Treatment of Acute Focal Ischemic Stroke with Peroxynitrite Decomposition Catalyst does not Improve Reperfusion, Infarct or Hemorrhage in Chronic Hypertensive Rats
Authors: Chan Siu Lung , Sweet Julie G , Cipolla Marilyn J 
Published: November 2023

Amajority of acute ischemic stroke patients has a history of chronic hypertension, which is associated with worse stroke outcome. Previously we found that ischemia and reperfusion enhanced myogenic tone in brain parenchymalarterioles (PAs) from normotensive rats, however, the impact of chronic hypertension on these vessels after acute ischemic stroke is unknown. We hypothesized that chronic hypertension further increases myogenic tone of PAs after ischemia and reperfusion that worsens early post‐ischemic reperfusion, leading to worse stroke outcome. Moreover, we previously found that the peroxynitrite decomposition catalyst FeTMPyP decreased myogenic tone of PAs after ischemia and reperfusion. We therefore further hypothesized that FeTMPyP treatment would improve reperfusion and hence stroke outcome. Male spontaneously hypertensive rats stroke‐prone (SHRSP, 18‐weeks) and age‐matched normotensive Wistar control(n=6–8/group) were subjected to transient middle cerebral artery occlusion or Sham operation. PAs, isolated after 2 hr of ischemia and 30 min of reperfusion, were pressurized in an arteriograph to study myogenic activity. In another set of animals, FeTMPyP (10 mg/kg, i.p.) or vehicle was given 10 min before reperfusion in Wistar or SHRSP. Early post‐ischemic reperfusion blood flow inbrain parenchyma within the peri‐infarct region was measured in anesthetized animals by hydrogen clearance. Brain infarct size and swelling after 2 hr of ischemia and 2 hr of reperfusion were determined by 2,3,5‐triphenyltetrazoliumchloride (TTC) staining. PAs from Sham SHRSP had increased myogenic tone compared to Sham Wistar (52 ± 2 vs. 43 ± 2 %; p<0.05). Ischemia and reperfusion increased myogenic tone in PAs from Wistar but did not further increase tone in SHRSP, leading to similar tone between groups (59 ± 2 vs. 52 ± 2 %; p>0.05). Brainparenchymal blood flow at 30 min reperfusion was significantly lower than base line in Wistar (54 ± 14 vs. 114 ± 13 ml/100 g tissue/min; p<0.05) and SHRSP (43 ±15 vs. 132 ± 9 ml/100 g tissue/min; p<0.05). However, reperfusion blood flow was similar between SHRSP and Wistar (43 ± 15 vs. 54 ± 14 ml/100 g tissue/min in Wistar). FeTMPyP did not alter reperfusion blood flow in Wistar (42 ± 9 vs. 54± 14 ml/100 g tissue/min in vehicle; p>0.05) and SHRSP (30 min: 28 ± 5 vs. 43± 15 ml/100 g tissue/min in vehicle; p>0.05). Compared to Wistar, SHRSP had increased brain infarct volume (31 ± 6 vs. 19 ± 6 % in Wistar; p<0.05) and swelling (6± 2 vs. 12 ± 2 % in Wistar; p<0.05). Hemorrhage within the infarct area was only found in SHRSP (~50 % of animals). FeTMPyP did not affect infarct volume, swelling, and incidence of hemorrhage in Wistar and SHRSP. Linear regression showed that early post‐ischemic reperfusion blood flow was related to infarctsize, with negative Pearson correlation coefficient in both Wistar (−0.472) and SHRSP (−0.694). In conclusion, worse stroke outcome in chronic hypertension does not appear to be related to further increase in myogenic tone of PA and worse reperfusion. Treatment with peroxynitrite decomposition catalyst does not improve or worsen reperfusion and stroke outcome.Support or Funding InformationThis study was supported by NIH NINDS Grant R01 NS‐093289 and NIH NHLBI Grant P01 HL‐095488.