Effect of intracarotid nitric oxide on primate cerebral vasospasm after subarachnoid hemorrhage

1995 ◽  
Vol 83 (1) ◽  
pp. 118-122 ◽  
Author(s):  
John K. B. Afshar ◽  
Ryszard M. Pluta ◽  
Robert J. Boock ◽  
B. Gregory Thompson ◽  
Edward H. Oldfield
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Primate Model ◽  
Content Type ◽  
Continuous Release ◽  
Blood Flow Velocities ◽  
The Right ◽  
Fine Print

✓ The continuous release of nitric oxide (NO) is required to maintain basal cerebrovascular tone. Oxyhemoglobin, a putative spasmogen, rapidly binds NO, implicating loss of NO in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). If vasospasm is mediated by depletion of NO in the vessel wall, it should be reversible by replacement with NO. To investigate this hypothesis, the authors placed blood clots around the right middle cerebral artery (RMCA) of four cynomolgus monkeys; four unoperated animals served as controls. Arteriography was performed before and 7 days after surgery to assess the presence and degree of vasospasm, which was quantified in the anteroposterior (AP) projection by computerized image analysis. On Day 7, cortical cerebral blood flow (CBF) in the distribution of the right MCA was measured during four to six runs in the right internal carotid artery (ICA) of brief infusions of saline followed by NO solution. Arteriography was performed immediately after completing the final NO infusion in three of the four animals with vasospasm. Right MCA blood flow velocities were obtained using transcranial Doppler before, during, and after NO infusion in two vasospastic animals. After ICA NO infusion, arteriographic vasospasm resolved (mean percent of preoperative AP area, 55.9%); that is, the AP areas of the proximal portion of the right MCA returned to their preoperative values (mean 91.4%; range 88%–96%). Compared to ICA saline, during ICA NO infusion CBF increased 7% in control animals and 19% in vasospastic animals (p < 0.002) without significant changes in other physiological parameters. During NO infusion, peak systolic right MCA CBF velocity decreased (130 to 109 cm/sec and 116 to 76 cm/sec) in two vasospastic animals. The effects of ICA NO on CBF and CBF velocity disappeared shortly after terminating NO infusion. Intracarotid infusion of NO in a primate model of vasospasm 1) increases CBF, 2) decreases cerebral vascular resistance, 3) reverses arteriographic vasospasm, and 4) decreases CBF velocity in the vasospastic artery without producing systemic hypotension. These findings indicate the potential for the development of targeted therapy to reverse cerebral vasospasm after SAH.

Association between cerebrospinal fluid levels of asymmetric dimethyl-L-arginine, an endogenous inhibitor of endothelial nitric oxide synthase, and cerebral vasospasm in a primate model of subarachnoid hemorrhage

2004 ◽  
Vol 101 (5) ◽  
pp. 836-842 ◽  
Author(s):  
Carla S. Jung ◽  
Brian A. Iuliano ◽  
Judith Harvey-White ◽  
Michael G. Espey ◽  
Edward H. Oldfield ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cerebrospinal Fluid ◽  
Cerebral Vasospasm ◽  
Primate Model ◽  
Content Type ◽  
Cerebrospinal Fluid Levels ◽  
Delayed Cerebral Vasospasm ◽  
The Right ◽  
Fluid Levels ◽  
Fine Print

