Aging and hypertension decrease endothelial NO-related dilating function and gamma-glutamyl transferase activity but not S-nitrosoglutathione-induced aortic vasodilation

Abstract

S-nitrosoglutathione (GSNO), which is involved in the transport and the storage of NO, induces vasorelaxation. It requires gamma-glutamyl transferase (GGT), an enzyme present on the endothelium, to transfer NO into the cell. We evaluated whether aging and hypertension, which induce NO-related dilating dysfunction, are associated with decreased vascular GGT activity and modify the vasorelaxant effect of GSNO. Thoracic aortic rings isolated from male spontaneous hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) aged 20-22 (adult) or 57-60 weeks (mature) were preconstricted with phenylephrine, then submitted to concentration-vasorelaxant response curves (maximal response: E_max ; pD₂ ) to GSNO and carbachol (the latter to measure NO-related dilating function). GGT activity was measured using chromogenic substrate. Both aging and hypertension lowered E_max values for carbachol (E_max -8% in adult SHR, -42% in mature SHR vs. age-matched WKY, p_age and p_hypertension < 0.05) demonstrating NO-related dilating dysfunction. Aortic GGT activity also decreased with aging and hypertension (-22% in adult and -75%, reaching 3 nmol/min/g of tissue, in mature SHR vs. 12 in age-matched WKY and 23 in adult WKY, p_age and p_hypertension < 0.05). The pD₂ values of GSNO were similar in mature SHR and WKY but higher in adult SHR (p_interaction < 0.05). Aging in hypertensive rats decreased NO-related vasorelaxant function and vascular GGT activity, but did not lower the vasorelaxant response to GSNO. This opens perspectives for GSNO-based therapeutics restoring nitric oxide bioavailability and vascular protection in a context of endothelial dysfunction.

Keywords: NO-dependent vasorelaxation; S-nitrosoglutathione; gamma-glutamyltransferase; spontaneous hypertensive rat.