Hydrogen sulphide: biopharmacological roles in the cardiovascular system and pharmaceutical perspectives.
Hydrogen sulphide (H(2)S) is now viewed as an important endogenous gasotransmitter, which exhibits many beneficial effects on the cardiovascular system. H(2)S is biosynthesized in mammalian tissues by both non-enzymatic processes and several enzymatic pathways ensured by cystathionine-β-synthase and cystathionine-γ-lyase. H(2)S is endowed with the antioxidant properties of inorganic and organic sulphites, being a scavenger of reactive oxygen species. Furthermore, H(2)S triggers other important effects and the activation of ATP-sensitive potassium channels (KATP) accounts for its vasorelaxing and cardioprotective effects. H(2)S also inhibits smooth muscle proliferation and platelet aggregation. Conversely, the impairment of H(2)S contributes to the pathogenesis of hypertension and is involved in cardiovascular complications associated with diabetes mellitus. There is also evidence of a link between H(2)S and endothelial nitric oxide (NO). Recent observations indicate a possible pathogenic link between deficiencies of H(2)S activity and the progress of endothelial dysfunction. These biological aspects of endogenous H(2)S led to consider this mediator as "the new NO" and to evaluate new attractive opportunities to develop innovative classes of drugs. In this review, the main roles played by H(2)S in the cardiovascular system and the first examples of H(2)S-donor drugs are discussed. Some hybrid drugs are also addressed in this review. In such compounds opportune H(2)S-releasing moieties are conjugated to well-known drugs to improve their pharmacodynamic profile or to reduce the potential for adverse effects.
Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Universita di Pisa, via Bonanno, 6, I- 56126 Pisa, Italy.
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Martelli
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Testai
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Marino
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Breschi
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Da Settimo
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Calderone
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology; D001775:Blood Circulation / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006862:Hydrogen Sulfide