Effect of the 21-aminosteroid U-74006F on cerebral vasospasm following subarachnoid hemorrhage

1989 ◽  
Vol 71 (1) ◽  
pp. 98-104 ◽  
Author(s):  
Mario Zuccarello ◽  
Jeffery T. Marsch ◽  
Gerald Schmitt ◽  
James Woodward ◽  
Douglas K. Anderson
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Basilar Artery ◽  
Autologous Blood ◽  
Contrast Material ◽  
Rabbit Model ◽  
Membrane Lipid ◽  
Basilar Arteries ◽  
Flow Through ◽  
Chronic Vasospasm

✓ The purpose of this study was to use a new 21-aminosteroid (U-74006F) with in vitro antioxidant and antilipolytic properties as a pharmacological probe to assess the role of lipid hydrolysis and peroxidation in a rabbit model of subarachnoid hemorrhage (SAH)-induced vasospasm. Cerebral angiograms were performed on 15 rabbits. Eighteen hours later, 1 cc/kg of autologous blood was infused into the cisterna magna of all 15 animals. Six rabbits received no treatment, six received U-74006F starting 30 minutes after SAH, and three rabbits received the vehicle for U-74006F starting 30 minutes after SAH. At 72 hours post-SAH, a second angiogram was obtained. Digital subtraction angiographic techniques were used to measure the diameter of and contrast material flow through the basilar artery. At 72 hours post-SAH, vasospasm was evident in all untreated and vehicle-treated rabbits. The diameter of and the flow through the basilar artery were significantly reduced 42.3% ± 6.6% and 46.8% ± 5.8%, respectively, below pre-SAH levels (means ± standard error of the means). Treatment with U-74006F eliminated the SAH-induced vasospasm; in treated animals, both the flow through and the diameter of the basilar arteries were at pre-SAH levels. These findings indicate that: 1) membrane lipid changes (that is, hydrolysis with eicosanoid production and/or peroxidation) contribute to the chronic vasospasm resulting from SAH, and 2) U-74006F prevents the SAH-induced chronic vasospasm in this model by limiting these pathological membrane events.

Alterations of mechanical properties in canine basilar arteries after subarachnoid hemorrhage

1989 ◽  
Vol 71 (3) ◽  
pp. 430-436 ◽  
Author(s):  
Phyo Kim ◽  
Thoralf M. Sundt ◽  
Paul M. Vanhoutte
Keyword(s):  
Mechanical Properties ◽  
Subarachnoid Hemorrhage ◽  
Autologous Blood ◽  
Myogenic Tone ◽  
Control Group ◽  
Resting Tension ◽  
Length Contraction ◽  
Basilar Arteries ◽  
Chronic Vasospasm

✓ The purpose of this study was to examine the hypotheses that structural stiffening of the arterial wall contributes to chronic cerebral vasospasm, and that alteration in properties of smooth muscle takes place after subarachnoid hemorrhage (SAH). Subarachnoid hemorrhage and subsequent chronic vasospasm were induced in dogs by two cisternal injections of autologous blood (on Day 0 and Day 2). Vasospasm was confirmed by angiography performed on Day 0 and Day 7. Animals in the control group underwent angiography only. On Day 8, the mechanical properties of the basilar arteries were studied in vitro. Passive compliance, measured under total inhibition of spontaneous myogenic tone with diltiazem (10−4 M) plus papaverine (10−4 M) was smaller in the SAH group. The length-contraction curve was shifted to the left and the optimum length for maximum contraction (Lmax) was significantly shorter in the spastic blood vessels. The spontaneous myogenic tone was augmented in the SAH group, resulting in an increase in resting tension at each length. By contrast, the maximum contractions in response to KCl and uridine 5′-triphosphate were markedly reduced in the SAH group, without changes in sensitivity to these agents. These differences in mechanical properties were observed in rings both with and without endothelium. The results indicate that, in chronic vasospasm, stiffening of the noncontractile component of the vasculature takes place as well as alterations in the contractile component, both of which presumably contribute to the shift in resting length-tension relationship and length-contraction relationship of the artery. The decreased distensibility, the increase in resting tension, and the shortening of the Lmax all favor a smaller diameter of the artery after SAH, possibly contributing to vasospasm.

