S5-2 Hydrogen sulfide accounts for the peripheral vascular effects of sulfhydrylated ace inhibitors beyond ace inhibition: A proof of concept of the role of H2S in cardiovascular?

Abstract

The therapeutic use of sulfhydrylated inhibitor zofenopril has raised different hypotheses regarding the role played by its thiol group in the beneficial clinical effects. In order to evaluate the involvement of the H 2 S pathway in the extra-beneficial effects in vascular function we performed an in vitro and an ex vivo study by using SHR and WKY rats. Both rat strains were treated with either zofenopril or enalapril in vivo. Aorta and carotid were harvested and ex vivo vascular reactivity to Ach and l -cysteine assessed. CBS, CSE and 3MST expression, as well as H 2 S 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). Zofenopril, but not enalapril, restored this response, while l -cysteine-induced relaxation was enhanced. CSE expression in vessels, and tissue/plasma H 2 S levels were restored to WKY values in SHR rats receiving zofenopril. In contrast, CBS and 3MST expression were not modified by treatments. Zofenoprilat, the active metabolite of zofenopril, releases H 2 S 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 H 2 S levels. In conclusion our findings establish that zofenopril improves vascular function by potentiating the H 2 S pathway in a model of spontaneous hypertension explaining the mechanism underlying the beneficial effects of sulfhydrylated ACE inhibitors beyond ACE inhibition reported in clinical literature. Moreover zofenopril can represent a proof of concept of the role played by H 2 S in hypertension.