Reply to 'Multiple and Opposite Effects of Angiotensin II Receptor Blockers on the Bioavailability of Epoxyeicosatrienoic Acids'.

We have read the letter against our recent research of the effects of angiotensin II receptor blockers (ARBs) on the production of arachidonic acid metabolites published in BCPT, from Bellien et al. with great interest, although some concerns were raised about their interpretations. They expanded results of some studies using only one agent of ARBs to the effect of all ARBs. The inhibitory effects of ARBs on the production of epoxyeicosatrienoic acids (EETs) were different among ARBs as shown in our reports 1, 2. Koh et al. 3 have reported that losartan exerted the different effect on plasma level of plasminogen activator I antigen, a thrombolytic marker, from irbesartan and candesartan in patients with hypertension. Thus, the effect of each ARB on the cardiovascular system might be inherent to the drugs. They stated that blockage of angiotensin II type I (AT1) receptor by ARB resulted in down-regulation of soluble epoxide hydrolase (sEH) and is expected to elevate EET levels. However, only high dosage of losartan (25 mg/kg/day) was used in the original report 4. It is uncertain whether the same phenomenon will be observed by the administration of losartan in clinical settings. They described as ‘it was demonstrated that angiotensin II stimulates the CYP450-dependent production of arachidonic acid metabolites in cultured endothelial cells 5, and further ex vivo experiments confirmed that EETs are in fact produced in response to angiotensin II type II (AT2) receptors stimulation and this effect is potentiated by AT1 receptors blockage 6, 7’. However, none of concentrations of EETs and dihydroxyeicosatrienoic acids (DHETs) were included in these articles 5-7. The in vitro study 5 was designed to examine the response to the stimulation induced by angiotensin II in the absence or presence of each EET regioisomer without monitoring any production of arachidonic acid metabolites. The results of the report 6 showed the interesting results using CV11974 (candesartan). Concomitant treatment with candesartan (10 nM) and miconazole, one of the typical cytochrome P450 (CYP) inhibitors, suppressed the vasodilation effect that was observed in the presence of candesartan, suggesting that EETs are associated with vasodilation mediated by AT2 receptor. As shown in our studies 1, 2, candesartan was a weak inhibitor of the production of EETs among ARBs. Thus, we should expand our study to examine the effect of telmisartan, which showed the most potent inhibitory effects on the production of EETs. AT2 receptor was not easy to find in healthy organs in the adults, and its expression is induced under pathophysiological conditions such as mechanical injury or ischaemia 8, 9. Recently, Romero-Nava et al. 10 reported that the hypertensive rats had a higher mRNA and protein expression of AT1 receptor than normotensive rats, while the AT2 expression in aorta remained unchanged. Thus, the effect through the activation of AT2 receptor of each ARB in patients with hypertension should be further evaluated. They stated that the activation of Mas receptors associated with ARB administration contributed to an increase in EET production. However, this evidence was limited to azilsartan (3 mg/kg/day), which showed a weak inhibition of the production of EETs (unpublished data). It should be noted that levels of EETs/DHETs did not alter before and after treatment with azilsartan in the original article 11. We are now conducting a clinical trial to evaluate the impact of ARBs on the circulating EET/DHET concentrations in patients with hypertension. We would like to report the results in near future. No author has any conflict of interest to declare regarding this reply.