Release of endothelium-derived relaxing factor after subarachnoid hemorrhage

1989 ◽  
Vol 70 (1) ◽  
pp. 108-114 ◽  
Author(s):  
Phyo Kim ◽  
Robert R. Lorenz ◽  
Thoralf M. Sundt ◽  
Paul M. Vanhoutte
Keyword(s):  
Smooth Muscle ◽  
Subarachnoid Hemorrhage ◽  
Basilar Artery ◽  
Arginine Vasopressin ◽  
Autologous Blood ◽  
Relaxing Factor ◽  
Basilar Arteries ◽  
Endothelium Derived Relaxing Factor ◽  
Chronic Vasospasm ◽  
Endothelium Dependent Relaxation

✓ The purpose of this study was to determine the cause of the loss of endothelium-dependent relaxation observed in chronic cerebral vasospasm. A bioassay system was developed to measure the release of endothelium-derived relaxing factor (EDRF) from canine basilar arteries. Subarachnoid hemorrhage (SAH) was induced in dogs by two injections of autologous blood into the cisterna magna. Angiograms were performed on the 7th day after SAH to check the presence of chronic vasospasm. The animals were sacrificed on the 8th day, and in vitro experiments were performed on rings harvested from the basilar artery. These confirmed loss of endothelium-dependent relaxation in response to bradykinin and arginine vasopressin in the group with SAH. The basilar arteries were perfused with modified Krebs-Ringer solution. The perfusate was bioassayed with a ring of coronary artery without endothelium (bioassay ring). The release of the EDRF was detected by relaxation of the bioassay ring contracted with prostaglandin F2α. Arginine vasopressin and bradykinin added to the perfusate upstream of the basilar artery caused concentration-dependent release of the EDRF. The direct effect of these peptides on the smooth muscle of the bioassay ring was to cause contraction. The release of the EDRF was identical in basilar arteries from the control and the SAH groups. These results indicate that the release of the EDRF is not impaired during chronic vasospasm, and thus that the loss of the endothelium-dependent relaxation is due to a decreased transfer of the EDRF or a reduced responsiveness of the smooth muscle to the factor.

A Study of the Effectiveness of the Iron-Chelating Agent Deferoxamine as Vasospasm Prophylaxis in a Rabbit Model of Subarachnoid Hemorrhage

Neurosurgery ◽  
1991 ◽  
Vol 28 (1) ◽  
pp. 27-32 ◽  
Author(s):  
Dennis G. Vollmer ◽  
Kazuhiro Hongo ◽  
Hisayuki Ogawa ◽  
Tetsuya Tsukahara ◽  
Neal F. Kassell
Keyword(s):  
Free Radicals ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Basilar Artery ◽  
Tissue Injury ◽  
Rabbit Model ◽  
Chelating Agent ◽  
Lipid Peroxides ◽  
Radical Mechanism ◽  
Basilar Arteries

Abstract The pathogenesis of cerebral vasospasm occurring after subarachnoid hemorrhage (SAH) is unknown. Several lines of experimentation have suggested a free radical mechanism in the etiology of vasospasm. Iron is an important catalyst in the generation of free radicals and lipid peroxides in response to tissue injury. We hypothesize that the elaboration of iron from the subarachnoid clot might result in enhanced generation of free radicals and lipid peroxidation. If so. then treatment with deferoxamine, an iron-chelating compound, might reduce the formation of free radicals and thereby ameliorate vasospasm. This hypothesis was examined in a rabbit model of experimental cerebral vasospasm. New Zealand White rabbits were divided into the following experimental groups: control (normal) animals (n = 7), control animals treated with deferoxamine (n = 3), animals subjected to SAH and killed on Day 2 (n = 7), animals subjected to SAH on Day 2 and treated with deferoxamine (n = 9), animals subjected to SAH killed on Day 3 (n = 7). and animals subjected to SAH on Day 3 and treated with deferoxamine (n = 7). Deferoxamine treatment (50 mg/kg/8 hours) was begun 16 hours before the induction of SAH and continued until the animals were killed by perfusion fixation. The basilar artery caliber was assessed using morphometric techniques. The diameter of the basilar arteries in the control animals was 0.64 ± 0.02 mm. Deferoxamine treatment alone did not alter the artery diameter. SAH resulted in a decrease in basilar artery diameter by 20% on Day 2 and 27% on Day 3. Deferoxamine treatment attenuated the SAH-induced spasm minimally on Day 2 but significantly on Day 3 (Day 3 diameter = 0.60 ± 0.04; P < 0.015). These preliminary results show promise for deferoxamine therapy in the treatment of vasospasm occurring after SAH. These data support the notion that SAH-induced vasospasm is mediated by iron, possibly via the generation of free radicals.

