Pre- and postsynaptic inhibitory potencies of the angiotensin AT1 receptor antagonists eprosartan and candesartan.

The aim of the present study was to determine the inhibitory potency of two selective angiotensin AT(1) receptor antagonists, eprosartan and candesartan, at the level of the sympathetic nerve terminal and the vascular smooth muscle. Male New Zealand White rabbits, weighing 2100-2550 g, were used. To study eprosartan and candesartan at the neuronal angiotensin AT(1) receptor, we investigated their influence on the angiotensin II-enhanced, electrical field stimulation-evoked sympathetic transmission in the rabbit isolated thoracic aorta in a noradrenaline spillover model. To study both antagonists at the vascular angiotensin AT(1) receptor, concentration-response curves for angiotensin II were constructed in the presence or absence of the two angiotensin AT(1) receptor antagonists. Angiotensin II (10 nM) caused a significant increase by 107+/-11.1% of the stimulation-evoked sympathetic outflow, which was concentration-dependently inhibited by both eprosartan (pIC(50) 7.91+/-0.12) and candesartan (pIC(50) 10.76+/-0.13). Angiotensin II (1 nM-0.3 microM) caused a concentration-dependent increase in contractile force (E(max) 20.62+/-2.24 mN, pD(2) 8.16+/-0.04). Both eprosartan (pA(2) 8.90+/-0.11, pIC(50) 8.87+/-0.12 (10 nM angiotensin II)) and candesartan (pD(2)' 10.80+/-0.13) counteracted the contractions evoked by cumulative concentrations of angiotensin II. Candesartan proved a more potent antagonist than eprosartan at both the pre- and postjunctional angiotensin AT(1) receptor. For eprosartan, vascular inhibitory concentrations were 10-fold lower than sympatho-inhibitory concentrations, whereas for candesartan, inhibitory concentrations at both sites were similar. The results may be explained by differences between the pre- and postjunctional angiotensin AT(1) receptor subtype.