Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH

Abstract

Nitric oxide (NO), also known as endothelium-derived relaxing factor, is produced by endothelial nitric oxide synthase (eNOS) in the intima and by neuronal nitric oxide synthase (nNOS) in the adventitia of cerebral vessels. It dilates the arteries in response to shear stress, metabolic demands, pterygopalatine ganglion stimulation and chemoregulation. Subarachnoid hemorrhage (SAH) interrupts this regulation of cerebral blood flow. Hemoglobin, gradually released from erythrocytes in the subarachnoid space, destroys nNOS-containing neurons in the conductive arteries. This deprives the arteries of NO, leading to initiation of delayed vasospasm. But such vessel narrowing increases shear stress, which stimulates eNOS. This mechanism normally would lead to increased production of NO and dilation of arteries. However, a transient eNOS dysfunction evoked by an increase in the endogenous competitive NOS inhibitor, asymmetric dimethylarginine (ADMA), prevents this vasodilation. eNOS dysfunction has been recently shown to be evoked by increased levels of ADMA in cerebrospinal fluid (CSF) in response to the presence of bilirubin-oxidized fragments (BOXes). A direct cause of the increased ADMA CSF level is most likely decreased ADMA elimination owing to disappearance of ADMA-hydrolyzing enzyme [dimethylarginine dimethylaminohydrolase II (DDAH II)] immunoreactivity in the arteries in spasm. This eNOS dysfunction sustains vasospasm. CSF ADMA levels are closely associated with the degree and time course of vasospasm; when CSF ADMA levels decrease, vasospasm resolves. Thus, exogenous delivery of NO, inhibiting the L-arginine-methylating enzyme or stimulating DDAH II, may provide new therapeutic modalities to prevent and treat vasospasm. This paper will present results of pre-clinical studies supporting the NO-based hypothesis of delayed cerebral vasospasm development and its prevention by increased NO availability.

Cerebral Blood Flow Regulation by Nitric Oxide: Recent Advances

“…The endogenous NOS inhibitor ADMA in cerebrospinal fluids was increased by the presence of bilirubinoxidized fragments, and disappearance of ADMA-hydrolyzing enzyme immunoreactivity in cerebral arteries in spasm decreased ADMA elimination; cerebrospinal fluid ADMA levels were associated with the degree and times of vasospasm (Pluta, 2005(Pluta, , 2006. Therefore, stimulation of ADMA-hydrolyzing enzymes and/or exogenous delivery of NO were suggested as therapeutic modalities to prevent and treat SAH.…”

A Phase I proof-of-concept and safety trial of sildenafil to treat cerebral vasospasm following subarachnoid hemorrhage

“…19,27 Decreased functionality of this pathway following SAH has been linked to the pathophysiology of DCI including CVS. 58,69,71,77,85 Studies investigating the eNOS-NO-cGMP pathway have shown that inhibition of PDE-V has substantial beneficial effects. In animal SAH studies, PDE-V inhibition (mainly via administration of sildenafil, an FDA-approved selective PDE-V inhibitor) acutely reverses SAH-induced CVS, 2,28,31,32,34,42 reduces neuronal cell death, 32 restores impaired autoregulatory mechanisms, 73 and improves neurological outcomes.…”

Preconditioning the Human Brain

“…This effect is largely mediated by a downregulation of vasodilatory substances through depletion of NO and upregulation of vasoconstrictive substances, such as endothelin-1 and bilirubin oxidation products. [36][37][38] There is loss of NOS in vessels with cerebral vasospasm and severe endothelial dysfunction. 39 Strategies to augment NO and inhibit endothelin-1 have become therapeutic targets for improving outcome after SAH.…”

“…34,35 Thick layering of blood around larger arteries is an important predictor of vasoconstriction, which results from a shift in the balance between the cerebral vasodilatory and the vasoconstrictive systems, as well as inflammation. 36 Periarterial oxyhemoglobin causes the release of vasoactive substances that result in vasoconstriction. This effect is largely mediated by a downregulation of vasodilatory substances through depletion of NO and upregulation of vasoconstrictive substances, such as endothelin-1 and bilirubin oxidation products.…”