| Summary: | Reduced angiotensin 1–7 bioavailability due to inhibition of angiotensin-converting enzyme 2 (ACE2) may contribute to increased mortality in hypertensive individuals during COVID-19. However, effects of ACE2 inhibitor MLN-4760 in brain functions remain unknown. We investigated the selected behavioural and hemodynamic parameters in spontaneously hypertensive rats (SHRs) after a 2-week s.c. infusion of MLN-4760 (dose 1 mg/kg/day). The biochemical and molecular effects of MLN-4760 were investigated in the brainstem and blood plasma. MLN-4760 had no effects on hemodynamic and behavioural parameters. However, MLN-4760 increased plasma hydrogen sulfide (H<sub>2</sub>S) level and total nitric oxide (NO) synthase activity and conjugated dienes in the brainstem. Increased NO synthase activity correlated positively with gene expression of <i>Nos3</i> while plasma H<sub>2</sub>S levels correlated positively with gene expressions of H<sub>2</sub>S-producing enzymes <i>Mpst</i>, <i>Cth</i> and <i>Cbs</i>. MLN-4760 administration increased gene expression of <i>Ace2</i>, <i>Sod1</i>, <i>Sod2</i>, <i>Gpx4</i> and <i>Hmox1</i>, which positively correlated with expression of <i>Nfe2l2</i> gene encoding the redox-sensitive transcription factor NRF2. Collectively, MLN-4760 did not exacerbate pre-existing hypertension and behavioural hyperactivity/anxiety in SHRs. However, MLN-4760-induced oxidative damage in brainstem was associated with activation of NO- and H<sub>2</sub>S-mediated compensatory mechanisms and with increased gene expression of antioxidant, NO- and H<sub>2</sub>S-producing enzymes that all correlated positively with elevated <i>Nfe2l2</i> expression.
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