Prevention of vasospasm by anti-CD11/CD18 monoclonal antibody therapy following subarachnoid hemorrhage in rabbits

2004 ◽  
Vol 101 (1) ◽  
pp. 88-92 ◽  
Author(s):  
Gustavo Pradilla ◽  
Paul P. Wang ◽  
Federico G. Legnani ◽  
Lynn Ogata ◽  
Gregory N. Dietsch ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Endothelial Cells ◽  
Subarachnoid Hemorrhage ◽  
Autologous Blood ◽  
Rabbit Model ◽  
Control Group ◽  
Lymphocyte Function ◽  
Content Type ◽  
Basilar Arteries ◽  
Fine Print

Object. Adhesion of leukocytes and their migration into the periadventitial space may be critical in the pathophysiology of vasospasm following subarachnoid hemorrhage (SAH). The cell adhesion molecules involved in this process are lymphocyte function—associated antigen—1 (CD11a/CD18) and macrophage antigen—1 (CD11b/CD18), which are present on neutrophils/macrophages, and intercellular adhesion molecule—1 (CD54), which is present in endothelial cells. A humanized monoclonal antibody (mAb), Hu23F2G, targets CD11/CD18 and prevents leukocyte adhesion to endothelial cells. In this study, systemic administration of Hu23F2G prevented vasospasm in the rabbit model of SAH. Methods. Twenty-six New Zealand White rabbits were injected with autologous blood into the cisterna magna to induce SAH, after which they were randomized to receive injections of either Hu23F2G (10 animals) or a placebo at 30 minutes and 24 and 48 hours after SAH (six animals). Control animals underwent sham operations (four animals) or SAH alone (six animals). The animals were killed 72 hours after SAH, their bodies perfused and fixed, and their basilar arteries processed for morphometric analysis. Peripheral white blood cells (WBCs) were counted at 72 hours. The percentages of lumen patency were compared using the Student t-test. The presence of neutrophils and macrophages was confirmed by immunohistochemical analysis in which a rat anti—rabbit anti-CD18 mAb and cresyl violet were used. Treatment with Hu23F2G resulted in the significant prevention of vasospasm. Animals treated with Hu23F2G had 90 ± 7% lumen patency compared with 65 ± 7% in the placebo group (p = 0.025). The percentage of lumen patency in the SAH-only group was 59 ± 10%. The mean WBC count was 16,300 ± 2710/µl in the treatment group, compared with 7000 ± 386/µl in the control group (p = 0.02). Administration of Hu23F2G produced increased numbers of WBCs in 70% of the animals treated. Conclusions. This study supports the concept that leukocyte—endothelial cell interactions play an important role in the pathophysiology of chronic vasospasm after SAH. Systemic therapy with an anti-CD11/CD18 mAb prevents vasospasm after SAH by inhibiting adhesion of neutrophils and macrophages and their migration into the periadventitial space.

scholarly journals Application of the 1-µsec pulsed-dye laser to the treatment of experimental cerebral vasospasm

1991 ◽  
Vol 75 (2) ◽  
pp. 271-276 ◽  
Author(s):  
Atsushi Teramura ◽  
Robert Macfarlane ◽  
Christopher J. Owen ◽  
Ralph de la Torre ◽  
Kenton W. Gregory ◽  
...  
Keyword(s):  
Cerebral Vasospasm ◽  
Basilar Artery ◽  
Laser Energy ◽  
Autologous Blood ◽  
Preliminary Investigation ◽  
Dye Laser ◽  
Pulsed Dye Laser ◽  
Content Type

