title: Dual effect of nitrate therapy for cyclosporine-induced hypertension on vascular and platelet morphofunctional markers; an animal model.
abstract: The present study sought to evaluate the prevention and reversion effects of isosorbide-5-mononitrate (Is-5-Mn) on the development of hypertension (HT) and on the underlying vascular and platelet morphofunctional disturbances, using an animal model of cyclosporine (CsA)-induced HT. The following rat groups (n = 8) were tested: (1) a control group (orange juice, for 7 weeks); (2) the CsA group (5 mg/kg/d for 7 weeks); (3) the Is-5-Mn group (150 mg/kg/d, twice a day for 7 weeks); (4) the prevention group (Is-5-Mn + CsA) treated for 2 weeks with Is-5-Mn only and thereafter with both drugs for 7 weeks; (5) the curative group (CsA + Is-5-Mn) beginning 7 weeks after CsA and following thereafter with both drugs for 5 weeks. Blood pressure, lipid profile, vascular lesion, platelet aggregation and morphology, and platelet thromboxane A(2)/vascular prostacyclin equilibrium were evaluated. Is-5-Mn + CsA therapy prevented (systolic blood pressure [SBP]: 114.3 +/- 1.9 mm Hg, P < .001; diastolic blood pressure [DBP]: 97.0 +/- 3.3 mm Hg, P < .001) the CsA-induced HT (SBP: 146.2 +/- 4.5 mm Hg, P < .001; DBP: 124.9 +/- 4.5 mm Hg, P < .001 vs control: SBP: 111.6 +/- 0.7 mm Hg; DBP: 94.6 +/- 1.0 mm Hg), as well as the vascular lesion and the platelet morphofunctional disturbances. The curative group did not show attenuated CsA-induced BP increase; it showed further enhancement of the HT effect (SBP: 159.7 +/- 5.5 mm Hg, P < .05; DBP: 132.8 +/- 2.8 mm Hg), as well as worsened vascular lesions and platelet function, namely a disruption in the TXA(2)/PGI(2) equilibrium. Our data suggested that Is-5-Mn therapy may be a valid choice to prevent the morphofunctional changes associated with CsA-induced HT, when used as a preventive therapy. A careful evaluation of the impact of nitrate therapy should be considered, particularly the negative effect on cardiovascular hemodynamics, when considering its use after previous CsA disturbances have been established.
authors.affiliation: Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, Coimbra University, 3004-504 Coimbra, Portugal.
authors.forename: F
authors.initials: F
authors.lastname: Reis
authors.forename: E
authors.initials: E
authors.lastname: Teixeira de Lemos
authors.forename: L
authors.initials: L
authors.lastname: Almeida
authors.forename: B
authors.initials: B
authors.lastname: Parada
authors.forename: A P
authors.initials: AP
authors.lastname: Garrido
authors.forename: P
authors.initials: P
authors.lastname: Rocha-Pereira
authors.forename: A
authors.initials: A
authors.lastname: Santos-Silva
authors.forename: J
authors.initials: J
authors.lastname: Santos-Dias
authors.forename: A
authors.initials: A
authors.lastname: Dinis
authors.forename: A
authors.initials: A
authors.lastname: Figueiredo
authors.forename: C
authors.initials: C
authors.lastname: Costa-Almeida
authors.forename: A
authors.initials: A
authors.lastname: Mota
authors.forename: F
authors.initials: F
authors.lastname: Teixeira
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000473:pathology / Q000648:ultrastructure; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects*; D016572:Cyclosporine / Q000009:adverse effects*; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced* / Q000188:drug therapy / Q000517:prevention & control; D008055:Lipids / Q000502:physiology; D008297:Male; D023421:Models, Animal; D009566:Nitrates / Q000627:therapeutic use*; D010974:Platelet Aggregation / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013928:Thromboxane A2 / Q000378:metabolism
chemical_list: D008055:Lipids; D009566:Nitrates; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; C034240:prostaglandin I3; D016572:Cyclosporine; D011464:Epoprostenol