Hydrogen sulfide accounts for the peripheral vascular effects of zofenopril independently of ACE inhibition

Mariarosaria Bucci, Valentina Vellecco, Anna Cantalupo, Vincenzo Brancaleone, Zongmin Zhou, Stefano Evangelista, Vincenzo Calderone, Andreas Papapetropoulos, Giuseppe Cirino

Research output: Contribution to journalArticlepeer-review

84 Scopus citations


AimsTherapeutic use of sulfhydrylated inhibitor S-zofenopril has raised different hypotheses regarding the role played by its thiol group in the beneficial clinical effects exerted compared with other angiotensin-converting enzyme (ACE) inhibitors. Here, we investigated hydrogen sulfide (H2S) pathway as accountable for extra-beneficial effects in vascular function.Methods and resultsSpontaneously hypertensive rat (SHRs) and control Wistar Kyoto (WKY) rats were treated with either S-zofenopril or enalapril in vivo. Aorta and carotid were harvested and ex vivo vascular reactivity to acetylcholine (Ach) and l-cysteine (l-cys) assessed. Cystathionine-β- synthase (CBS), cystathionine-γ-lyase (CSE), and 3-mercaptosulfur- transferase (3MST) expression, as well as H2S levels, were evaluated in both vascular tissues. The vascular response to Ach in both carotid and aorta was impaired in SHR (∼30%, P < 0.001). S-zofenopril, but not enalapril, restored this response, while l-cys-induced relaxation was enhanced. CSE expression in vessels and tissue/plasma H2S levels were restored to WKY values in SHRs receiving S-zofenopril. In contrast, CBS and 3MST expression were not modified by treatments. S-zofenoprilat, an active metabolite of S-zofenopril, releases H2S in a 'cell-free' assay and it directly relaxed vessels in vitro in a concentration-dependent manner (P < 0.001). In vivo administration of R-zofenoprilat diasteroisomer, which does not inhibit ACE, did not modify blood pressure; nonetheless, it retained the beneficial effect on SHR vascular function as well as restored plasma/tissue H2S levels.ConclusionOur findings establish that S-zofenopril improves vascular function by potentiating the H2S pathway in a model of spontaneous hypertension. This novel mechanism, unrelated to ACE inhibition and based on H2S release, could explain the beneficial effects of sulfhydrylated ACE inhibitors reported in the clinical literature.

Original languageEnglish (US)
Pages (from-to)138-147
Number of pages10
JournalCardiovascular research
Issue number1
StatePublished - Apr 2014


  • ACE inhibitors
  • Hydrogen sulfide
  • Hypertension

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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