Nitric oxide: considerations for the treatment of ischemic stroke

Abstract

Some 40 years ago it was recognized by Furchgott and colleagues that the endothelium releases a vasodilator, endothelium-derived relaxing factor (EDRF). Later on, several groups identified EDRF to be a gas, nitric oxide (NO). Since then, NO was identified as one of the most versatile and unique molecules in animal and human biology. Nitric oxide mediates a plethora of physiological functions, for example, maintenance of vascular tone and inflammation. Apart from these physiological functions, NO is also involved in the pathophysiology of various disorders, specifically those in which regulation of blood flow and inflammation has a key role. The aim of the current review is to summarize the role of NO in cerebral ischemia, the most common cause of stroke.

Figure 1

Summary of therapeutical strategies influencing nitric oxide signaling in ischemic stroke. eNOS, endothelial nitric oxide synthases; iNOS, inducible NOS; nNOS, neuron NOS; PDE, phosphodiesterase.

Figure 2

Nitric oxide (NO) inhalation (iNO). (A) Upon inhalation, NO is transported to the brain via the blood in a bioactive form; the nature of this NO carrier (X) is not fully elucidated yet. Among the molecules discussed are S-nitroso-hemoglobin, S-nitrosothiols, and nitrite. In the brain, inhaled NO leads to an increase of NO in the vessel wall (left inlet, in vivo NO fluorescence imaged with NO-sensitive dye DAF-FM) and to dilatation of cerebral venules (right inlet, in vivo imaging of vessel diameter using FITC-dextran). (B) NO inhalation—Putative mode of action: Bioactive NO is released via an oxygen-tension-dependent mechanism; under physiological conditions this happens in the venular compartment of the cerebrovasculature. Release of NO leads to venular dilatation and—thus—to an increase in cerebral blood volume (CBV) without influencing cerebral blood flow (CBF). During cerebral ischemia, oxygen extraction fraction (OEF) increases leading to increased oxygen desaturation, lowering of arteriolar pO₂ and pH on the arteriolar side of the cerebrovasculature. Under these conditions, NO release occurs also on the arteriolar side. This induces arteriolar dilatation and, thereby, increase of CBF. Since the mechanism is restricted to ischemic vessels, normally perfused tissue is not affected. NO inhalation therefore seems to be an ideal tool to counteract regional ischemia by increasing blood flow exclusively to malperfused tissue. DAF-FM, 4-amino-5-(N-methylamino)-3′,6′-bis(acetyloxy)-2′,7′-difluoro-spiro[isobenzofuran-1(3H),9′-[9H]xanthen]-3-one, diaminofluorescein-FM diacetate; FITC, fluorescein 5-isothiocyanate.