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

Nap, A.; Balt, J.C.; Pfaffendorf, M.; Van Zwieten, P.A.

Journal of Hypertension 20(9): 1821-1828

2002


ISSN/ISBN: 0263-6352
PMID: 12195125
DOI: 10.1097/00004872-200209000-00028
Accession: 011435637

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 mumol/l) caused a concentration-dependent enhancement of EFS-evoked noradrenaline release (control versus concentrations 0.1 nmol/l-0.1 mumol/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 mumol/l) produced less than maximal facilitation. The AT1-receptor antagonists losartan (0.1 nmol/l-0.1 mumol/l), telmisartan (0.01-10 nmol/l) and irbesartan (0.1 nmol/l-0.1 mumol/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.

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