The present study intended to investigate if ramipril and telmisartan affect endothelial function differently from each other after the treatment for eight weeks in hypertensive patients. During short period of treatment, while endothelial function estimated with RHI did not change in both groups. Both agents reduced systolic and diastolic blood pressure effectively without difference between two groups.
But, the effects of 8 weeks of treatment on PP were more marked and significant in telmisartan group. Despite these favorable hemodynamic changes, telmisartan didn’t show improving endothelial function. Although mean RHI was stationary in ramipril group during the treatment, what extent RHI changed by is well positively correlated with changes of PP, which means the more decrease PP, the better endothelial function. However, this correlation was not seen in telmisartan group.
A few studies postulated wide PP adversely affect endothelial function [12–15]. Because any other factors associated with endothelial function such as lipid profile, smoking history, were not different between groups, the fact improvement of endothelial function is not correlated with decrease of PP in telmisartan group suggests telmisartan itself may negatively influence endothelium dependent vasodilatation.
Ramipril, a kind of ACEIs reduces the AT II level by inhibition of AT I converts to AT II, increases NO and other endothelial mediators induced by bradykinin via inhibition of kininase II, which is responsible for the degradation of bradykinin . Bradykinin affects vasodilatation via NO, prostacyclin and hyperpolarizing factor .
Telmisartan, a kind of ARBs inhibits the renin angiotensin system (RAS) in different way from ACEIs. ARBs bind to the AT1 receptor, interrupting its activation. As a result of AT1 receptor blockade, ARBs increase AT II concentration by a positive feedback resulting in stimulating AT II type 2 receptors (AT2Rs) as alternative pathway. AT2Rs have a role in vasodilatation by counteracting AT1 receptor mediated vasoconstriction . And ARBs lead to bradykinin-dependent NO release through AT2R . AT II binding to AT2Rs induces intracellular acidification, which activates a kininogenase. This increases production of bradykinin, which increases NO and vascular smooth muscle cell relaxation [10, 19]. But, many studies have demonstrated negative effects of persistent AT2R stimulation recently. AT2Rs mediate arterial hypertrophy, cardiac hypertrophy and fibrosis and anti-angiogenic effect on cardiovascular tissues, although it’s uncertain if all of these changes accompany endothelial dysfunction [18, 20, 21].
In this respect, ‘ARB-acute myocardial infarction (MI) paradox’ was issued in 2004 after releasing VALUE trial. This theory focused on increase of MI in valsartan arm compared with amlodipine arm in the VALUE trial (hazard ratio = 1.19, 95% CI 1.02 to 1.38, p = 0.02) [22, 23]. Other meta-analysis of ACEIs and ARBs trials showed that ACEIs (versus placebo, non ARBs comparator and ARBs) reduced the relative risk of MI by 14% (OR 0.86, 95% CI 0.82 to 0.90, p < 0.001), whereas ARBs (versus placebo, non ACEIs comparator and ACEIs) increased the risk of MI (OR 1.08, 95% CI 1.01 to 1.16, p = 0.03) . Although a meta-analysis of Tsuyuki and McDonald reported that ARBs did not increase the risk of MI with OR of 1.03 (95% CI 0.93 to 1.13) compared to ACEIs, many subsequent studies disproved the results . The BPLTTC meta-regression analysis of 26 trials (17 trials with ACEIs and 9 trials with ARBs) showed that both ACEIs and ARBs have BP dependent risk reduction of stroke, coronary heart disease and heart failure . However, after adjusted for BP reduction within trials, the estimated risk reduction for coronary heart disease was 9% (3 to 14%, p = 0.004), whereas ARBs do not. Furthermore, ONTARGET compared telmisartan with ramipril in patients with vascular disease or high risk diabetes . Telmisartan bad better BP lowering effect than ramipril, but increased MI by 7%, although statistically insignificant.
This randomized trial showed patients in both groups didn’t show improvement of endothelial function than baseline after 8 week treatment, even though blood pressure reduction was enough. This finding the improvement of endothelial function and reduction of BP are not corresponding has ever been reported by Ghiadoni et al. . In his study, ACEIs, calcium antagonists, ARBs, and beta blockers similarly reduced BP, but only perindopril, one type of ACEI, improved endothelial function.
It’s notable the reduction of PP is well correlated with the improvement of endothelial function expressed as a RHI not in telmisartan group, but in ramipril group. Higher PP exerts lower shear stress against arterial wall subsequently resulting in larger oxidative stress and reduced NO production . In telmisartan group, PP decreased significantly after treatment. However, PP reduction was not related with endothelial function improvement in telmisartan group. This finding suggests telmisartan is likely to have a prohibiting effect on endothelial functional recovery initiated by PP reduction.
Several limitations of our study should be mentioned. First, the present study is too small study to make a confirmatory conclusion regarding inferiority of telmisartan in the aspect of endothelial function. Actually, there are many studies revealing favorable effects of ARBs on endothelial function. Shuang Li et al. investigated 1737 patients of 22 trials with endothelial dysfunction, and showed that ARBs could improve endothelial function assessed by FMD compared with placebo or other hypertensive medication such as calcium channel blockers, beta-blockers and diuretics . But, ARBs have no significant difference with ACEIs. Other many studies show ARBs and ACEIs improved endothelial function without difference. Hornig et al. demonstrated that ACEIs and ARBs improved endothelial vasodilatation to a similar extent in coronary artery disease patients through increasing NO availability . Second, blood flow in cutaneous vessels is known to depend on sympathetic and autonomic nervous systems. Therefore, it is possible that changes in the finger RHI may occur due to changes in room temperature and mental status. We attempted to control these confounders by studying in a quiet and automatically thermostatic room and adjusting pulse amplitude of study arm with one of the contralateral control arm as a reference. Third, we just investigated short term effects of ACEIs and ARBs. It should be further evaluated the results shown in this study can be consistent in long term aspect.