Acute Retinal Ischemia Inhibits Endothelium-Dependent Nitric Oxide–Mediated Dilation of Retinal Arterioles via Enhanced Superoxide Production

Abstract

PURPOSE.Because retinal vascular disease is associated with ischemia and increased oxidative stress, the vasodilator function of retinal arterioles was examined after retinal ischemia induced by elevated intraocular pressure (IOP). The role of superoxide anions in the development of vascular dysfunction was assessed. METHODS. IOP was increased and maintained at 80 to 90 mm Hg for 30, 60, or 90 minutes by infusing saline into the anterior chamber of a porcine eye. The fellow eye with normal IOP (10 -20 mm Hg) served as control. In some pigs, superoxide dismutase mimetic TEMPOL (1 mM) or vehicle (saline) was injected intravitreally before IOP elevation. After enucleation, retinal arterioles were isolated and pressurized without flow for functional analysis by recording diameter changes using videomicroscopic techniques. Dihydroethidium (DHE) was used to detect superoxide production in isolated retinal arterioles. RESULTS. Isolated retinal arterioles developed stable basal tone and the vasodilations to endothelium-dependent nitric oxide (NO)-mediated agonists bradykinin and L-lactate were significantly reduced only by 90 minutes of ischemia. However, vasodilation to endothelium-independent NO donor sodium nitroprusside was unaffected after all time periods of ischemia. DHE staining showed that 90 minutes of ischemia significantly increased superoxide levels in retinal arterioles. Intravitreal injection of membrane-permeable radical scavenger but not vehicle before ischemia prevented elevation of vascular superoxide and preserved bradykinin-induced dilation. CONCLUSIONS. Endothelium-dependent NO-mediated dilation of retinal arterioles is impaired by 90 minutes of ischemia induced by elevated IOP. The inhibitory effect appears to be mediated by the alteration of NO signaling via vascular superoxide. T he neural retina tissue in patients exposed to acute periods of retinal ischemia suffers from blood flow deficit, which can lead to visual impairment and blindness.1,2 Ocular diseases and complications such as acute angle-closure glaucoma, retinal vascular occlusion, and elevated intraocular pressure during vitreous surgery or after vitreoretinal surgery, are associated with retinal ischemia.1-3 Currently, treatment modalities for restoring neural retina function are relatively limited. Experimental evidence demonstrating a reduction in retinal blood flow after the initial retinal ischemia suggests that dysfunction of arterioles, the major site for flow regulation, contributes to the persistent retinal damage. 4,5 However, studies are lacking to directly address whether vasomotor function of retinal arterioles is altered after acute retinal ischemia.In the retinal circulation, the vascular endothelium is important in regulating local blood flow by the release of vasoactive factors such as the potent vasodilator nitric oxide (NO) 6 and vasoconstrictor endothelin-1. 7 It has been shown in pigs that endothelium-dependent arterial dilation and release of NO surrounding the retinal arterioles are reduced in vivo after acute ...

Relaxation of Porcine Retinal Arterioles During Acute HypoxiaIn VitroDepends on Prostaglandin and NO Synthesis in the Perivascular Retina

“…The finding may be due to the limited observation time after each change in oxygen concentration, but argues against the involvement of endothelial NO in the postischaemic tone response. 24 However, the finding is in accordance with the observation that ischemia reperfusion damage may lead to upregulation of COX-2, although this may take several days to develop in animal models in vivo. 35 Also, the ischemia reperfusion response from the endothelium has been shown to involve an effect of COX products.…”

“…23 Conversely, a recent finding showed that exposure to ischaemia for 90 minutes may even inhibit vasodilatation induced by endothelial NO. 24 Altogether, the findings suggest that NO is involved in neurovascular coupling regulating retinal blood flow, 25,26 and may explain the involvement of NO in flicker-induced vasodilatation, 27 probably because this stimulation induces hypoxia secondary to increased metabolism.…”

Oxidative stress induces autophagy in response to multiple noxious stimuli in retinal ganglion cells

“…A frequently used model for retinal ischemia is established by using elevated IOP. 60 Both acute and chronic ischemia contribute to oxidative stress, brought on by an imbalanced metabolic demand and associated with production of free radicals or reactive oxygen species.…”

TEMPOL has limited protective effects on renal oxygenation and hemodynamics but reduces kidney damage and inflammation in a rat model of renal ischemia/reperfusion by aortic clamping

“…piperidinoxyl) is a membrane-permeable, metal-independent SOD mimetic with specific reactivity towards superoxide [51] and hence capable of intervening early in the injurious redox chain and renal pathogenesis ( Figure 1). Also, TEMPOL has been shown to cause dilation of I/R-constricted (inflamed) coronary blood vessels [52] and retinal arterioles [53]. Accordingly, numerous studies have shown that TEMPOL reduces I/R AKI in different species, including rats [54].…”