Constriction Of Basilar Artery Research Articles

Validity of D-penicillamine in experimental cerebral vasospasm therapy

BackgroundCerebral vasospasm is a reversible vessel constriction following subarachnoid hemorrhage. Immunoreactive and inflammatory mechanisms induce long-term vasoconstriction and vessel dilatation inhibition. We hypothesized that D-penicillamine depresses this process given that it reduces the concentration of free oxygen (O2) radicals. We evaluated the effects of D-penicillamine on cerebral vasospasm in rabbits induced with subarachnoid hemorrhage, achieved by autologous blood injection in the basal cistern. Materials and methodsFour experimental groups were studied: Group 1: basilar angiography, Group 2: basilar angiography + D-penicillamine, Group 3: subarachnoid hemorrhage (SAH), and Group 4: SAH + D-penicillamine. Vessel diameter and cerebral vasospasm were evaluated angiographically in each group. Vascular degeneration was studied by electron microscopy of the basilar artery. Free O2 radicals were investigated based on measurements of the levels of vascular superoxide dismutase and malondialdehyde. Myasthenia gravis–like side effects of D-penicillamine application were analyzed by electromyography and electron microscopy of the orbicularis oculi muscle. ResultsWe detected a 9.03% decrease in basilar artery constriction in Group 4 compared with Group 3. In addition, levels of free O2 radicals were reduced in Groups 2 and 4. Application of D-penicillamine resulted in the prevention of basilar artery wall degeneration, without myasthenia gravis–like side effects. ConclusionOur study indicated that D-penicillamine application induced vasodilatation and had anti-inflammatory effects.

Migraine with Brainstem Aura Accompanied by Disorders of Consciousness

Migraine with brainstem aura (MBA) accompanied by disorders of consciousness (DOC) is a rare subtype of migraine. The pathophysiology of MBA with DOC has not been elucidated yet. Some patients have a family history of migraine, and women are more affected than men. The aura symptoms are diverse; however, when MBA is combined with DOC, the clinical manifestations are more complicated. Coma is the most common clinical manifestation. The overall duration of the patient’s DOC is short and can often return to normal within half an hour. Headache often occurs after regaining consciousness and can also occur at the same time as DOC. The most common headache is located at the occipital region. Although DOC is reversible, considering the current small number of cases, we still need to improve our understanding of the disease to avoid misdiagnosis. The MBA patient’s electroencephalogram and cerebral blood flow perfusion may have transient changes and may return to normal in the interictal period or after the DOC. Although triptans have traditionally been contraindicated in MBA under drug instructions, the evidence of basilar artery constriction, as postulated in MBA, is lacking. Lasmiditan is currently the first and only 5-HT 1F receptor agonist approved by the Food and Drug Administration. The calcitonin gene-related peptide receptor antagonists and monoclonal antibody therapies may be the most promising for future consideration. Here, the pathophysiology, clinical manifestations, diagnostic tools, and treatment progress for MBA with DOC are reviewed.

Getting to the Heart of the Matter: Migraine, Triptans, DHE, Ditans, CGRP Antibodies, First/Second-Generation Gepants, and Cardiovascular Risk.

The science of migraine pathophysiology has advanced significantly since the 1930's. Imaging techniques, neurochemical analysis, clinical trials, and the clinical experience of providers treating migraine patients have not only sharpened our understanding of the disease, but have also led to the development of novel neural-based targets. Targeted therapies such as calcitonin gene-related peptide (CGRP) antibodies and "Second Generation" CGRP receptor antagonists (Gepants) have not only demonstrated efficacy, but have not resulted in any significant cardiovascular nor other serious adverse events. "First Generation" Gepants were associated with liver toxicity. Triptans and dihydroergotamine (DHE) are contraindicated in patients with hemiplegic and basilar migrainebased on theories of migraine pathophysiology from the 1930s. While our understanding of migraine has evolved substantially, perceived concerns of safety from almost a century ago continue to preclude their use in certain patient populations. While migraine aura was once thought to be primarily due to vasoconstriction, current evidence debunks this concept. For instance, hemiplegic migraine is the consequence of genetic mutations resulting in channelopathies without evidence of cerebral ischemia or infarction. Evidence of basilar artery constriction as postulated in basilar migraine is also lacking. This recognition has led the International Headache Society to rename basilar-type migraine to migraine with brainstem aura. The following discussion reviews current literature with respect to migraine as a neuronal disorder, as well as the published data on the safety of triptans, DHE, Ditans (a novel class of 5-HT1f receptor agonists), CGRP antibodies, and Gepants.

