Curative isosorbide-5-mononitrate treatment, in opposition to the beneficial preventive one, aggravates the prothrombotic and proconstrictor state in cyclosporine-induced hypertensive rats.
1. The aim of the present study was to evaluate the effect of preventive and curative isosorbide-5-mononitrate (Is-5-Mn) treatment on the development of hypertension, cGMP content, thromboxane (TX) A(2)/prostaglandin (PG) I2 balance, the peripheral serotonergic system, platelet activation, lipid peroxidation and plasma lipids in cyclosporine A (CsA)-induced hypertensive rats. 2. Control, CsA (5 mg/kg per day) and Is-5-Mn (150 mg/kg per day, b.i.d.) rat groups were treated orally over a period of 7 weeks. The preventive Is-5-Mn group (Is-5-Mn + CsA) was first treated for 2 weeks with Is-5-Mn, followed by 7 weeks with both drugs; the curative Is-5-Mn group (CsA + Is-5-Mn) was treated for a period of 7 weeks with CsA and with both drugs for an additional 5 weeks. The control group received oral vehicle. 3. Whereas in the group undergoing preventive treatment the CsA-induced increase in blood pressure (BP), compared with the control group, was avoided, in the group undergoing curative treatment, the increase in BP was even higher. The decreased arterial cGMP content in the CsA group was prevented and reverted when Is-Mn was administered either preventatively or curatively with CsA. Platelet TXA2 production, although unaffected in the Is-5-Mn + CsA group, was significantly higher in the CsA + Is-5-Mn group compared with the group receiving CsA alone. Furthermore, plasma TXA2 was reduced following preventive Is-5-Mn treatment, but was worsened in the group undergoing curative therapy. Aortic PGI2 synthesis was identical in all groups. Consequently, the TXA2/PGI2 ratio was only altered in the CsA + Is-5-Mn group, demonstrating a markedly higher value. In both groups treated simultaneously with CsA and Is-5-Mn, a higher platelet 5-hydroxytryptamine (5-HT) content was obtained compared with CsA treatment alone, but only preventive treatment with Is-5-Mn resulted in a significant reduction in plasma 5-HT. Changes in ADP and collagen-induced platelet aggregation paralleled those of plasma 5-HT and TXA2: the hyperaggregation profile of the CsA group, although partially prevented, was not reverted by simultaneous treatment with Is-5-Mn and CsA. Lipid peroxidation and lipid profile values also worsened in the CsA + Is-5-Mn group compared with the group administered CsA alone. 4. In conclusion, the beneficial effects of concomitant Is-5-Mn and CsA treatment were demonstrated when Is-5-Mn was administered preventatively because not only was arterial hypertension prevented, but platelet aggregation and plasma TXA2 and 5-HT levels were also reduced. In contrast, following curative treatment, the BP, platelet/vascular vasoconstrictor balance, lipid peroxidation and plasma lipids were aggravated, recommending a judicious evaluation of the impact of nitrate therapy throughout the period of its administration.
Reis
F
F
Therapeutics Unit, Institute of Pharmacology and Experimental Therapeutics, Coimbra University, Coimbra, Portugal.
Ponte
L
L
Rocha
L
L
Teixeira-Lemos
E
E
Almeida
L
L
Alcobia
T
T
Lourenço
M
M
Palmeiro
A
A
Ferrer-Antunes
C A
CA
Costa-Almeida
C
C
Teixeira
F
F
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D016572:Cyclosporine / Q000633:toxicity*; D011464:Epoprostenol / Q000097:blood / Q000378:metabolism; D006973:Hypertension / Q000097:blood / Q000139:chemically induced* / Q000188:drug therapy* / Q000503:physiopathology; D007548:Isosorbide Dinitrate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D015227:Lipid Peroxidation / Q000187:drug effects; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013928:Thromboxane A2 / Q000097:blood / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects
D013928:Thromboxane A2; D016572:Cyclosporine; D011464:Epoprostenol; D006152:Cyclic GMP; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate