Department of Clinical and Molecular Biomedicine, Catania University, Catania, Italy.
Université Paris-Est, UMR_S955, UPEC, F-94000 Créteil, France; Inserm U955, Equipe 3, F-94000 Créteil, France.
Biochem Pharmacol. 2014 Dec 15;92(4):661-8. doi: 10.1016/j.bcp.2014.10.011. Epub 2014 Oct 29.
Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulphide (H2S) modulate vascular tone. In view of their therapeutic potential for ocular diseases, we examined the effect of exogenous CO and H2S on tone of isolated rabbit ophthalmic artery and their interaction with endogenous and exogenous NO. Ophthalmic artery segments mounted on a wire myograph were challenged with cumulative concentrations of phenylephrine (PE) in the presence or absence of NG-nitro-L-arginine (LNNA) to inhibit production of NO, the CO-releasing molecules CORMs or the H2S-donor GYY4137. The maximal vasoconstriction elicited by PE reached 20-30% of that induced by KCl but was dramatically increased by incubation with LNNA. GYY4137 significantly raised PE-mediated vasoconstriction, but it did not change the response to PE in the presence of LNNA or the relaxation to sodium nitroprusside (SNP). CORMs concentration-dependently inhibited PE-induced constriction, an effect that was synergistic with endogenous NO (reduced by LNNA), but insensitive to blockade of guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3,-α]quinoxalin-1-one (ODQ). In vascular tissues cyclic GMP (cGMP) levels seemed reduced by GYY4137 (not significantly), but were not changed by CORM. These data indicate that CO is able per se to relax isolated ophthalmic artery and to synergize with NO, while H2S counteracts the effect of endogenous NO. CO does not stimulate cGMP production in our system, while H2S may reduce cGMP production stimulated by endogenous NO. These findings provide new insights into the complexities of gas interactions in the control of ophthalmic vascular tone, highlighting potential pharmacological targets for ocular diseases.
一氧化氮（NO）、一氧化碳（CO）和硫化氢（H2S）调节血管张力。鉴于它们在眼部疾病治疗方面的潜在作用，我们研究了外源性 CO 和 H2S 对分离的兔眼动脉张力的影响及其与内源性和外源性 NO 的相互作用。将眼科动脉段安装在张力换能器上，用累积浓度的苯肾上腺素（PE）刺激，同时或不使用 NG-硝基-L-精氨酸（LNNA）抑制 NO 生成，CO 释放分子 CORMs 或 H2S 供体 GYY4137。PE 引起的最大血管收缩达到 KCl 诱导的 20-30%，但孵育 LNNA 后显著增加。GYY4137 显著增加了 PE 介导的血管收缩，但在 LNNA 存在下不会改变对 PE 的反应或对硝普钠（SNP）的舒张。CORMs 浓度依赖性地抑制 PE 诱导的收缩，这种作用与内源性 NO 协同（被 LNNA 减少），但对 1H-[1,2,4]恶二唑并[4,3-α]喹喔啉-1-酮（ODQ）阻断鸟苷酸环化酶不敏感。在血管组织中，cGMP 水平似乎被 GYY4137 降低（不显著），但不受 CORM 影响。这些数据表明，CO 本身能够松弛分离的眼动脉，并与 NO 协同作用，而 H2S 拮抗内源性 NO 的作用。在我们的系统中，CO 不会刺激 cGMP 的产生，而 H2S 可能会减少内源性 NO 刺激产生的 cGMP。这些发现为控制眼血管张力的气体相互作用的复杂性提供了新的见解，突出了眼部疾病的潜在药理学靶点。