Icariin ameliorates angiotensin II-induced cerebrovascular remodeling by inhibiting Nox2-containing NADPH oxidase activation.

Cerebrovascular smooth muscle cells (SMCs) hyperplasia is an important contributor to cerebrovascular remodeling during hypertension. The aim of present study was to investigate the effects of Icariin on cerebrovascular SMCs proliferation and remodeling and the underlying mechanisms. The results revealed that Icariin administration attenuated the enhanced basilar artery constriction in angiotensin II (AngII)-induced hypertension rat model, as well as the inhibition of basilar artery diameter reduction in response to AngII and phenylephrine. In addition, histological analyses showed that Icariin also significantly ameliorated basilar artery remodeling in AngII hypertensive rats. In human brain vascular SMCs (HBVSMCs), AngII-induced cell proliferation, migration and invasion were markedly inhibited by Icariin treatment. Moreover, Icariin treatment largely limited AngII-induced the increase of reactive oxygen species (ROS) production in HBVSMCs, which was closely associated with cell proliferation. Analysis of the mechanisms showed that Icariin decreased ROS production via inhibiting NADPH oxidase activity but not mitochondria-derived ROS production. Further, Icariin promoted Nox2 degradation and consequently reduced its protein expression. In conclusion, these findings demonstrate that Icariin attenuates cerebrovascular SMCs hyperplasia and subsequent remodeling through inhibiting Nox2-containing NADPH oxidase activation, suggesting Icariin may be a potential therapeutic agent to prevent the onset and progression of stroke.

TMEM16A contributes to angiotensin II-induced cerebral vasoconstriction via the RhoA/ROCK signaling pathway.

Calcium activated chloride channels (CaCCs) are critical in vascular smooth muscle function as they regulate proliferation/apoptosis of smooth muscle cells (SMCs) and vascular tone. Transmembrane protein 16A (TMEM16A) was demonstrated to encode CaCCs in basilar artery SMCs (BASMCs) and participate in basilar artery remodeling during hypertension. In addition, TMEM16A has recently been illustrated to contribute to pressure‑induced myogenic response in cerebral vasculature. However, whether TMEM16A is involved in cerebral vasoconstriction that is stimulated by other vasoconstrictors remains unclear. The aim of the present study was to establish whether TMEM16A is involved in the progression of angiotensin II (Ang II)‑induced basilar artery constriction and elucidate its potential role during hypertension. The study demonstrated that the specific inhibitor of TMEM16A, T16A‑inhA01 attenuated Ang II‑induced constriction in rat basilar arteries, and that this effect was weakened in parallel with the decline of TMEM16A expression in basilar arteries of 2‑kidney, 2‑clip hypertensive rats. Furthermore, it was found that 100 nM Ang II evoked a chloride current in cultured BASMCs with a basal 100‑nM intracellular Ca2+ ([Ca2+]i) level. In addition, the current could be abolished by TMEM16A small interfering RNA pretreatment and Ang II receptor type 1 (AT1) receptor blocker, losartan, while Ang II failed to cause a further increase to Ca2+‑dependent Cl‑ currents activated by 500 nM [Ca2+]i. In addition, in cultured BASMCs, Ang II induced phosphorylation of myosin phosphatase‑targeting subunit 1, and myosin light chains were significantly enhanced by TMEM16A overexpression, which were reversed by Rho‑associated protein kinase (ROCK) inhibitor, Y‑27632, while TMEM16A silencing demonstrated an opposing result. Furthermore, Ang II‑induced RhoA activation was enhanced by TMEM16A overexpression. In conclusion, the present study revealed that Ang II elicited a TMEM16A‑mediated current and TMEM16A participated in Ang II‑induced basilar constriction via the RhoA/ROCK signaling pathway.

