Reversal and prevention of cerebral vasospasm by intracarotid infusions of nitric oxide donors in a primate model of subarachnoid hemorrhage

Abstract

Decreased endothelium-derived relaxing factor, nitric oxide (NO), in the arterial wall has been hypothesized to be a potential cause of cerebral vasospasm following subarachnoid hemorrhage (SAH). The authors sought to determine whether intracarotid infusions of newly developed NO-donating compounds (NONOates) could reverse vasospasm or prevent the occurrence of cerebral vasospasm in a primate model of SAH. Twenty-one cynomolgus monkeys were studied in two experimental settings. In an acute infusion experiment, saline or NONOate was infused intracarotidly in four normal monkeys and in four monkeys after onset of SAH. During the infusions regional cerebral blood flow (rCBF) was measured in eight animals and CBF velocity in two. In a chronic infusion experiment, saline (four animals) or NONOate (diethylamine-NO [three animals] or proli-NO [six animals]) was infused intracarotidly in monkeys for 7 days after SAH. In acute infusion experiments, 3-minute intracarotid diethylamine-NO infusions reversed arteriographically confirmed vasospasm of the right middle cerebral artery (MCA) (as viewed on anteroposterior projection, the decrease in area was 8.4+/-4.3% in the treatment group compared with 35+/-12% in the control group; p < 0.004), increased rCBF by 31+/-1.9% (p < 0.002), and decreased the mean systolic CBF velocity in the right MCA. In a long-term infusion experiment, the area of the right MCA in control animals decreased by 63+/-5%. In animals undergoing a 7-day continuous glucantime-NO intracarotid infusion, the area of the right MCA decreased by 15+/-6.2%, and in animals undergoing a 7-day proli-NO infusion, the area of the right MCA decreased by 11+/-2.9% (p < 0.05). The mean arterial blood pressure decreased in the glucantime-NO group from 75+/-12 mm Hg (during saline infusion) to 57+/-10 mm Hg (during glucantime-NO infusion; p < 0.05), but it was unchanged in animals undergoing proli-NO infusion (76+/-12 mm Hg vs. 78+/-12 mm Hg). Results of these experiments show that cerebral vasospasm is both reversed and completely prevented by NO replacement. However, only the use of regional infusion of the NONOate with an extremely short half-life avoided a concomitant decrease in arterial blood pressure, which could produce cerebral ischemia in patients with impaired autoregulation of CBF after the rupture of an intracranial aneurysm.

Tumor Necrosis Factor-α Mediates Hemolysis-Induced Vasoconstriction and the Cerebral Vasospasm Evoked by Subarachnoid Hemorrhage

“…In fact, oxyhemoglobin appears early after SAH, 9 thus triggering the whole course of events flowing into cerebral vasoconstriction and hypoperfusion. On the other hand, the use of a symptomatic treatment of cerebral vasospasm with vasodilators has several limitations, because the hypotensive effect favors cerebral ischemia, 37 which is further aggravated by impaired autoregulation of cerebral blood flow after the rupture of the intracranial aneurysm.…”

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

“…Among all NO donors, NONOates have received the most attentions: NONOates owing to release of NO with predictable pharmacokinetics (half life ranging from a second to several hours). ProliNO with a T 1/2 =1.7 seconds was an obvious favorite to study NO effect on cerebral vasculature 72,74,108 . However, because of the obvious disadvantages of intracarotid/ intracerebral arterial drug administration that include increased risk of severe complications, patient and family anxiety and necessity of around-the-clock accessibility of the neurointerventional team, this treatment was not clinically attractive.…”

“…Thus, to avoid the peripheral vasodilatory effect of systemic NO donor administration, two changes have been made: route of administration was changed to direct intracarotid/intracerebral arteries infusion 2,41,51,74 and nitrates were replaced by nonenzymatic NO donors. These donors included: NO gas solution 2 , 3-morpholinosydnonimine, SNAP, S-nitrosoglutathione 111 , diazeniumdiolates (NONOates) 74,82 and recently nitrite 76 . Among all NO donors, NONOates have received the most attentions: NONOates owing to release of NO with predictable pharmacokinetics (half life ranging from a second to several hours).…”

In Vitro Effects of New Generation Fungal Derived Nitric Oxide Donors on Rabbit Basilar Artery

“…3,4,12,20,25) Although remarkable vasorelaxation was observed, those studies were associated with some limitations, for example, necessity for repeated and continuous administration, development of systemic hypotension, and other toxic effects. Sodium nitroprusside causes wide fluctuations of blood pressure and increases intracranial pressure.…”