Antagonism of R-type calcium channels significantly improves cerebral blood flow after subarachnoid hemorrhage in rats.
The effects of R-type calcium channels on cerebral blood flow (CBF) and vasospasm pathways following subarachnoid hemorrhage (SAH) have not been well studied. The aim of this study was to investigate the role of R-type calcium channels in vasospasm development and treatment. Sixty-five rats were randomly divided into four groups: sham (n = 14), SAH (n = 17), SAH + nimodipine (n = 17), and SAH + SNX-482 (n = 17). A prechiasmatic SAH model was constructed on day 0. Then 5 μg of nimodipine (an L-type calcium channel antagonist) or 0.1 μg of SNX-482 (an R-type calcium channel antagonist) was infused intracisternally on days 1 and 2. On day 3, neurological status was evaluated and CBF was determined using fluorescent microspheres. The extent of myosin light chain-2 (MLC2) phosphorylation was determined by urea-glycerol polyacrylamide gel electrophoresis, followed by immunoblotting. The relative presence of R-type calcium channels and calponin was determined by SDS polyacrylamide gel electrophoresis, followed by immunoblotting. Numbers of R-type calcium channels increased following SAH, and neurological deficit, CBF reduction, and enhancement of MLC2 phosphorylation as well as calponin degradation were all found to be present. There were no statistically significant differences in neurological scores among the SAH, SAH + nimodipine, and SAH + SNX-482 groups. Nimodipine had no significant effect on CBF reduction compared to the SAH group (p > 0.008), whereas SNX-482 significantly inhibited CBF reduction (p < 0.008). Both MLC2 phosphorylation and calponin degradation appeared to be inhibited by SNX-482, whereas the effects of nimodipine were relatively blunted. We concluded that an R-type calcium channel antagonist may improve CBF following SAH by partially inhibiting MLC2 phosphorylation and calponin degradation, and may exceed the potential of an L-type calcium channel antagonist, which suggests a more crucial role for R-type calcium channels in the development of SAH vasospasm and its treatment.
Wang
Fei
F
Department of Neurosurgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Yin
Yu-Hua
YH
Jia
Feng
F
Jiang
Ji-Yao
JY
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D020908:Calcium Channels, R-Type / Q000096:biosynthesis* / Q000378:metabolism; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D002536:Cerebral Arteries / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*
C498917:Cacna1e protein, rat; D002121:Calcium Channel Blockers; D020908:Calcium Channels, R-Type; D027682:Cation Transport Proteins