Effects of aliskiren on stroke in rats expressing human renin and angiotensinogen genes.
OBJECTIVE
Pre-treatment with angiotensin receptor blockers is known to improve neurological outcome after stroke. This study investigated for the first time, whether the renin inhibitor aliskiren has similar neuroprotective effects.


METHODS
Since aliskiren specifically blocks human renin, double transgenic rats expressing human renin and angiotensinogen genes were used. To achieve a systolic blood pressure of 150 or 130 mmHg animals were treated with aliskiren (7.5 or 12.5 mg/kg*d) or candesartan (1.5 or 10 mg/kg*d) via osmotic minipump starting five days before middle cerebral artery occlusion with reperfusion. Infarct size was determined by magnetic resonance imaging. mRNA of inflammatory marker genes was studied in different brain regions.


RESULTS
The mortality of 33.3% (7 of 21 animals) in the vehicle group was reduced to below 10% by treatment with candesartan or aliskiren (p<0.05). Aliskiren-treated animals had a better neurological outcome 7 days post-ischemia, compared to candesartan (Garcia scale: 9.9±0.7 vs. 7.3±0.7; p<0.05). The reduction of infarct size in the aliskiren group did not reach statistical significance compared to candesartan and vehicle (24 h post-ischemia: 314±81 vs. 377±70 and 403±70 mm(3) respectively). Only aliskiren was able to significantly reduce stroke-induced gene expression of CXC chemokine ligand 1, interleukin-6 and tumor necrosis factor-alpha in the ischemic core.


CONCLUSIONS
Head-to-head comparison suggests that treatment with aliskiren before and during cerebral ischemia is at least as effective as candesartan in double transgenic rats. The improved neurological outcome in the aliskiren group was blood pressure independent. Whether this effect is due to primary anti-inflammatory mechanisms has to be investigated further.
Center for Cardiovascular Research/Institute of Pharmacology, Charité, Berlin, Germany.
Kristin
K
Schmerbach
Thiemo
T
Pfab
Yi
Y
Zhao
Juraj
J
Culman
Susanne
S
Mueller
Arno
A
Villringer
Dominik N
DN
Muller
Berthold
B
Hocher
Thomas
T
Unger
Christa
C
Thoene-Reineke
D000577:Amides / Q000494:pharmacology*; D000808:Angiotensinogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D002545:Brain Ischemia / Q000235:genetics / Q000503:physiopathology; D002539:Cerebral Arterial Diseases / Q000503:physiopathology; D002561:Cerebrovascular Disorders / Q000503:physiopathology; D054360:Chemokine CXCL1 / Q000235:genetics; D005650:Fumarates / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D051381:Rats; D012083:Renin / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020521:Stroke / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D013777:Tetrazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D000092502:Renin Inhibitors
D000577:Amides; D000808:Angiotensinogen; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D054360:Chemokine CXCL1; D005650:Fumarates; D015850:Interleukin-6; D012083:Renin; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D000092502:Renin Inhibitors; C513297:Cxcl1 protein, rat; C446481:aliskiren; C081643:candesartan