Renal and hormonal responses to direct renin inhibition with aliskiren in healthy humans.
BACKGROUND
Pharmacological interruption of the renin-angiotensin system focuses on optimization of blockade. As a measure of intrarenal renin activity, we have examined renal plasma flow (RPF) responses in a standardized protocol. Compared with responses with angiotensin-converting enzyme inhibition (rise in RPF approximately 95 mL x min(-1) x 1.73 m(-2)), greater renal vasodilation with angiotensin receptor blockers (approximately 145 mL x min(-1) x 1.73 m(-2)) suggested more effective blockade. We predicted that blockade with the direct oral renin inhibitor aliskiren would produce renal vascular responses exceeding those induced by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.


RESULTS
Twenty healthy normotensive subjects were studied on a low-sodium (10 mmol/d) diet, receiving separate escalating doses of aliskiren. Six additional subjects received captopril 25 mg as a low-sodium comparison and also received aliskiren on a high-sodium (200 mmol/d) diet. RPF was measured by clearance of para-aminohippurate. Aliskiren induced a remarkable dose-related renal vasodilation in low-sodium balance. The RPF response was maximal at the 600-mg dose (197+/-27 mL x min(-1) x 1.73 m(-2)) and exceeded responses to captopril (92+/-20 mL x min(-1) x 1.73 m(-2); P<0.01). Furthermore, significant residual vasodilation was observed 48 hours after each dose (P<0.01). The RPF response on a high-sodium diet was also higher than expected (47+/-17 mL x min(-1) x 1.73 m(-2)). Plasma renin activity and angiotensin levels were reduced in a dose-related manner. As another functional index of the effect of aliskiren, we found significant natriuresis on both diets.


CONCLUSIONS
Renal vasodilation in healthy people with the potent renin inhibitor aliskiren exceeded responses seen previously with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. The effects were longer lasting and were associated with significant natriuresis. These results indicate that aliskiren may provide more complete and thus more effective blockade of the renin-angiotensin system.
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. nfisher@partners.org
Naomi D L
ND
Fisher
A H
AH
Jan Danser
J
J
Nussberger
William P
WP
Dole
Norman K
NK
Hollenberg
D000284:Administration, Oral; D000328:Adult; D000577:Amides / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000803:Angiotensin I / Q000097:blood / Q000187:drug effects*; D000804:Angiotensin II / Q000097:blood / Q000187:drug effects*; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002216:Captopril / Q000008:administration & dosage / Q000494:pharmacology; D004032:Diet; D004305:Dose-Response Relationship, Drug; D005260:Female; D005650:Fumarates / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009318:Natriuresis / Q000187:drug effects; D011237:Predictive Value of Tests; D012016:Reference Values; D012079:Renal Circulation / Q000187:drug effects* / Q000502:physiology; D017595:Renal Plasma Flow / Q000187:drug effects* / Q000502:physiology; D012083:Renin / Q000097:blood; D012964:Sodium / Q000652:urine; D012982:Sodium, Dietary; D014664:Vasodilation / Q000187:drug effects; D000092502:Renin Inhibitors
D000577:Amides; D000803:Angiotensin I; D000804:Angiotensin II; D000959:Antihypertensive Agents; D002216:Captopril; D005650:Fumarates; D012083:Renin; D012964:Sodium; D012982:Sodium, Dietary; D000092502:Renin Inhibitors; C446481:aliskiren