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.

Circadian and seasonal variation of endogenous ubiquinone plasma level.

Coenzyme Q10 (CoQ10) or ubiquinone, a redox component of the mitochondrial electron transport chains, is a powerful antioxidant and membrane stabilizer that may prevent cellular damage during myocardial ischemia and reperfusion therapy. Coenzyme Q10 has been used primarily as an adjuvant therapy for some cardiomyopathies. However, one of the main problems in CoQ10 administration is the high variability of endogenous plasma and tissue levels, which seems to be dependent on several factors. This work explores temporal 24h and seasonal variation as well as gender and racial differences in endogenous plasma ubiquinone concentration. Coenzyme Q10 measurements (quantified by HPLC-UV) of 16 healthy volunteers were done during the daytime hours of activity beginning at 09:00h one day and ending at 09:00h the next day (13 different determinations) in two distinct months. April and October, of the year. A statistically significant circadian rhythm in plasma ubiquinone concentration that includes only the fundamental 24h component was demonstrated both in the April and October data. Furthermore, the time-point means of the ubiquinone concentration in the October study were invariably higher than those obtained in the April study. No statistically significant differences were found in CoQ10 concentration between male and female subjects, both in April and in October. In addition, racial differences were demonstrated; lower plasma ubiquinone levels were found in Caucasian compared to African subjects. However, the latter small group of subjects failed to demonstrate a circadian rhythm, neither in the April nor in the October analysis.