Aliskiren, a novel, orally effective renin inhibitor, lowers blood pressure in marmosets and spontaneously hypertensive rats.
OBJECTIVE
Aliskiren is a new renin inhibitor of a novel structural class that has recently been shown to be efficacious in hypertensive patients after once-daily oral dosing. We report the results of animal experiments performed in marmosets and rats in order to characterize aliskiren before its recent investigation in humans.


METHODS
The effects of aliskiren were investigated in sodium-depleted marmosets (oral dosing) and in spontaneously hypertensive rats (dosing via subcutaneous osmotic minipumps). Blood pressure (BP) and heart rate were measured by radiotelemetry.


RESULTS
In sodium-depleted marmosets, single oral doses of aliskiren (1-30 mg/kg) dose-dependently lowered BP. At a dose of 3 mg/kg, peak effects were observed 1 h after dosing (-30 +/- 4 mmHg, n = 6) and the response persisted for more than 12 h. A single oral dose of 3 mg/kg aliskiren was more effective than the same dose of either remikiren or zankiren, two orally active renin inhibitors previously tested in humans. Aliskiren (10 mg/kg) was at least as effective as equal doses of the AT1-receptor blocker valsartan or the angiotensin-converting enzyme inhibitor benazepril. In spontaneously hypertensive rats, aliskiren dose-dependently (10-100 mg/kg per day) decreased BP. Aliskiren also potentiated the antihypertensive effects of low doses of valsartan or benazeprilat (1 or 3 mg/kg per day).


CONCLUSIONS
Aliskiren is an orally effective, long-lasting renin inhibitor that shows antihypertensive efficacy in animals superior to previous renin inhibitors and at least equivalent to angiotensin-converting enzyme inhibitors and AT1-receptor blockers. Aliskiren may therefore represent an effective, novel approach to the treatment of hypertension and related disorders, alone or in combination with other antihypertensive agents.
Wood
Jeanette M
JM
Novartis Institute for BioMedical Research, Basel, Switzerland.
Schnell
Christian R
CR
Cumin
Frederic
F
Menard
Joël
J
Webb
Randy L
RL
D000284:Administration, Oral; D000577:Amides; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D002144:Callithrix; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D005260:Female; D005650:Fumarates / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D012083:Renin / Q000097:blood; D013686:Telemetry; D013777:Tetrazoles / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan; D000092502:Renin Inhibitors
D000577:Amides; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D005650:Fumarates; D007093:Imidazoles; D010879:Piperazines; D012083:Renin; D013777:Tetrazoles; D013844:Thiazoles; D014633:Valine; D000068756:Valsartan; D000092502:Renin Inhibitors; C446481:aliskiren; C076903:zankiren hydrochloride; C052133:benazeprilat; C065581:remikiren