Kidney Transplantation; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009543:Nifedipine / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000097:blood; D019001:Nitric Oxide Synthase / Q000097:blood / Q000187:drug effects; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress / Q000187:drug effects*; D011183:Postoperative Complications / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D011412:Propanolamines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000097:blood / Q000187:drug effects*; D016896:Treatment Outcome; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000097:blood / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D002227:Carbazoles; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D011412:Propanolamines; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D000077261:Carvedilol; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D016572:Cyclosporine; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D009543:Nifedipine