✓ Laser energy of 480 nm was applied in 1-µsec pulses varying between 2.2 and 10 mJ to in vitro and in vivo models of cerebral vasospasm. First, the pulsed-dye laser was applied intravascularly via a 320-µm fiber to basilar artery segments from six dogs. The segments were mounted in a vessel-perfusion apparatus and constricted to, on average, 70% of resting diameter by superfusion with dog hemolysate. Immediate increase in basilar artery diameter occurred to a mean of 83% of control. In a second model, the basilar artery was exposed transclivally in the rabbit. In three normal animals, superfusion of the artery with rabbit hemolysate resulted in a reduction of mean vessel diameter to 81% of control. Following extravascular application of the laser, vessels returned to an average of 106% of the resting state. In six rabbits, the basilar artery was constricted by two intracisternal injections of autologous blood, 3 days apart. Two to 4 days after the second injection, the basilar artery was exposed. Extravascular laser treatment from a quartz fiber placed perpendicular to the vessel adventitia resulted in an immediate 53% average increase in caliber to an estimated 107% of control. No reconstriction was observed over a period of up to 5 hours. Morphologically, damage to the arterial wall was slight. This preliminary investigation suggests that the 1-µsec pulsed-dye laser may be of benefit in the treatment of cerebral vasospasm.

Accelerated Non-Muscle Contraction after Subarachnoid Hemorrhage: Cerebrospinal Fluid Testing in a Culture Model

Neurosurgery ◽  
1990 ◽  
Vol 27 (6) ◽  
pp. 921-928 ◽  
Author(s):  
Yoshihiro Yamamoto ◽  
David H. Bernanke ◽  
Robert R. Smith
Keyword(s):  
Cerebrospinal Fluid ◽  
Subarachnoid Hemorrhage ◽  
Collagen Matrix ◽  
Aneurysm Rupture ◽  
Lattice Contraction ◽  
Symptomatic Vasospasm ◽  
Luminal Narrowing ◽  
Chronic Vasospasm ◽  
Vitro Model

Abstract The cause of chronic cerebral vasospasm after subarachnoid hemorrhage has been studied intensively, but it is still controversial whether the observable luminal narrowing should be attributed to the contraction of vascular smooth muscle cells or whether it results from some organic change in the wall. A proliferation of myointimal cells, accompanied by increased deposition of collagen, as well as myonecrosis, have been frequently observed several days after aneurysm rupture. Studies from our laboratory showed that these myointimal cells had characteristics identical to myofibroblasts. In this study, we quantitatively and morphologically examined the effect of cerebrospinal fluid on the ability of myofibroblasts to alter collagen matrices using an in vitro model. Myofibroblasts contract the collagen matrix by rearranging or compacting the framework of collagen fibers. Cerebrospinal fluid obtained from patients with recently ruptured aneurysms significantly accelerated lattice contraction, especially when the patient developed symptomatic vasospasm. This study suggests that myofibroblasts in the spastic artery can produce a contractile force that contributes to chronic vasospasm, tightening the proliferated collagen. Some unknown agent present in bloody cerebrospinal fluid accelerates the rearrangement of the collagen lattice by myofibroblasts, both of which have, until now, been considered non-contractile components.

scholarly journals Alteration of Basilar Artery Rho-Kinase and Soluble Guanylyl Cyclase Protein Expression in a Rat Model of Cerebral Vasospasm following Subarachnoid Hemorrhage

2014 ◽  
Vol 2014 ◽  
pp. 1-8
Author(s):  
Chih-Jen Wang ◽  
Pei-Yu Lee ◽  
Bin-Nan Wu ◽  
Shu-Chuan Wu ◽  
Joon-Khim Loh ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Protein Kinase ◽  
Protein Expression ◽  
Cerebral Vasospasm ◽  
Basilar Artery ◽  
Guanylyl Cyclase ◽  
Autologous Blood ◽  
Rho Kinase ◽  
Soluble Guanylyl Cyclase ◽  
Western Blots

