PhD Scientific Days 2022

Translational Medicine III.

Roles of Nitric Oxide and Prostanoid Mediators in the Adaptation of the Cerebrocortical Blood Flow to Carotid Artery Occlusion

Text of the abstract

Introduction: Understanding the cerebral autoregulation mechanisms has become of notable importance due to the increased incidence of carotid artery stenosis worldwide, one of the main causes of stroke. The role of endothelial and neuronal nitric oxide (NO) synthases (eNOS and nNOS) and prostanoid mediators (PMs) are unquestionable in the adaptational process; however, the exact mechanisms are still contradictory in the scientific literature.
Aims and Methods: In our present study, we aimed to analyze the combined lack of eNOS and nNOS in eNOS/nNOS double knock-out (KO) animals. The role of PMs in cerebrovascular autoregulation was studied with indomethacin (1 mg/kg, i.p.) and NS-398 (10 mg/kg, i.p.) treatment and in thromboxane receptor knock-out (TPR-KO) mice. Regional CoBF changes were analyzed using laser-speckle imaging in anesthetized adult male mice. The adaptational capability of cerebrovascular autoregulation was determined by analyzing the changes of CoBF after reducing the cerebral perfusion pressure by unilateral CAO.
Results: In WT animals, CoBF reduction in the left temporal cortex started immediately after CAO, reaching its maximum (-27%) at 6-9 s. Thereafter, CoBF recovered close to the pre-occlusion level within 30 s, indicating the activation of regulatory pathway(s). However, the double-knockout animals showed a significantly diminished recovery in the subacute phase (30-300s after the occlusion), although the percentual reduction of the blood flow after the occlusion was unaltered compared to WT animals. Indomethacin treatment resulted in a faster, while NS-398 treatment in an impaired recovery in the temporal region. In TPR-KO animals, however, the recovery of the CoBF was only slightly diminished.
Conclusion: These results indicate that (1) the combined lack of eNOS and nNOS and the COX-2 inhibition impair only the subacute phase of the recovery after unilateral CAO and (2) indomethacin treatment results in a faster recovery, probably by inhibiting the release of a vasoconstrictor prostanoid, which is not thromboxane A2.
Grant support: NKFIH K-125174, K-135683 and K-139230 as well as 2020-1.1.6-JÖVŐ-2021-00010, TKP2021-EGA-25 and EFOP-3.6.3-VEKOP-16-2017-00009.