Cocaine Constriction of Rat Basilar Artery in situ: Roles of Nitric Oxide and Endothelin-1

This study investigated whether cocaine constriction of rat basilar artery in situ is mediated by nitric oxide (NO) inhibition and/or endothelin (ET)-1 release. Cocaine (3-100 µmol/l) concentration-dependently constricted the basilar artery to a maximum of 18%. N_ω-nitro-<smlcap>L</smlcap>-arginine (100 µmol/l) was without effect on constriction to 3 and 10 µmol/l cocaine. PD145065 (1 and 10 µmol/l), an ET_A/B receptor antagonist, variably and at most partially inhibited the 100 µmol/l cocaine constriction. Capsaicin denervation of sensory nerves innervating the basilar, which contain ET-1 and NO synthase, also failed to influence cocaine constriction. These findings suggest that cocaine constriction of cerebral vessels (1) varies with respect to the involvement of ET-1 release and (2) unlike findings in the peripheral vasculature, the constriction is not mediated by inhibition of NO.

Preclinical efficacy and safety of Kv7 potassium channel openers in the treatment of cerebral vasospasm

Cerebral vasospasm is a sequel to subarachnoid hemorrhage (SAH) that leads to death or disability due to cerebral ischemia. The persistent constriction of the conduit arteries in the brain is due to sustained depolarization of myocytes lining the arteries, resulting in continuous influx of calcium (Ca2+) through voltage‐gated Ca2+ channels. Ca2+ channel blockers (CCB) or potassium (K+) channel openers that oppose membrane depolarization are expected to dilate the arteries and reduce ischemia. CCBs have limited efficacy because of heterogenous expression of Ca2+ channel subunits in myocytes and their propensity to induce hypotension. We recently reported that Kv7channels are expressed in rat basilar artery myocytes and Kv7 channel openers reverse the constriction of rat basilar artery produced by spasmogens — endothelin, serotonin and vasopressin. Here we demonstrate that Kv7 channel activators, retigabine and celecoxib significantly attenuate basilar artery spasm in a rat SAH model, when administered intraperitoneally every 12 hours for 48 hours. Both Kv7 channel openers induced hypothermia, an effect expected to limit neuronal damage. They also induced a transient drop in blood pressure (BP) generally lasting 30–60 min after each administration, but mean 24‐h BP measured using radio‐telemetry in normal rats was not changed. These results indicate that Kv7 channel openers can attenuate vasospasm without sustained hypotension.

Reply to Chadha et al.

Reply to Chadha et al.

Activation of vascular KCNQ (Kv7) potassium channels reverses spasmogen-induced constrictor responses in rat basilar artery.