Background and Purpose. The vasoconstrictor endothelin-1 (ET-1) has been implicated in the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage (SAH). Previous results showed that CGS 26303, an endothelin converting enzyme (ECE) inhibitor, effectively prevented and reversed arterial narrowing in animal models of SAH. In the present study, we assessed the effect of CGS 26303 on neurological deficits in SAH rats. The involvement of vasoactive pathways downstream of ET-1 signaling in SAH was also investigated.Methods. Sprague-Dawley rats were divided into five groups (n=6/group): (1) normal control, (2) SAH, (3) SAH+vehicle, (4) SAH+CGS 26303 (prevention), and (5) SAH+CGS 26303 (reversal). SAH was induced by injecting autologous blood into cisterna magna. CGS 26303 (10 mg/kg) was injected intravenously at 1 and 24 hr after the initiation of SAH in the prevention and reversal protocols, respectively. Behavioral changes were assessed at 48 hr after SAH. Protein expression was analyzed by Western blots.Results. Deficits in motor function were obvious in the SAH rats, and CGS 26303 significantly improved the rate of paraplegia. Expressions of rho-kinase-II and membrane-bound protein kinase C-δand rhoA were significantly increased, while those of soluble guanylyl cyclaseα1andβ1as well as protein kinase G were significantly decreased in the basilar artery of SAH rats. Treatment with CGS 26303 nearly normalized these effects.Conclusions. These results demonstrate that the rhoA/rho-kinase and sGC/cGMP/PKG pathways play pivotal roles in cerebral vasospasm after SAH. It also shows that ECE inhibition is an effective strategy for the treatment of this disease.

Effects of the Ca++-permeable nonselective cation channel blocker LOE 908 on subarachnoid hemorrhage—induced vasospasm in the basilar artery in rabbits

2003 ◽  
Vol 98 (3) ◽  
pp. 561-564 ◽  
Author(s):  
Yoshifumi Kawanabe ◽  
Tomoh Masaki ◽  
Nobuo Hashimoto
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Intravenous Administration ◽  
Basilar Artery ◽  
Channel Blocker ◽  
Autologous Blood ◽  
Content Type ◽  
Dependent Part ◽  
Before And After ◽  
Fine Print

Object. The Ca++ influx into vascular smooth-muscle cells (VSMCs) plays a fundamental role in the development and chronic effects of vasospasm after subarachnoid hemorrhage (SAH). The Ca++-permeable nonselective cation channels (NSCCs) are activated by several endothelium-derived constricting factors such as endothelin 1 (ET-1) and thromboxane A2. Moreover, the receptor-operated Ca++ channel blocker LOE 908 inhibits ET-1—induced extracellular Ca++ influx via NSCCs in the VSMCs of the basilar artery (BA) and the NSCC-dependent part of ET-1—induced vasoconstriction of BA rings. The purpose of the present study was to evaluate the in vivo role of LOE 908 on SAH-induced vasospasm. Methods. Forty-two Japanese white rabbits were assigned to seven groups. Treatment groups consisted of the following: 1) control rabbits without SAH that received a cisternal injection of saline; 2) rabbits with SAH that were subjected to the intravenous administration of saline; 3 through 6) rabbits with SAH that underwent the intravenous administration of 0.01, 0.1, 1, or 10 mg/kg LOE 908, respectively; and 7) rabbits without SAH that underwent the intravenous administration of 10 mg/kg LOE 908. Autologous blood was injected into the cisterna magna. The caliber of the BA was measured on angiographic studies before and after the cisternal injection of autologous blood. The intravenous injection of LOE 908 inhibited the magnitude of an SAH-induced vasosapsm. In addition, the concentration of LOE 908 required to relax vasospasm (1 mg/kg) correlated with that required to block Ca++ influx into VSMCs. Conclusions. The Ca++ channel blocker LOE 908 may inhibit the magnitude of an SAH-induced vasospasm by blocking the influx of Ca++ through NSCCs in rabbit BAs. Blocking the NSCCs may represent a new treatment for cerebral vasospasm after SAH.