Object. Decreased availability of nitric oxide (NO) has been proposed to evoke delayed cerebral vasospasm after subarachnoid hemorrhage (SAH). Asymmetric dimethyl-l-arginine (ADMA) inhibits endothelial NO synthase (eNOS) and, therefore, may be responsible for decreased NO availability in cases of cerebral vasospasm. The goal of this study was to determine whether ADMA levels are associated with cerebral vasospasm in a primate model of SAH. Methods. Twenty-two cynomolgus monkeys (six control animals and 16 with SAH) were used in this study. The levels of ADMA, l-arginine, l-citrulline, nitrites, and nitrates in cerebrospinal fluid (CSF) and serum were determined on Days 0, 7, 14, and 21 following onset of SAH. Cerebral arteriography was performed to assess the degree of vasospasm. Western blot analyses of the right and left middle cerebral arteries (MCAs) were performed to assess the expression of eNOS, type I protein—arginine methyl transferase (PRMT1) and dimethylarginine dimethylaminohydrolase (DDAH2). Cerebrospinal fluid levels of ADMA remained unchanged in the control group (six animals) and in animals with SAH that did not have vasospasm (five animals; p = 0.17), but the levels increased in animals with vasospasm (11 animals) on Day 7 post-SAH (p < 0.01) and decreased on Days 14 through 21 (p < 0.05). Cerebrospinal fluid levels of ADMA correlated directly with the degree of vasospasm (correlation coefficient = 0.7, p = 0.0001; 95% confidence interval: 0.43–0.83). Levels of nitrite and nitrate as well as those of l-citrulline in CSF were decreased in animals with vasospasm. Furthermore, DDAH2 expression was attenuated in the right spastic MCA on Day 7 post-SAH, whereas eNOS and PRMT1 expression remained unchanged. Conclusions. Changes in the CSF levels of ADMA are associated with the development and resolution of vasospasm found on arteriograms after SAH. The results indicate that endogenous inhibition of eNOS by ADMA may be involved in the development of delayed cerebral vasospasm. Inhibition of ADMA production may provide a new therapeutic approach for cerebral vasospasm after SAH.

Increased cerebral blood flow but no reversal or prevention of vasospasm in response to l-arginine infusion after subarachnoid hemorrhage

2000 ◽  
Vol 92 (1) ◽  
pp. 121-126 ◽  
Author(s):  
Ryszard M. Pluta ◽  
John K. B. Afshar ◽  
B. Gregory Thompson ◽  
Robert J. Boock ◽  
Judith Harvey-White ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Primate Model ◽  
Arginine Infusion ◽  
Content Type ◽  
Infusion Experiment ◽  
The Right ◽  
Fine Print

Object. The reduction in the level of nitric oxide (NO) is a purported mechanism of delayed vasospasm after subarachnoid hemorrhage (SAH). Evidence in support of a causative role for NO includes the disappearance of nitric oxide synthase (NOS) from the adventitia of vessels in spasm, the destruction of NO by hemoglobin released from the clot into the subarachnoid space, and reversal of vasospasm by intracarotid NO. The authors sought to establish whether administration of l-arginine, the substrate of the NO-producing enzyme NOS, would reverse and/or prevent vasospasm in a primate model of SAH.Methods. The study was composed of two sets of experiments: one in which l-arginine was infused over a brief period into the carotid artery of monkeys with vasospasm, and the other in which l-arginine was intravenously infused into monkeys over a longer period of time starting at onset of SAH. In the short-term infusion experiment, the effect of a 3-minute intracarotid infusion of l-arginine (intracarotid concentration 10−6 M) on the degree of vasospasm of the right middle cerebral artery (MCA) and on regional cerebral blood flow (rCBF) was examined in five cynomolgus monkeys. In the long-term infusion experiment, the effect of a 14-day intravenous infusion of saline (control group, five animals) or l-arginine (10−3 M; six animals) on the occurrence and degree of cerebral vasospasm was examined in monkeys. The degree of vasospasm in all experiments was assessed by cerebral arteriography, which was performed preoperatively and on postoperative Days 7 (short and long-term infusion experiments) and 14 (long-term infusion experiment). In the long-term infusion experiment, plasma levels of l-arginine were measured at these times in the monkeys to confirm l-arginine availability.Vasospasm was not affected by the intracarotid infusion of l-arginine (shown by the reduction in the right MCA area on an anteroposterior arteriogram compared with preoperative values). However, intracarotid l-arginine infusion increased rCBF by 21% (p < 0.015; PCO2 38–42 mm Hg) in all vasospastic monkeys compared with rCBF measured during the saline infusions. In the long-term infusion experiment, vasospasm of the right MCA occurred with similar intensity with or without continuous intravenous administration of l-arginine on Day 7 and had resolved by Day 14. The mean plasma l-arginine level increased during infusion from 12.7 ± 4 µg/ml on Day 0 to 21.9 ± 13.1 µg/ml on Day 7 and was 18.5 ± 3.1 µg/ml on Day 14 (p < 0.05).Conclusions. Brief intracarotid and continuous intravenous infusion of l-arginine did not influence the incidence or degree of cerebral vasospasm. After SAH, intracarotid infusion of l-arginine markedly increased rCBF in a primate model of SAH. These findings discourage the use of l-arginine as a treatment for vasospasm after SAH.

