Impairment of vascular and platelet levels of nitric oxide and cyclic guanosine-3',5'-monophosphate in cyclosporin A-induced hypertensive rats.
The therapeutic use of the immunosuppressive agent cyclosporin A (CsA) is associated with arterial hypertension and increased risk of thromboembolism. Impaired endothelium-mediated relaxation is one of the main hypotheses explaining the CsA-induced vascular hyper-reactivity. Since nitric oxide (NO) modulates both vascular and platelet activity, we studied the effects of CsA on the levels of arterial and platelet NO as well as 3',5'-cyclic guanosine monophosphate (cGMP) levels which are influenced by NO. An animal model of CsA-induced hypertension was used. Wistar rats were treated with a clinically relevant, oral dose of 5 mg/kg CsA, daily, for 4 weeks. CsA increased both systolic and diastolic blood pressures compared to non-treated rats (P < 0.01). Nitrite, a NO metabolite, decreased in the entire aorta wall (30%, P < 0.05) and in the aorta wall without the endothelial layer (70 %, P < 0.05) in CsA-treated vs. control groups. cGMP content was also decreased in the CsA-treated group (67%, P < 0.01) vs. control. Taken together, these results suggest a defect on the endothelial NO generation, acceleration of breakdown and/or consumption of NO, as well as marked alterations directly on cGMP metabolism. Conversely, platelet nitrite and cGMP content significantly increased in the CsA-treated rats, which was also observed in in vitro studies of platelet nitrite release following CsA treatment. This suggests a platelet self-regulation mechanism against CsA-induced platelet hyper-reactivity, which, in turn, could compensate vascular impairment.
Santiago
Margarida
M
Unit of Therapeutics, Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Reis
Flávio
F
Almeida
Luís
L
Alcobia
Teresa
T
Dionísio
Joaquim
J
Teixeira
Frederico
F
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D016572:Cyclosporine / Q000009:adverse effects* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects
D007166:Immunosuppressive Agents; D009569:Nitric Oxide; D016572:Cyclosporine; D006152:Cyclic GMP