Enhanced endothelium derived hyperpolarising factor activity in resistance arteries from normal pressure glaucoma patients: implications for vascular function in the eye

Abstract

Background/aims: Endothelial cell dysfunction in the ocular circulation may contribute to normal pressure glaucoma (NPG). This study aimed to investigate the contributions made by endothelium derived relaxing factors to relaxation of (1) subcutaneous resistance arteries from patients with NPG, and (2) porcine ciliary arteries. Methods: Human gluteal resistance arteries were isolated from seven patients with NPG and matched controls. Human and porcine arteries produced endothelium dependent relaxation when exposed to acetylcholine (ACh) (10 29 23610 25 M) or bradykinin (10 210 23610 26 M). Pharmacological agents were used to inhibit the nitric oxide pathway (L-arginine analogues, soluble guanylate cyclase inhibitor), endothelium derived hyperpolarising factor (EDHF) activity (potassium channel antagonists), and prostaglandin synthesis (cyclo-oxygenase inhibitors). Results: In all arteries, endothelium dependent relaxation was attenuated by nitric oxide (NO) inhibition or potassium channel blockade, but not by cyclo-oxygenase inhibition. Inhibition of ACh mediated relaxation by potassium channel antagonists was greater (p,0.05) in patients with NPG (Emax, 55.4% (SD 8.16%) relaxation, n = 4) than controls (Emax, 81.8% (6.0%), n = 5). In contrast, combined inhibition of NO synthase (NOS) and cyclo-oxygenase produced similar inhibition of ACh mediated relaxation in both groups. Conclusions: The enhanced contribution of EDHF to ACh mediated relaxation in systemic resistance arteries from NPG patients may contribute to the maintained endothelium mediated relaxation in these vessels. EDHF also contributes significantly to bradykinin mediated relaxation in porcine ocular ciliary arteries. Therefore, similar changes in the balance of relaxing factors in the ocular circulation could influence the response of the eye to vascular endothelial dysfunction in NPG.

Altered Endothelin-1 Vasoreactivity in Patients with Untreated Normal-Pressure Glaucoma

“…This finding is consistent with our previous reports of a defect in the peripheral endothelium-derived NO activity in the human forearm 25 and subcutaneous resistance vessels. 26,27 These alterations support the proposition that NPG represents an ocular manifestation of a systemic vascular dysfunction.…”

“…20 The possibility that ET-1 contributes to vasospasm in NPG is supported by the demonstration of elevated basal plasma ET-1 concentrations in patients 21,22 combined with an abnormal response of plasma ET-1 concentrations to postural 23 and temperature changes. 24 We have shown, using direct measurement of vascular function, that peripheral endothelium-dependent relaxation is impaired, 25 or altered, 26 in patients with NPG. Furthermore, enhanced ET-1-dependent contraction in isolated subcutaneous resistance arteries from these individuals suggests impaired ET B -mediated release of endothelial NO.…”

Molecular complexity of primary open angle glaucoma: current concepts

“…Thus, blood flow of the retina is largely regulated by the endothelial cell derived substances that are collectively known as endothelium derived vasoactive compounds (EDVCs) (Haefliger et al 2001), acting both abluminally and intraluminally. Patients with primary vascular dysregulation often have high level of endothelin-1 (ET-1) Cleary et al 2005) and matrixmetalloproteinase such as MMP-9 (Golubnitschaja et al 2004). ET-1 has the capability of vasoconstriction Haefliger et al 2001) and also interferes with vascular permeability.…”

The Significance of Endothelium-Derived Hyperpolarizing Factor in the Human Circulation

“…To date, the existence of EDHF has been demonstrated in the following vascular systems in humans: 1) Cardiovascular system including coronary arteries from ventricles and right atrial appendages [14][15][16][17][18]; 2) Renal arterial system [19,20]; 3) Gastrointestinal vascular system with the involvement of gastroepiploic arteries and distal microvessels [21] as well as mesenteric arteries [22][23][24]; 4) Peripheral circulatory system including radial arteries, internal mammary arteries, saphenous veins [25][26][27][28][29][30][31], forearm arteries/veins [32][33][34][35], subcutaneous arteries [36][37][38][39][40] and omental arteries/veins [41,42]; 5) Vasculatures in the reproductive system including the penile resistance artery [43,44], oviductal artery [45] and myometrial artery [46,47].…”