Neuropeptide Y in the primate model of subarachnoid hemorrhage

1992 ◽  
Vol 77 (3) ◽  
pp. 417-423 ◽  
Author(s):  
Ryszard M. Pluta ◽  
Anna Deka-Starosta ◽  
Alois Zauner ◽  
Jay K. Morgan ◽  
Karin M. Muraszko ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Neuropeptide Y ◽  
Cerebral Vasospasm ◽  
Primate Model ◽  
Content Type ◽  
Peripheral Plasma ◽  
Delayed Cerebral Vasospasm ◽  
Arterial Plasma ◽  
Fine Print

✓ The cause of cerebral vasospasm after subarachnoid hemorrhage (SAH) remains unknown. Recently, an association between the potent vasoconstricting peptide, neuropeptide Y, and delayed cerebral vasospasm after SAH has been postulated. This was based on the findings of increased neuropeptide Y levels in the cerebrospinal fluid (CSF) and plasma after SAH in animals and humans. For this study, the primate model of SAH was used to assess the possible role of neuropeptide Y in delayed vasospasm after SAH. Fifteen cynomolgus monkeys underwent placement of a clot of either whole blood or red blood cells in the subarachnoid space around the middle cerebral artery (MCA). Sequential arteriography for assessment of MCA diameter and sampling of blood and CSF for neuropeptide Y were performed: before SAH (Day 0); 7 days after SAH, when signs of delayed cerebral vasospasm peak in this model and in humans; 12 days after SAH; and 28 days after SAH. Subarachnoid hemorrhage did not evoke changes in CSF or plasma levels of neuropeptide Y. Nine monkeys had arteriographic evidence of vasospasm on Day 7, but no change in neuropeptide Y levels occurred in plasma or CSF. In addition, neuropeptide Y levels did not change, even after resolution of vasospasm on Day 12 or Day 28. Neuropeptide Y levels were substantially higher in CSF than in arterial plasma (p < 0.003 at each interval). No correlation was found between neuropeptide Y levels in CSF and in plasma. These results do not confirm a relationship between neuropeptide Y levels in the CSF or peripheral plasma and delayed cerebral vasospasm in SAH.

Nitric oxide mediation of chemoregulation but not autoregulation of cerebral blood flow in primates

1996 ◽  
Vol 84 (1) ◽  
pp. 71-78 ◽  
Author(s):  
B. Gregory Thompson ◽  
Ryszard M. Pluta ◽  
Mary E. Girton ◽  
Edward H. Oldfield
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
No Production ◽  
Direct Role ◽  
Content Type ◽  
Continuous Release ◽  
Fine Print

