Semi-Synthetic H₂S Releasing Compounds with Antioxidant and Vasorelaxant Properties

Area of Science:

• Cardiovascular Research
• Molecular Pharmacology
• Biochemistry

Background:

• Hypertension is a cardiovascular disease exacerbated by increased reactive oxygen species (ROS), which impair blood vessel function.
• Current treatments often focus on single targets, necessitating novel strategies for complex pathologies like hypertension.

Purpose of the Study:

• To synthesize and evaluate hybrid compounds combining hydrogen sulfide (H₂S) release with Nrf2 pathway activation for hypertension treatment.
• To investigate the multitarget therapeutic potential of these hybrids in mitigating oxidative stress and inducing vasorelaxation.

Main Methods:

• Synthesis of hybrid molecules incorporating H₂S-releasing moieties and Nrf2-activating scaffolds.
• In vitro assays using human aortic smooth muscle cells to assess ROS production, cytotoxicity, and potassium channel activation.
• Amperometric and cellular assays to quantify H₂S release.
• Ex vivo studies using isolated rat aortic rings to evaluate vasorelaxation.

Main Results:

• The itaconate derivative, compound 8b, demonstrated efficient H₂S release and Nrf2 pathway activation.
• Compound 8b effectively counteracted ROS production and H₂O₂-induced cytotoxicity in smooth muscle cells.
• 8b induced cell hyperpolarization via potassium channel activation, leading to vasorelaxation in vitro and in isolated rat aortic rings.

Conclusions:

• Simultaneous Nrf2 activation and H₂S release represent a promising multitarget therapeutic strategy for hypertension.
• Compound 8b showcases significant potential for managing hypertension by addressing both oxidative stress and impaired vascular function.