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- Title
Hydrogen sulfide accounts for the peripheral vascular effects of zofenopril independently of ACE inhibition.
- Authors
Bucci, Mariarosaria; Vellecco, Valentina; Cantalupo, Anna; Brancaleone, Vincenzo; Zhou, Zongmin; Evangelista, Stefano; Calderone, Vincenzo; Papapetropoulos, Andreas; Cirino, Giuseppe
- Abstract
Aims 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. Methods and 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. Conclusion 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.
- Subjects
HYDROGEN sulfide; PERIPHERAL vascular diseases; ACE inhibitors; ACETYLCHOLINE; CYSTATHIONINE beta-synthase; CARDIOVASCULAR system physiology; HYPERTENSION
- Publication
Cardiovascular Research, 2014, Vol 102, Issue 1, p138
- ISSN
0008-6363
- Publication type
Article
- DOI
10.1093/cvr/cvu026