Cerebral vasospasm is the persistent constriction of large conduit arteries in the base of the brain. This pathologically sustained contraction of the arterial myocytes has been attributed to locally elevated concentrations of vasoconstrictor agonists (spasmogens). We assessed the presence and function of KCNQ (K(v) 7) potassium channels in rat basilar artery myocytes, and determined the efficacy of K(v) 7 channel activators in relieving spasmogen-induced basilar artery constriction. Expression and function of K(v) 7 channels in freshly isolated basilar artery myocytes were evaluated by reverse transcriptase polymerase chain reaction and whole-cell electrophysiological techniques. Functional responses to K(v) 7 channel modulators were studied in intact artery segments using pressure myography. All five mammalian KCNQ subtypes (KCNQ1-5) were detected in the myocytes. K(v) currents were attributed to K(v) 7 channel activity based on their voltage dependence of activation (V(0.5) ∼-34 mV), lack of inactivation, enhancement by flupirtine (a selective K(v) 7 channel activator) and inhibition by 10,10-bis(pyridin-4-ylmethyl)anthracen-9-one (XE991; a selective K(v) 7 channel blocker). XE991 depolarized the myocytes and constricted intact basilar arteries. Celecoxib, a clinically used anti-inflammatory drug, not only enhanced K(v) 7 currents but also inhibited voltage-sensitive Ca(2+) currents. In arteries pre-constricted with spasmogens, both celecoxib and flupirtine were more effective in dilating artery segments than was nimodipine, a selective L-type Ca(2+) channel blocker. K(v) 7 channels are important determinants of basilar artery contractile status. Targeting the K(v) 7 channels using flupirtine or celecoxib could provide a novel strategy to relieve basilar artery constriction in patients with cerebral vasospasm. To view two letters to the Editor regarding this article visit http://dx.doi.org/10.1111/j.1476-5381.2011.01454.x and http://dx.doi.org/10.1111/j.1476-5381.2011.01457.x.

S1P‐induced vasoconstriction increased in basilar artery of a subarachnoid hemorrhage model in rats

Sphingosine‐1‐phosphate (S1P) potently constricts cerebral arteries and plays key functions in the immune, inflammatory, and cardiovascular systems. Inflammation has an important function in the development of cerebral vasospasm after subarachnoid hemorrhage (SAH). S1P is generated and stored in erytrocytes, leukocytes, endothelial cells and platelets and released by platelets during blood clotting. We investigated the functional effect of S1P in basilar artery in a rat subarachnoid hemorrhage model. Using an infusion pump 400μl blood or saline was given with intracysternal injection to young (200–300g) Sprague‐Dawley male rats. After 48 hours brain was removed and basilar artery was isolated and mounted into a wire myograph. Vasoconstricton to KCl, S1P, serotonin (5‐HT), endothelin‐1 (ET‐1), U46619 (a tromboxane A2 agonist) and vasodilatation to acetylcholine (Ach) and sodium nitroprusside (SNP) responses were measured. Compared to saline group, 5‐HT‐, S1P‐ and ET‐1‐induced vasoconstrictions were significantly increased in blood given group whereas KCl and U46619 did not show a difference. There was no difference in Ach‐ and SNP‐induced vasodilations between saline and blood group. In summary, our results suggest that basilar artery constriction to S1P, 5‐HT and ET‐1 are increased in a rat model of SAH and can be a new target for the treatment of vasospasm after SAH.

Vascular KCNQ Potassium Channels as Therapeutic Targets in Cerebral Vasospasm

Following subarachnoid hemorrhage, chronic narrowing of cerebral arteries, including basilar artery, leads to reduction of blood flow to the brain and results in high morbidity and mortality. During vasospasm, cerebrospinal fluid levels of putative spasmogens, endothelin‐1, serotonin, and vasopressin (AVP) are elevated. However the mechanisms by which they produce vasospasm are not clear. We recently found that AVP suppresses KCNQ (Kv7) potassium currents in mesenteric artery myocytes. This depolarizes the membrane leading to activation of voltage‐gated Ca2+ channels and arterial constriction. Here we propose that KCNQ channels are also central mediators of cerebral vasospasm. We used patch clamp electrophysiology in myocytes and pressure myography in isolated artery segments to characterize the role of KCNQ channels in rat basilar artery vasospasm. The spasmogens all suppress KCNQ currents in basilar artery myocytes. Flupirtine, a KCNQ channel opener, reversed the suppression of KCNQ currents and basilar artery constriction induced by the spasmogens. Celecoxib, a dual KCNQ channel opener and Ca2+ channel blocker was more effective than nimodipine in dilating basilar arteries. These findings provide the first evidence that KCNQ channels are expressed and functional in basilar artery and suggest that these channels are potential novel targets for therapeutic intervention in cerebral vasospasm. This work was supported by the NIH (R01‐HL089564 to KLB) and the AHA (09PRE2260209 to BKM)

