The preferential inhibitory effect of olmesartan, a new angiotensin II type 1 antagonist, on sympathetic nerve terminals in isolated canine splenic artery.
Effects of olmesartan (RNH-6270: (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxy-4-(1-hydroxy-1-methylethyl)-2-propyl[4-[2-(tetrazol-5-yl)-phenyl]phenyl]methylimidazol-5-carboxylase, an active form of olmesartan medoxomil (CS-866)) was investigated in isolated, perfused canine splenic arterial preparations. Neither exogenous noradrenaline- nor ATP-induced vasoconstrictor responses were modified by treatment with the used concentrations of olmesartan (1-100 nM). A high concentration of 10 nM angiotensin II caused a potentiation of either noradrenaline- and ATP-induced constrictions, although 1 nM angiotensin II did not induce any potentiating effects for these responses. These potentiations were inhibited by olmesartan in a concentration-related manner. Periarterial nerve electrical stimulation (PNS) readily induced a biphasic constriction consisting of an initial P2X purinoceptor-mediated vasoconstriction followed by a prolonged mainly alpha(1)-adrenoceptor-mediated response. PNS-induced 1st and 2nd peaked responses were significantly inhibited by olmesartan in a concentration-related manner. With a low concentration of 1 nM angiotensin II, which did not induce any vascular effects by itself, PNS-induced responses were markedly enhanced. The enhanced responses were inhibited by olmesartan. It is concluded that endogenous angiotensin II exerts its stimulating action on the releases of ATP and noradrenaline from the periarterial sympathetic nerve terminal, and olmesartan has an inhibitory property on angiotensin II-induced potentiation of endogenous ATP- and noradrenaline-induced responses.
Chiba
Shigetoshi
S
Department of Pharmacology, Shinshu University School of Medicine, Matsumoto, Japan. chiba@sch.md.shinshu-u.ac.jp
Yang
Xiao-Ping
XP
D000320:Adrenergic Fibers / Q000187:drug effects* / Q000502:physiology; D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000502:physiology; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D013157:Splenic Artery / Q000187:drug effects* / Q000502:physiology
D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II