Hypertension Knowledge Centre
Angiotensin II Antagonists
A Dual Mechanism of Action
Eprosartan has emerged as an AIIA with unique pharmacological properties, setting it apart from other drugs in this class. It has been described as a ‘fourth generation’ AIIA.36 Its therapeutic profile and effectiveness in essential hypertension, as described in this Monograph, are well established and continue to be confirmed as new data become available.
Eprosartan has a dual mode of action, which distinguishes it from other AIIAs.10,11 It not only inhibits the renin-angiotensin system by blocking postsynaptic AT1 receptors on the blood vessel wall, but it also inhibits presynaptic AT1 receptors on sympathetic neurones, decreasing norepinephrine release into the synapse. It therefore has a dual action on the RAS and the sympathetic nervous system (figure 7).
Figure 7: Dual mode of action of eprosartan on postsynaptic and presynaptic angiotensin II receptors. Adapted from 16
Affinity for AT1 receptors
Eprosartan has a high affinity for the AT1 receptor. The inhibition of AT1 receptors by eprosartan is dose-dependent, indicating that the blockade represents true competitive antagonism (‘surmountable’).37 This means that if the body produces increased amounts of angiotensin II, for example in response to a fall in blood volume, eprosartan can be displaced from its binding sites. By contrast, valsartan, irbesartan, candesartan, and the active metabolite of losartan all have non-competitive kinetics, and their binding to angiotensin II receptor sites is insurmountable.38
The competitive binding of eprosartan has been confirmed in man. A double-blind study in healthy volunteers evaluated the in vivo effects of different dosages of eprosartan and placebo on the response to infusions of angiotensin II.39 Eprosartan produced a dose-related inhibition of the effects of angiotensin II, which started about 1 hour after administration (figure 8). Eprosartan given alone, without prior infusion of angiotensin II, did not increase blood pressure. This means it did not partially stimulate the angiotensin II receptors.
Figure 8: Percentage inhibition of the effects of angiotensin II by various doses of eprosartan in healthy volunteers. Adapted from 39
Sympathetic inhibition
Spinal cord stimulation in a pithed rat model increases thoracolumbar sympathetic outflow, resulting in a frequency-dependent increase in blood pressure. In a comparative study using this animal model, the pressor response to spinal cord stimulation was significantly attenuated by eprosartan, whereas losartan, valsartan and irbesartan had little effect (figure 9).10
Figure 9. Acute effects on the pressor response to spinal cord stimulation in pithed rats of eprosartan, losartan, valsartan irbesartan (each given at a dose of 0.3mg/kg iv; n=4 for each AIIA). Adapted from 10
Another study using a similar animal model compared the inhibitory potency of eprosartan, valsartan, candesartan and embusartan in blocking presynaptically and postsynaptically located AT1 receptors. Eprosartan was statistically significantly (p<0.05) more potent in its sympatho-inhibitory properties than the other three AT1 receptor inhibitors.11
The sympatho-inhibitory effects of eprosartan have also been shown in man. In a randomised, double-blind, crossover study, 16 healthy male volunteers received a single dose of eprosartan 600mg or placebo followed by insulin-induced hypoglycaemia.40 The hypoglycemic-induced pulse pressure response to sympathoadrenal activation was statistically significantly reduced by eprosartan compared with placebo(p=0.02).