title: Significance of the vascular concentration of angiotensin II-receptor blockers on the mechanism of lowering blood pressure in spontaneously hypertensive rats.
abstract: To clarify the hypotensive mechanism of angiotensin II receptor-blockers (ARBs), drug concentrations in plasma and vascular tissues were measured using matrix-assisted laser desorption ionization time-of-flight mass spectrometry and imaging mass spectrometry. In spontaneously hypertensive rats, systolic blood pressure (SBP) was measured 2 and 24 h after administration of candesartan cilexetil (0.3, 1, or 3 mg/kg) or azilsartan (0.3, 1, or 3 mg/kg). SBP was similarly lowered 2 h after administration of azilsartan or candesartan cilexetil, but it was significantly lower in the azilsartan-treated group than in the candesartan cilexetil-treated group at 24 h. Angiotensin II-induced vascular contractions were similarly attenuated 2 h after administration of these drugs, and the contractions were significantly lower in the azilsartan-treated group at 24 h. Although plasma concentration was significantly lower in the azilsartan-treated group at 24 h, vascular concentration of azilsartan was significantly greater than that of candesartan. Significant correlations between SBP and vascular concentrations were observed both at 2 and 24 h, while no significant correlation was observed between plasma and vascular concentrations. In conclusion, the mechanism of ARB-induced hypotension is likely to depend on vascular concentrations rather than plasma concentrations.
authors.affiliation: Department of Pharmacology, Osaka Medical College, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takai
authors.forename: Denan
authors.initials: D
authors.lastname: Jin
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakonjo
authors.forename: Takayuki
authors.initials: T
authors.lastname: Takubo
authors.forename: Toyofumi
authors.initials: T
authors.lastname: Nakanishi
mesh_terms: D000284:Administration, Oral; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D001808:Blood Vessels / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D010069:Oxadiazoles / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D013777:Tetrazoles / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D010069:Oxadiazoles; D013777:Tetrazoles; C521273:azilsartan; C077793:candesartan cilexetil