[Arterial hypertension and oxidative stress induced by cyclosporin. Effect of carvedilol].
Cyclosporin-induced hypertension and endothelial dysfunction have been attributed to the effects of cyclosporin on factors controlling vasomotor tone. Endothelial nitric oxide (NO) regulates basal vasodilation, and an NO-mediated protective mechanism from cyclosporin-induced vasoconstriction has been proposed. In transplanted patients with cyclosporin-induced hypertension, we have recently demonstrated upregulation of the NO system and superoxide and free radical overproduction, which, by increasing NO metabolism, could induce hypertension, vascular remodeling and chronic rejection. In the present work, we have evaluated endothelial constitutive NO synthase (ecNOS), transforming growth factor beta and heme oxygenase-1 (protective against oxidative stress), mRNA production and plasma NO metabolites, peroxynitrite and antioxidant power in 15 kidney transplanted patients before and after 4 months of treatment with carvedilol alpha 1-beta-blocker and potent antioxidant. Our aim was to study the efficacy of the reduction of oxidative stress on complications such as endothelial dysfunction and fibrogenesis. Monocyte ecNOS and plasma NO metabolites remained higher versus those of control subjects and were unchanged by carvedilol, while antioxidant power and heme oxygenase-1 mRNA production increased. Peroxynitrite, as well as transforming growth factor beta mRNA, were reduced by carvedilol. It also normalized blood pressure. In conclusion, carvedilol reduces oxidative stress and normalizes blood pressure; ecNOS remains upregulated while mRNA for transforming growth factor beta, a key fibrogenic cytokine, is reduced by carvedilol, which seems to preserve protective mechanisms such as NO and heme oxygenase-1 against long-term complications of oxidative stress, e.g., endothelial dysfunction, fibrogenesis and chronic rejection.
Pagnin
E
E
Clinica Medica 4, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Padova.
Giacon
B
B
Zaghetto
F
F
Vianello
D
D
Bonfante
L
L
Huber
W
W
Antonello
A
A
Semplicini
A
A
Calò
L
L
D000328:Adult; D000975:Antioxidants / Q000627:therapeutic use*; D002227:Carbazoles / Q000627:therapeutic use*; D000077261:Carvedilol; D016572:Cyclosporine / Q000009:adverse effects*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000188:drug therapy*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects*; D011183:Postoperative Complications / Q000139:chemically induced* / Q000188:drug therapy*; D011412:Propanolamines / Q000627:therapeutic use*
D000975:Antioxidants; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D016572:Cyclosporine