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.


METHODS
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 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).


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.
Department of Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands. a.nap@amc.uva.nl
Alexander
A
Nap
Jippe C
JC
Balt
Martin
M
Pfaffendorf
Pieter A
PA
Van Zwieten
D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000294:innervation; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D066298:In Vitro Techniques; D000077405:Irbesartan; D019808:Losartan / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D009994:Osmolar Concentration; D011817:Rabbits; D044140:Receptor, Angiotensin, Type 1; D013564:Sympathetic Nervous System / Q000502:physiology; D013565:Sympatholytics / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects; D000077333:Telmisartan; D013777:Tetrazoles / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001565:Benzoates; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013565:Sympatholytics; D013777:Tetrazoles; D000804:Angiotensin II; D000077405:Irbesartan; D019808:Losartan; D000077333:Telmisartan; D009638:Norepinephrine