Renal vascular responses to renin inhibition with zankiren in men.
Renin inhibition represents an alternative to angiotensin-converting enzyme (ACE) inhibition for pharmacologic interruption of the renin-angiotensin system. In addition to inhibiting the formation of angiotensin II, ACE inhibitors also inhibit the degradation of kinin and result in accumulation of powerful renal vasodilator prostaglandins and bradykinin. We were therefore surprised by the large renal vasodilator response achieved with the renin inhibitor enalkiren, because substrate-specific renin inhibitors reduce the formation of angiotensin II without affecting other vasodilator mechanisms. To determine whether previous findings were reflective of the renin inhibitor class, we studied 12 healthy men on a sodium-restricted diet, each of whom received two or three escalating oral doses of zankiren, a new agent. Plasma renin activity decreased with the smallest dose (5 mg), and this effect was sustained. The increase in renal plasma flow was clearly related to dose (r = 0.86, F = 9.67), reaching a maximum of 134 +/- 26 ml/min/1.73 m2 at 250 mg, the highest dose. Renin inhibition exerts a remarkable renal vasodilator action, perhaps reflecting the lipophilicity of the agents developed to date, an action that may have clinical implications for the prevention of renal injury in patients at risk.
Fisher
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Department of Medicine, Harvard Medical School, Boston, MA, USA.
Hollenberg
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N
D000328:Adult; D000450:Aldosterone / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009318:Natriuresis / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D012016:Reference Values; D017595:Renal Plasma Flow / Q000187:drug effects*; D012083:Renin / Q000097:blood; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D000092502:Renin Inhibitors
D000450:Aldosterone; D006854:Hydrocortisone; D010879:Piperazines; D012083:Renin; D013844:Thiazoles; D000092502:Renin Inhibitors; C076903:zankiren hydrochloride