Abstract 133: Inhibition of TRPV4 is Protective of the Brain and Cerebral Circulation During Ischemic Stroke
Background: Transient receptor potential vanilloid 4 (TRPV4) channels are highly calcium permeable channels expressed in brain and cerebral endothelium and are regulated by a diverse array of stimuli including shear stress, cell swelling and second messengers. We hypothesized that inhibition of TRPV4 during postischemic reperfusion would be protective of the brain and cerebral endothelium.
Methods: Transient MCAO was used for all experiments. Infarction (by TTC) was measured in TRPV4 knockout mice (n=3) or C57B mice treated upon reperfusion with the TRPV4 inhibitor HC067047 (1mg/kg; n=7) or vehicle (n=8) after 90 minutes of ischemia with 24 hours of reperfusion. To determine the effect of TRPV4 inhibition on BBB permeability, hyperglycemic male Wistar rats (3 days by STZ) were treated with HC067047 (1mg/kg; n=6) or vehicle (n=6) upon reperfusion after 2 hours of ischemia and edema measured at 2 hours by wet:dry weights. Lastly, basal tone of MCAs isolated from male Wistar rats after 2 hours of ischemia with 2 hours of reperfusion (MCAO, n=7) or sham controls (Sham, n=6) was measured before and after addition of HC067047 (1μM) at 75 mmHg.
Results: Infarct volume was significantly reduced in TRPV4 knockout mice and with HC067047 treatment vs. vehicle (17.8 ± 2.8% for KO, 22.9 ± 2.7% for HC067047 vs. 39.8 ± 3.3% for vehicle; p<0.05). Hyperglycemic stroke caused considerable edema formation the ipsilateral vs. contralateral brain in vehicle-treated rats (81.38 ± 0.21% vs. 78.64 ± 0.12%; p<0.01) that was prevented by treatment with HC067047 (78.58 ± 0.22% vs. 78.24 ± 0.11%;p>0.05). MCAO diminished basal tone of MCAs vs. sham (16.3 ± 3.3 vs. 26.4 ± 2.8%; p<0.05) that was restored by HC067047 (25.9 ± 3.0%; p<0.05). The constriction to HC067047 did not occur in MCA that were denuded of endothelium or from sham animals.
Conclusion: These results suggest that postischemic reperfusion activates TRPV4 in cerebral endothelium to cause dilation and BBB permeability. The decreased infarct size after TRPV4 inhibition suggests that activation of TRPV4 during ischemia contributes to neuronal cell death. Thus, inhibition of TRPV4 may be an effective treatment for acute ischemic stroke.
Author Disclosures: M.J. Cipolla: None. J.G. Sweet: None. S. Chan: None. M.T. Nelson: None.
- © 2014 by American Heart Association, Inc.