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. Keywords:: angiotensin II, angiotensin II receptor blocker, hypertension, imaging mass spectrometry, vascular contraction