✓ The authors sought to develop a model for assessing in vivo regulation of cerebral vasoregulation by nitric oxide (NO), originally described as endothelial-derived relaxing factor, and to use this model to establish the role of NO in the regulation of cerebral blood flow (CBF) in primates. By using regional intraarterial perfusion, the function of NO in cerebral vasoregulation was examined without producing confounding systemic physiological effects. Issues examined were: whether resting vasomotor tone requires NO; whether NO mediates vasodilation during chemoregulation and autoregulation of CBF; and whether there is a relationship between the degree of hypercapnia and hypotension and NO production. Twelve anesthetized (0.5% isoflurane) cynomolgus monkeys were monitored continuously for cortical CBF, PaCO2, and mean arterial pressure (MAP), which were systematically altered to provide control and experimental curves of chemoregulation (CBF vs. PaCO2) and autoregulation (CBF vs. MAP) during continuous intracarotid infusion of 1) saline and 2) an NO synthase inhibitor (NOSI), either l-n-monomethyl arginine or nitro l-arginine. During basal conditions (PaCO2 of 38–42 mm Hg) NOSI infusion of internal carotid artery (ICA) reduced cortical CBF from 62 (saline) to 53 ml/100 g/per minute (p < 0.01), although there was no effect on MAP. Increased CBF in response to hypercapnia was completely blocked by ICA NOSI. The difference in regional (r)CBF between ICA saline and NOSI infusion increased linearly with PaCO2 when PaCO2 was greater than 40 mm Hg, indicating a graded relationship of NO production, increasing PaCO2, and increasing CBF. Diminution of CBF with NOSI infusion was reversed by simultaneous ICA infusion of l-arginine, indicating a direct role of NO synthesis in the chemoregulation of CBF. Hypotension and hypertension were induced with trimethaphan camsylate (Arfonad) and phenylephrine at constant PaCO2 (40 ± 1 mm Hg). Autoregulation in response to changes in MAP from 50 to 140 mm Hg was unaffected by ICA infusion of NOSI. In primates, cerebral vascular tone is modulated in vivo by NO; continuous release of NO is necessary to maintain homeostatic cerebral vasodilation; vasodilation during chemoregulation of CBF is mediated directly by NO production; autoregulatory vasodilation with hypotension is not mediated by NO; and increasing PaCO2 induces increased NO production.

Loss of nitric oxide synthase immunoreactivity in cerebral vasospasm

1996 ◽  
Vol 84 (4) ◽  
pp. 648-654 ◽  
Author(s):  
Ryszard M. Pluta ◽  
B. Gregory Thompson ◽  
Ted M. Dawson ◽  
Solomon H. Snyder ◽  
Robert J. Boock ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Cerebral Vasospasm ◽  
Cerebral Artery ◽  
Cerebral Arteries ◽  
Nerve Fibers ◽  
Content Type ◽  
The Right ◽  
Oxide Synthase ◽  
Fine Print

✓ To determine the distribution of nitric oxide synthase (NOS) in the primate cerebral artery nervi vasorum and to examine the potential role of NOS in cerebral vasospasm after subarachnoid hemorrhage (SAH) in primates, the distribution of NOS immunoreactivity (NOS-IR) in the major cerebral arteries was examined immunohistochemically in cynomolgus monkeys by the use of whole, mounted preparations of the circle of Willis. In four normal monkeys, NOS-IR was localized to the endothelial and adventitial layers of the large cerebral arteries. On the abluminal side, NOS-IR staining was densely concentrated in perivascular nerve fibers (nervi vasorum) of the anterior circulation. Staining was less prominent in the posterior circulation. In six monkeys with vasospasm on Day 7 after placement of preclotted arterial blood to form an SAH around the right middle cerebral artery (MCA) (42% ± 8.3% decrease of MCA area, mean ± standard deviation), NOS-IR was virtually absent in nerve fibers around the spastic right MCA but was normal on the contralateral side. In five monkeys in which vasospasm resolved by Day 14 after SAH (36% ± 14% decrease of right MCA area on Day 7, and 5% ± 14% decrease on Day 14), NOS-IR was also absent in the right MCA adventitial nerve fibers and remained normal in the left MCA. Adventitial NOS-IR was also normal in cerebral vessels of a sham-operated, nonspastic monkey. These findings provide further evidence that nitric oxide (NO) functions as a neuronal transmitter to mediate vasodilation in primates and indicate a role for adventitial NO in the pathogenesis of cerebral vasospasm after SAH in humans.

