TY - JOUR
T1 - Hydrogen sulfide accounts for the peripheral vascular effects of zofenopril independently of ACE inhibition
AU - Bucci, Mariarosaria
AU - Vellecco, Valentina
AU - Cantalupo, Anna
AU - Brancaleone, Vincenzo
AU - Zhou, Zongmin
AU - Evangelista, Stefano
AU - Calderone, Vincenzo
AU - Papapetropoulos, Andreas
AU - Cirino, Giuseppe
N1 - Funding Information:
This work has been co-financed by: (1) Menarini IFR, Firenze Italy; (ii) the European Union (European Social Fund—ESF), and Greek national funds through the Operational Program ‘Education and Lifelong Learning’ of the National Strategic Reference Framework (NSRF)—Research Funding Program: Aristeia 2011 (1436) to A.P., by EU FP7 REGPOT CT-2011-285950—‘SEE-DRUG’, and by the COST Action BM1005 (ENOG: European Network on Gasotransmitters); and (iii) P.O.R. Campania FSE 2007–2013, Progetto CREMe, CUP B25B09000050007.
PY - 2014/4
Y1 - 2014/4
N2 - 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.
AB - 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.
KW - ACE inhibitors
KW - Hydrogen sulfide
KW - Hypertension
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U2 - 10.1093/cvr/cvu026
DO - 10.1093/cvr/cvu026
M3 - Article
C2 - 24501330
AN - SCOPUS:84896902580
SN - 0008-6363
VL - 102
SP - 138
EP - 147
JO - Cardiovascular research
JF - Cardiovascular research
IS - 1
ER -