Hemoglobin, NO, and 20-HETE interactions in mediating cerebral vasoconstriction following SAH

Abstract

Recent studies have indicated that 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to the fall in cerebral blood flow (CBF) after subarachnoid hemorrhage (SAH), but the factors that stimulate the production of 20-HETE are unknown. This study examines the role of vasoactive factors released by clotting blood vs. the scavenging of nitric oxide (NO) by hemoglobin (Hb) in the fall in CBF after SAH. Intracisternal (icv) injection of blood produced a greater and more prolonged (120 vs. 30 min) decrease in CBF than that produced by a 4% solution of Hb. Pretreating rats with N -nitro-L-arginine methyl ester (L-NAME; 10 mg/kg iv) to block the synthesis of NO had no effect on the fall in CBF produced by an icv injection of blood. L-NAME enhanced rather than attenuated the fall in CBF produced by an icv injection of Hb. Blockade of the synthesis of 20-HETE with TS-011 (0.1 mg/kg iv) prevented the sustained fall in CBF produced by an icv injection of blood and the transient vasoconstrictor response to Hb. Hb (0.1%) reduced the diameter of the basilar artery (BA) of rats in vitro by 10 Ϯ 2%. This response was reversed by TS-011 (100 nM). Pretreatment of vessels with L-NAME (300 M) reduced the diameter of BA and blocked the subsequent vasoconstrictor response to the addition of Hb to the bath. TS-011 returned the diameter of vessels exposed to L-NAME and Hb to that of control. These results suggest that the fall in CBF after SAH is largely due to the release of vasoactive factors by clotting blood rather than the scavenging of NO by Hb and that 20-HETE contributes the vasoconstrictor response of cerebral vessels to both Hb and blood. subarachnoid hemorrhage; nitric oxide; 20-hydroxyeicosatetraenoic acid CEREBRAL VASOSPASM IS A CRITICAL complication of subarachnoid hemorrhage (SAH). Vasospasm occurs in 70% of patients with aneurysmal SAH and leads to ischemic deficits in 36% of patients (5). Despite extensive investigation, the factors that trigger the decline in cerebral blood flow (CBF) after SAH remain to be determined.The fall in CBF after SAH correlates with the amount of hemoglobin (Hb) released into cerebrospinal fluid (CSF), and vasospasm can be triggered by an injection of Hb alone into the CSF (31, 51). Hb induces hemeoxygenase-1 (24) that increases iron levels, which generate superoxide radicals (30). Superoxide radicals at low concentration have been reported to constrict vessels in several vascular beds in part by decreasing the levels of nitric oxide (NO) (13, 42), and there is a recent report that supports a similar mechanism in cerebral arteries (55). Free radicals also increase the production of lipid peroxides and isoprostanes (20, 44) that are potent constrictors of cerebral arteries (19).Previous studies have focused on the role of various vasoconstrictor pathways in the development of cerebral vasospasm. The levels of endothelin (46), thromboxane (36), ATP (31), isoprostanes (44), glutamate (4), platelet-activating factor (PAF) (17) and serotonin (5-HT) (6, 43) in CSF all increase after SAH, and the ...

20-Hydroxyeicosatetraenoic acid is a potent dilator of mouse basilar artery: role of cyclooxygenase

“…As opposed to what has been reported in the rat middle cerebral, rat basilar, and canine basilar arteries (16,26,36), we find that 20-HETE produces potent, concentration-dependent dilation of the mouse basilar artery after submaximal constriction with U-46619. Additional studies were done to identify mechanisms responsible for the unexpected 20-HETE-mediated dilation in this preparation.…”

Expression of CYP 4A ω-hydroxylase and formation of 20-hydroxyeicosatetreanoic acid (20-HETE) in cultured rat brain astrocytes

“…Because astrocytes out number neurons more than two to one in the brain, the capacity of astrocytes to synthetize and release 20-HETE could have a significant impact on susceptibility of neurons and other brain cell types to the adverse effects of a variety of pathological insults. For instance, an increased production of 20-HETE was found to induce oxidative stress through NADPH oxidase-dependent generation of reactive oxygen species [29,48], whereas increased production and action of 20-HETE was reported to promote delayed vasospasm following subarachnoid hemorrhage (SAH) [44,45,47,49,50] and to increase infarct volume evoked by ischemia reperfusion injury [11]. Moreover the use of specific inhibitors of the synthesis or actions of 20-HETE has been indicated as possible mode of therapy for reduction of brain ischemic infarcts and vasospasm resulting from ischemia and SAH, respectively, as determined using experimental model animals [11,45,46,50,51], whereas administration of 20-HETE or its pharmacological agonists exacerbate brain tissue or neuronal damage.…”

Cerebral Blood Flow Regulation by Nitric Oxide: Recent Advances

“…Phosphorylation of Akt/eNOS may contribute to the protective effect of erythropoietin against cerebral vasospasm induced by SAH (Santhanam and Katusic, 2006). Takeuchi et al (2006) provided evidence that the fall in cerebral blood flow after SAH was largely due to the release of vasoactive factors by clotting blood rather than the scavenging of NO by hemoglobin in rats and that 20-hydroxyeicosatetraenoic acid contributed to the vasoconstrictor response of cerebral vessels to both hemoglobin and blood. Immunohistochemical expression of eNOS was comparable in control rats and those sacrificed on day 3 and day 5 after SAH; the soluble guanylyl cyclase ␣-and ␤-subunits were diminished on day 3, but recovered by day 5; the relaxation of basilar arteries to ACh and 8-bromo-cyclic GMP was virtually identical in controls and during cerebral vasospasm (Vatter et al, 2007b).…”