Isosorbide-5-mononitrate treatment prevents cyclosporin A-induced platelet hyperactivation and the underlying nitric oxide-cyclic guanosine-3',5'-monophosphate disturbances.
BACKGROUND
The clinical use of cyclosporin A (CsA) is commonly associated with the development of hypertension and increased risk of thromboembolic events. Decreased endothelium-dependent relaxation and increased platelet activation seems to be involved on those side effects, but the underlying mechanisms are not yet elucidated. The present study aimed to evaluate the CsA effect on the platelet NO-cyclic guanosine-3',5'-monophosphate (cGMP) pathway and the putative benefits of concomitant isosorbide-5-mononitrate (IS-5-MN) administration on CsA-induced hypertension and on platelet hyperactivation.


METHODS
Blood pressures, platelet NO synthase activity and cGMP content, intracellular free calcium concentration ([Ca2+]i) and whole blood platelet aggregation were assessed in three rat groups orally treated, during 7 weeks, with the following diets: orange juice (control group), 5 mg/kg/day of CsA (CsA group) and 150 mg/kg/day, b.i.d., of IS-5-MN for 2 weeks and IS-5-MN plus 5 mg/kg/day of CsA for 7 weeks (IS-5-MN+CsA group).


RESULTS
IS-5-MN treatment has prevented hypertension development obtained in the solely CsA-treated rats. CsA treatment has inhibited NOS activity, which was reverted by the concomitant IS-5-MN and CsA administration. On the contrary, platelets from CsA-treated rats had cGMP content increased when compared with the control rats. The variation obtained when ISMN was present was less predominant. Therefore, the organic nitrate treatment has prevented platelet hyperactivation, namely, by decreasing thrombin-evoked [Ca2+]i and collagen-evoked platelet aggregation, when compared with the solely CsA-treated group. The preventive effect of IS-5-MN was reinforced by electron microscopy studies of platelet activation.


CONCLUSIONS
By increasing [Ca2+]i and aggregation, CsA induces platelet hyperactivation and simultaneously increases cGMP content, which might represent a compensatory inhibitory mechanism. The concomitant IS-5-MN treatment prevents the above-mentioned platelet hyperreactivity and tends to normalize the NO-cGMP pathway as well as the development of hypertension.
Reis
Flávio
F
Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, Coimbra University, 3004-504, Coimbra, Portugal.
Almeida
Luís
L
Alcobia
Teresa
T
Santos-Dias
José D
JD
Lourenço
Margarida
M
Palmeiro
Aida
A
Ferrer-Antunes
Carlos A
CA
Mesquita
José F
JF
Pontes
Fausto
F
Teixeira
Frederico
F
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D016572:Cyclosporine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000378:metabolism; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D008854:Microscopy, Electron; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009994:Osmolar Concentration; D051381:Rats; D017208:Rats, Wistar
D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D016572:Cyclosporine; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate; D002118:Calcium