title: Hydrogen sulfide accounts for the peripheral vascular effects of zofenopril independently of ACE inhibition.
abstract: OBJECTIVE
  Therapeutic 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.
  
  
  RESULTS
  Spontaneously 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.
  
  
  CONCLUSIONS
  Our 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.
authors: Department of Pharmacy, University of Naples 'Federico II', Via D. Montesano 49, Naples 80131, Italy.
authors: Mariarosaria
authors: M
authors: Bucci
authors: Valentina
authors: V
authors: Vellecco
authors: Anna
authors: A
authors: Cantalupo
authors: Vincenzo
authors: V
authors: Brancaleone
authors: Zongmin
authors: Z
authors: Zhou
authors: Stefano
authors: S
authors: Evangelista
authors: Vincenzo
authors: V
authors: Calderone
authors: Andreas
authors: A
authors: Papapetropoulos
authors: Giuseppe
authors: G
authors: Cirino
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects*; D002216:Captopril / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; C044958:zofenopril; D002216:Captopril; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide
keywords: ACE inhibitors; Hydrogen sulfide; Hypertension