Inducible nitric oxide synthase: a possible key factor in the pathogenesis of chronic vasospasm after experimental subarachnoid hemorrhage

1999 ◽  
Vol 90 (6) ◽  
pp. 1098-1104 ◽  
Author(s):  
Darius C. Widenka ◽  
Ralph J. Medele ◽  
Walter Stummer ◽  
Karl Bise ◽  
Hans J. Steiger
Keyword(s):  
Nitric Oxide ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Inducible Nitric Oxide Synthase ◽  
Immunohistochemical Staining ◽  
Content Type ◽  
Chronic Vasospasm ◽  
Oxide Synthase ◽  
Fine Print ◽  
Inducible Nitric Oxide

Object. The role of nitric oxide (NO) in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH) is not well understood. Nitric oxide is a well-established vasodilatory substance; however, in SAH, NO may become a major source for the production of injurious free-radical species, leading to chronic cerebral vasospasm. Reactive overproduction of NO to counteract vascular narrowing might potentiate the detrimental effects of NO. The focus of the present study is to determine the extent of reactive induction of inducible nitric oxide synthase (iNOS) after experimental SAH.Methods. Chronic vasospasm was induced in male Wistar rats by an injection of autologous blood (100 µl) into the cisterna magna followed by a second injection 24 hours later. A control group of 10 animals was treated with injections of 0.9% sodium chloride solution. Vasospasm was verified by pressure-controlled angiography after retrograde cannulation of the external carotid artery 7 days later. In 11 of 15 animals radiographic evidence of cerebral vasospasm was seen. The animals were perfusion fixed and their brains were removed for immunohistochemical assessment. With the aid of a microscope, staining for iNOS was quantified in 40-µm floating coronal sections.Immunohistochemical staining for iNOS was markedly more intense in animals with significant angiographic evidence of vasospasm. Virtually no staining was observed in control animals. Seven days after the second experimental SAH, labeling of iNOS was found in endothelial cells, in vascular smooth-muscle cells, and, above all, in adventitial cells. Some immunohistochemical staining of iNOS was observed in rod cells (activated microglia), in glial networks, and in neurons.Conclusions. The present study demonstrates induction of iNOS after experimental SAH.

Is vasospasm related to proliferative arteriopathy?

1992 ◽  
Vol 77 (5) ◽  
pp. 740-748 ◽  
Author(s):  
Ryszard M. Pluta ◽  
Alois Zauner ◽  
Jay K. Morgan ◽  
Karin M. Muraszko ◽  
Edward H. Oldfield
Keyword(s):  
Cerebral Vasospasm ◽  
Vessel Diameter ◽  
Limited Range ◽  
Primate Model ◽  
Content Type ◽  
Morphological Studies ◽  
Dividing Cells ◽  
The Right ◽  
Fine Print

✓ Although proliferative arteriopathy has been postulated to play a role in the etiology of vasospasm after subarachnoid hemorrhage (SAH), histological and morphological studies examining cerebral vasospasm have produced conflicting results. To help settle this controversy, the authors used an in vivo label of cell division, bromodeoxycytidine, to assess cell proliferation in a primate model of SAH. Fifteen cynomolgus monkeys received a clot of either whole blood (11 animals) or red blood cells (four animals) placed around the right middle cerebral artery (MCA). On the day of surgery continuous intravenous infusion of bromodeoxycytidine was begun and continued until the animal was sacrificed immediately after arteriography on Day 7, 12, or 27 following surgery. Sections from the right and left MCA's were stained with a monoclonal antibody against bromodeoxcytidine, and labeled cells were counted. Arteriographic evidence of vasospasm occurred in nine monkeys on Day 7. On Day 12 and Day 27 no monkeys had persistent vasospasm. Placement of subarachnoid clot around the right MCA increased proliferative activity across all layers of the arterial wall. Most of the labeled cells were in the adventitia and the endothelium. Although there were more dividing cells in all layers of the right MCA than the left MCA (p < 0.01), the number of stained cells per section was limited (range 0.1 to 21.2, mean 8) and the occurrence of vasospasm was not associated with the number of dividing cells in the right MCA on Day 7, 12, 27, or for all days combined (p > 0.6). Cerebral vasospasm after SAH was not associated with the extent of proliferation of cells in the vessel wall, nor could the intensity of the limited proliferative changes have been responsible for narrowing of the vessel diameter.

