title: Prejunctional and postjunctional inhibitory actions of eprosartan and candesartan in the isolated rabbit mesenteric artery.
abstract: Effects of angiotensin II type 1 (AT1) receptor antagonists eprosartan and candesartan and AT2 receptor antagonist PD123319 on Ang II-induced facilitation of noradrenergic neurotransmission were investigated in isolated rabbit mesenteric artery under isometric conditions. Sympathoinhibitory potency of AT1 blockers was compared with their potency concerning inhibition of direct vasoconstrictor effect of Ang II. To investigate blockade of presynaptic AT1 and AT2 receptors, effects of Ang II on electrical field stimulation (EFS)-induced contractions in presence or absence of eprosartan, candesartan, or PD123319 were studied. To investigate blockade of postsynaptic AT1 receptors, effects of either eprosartan or candesartan on concentration-response curves of Ang II were studied. In addition, effect of Ang II on postsynaptic alpha-adrenoceptor-mediated responses was studied using noradrenaline. EFS (1, 2, and 4 Hz) caused an increase of contractile force. At stimulation frequencies of 1, 2, and 4 Hz, a subpressor concentration of Ang II (0.5 nM) increased stimulation-induced vasoconstrictor responses by 2.8 +/- 0.5, 2.4 +/- 0.4, and 1.6 +/- 0.1 of control values, respectively (p < 0.05 compared with control for all frequencies). The enhancement could be antagonized by eprosartan (1 nM-0.1 microM) and candesartan (1 nM-0.1 microM). The AT2 antagonist PD123319 (10 nM) did not influence Ang II-induced facilitation of stimulation-induced contractions. Contractile responses to exogenous noradrenaline were unaltered in presence of Ang II 0.5 nM. Ang II (1 nM-0.3 microM) caused a concentration-dependent increase in contractile force, which could be antagonized by eprosartan (pD2; 8.8 +/- 0.19) and candesartan (pD2; 11.3 +/- 0.23). Thus, the facilitating effect of Ang II on noradrenergic neurotransmission is mediated by presynaptically located AT1 receptors and not by AT2 receptors. For eprosartan, sympathoinhibition was achieved at concentrations that also block AT1 receptors on vascular smooth muscle. In contrast, for candesartan, presynaptic inhibitory concentrations were considerably higher than those required for postsynaptic inhibition.
authors.affiliation: Department of Pharmacotherapy, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. J.C.Balt@amc.uva.nl
authors.forename: Jippe C
authors.initials: JC
authors.lastname: Balt
authors.forename: Marie-Jeanne
authors.initials: MJ
authors.lastname: Mathy
authors.forename: Alexander
authors.initials: A
authors.lastname: Nap
authors.forename: Martin
authors.initials: M
authors.lastname: Pfaffendorf
authors.forename: Pieter A
authors.initials: PA
authors.lastname: van Zwieten
mesh_terms: D000179:Acrylates / Q000494:pharmacology*; D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D004305:Dose-Response Relationship, Drug; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000502:physiology; D017661:Receptors, Presynaptic / Q000037:antagonists & inhibitors* / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology*; D013876:Thiophenes
chemical_list: D000179:Acrylates; D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D017661:Receptors, Presynaptic; D013777:Tetrazoles; D013876:Thiophenes; D000804:Angiotensin II; C068373:eprosartan; C081643:candesartan