RESUMO
BACKGROUND: Renin inhibition with aliskiren induced the largest increases in renal plasma flow (RPF) in salt-depleted healthy volunteers of all renin-angiotensin system (RAS) blockers. However, given its side-effects at doses higher than 300âmg, no maximum effect of renin inhibition could be established. We hypothesized that VTP-27999, a novel renin inhibitor without major side-effects at high doses, would allow us to establish this. METHODS AND RESULTS: The effects of escalating VTP-27999 doses (75-600âmg) on RPF, glomerular filtration rate (GFR), and plasma RAS components were compared with those of 300âmg aliskiren in 22 normal volunteers on a low-sodium diet. VTP-27999 dose-dependently increased RPF and GFR; its effects on both parameters at 600âmg (increases of 18â±â4 and 20â±â4%, respectively) were equivalent to those at 300âmg, indicating that a maximum had been reached. The effects of 300âmg aliskiren (increases of 13â±â5 and 8â±â6%, respectively; Pâ<â0.01 vs. 300 and 600âmg VTP-27999) resembled those of 150âmg VTP-27999. VTP-27999 dose-dependently increased renin, and lowered plasma renin activity and angiotensin II to detection limit levels. The effects of aliskiren on RAS components were best comparable to those of 150âmg VTP-27999. CONCLUSION: Maximum renal renin blockade in healthy, salt-depleted volunteers, requires aliskiren doses higher than 300âmg, but can be established with 300âmg VTP-27999. To what degree such maximal effects (exceeding those of angiotensin-converting enzyme inhibitors and AT1-receptor blockers) are required in patients with renal disease, given the potential detrimental effects of excessive RAS blockade, remains to be determined.