Solvay Pharmaceuticals GmBH

Benefits of a Dual Blockade of Angiotensin II and Catecholamines

Adverse effects of increased angiotensin II levels and catecholamines have traditionally been considered as two different therapeutic targets. Increasing evidence indicates, however, that drugs are available which affect both, angiotensin II and catecholamines. A lead compound of this promising class of drugs is the AT1 receptor blocker eprosartan

Eprosartan differs from currently used AT1 receptor blockers in various aspects. In contrast to the other AT1 receptor blockers, eprosartan has a distinct chemical structure.
It is the first non-biphenyl, non-tetrazole, non-peptide AT1 receptor blocker used as antihypertensive drug. The results of preclinical studies to date indicate that the inhibition of norepinephrine release from sympathetic nerve terminals by AT1 receptor blockers is a class effect, with eprosartan being significantly more potent than other agents in this class. This increased potency may be due to differences in the chemical structure and receptor binding characteristics of eprosartan when compared with other AT1 receptor blockers. In a recent study by Pinheiro et al.
Eprosartan was found to reduce both the presynaptic norepinephrine release and the postsynaptic contraction at comparable doses. By contrast, losartan and candesartan required higher concentrations for observing a pre-synaptic effect. Since the therapeutic dose is most probably targeted at the postsynaptic action, i.e. reduction of angiotensin II mediated vasoconstriction, it appears that only eprosartan has an action at the presynaptic level using a therapeutic dose.
The dual inhibitory action of eprosartan on adrenergic influences and angiotensin II could be of particular relevance in hypertensive patients with a severely remodeled vasculature associated with an increased pulse pressure.

Eprosartan effectively lowers blood pressure when compared with other first-line drugs involving beta-blockers, calcium antagonists and diuretics. Eprosartan has been shown to reduce blood pressure in a number of trials. In the case of mild to moderate hypertension (sitSBP > or = 160 mm Hg and sitDBP 90-114 mmHg), eprosartan was at least as effective as the ACE inhibitor enalapril, but with a significantly lower incidence of side effects

In the case of severe hypertension (sitDBP > 115 and < 125 mm Hg), eprosartan lowered systolic blood pressure to a greater extent
It remains to be examined whether a treatment duration of a few months is adequate for demonstrating any "reversed remodeling" of the vasculature arising from the benefits postulated for eprosartan when compared with an ACE-I or other AT1 blockers.

Since a remodeling of the vasculature involves both, angiotensin II and catecholamines, it has been suggested that the dual mechanism of action of eprosartan might be particularly advantageous when prevention of a further adverse vascular remodeling is crucial. This is the case in hypertensive patients when the remodeling process has reached the large arteries and the aorta leading to an impaired coronary perfusion.