Sympatholytic properties of several AT1-receptor antagonists in the isolated rabbit thoracic aorta

OBJECTIVE To evaluate the facilitating effect of angiotensin II on sympathetic neurotransmission to quantitatively compare the sympatho-inhibitory potencies of the selective AT1-receptor antagonists losartan, irbesartan and telmisartan in the isolated rabbit thoracic aorta. DESIGN To investigate the influence of pharmacological compounds on pre-junctional sympathetic transmission, the quantification of sympathetic transmitter release is the most straightforward approach. METHODS To investigate the sympatholytic properties of AT1-blockers, we studied their effects on the enhancement by angiotensin II of electrical field stimulation (EFS)-evoked (2 Hz) sympathetic transmission in a modified spillover model. RESULTS Angiotensin II (0.01 nmol/l−0.1 μmol/l) caused a concentration-dependent enhancement of EFS-evoked noradrenaline release (control versus concentrations 0.1 nmol/l−0.1 μmol/l, P < 0.05). The maximal augmentation, by almost 100%, was observed at a concentration of 1 nmol/l (FR2/ FR1, 2.03 ± 0.11 versus control, 0.99 ± 0.03). Higher concentrations (up to 0.1 μmol/l) produced less than maximal facilitation. The AT1-receptor antagonists losartan (0.1 nmol/l−0.1 μmol/l), telmisartan (0.01–10 nmol/l) and irbesartan (0.1 nmol/l−0.1 μmol/l) concentration dependently attenuated the angiotensin II-mediated (1 nmol/l) enhancement of EFS-evoked sympathetic outflow. The concentrations that reduced the enhancement by 50% (IC50 values, expressed as −log mol/l ± SEM) were 9.05 ± 0.16 losartan, 10.28 ± 0.20 telmisartan and 9.20 ± 0.23 irbesartan. Accordingly, the order of potency with respect to sympatho-inhibition proved telmisartan > irbesartan = losartan (where > signifies P < 0.05). CONCLUSIONS The facilitating effect of angiotensin II on the sequelae of neuronal stimulation appears to be mediated by pre-synaptically located AT1-receptors. Facilitation can be concentration dependently attenuated by AT1-blockade. The order of potency with respect to sympatho-inhibition is telmisartan > irbesartan = losartan. These differences may be explained by differences in affinity for the pre-synaptic AT1-receptor.