Abstract
Angiotensin II (Ang II) receptor blockers lower blood pressure (BP) by blocking the binding of Ang II to the AT1 receptor. Blockade of the RAAS at the level of the AT1 receptor causes a compensatory rise in plasma renin activity (PRA), which can be used as an indirect measure of the degree and persistence of receptor blockade. This 5-way crossover study compared the increase in PRA (ΔPRA) over 24 hr, following single doses of placebo (PLA), OLM 20 mg, OLM 40 mg, VAL 80 mg and VAL 160 mg in normal volunteers (N=20), with a 7-day washout period between doses. The primary endpoint was ΔPRA from pre-dose to 24 hr. All doses of OLM and VAL increased PRA compared with PLA. At 24 hr post-dose (Figure), PRA remained increased with OLM 20 and 40 mg and with VAL 160 mg, but not 80 mg, compared with PLA (P=0.002, P<0.001, P=0.029). At 24 hr, ΔPRA was significantly higher with OLM 40 mg than with OLM 20 mg (P=0.004) or either VAL dose (P<0.001). At 4 hr post-dose, ΔPRA was similar for OLM and VAL at all doses. With OLM, there was a clear relationship between dose and ΔPRA at 8, 16 and 24 hr. Thus, during treatment with OLM 40 mg ΔPRA was significantly greater than with OLM 20mg (P=0.002, P=0.016, P=0.004 at 8, 16 and 24 hr, respectively). Between VAL 80 and 160 mg, however, there were no significant differences in ΔPRA at these times. Twenty-four hr urine aldosterone excretion rates were significantly lower than PLA with OLM 20 mg (P=0.008) and 40 mg (P=0.040) and VAL 160 mg (P=0.036) but not with VAL 80 mg (P=0.689). These results demonstrate more prolonged AT1 receptor blockade with OLM 40 mg than with either dose of VAL.