Alterations in endothelium-dependent responsiveness of the canine basilar artery after subarachnoid hemorrhage

1988 ◽  
Vol 69 (2) ◽  
pp. 239-246 ◽  
Author(s):  
Phyo Kim ◽  
Thoralf M. Sundt ◽  
Paul M. Vanhoutte
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Basilar Artery ◽  
Calcium Ionophore ◽  
Adenosine Diphosphate ◽  
Canine Model ◽  
Calcium Ionophore A23187 ◽  
Ionophore A23187 ◽  
Content Type ◽  
Endothelium Dependent Relaxation

✓ To investigate the alteration of endothelium-dependent responses in chronic vasospasm after subarachnoid hemorrhage (SAH), experiments were carried out in the double-hemorrhage canine model. After the presence of vasospasm was confirmed by cerebral angiography on Days 0 and 7, pharmacological studies on the basilar artery were conducted in vitro on Day 8. In the SAH group, endothelium-dependent relaxation was abolished in response to arginine vasopressin and was significantly reduced in response to thrombin. Endothelium-independent relaxation in the SAH group was preserved in response to papaverine and was minimally reduced in response to sodium nitroprusside. Endothelium-dependent contraction in response to arachidonic acid, acetylcholine, the calcium ionophore A23187, adenosine diphosphate, mechanical stretching, and hypoxia persisted in the SAH group. The maximal contraction to KCl and uridine triphosphate, which is endothelium-independent, was diminished in the SAH group, but no changes in sensitivity were noted in the concentration-response relationships. A significant correlation was observed between the degree of vasospasm determined angiographically and the loss of endothelium-dependent relaxation. The loss of endothelium-dependent relaxation and the persistence of endothelium-dependent contraction suggest that the deterioration in the endothelium-dependent responses may be an important component in the pathogenesis of cerebral vasospasm.

Calcium sensitivity of vasospastic basilar artery after experimental subarachnoid hemorrhage

2006 ◽  
Vol 290 (6) ◽  
pp. H2329-H2336 ◽  
Author(s):  
R. Loch Macdonald ◽  
Zhen-Du Zhang ◽  
Masataka Takahashi ◽  
Elena Nikitina ◽  
J. Young ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Subarachnoid Hemorrhage ◽  
Smooth Muscle Cells ◽  
Arterial Wall ◽  
Arterial Compliance ◽  
Smooth Muscle Actin ◽  
Muscle Cells ◽  
Calcium Sensitivity ◽  
Basilar Arteries

Arteries that develop vasospasm after subarachnoid hemorrhage (SAH) may have altered contractility and compliance. Whether these changes are due to alterations in the smooth muscle cells or the arterial wall extracellular matrix is unknown. This study elucidated the location of such changes and determined the calcium sensitivity of vasospastic arteries. Dogs were placed under general anesthesia and underwent creation of SAH using the double-hemorrhage model. Vasospasm was assessed by angiography performed before and 4, 7, or 21 days after SAH. Basilar arteries were excised from SAH or control dogs ( n = 8–52 arterial rings from 2–9 dogs per measurement) and studied under isometric tension in vitro before and after permeabilization of smooth muscle with α-toxin. Endothelium was removed from all arteries. Vasospastic arteries demonstrated significantly reduced contractility to KCl with a shift in the EC50 toward reduced sensitivity to KCl 4 and 7 days after SAH ( P < 0.05, ANOVA). There was reduced compliance that persisted after permeabilization ( P < 0.05, ANOVA). Calcium sensitivity was decreased during vasospasm 4 and 7 days after SAH, as assessed in permeabilized arteries and in those contracted with BAY K 8644 in the presence of different concentrations of extracellular calcium ( P < 0.05, ANOVA). Depolymerization of actin with cytochalasin D abolished contractions to KCl but failed to alter arterial compliance. In conclusion, it is shown for the first time that calcium sensitivity is decreased during vasospasm after SAH in dogs, suggesting that other mechanisms are involved in maintaining the contraction. Reduced compliance seems to be due to an alteration in the arterial wall extracellullar matrix rather than the smooth muscle cells themselves because it cannot be alleviated by depolymerization of smooth muscle actin.

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