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

Abstract

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. To investigate the influence of pharmacological compounds on pre-junctional sympathetic transmission, the quantification of sympathetic transmitter release is the most straightforward approach. 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. Angiotensin II (0.01 nmol/l-0.1 micromol/l) caused a concentration-dependent enhancement of EFS-evoked noradrenaline release (control versus concentrations 0.1 nmol/l-0.1 micromol/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 micromol/l) produced less than maximal facilitation. The AT1 -receptor antagonists losartan (0.1 nmol/l-0.1 micromol/l), telmisartan (0.01-10 nmol/l) and irbesartan (0.1 nmol/l-0.1 micromol/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). 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.