Experimental cerebral vasospasm

1974 ◽  
Vol 41 (3) ◽  
pp. 285-292 ◽  
Author(s):  
Hajime Nagai ◽  
Yoshiaki Suzuki ◽  
Mitsuo Sugiura ◽  
Satoshi Noda ◽  
Hideo Mabe
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Posterior Communicating Artery ◽  
Content Type ◽  
Aneurysmal Rupture ◽  
Experimental Subarachnoid Hemorrhage ◽  
Fine Print

✓The authors describe a model for making an experimental subarachnoid hemorrhage that closely simulates human aneurysmal rupture. A needle previously inserted into the posterior communicating artery is subsequently withdrawn by traction on a thread. Using this model they demonstrate biphasic spasm by measurement of cerebral blood flow and angiography after rupture of the artery; the early spasm lasted 60 minutes and the late spasm began 3 or 4 hours after subarachnoid hemorrhage and continued for several days. The authors discuss the pathogenesis of early and late spasm.

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

1997 ◽  
Vol 87 (5) ◽  
pp. 746-751 ◽  
Author(s):  
Ryszard M. Pluta ◽  
Edward H. Oldfield ◽  
Robert J. Boock
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Subarachnoid Hemorrhage ◽  
Arterial Blood Pressure ◽  
Cerebral Vasospasm ◽  
Primate Model ◽  
Arterial Blood ◽  
Infusion Experiment ◽  
The Mean ◽  
The Right

✓ 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.

Controlled release of a nitric oxide donor for the prevention of delayed cerebral vasospasm following experimental subarachnoid hemorrhage in nonhuman primates

2005 ◽  
Vol 103 (4) ◽  
pp. 745-751 ◽  
Author(s):  
Richard E. Clatterbuck ◽  
Philippe Gailloud ◽  
Travis Tierney ◽  
Victoria M. Clatterbuck ◽  
Kieran J. Murphy ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Subarachnoid Hemorrhage ◽  
Controlled Release ◽  
Cerebral Vasospasm ◽  
Cerebral Angiography ◽  
Nonhuman Primates ◽  
Content Type ◽  
Delayed Cerebral Vasospasm ◽  
The Mean ◽  
Fine Print

Object. Results of prior studies in rats and rabbits show that the alteration of vasomotor tone in vasospasm following periadventitial blood exposure may be reversed, at least in part, by the administration of compounds releasing nitric oxide (NO). The authors have now generalized this finding to nonhuman primates. Methods. Ten cynomolgus monkeys underwent cerebral angiography before and 7 days following the induction of subarachnoid hemorrhage (SAH) by the placement of 2 to 3 ml clotted autologous blood around the supraclinoid carotid, proximal anterior cerebral, and proximal middle cerebral arteries. An ethylene vinyl acetate copolymer, either blank (five animals) or containing 20% w/w (Z)-1-[2-(2-aminoethyl)-N-(2-aminoethyl)amino]diazen-1-ium-1,2-diolate (DETA/NO, 4.3 mg/kg; five animals) was placed adjacent to the vessels at the time of surgery. Animals were killed on Day 7 post-SAH following repeated cerebral angiography. The mean percentage of control vascular areal fraction was calculated from angiograms. Cerebral vessels were sectioned and the mean percentage of lumen patency was calculated. One animal that had received the DETA/NO polymer died prior to repeated angiography. In the remaining animals, DETA/NO caused a significant decrease in vasospasm compared with controls, according to both angiographic (84.8 ± 8.6 compared with 56.6 ± 5.2%, respectively, p < 0.05) and histological studies (internal carotid artery 99.3 ± 1.8 compared with 60.1 ± 4.4%, respectively, p < 0.001; middle cerebral artery 98.4 ± 3 compared with 56.1 ± 3.7%, respectively, p < 0.001; and anterior cerebral artery 89.2 ± 8.5 compared with 55.8 ± 6.3%, respectively, p < 0.05). Conclusions. The controlled release of DETA/NO is effective in preventing delayed cerebral vasospasm in an SAH model in nonhuman primates. The death of one animal in the treatment group indicates that the present dosage is at the threshold between therapeutic efficacy and toxicity.

Sign in / Sign up

Export Citation Format

Share Document