Eprosartan is an angiotensin II receptor antagonist approved for the treatment of essential hypertension with particular benefit for the secondary prevention of stroke beyond the absolute level of blood pressure reduction [1,2]. However, the effect of eprosartan on various metabolic parameters is currently not extensively documented. Any such effects may be useful, as vascular damage is considered to be a sequel of various underlying mechanisms that are present in hypertensive patients. Some of these mechanisms involve alterations in clotting/fibrinolytic activity, the oxidative damage of vessels and the inflammatory process [3,4]. Moreover, the lipid profile and glucose homeostasis represent additional well-known risk factors for the development of vascular disease in hypertensive patients [5].

Additional actions that could differentiate some of the anti-hypertensive drugs, even within the same class, may affect the evolution of vascular damage. Therefore, we assessed whether eprosartan exerts additional effects on parameters involved in atherogenesis, oxidative stress and clotting activity, beyond its antihypertensive action.

Forty Caucasians (19 females) with essential hypertension were enrolled in the study. Their mean age was 57 years. Most of them were overweight, 17 had metabolic syndrome according to the updated AHA NHLBI statement (defined as 3 or more of the following: waist circumference > 102 cm in men and > 88 cm in women, blood pressure ≥ 130/85 mmHg, triglycerides > 150 mg/dl, HDL-C < 40 mg/dl in men and < 50 mg/dl in women, and fasting glucose ≥ 100 mg/dl), 8 had type 2 diabetes and 18 were smokers (Table 1).

Eprosartan reduced SBP by 8% (p<0.001) and DBP by 13% (p<0.001), while it had a neutral effect on the lipid profile and apolipoprotein levels (Table 2).

Eprosartan did not affect plasma 8-epiPGF2a levels, whereas it significantly increased by 24% the lag time of total serum oxidation (145 ± 54 min vs 180 ± 58 min, p=0.001) (Table 2). Eprosartan reduced by 14% the aspartate aminotransferase (form 21 to 18 U/L, p=0.04) and by 21% the alanine aminotransferase (from 24 to 19 U/L, p=0.05) activity (Table 2).

The administration of eprosartan had no influence on glucose homeostasis, as well as on creatinine and uric acid levels (Table2). In addition, eprosartan did not affect clotting or fibrinolytic activity as this was estimated by PAI-1, tPA and a2-antiplasmin (Table2). The enzymatic activity of Lp-PLA₂ and PON1 were not altered significantly following eprosartan treatment (Table 2).

We found that eprosartan reduced BP levels, but its effects beyond its anti-hypertensive action were limited. Across a wide range of markers related to atherogenesis, such as lipid metabolism, glucose homeostasis, clotting/fibrinolytic process, oxidative stress, and inflammatory mediators for vascular damage, the only additional finding following eprosartan therapy was the reduction in the susceptibility of serum lipids to oxidation as estimated by the increase in lag time, while 8-epiPGF2a, the other marker of oxidative stress, remained unaltered. Thus, any beneficial effect of eprosartan on morbidity/mortality should be mainly attributed to its anti-hypertensive action.

Atherogenesis is considered to be a complex phenomenon implicating vascular oxidative stress, inflammatory pathways and abnormalities in the coagulation/fibrinolysis equilibrium [11]. We estimated the oxidative stress by measurement of 8-epiPGF2a levels, as well as the lag time for the copper-induced oxidation of lipids. 8-epiPGF2a is the most abundant isomer of the F2-isoprostanes, which are isomers of the F2a prostaglandin produced by nonenzymatic peroxidation of arachidonic acid. 8-epiPGF2a is considered to be a marker of oxidative stress, especially of endogenous lipid peroxidation [12-15]. Interestingly, eprosartan increased by 24% the time needed to produce oxidative by-products, while 8-epiPGF2a levels remained unchanged. The

increase of the lag time for LDL oxidation has been previously reported in patients with mild to moderate essential hypertension, and was attributed to the modulation of NADH/NADPH oxidase, which counteracts superoxide production [16].

Eprosartan had no effect on lipid profile, as well as on PON1 and Lp-PLA₂ that are determinants of lipoprotein function and therefore are involved in atherosclerosis. The neutral effect of eprosartan on lipid profile has been previously reported [17], and was also evident in diabetic patients [18]. PON1 and Lp-PLA₂ are enzymes related to the inflammatory mechanisms that take part in atherogenesis. PON1 is an esterase that is exclusively associated with HDL in plasma and catalyses the hydrolysis of phospholipid hydroperoxides and cholesteryl ester hydroperoxides, which are formed during LDL oxidation. Thus, PON1 may play an important role in the anti-atherogenic activity of HDL. In contrast, Lp-PLA₂, an enzyme mainly associated with LDL, is currently related to the inflammatory mechanisms of the atherogenic process. Lp-PLA₂ exhibits a Ca⁺²-independent phospholipase A₂ activity and catalyses the hydrolysis of the ester bond at the sn-2 position of the proinflammatory phospholipid mediator PAF. Lp-PLA₂ also degrades oxidatively fragmented phospholipids, which are formed during the oxidative modification of LDL and are implicated in atherogenesis [19,20]. Neither PON1 nor Lp-PLA₂ activity were significantly altered after eprosartan therapy, in accordance with the neutral effect of other anti-hypertensive agents on these enzymes [21].

On the other hand, the decrease of transaminase activity following eprosartan administration was consistent with a similar effect following losartan treatment [22]. These findings should be interpreted with caution, because a liver biopsy was not performed in any of our patients to diagnose non-alcoholic fatty liver disease (NAFLD). However, this reduction in liver transaminases may represent a beneficial effect of angiotensin receptor blockers on NAFLD.

Eprosartan had no influence on glucose homeostasis, as was evident from the measurement of glucose, insulin and HOMA index. Consistent with our results, in experimental studies with animals eprosartan failed to induce peroxisome-proliferator–activated receptor (PPAR) γ activity and accordingly failed to demonstrate insulin-sensitizing/antidiabetic effects [23,24]. In humans, eprosartan also has been reported to exert a neutral effect on glucose and insulin levels [17], even in diabetic patients [18].

Eprosartan had a neutral effect on creatinine and uric acid levels, as previously reported [25-27].

Finally, eprosartan did not interfere with the coagulation/fibrinolysis status, although in one report eprosartan seemed to favourably affect these variables [28].

Currently, the anti-hypertensive potency of a drug is considered to be the principal factor that lowers morbidity/mortality and guidelines focus on BP levels as the main target of therapy. In this respect, eprosartan lowered both the SBP and DBP. In contrast, eprosartan had a neutral effect on various metabolic parameters related to the development of vascular disease. The novel findings that eprosartan increased the time needed to produce oxidative by-products and the effect of eprosartan on liver transaminases requires confirmation from larger studies, focusing specifically on eprosartan. This is because there are differences in the properties of the drugs, even in the same class, as was evident from the PPAR γ agonist activity of telmisartan and the uricosuric activity of losartan [29].

In conclusion, based on our findings, eprosartan should be mainly considered as an anti-hypertensive medication with neutral effects on most of the underlying metabolic parameters in hypertensive patients.