Reduction of cerebral infarct size by the AT1-receptor blocker candesartan, the HMG-CoA reductase inhibitor rosuvastatin and their combination. An experimental study in rats.
Our purpose was to test the impact of single and/or combined treatment with the AT(1)-receptor blocker candesartan and the HMG-CoA reductase inhibitor rosuvastatin on infarct size and neuroscore in transient cerebral ischemia in rats. L-NAME was used to test whether any potential effect was due to activation of endothelial nitric oxide synthase (eNOS). Therefore, the middle cerebral artery was occluded for 1 h (MCAO) followed by 7 days reperfusion. Rats received candesartan 2h before and daily after MCAO (pretreatment) or daily after MCAO (posttreatment); rosuvastatin was given daily for 7 days before MCAO without or with candesartan pre- and posttreatment. In addition, candesartan and rosuvastatin were combined with L-NAME. Infarct size and neuroscore at day 7 were compared to those of controls. As result, compared to controls (109+/-12 mm(3)) infarct size with candesartan (pretreatment: 21+/-5 mm(3); posttreatment: 68+/-29 mm(3); P<0.05) or rosuvastatin (69+/-14 mm(3); P<0.05) was smaller. Combined treatment also reduced infarct size (pretreatment: 37+/-15 mm(3); posttreatment 57+/-20mm(3); P<0.05); but there was no benefit of combined treatment over candesartan pretreatment alone. Compared to controls (2.08+/-0.28) only candesartan pretreatment and combined treatment improved the neuroscore (0.97+/-0.05, 1.10+/-0.33; P<0.05). L-NAME abolished the reduction in infarct size and improvement in neuroscore. In conclusion, both, candesartan or rosuvastatin treatment alone reduced infarct size in transient cerebral ischemia, and the best result was achieved with candesartan pretreatment. Combined treatment was superior to rosuvastatin alone, but not to candesartan. The therapeutic benefit of both agents was at least in parts mediated by eNOS-activation.
Engelhorn
Tobias
T
Department of Neuroradiology, University of Erlangen, School of Medicine, Schwabachanlage 6, D-91054 Erlangen, Germany. tobias.engelhorn@nrad.imed.uni-erlangen.de
Doerfler
Arnd
A
Heusch
Gerd
G
Schulz
Rainer
R
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005464:Fluorobenzenes / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000503:physiopathology; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000627:therapeutic use*; D013777:Tetrazoles / Q000627:therapeutic use*; D016896:Treatment Outcome
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D044140:Receptor, Angiotensin, Type 1; D013449:Sulfonamides; D013777:Tetrazoles; D009569:Nitric Oxide; D000068718:Rosuvastatin Calcium; D052250:Nitric Oxide Synthase Type III; C081643:candesartan; D019331:NG-Nitroarginine Methyl Ester