Effect of a platelet-activating factor antagonist, E5880, on cerebrovasospasm following subarachnoid hemorrhage in a canine double-hemorrhage model

We investigated the effects of a platelet-activating factor (PAF) antagonist, E5880 (1-ethyl-2-[ N-(2-methoxy)benzoyl- N-[(2)-2-methoxy-3-(4-octadecycarbamoylox)piperidinocarbonyloxy-propyloxy]carbonyl]aminomethyl-pyridiniumchloride), on subarachnoid hemorrhage-induced prolongation of cerebral circulation time and decrease in the basilar artery diameter in a canine double-hemorrhage model. Animals were assigned to three groups, control (saline), E5880 1.2 mg/kg and E5880 2.4 mg/kg. For measurement of cerebral circulation time, regions of interest were chosen at the basilar artery and the straight sinus in order to obtain time–density curves. Cerebral circulation time was defined as the difference between the arterial and venous peaks. Cerebral circulation time and basilar artery diameter were assessed by intra-arterial digital subtraction angiography (IA-DSA) on Days 0, 2 and 7. The prolongation of cerebral circulation time following subarachnoid hemorrhage was significantly inhibited by intravenous administration of 2.4 mg/kg of E5880. Basilar artery constriction was also reduced by E5880. Thus, E5880 had preventive effects on the prolongation of cerebral circulation time and the vasoconstriction of basilar artery in this model. These results suggest that E5880 may have a preventive effect on neurological symptoms aggravated by cerebrovascular lesions following subarachnoid hemorrhage.

Reversal of hypercapnia induces endothelin-dependent constriction of basilar artery in rabbits with acute metabolic alkalosis

We recently concluded that constriction of basilar artery due to respiration-induced hypocapnia in rabbits with acute metabolic alkalosis and accompanying compensatory hypercapnia was independent of NO and K ATP channels. Based on reports that endothelin-1-mediated hypocapnic constriction of the rabbit basilar artery in vitro, we further investigated whether the respiration-induced hypocapnic constriction was endothelin-1 mediated. Metabolic alkalosis was induced acutely following ketamine/xylazine injection. The ET A plus ET B receptor antagonist, PD145065 (1 μM), and the selective ET A receptor antagonist, BQ610 (3 μM), completely relaxed the hypocapnic constriction, as determined in a cranial window. Unexpectedly, the ET B receptor antagonists, BQ788 and RES-701-1 (3 μM), relaxed the constriction by 72.1±2.8% (4) and 77.2±8.7% (5), respectively (means±S.E. ( n)). To investigate whether the large magnitudes of relaxation to both ET A and ET B receptor antagonists were due to nonselectivity of the antagonists, the effects of the antagonists on the constriction to exogenous endothelin-1 were evaluated. BQ610, BQ788, and RES-701-1 relaxed the 3–5 nM endothelin-1 constriction by only 64.3±7.6% (4), 43.5±8.5% (5), and 26.7±4.8% (3) (means±S.E. ( n)), respectively, consistent with the selective blocking action of these antagonists. To investigate whether the greater magnitude of BQ610, BQ788, and RES-701-1 relaxation of hypocapnic constricted versus exogenous endothelin-1-constricted vessels was due to differences between constriction elicited by endogenous versus exogenous endothelin-1, the effects of the endothelin receptor antagonists on constriction to isocapnic alkaline suffusate were evaluated. PD145065 (1 μM) and 0.1 mM phosphoramidon, an endothelin-converting enzyme inhibitor, inhibited the constriction to isocapnic alkaline suffusate by 83.8±7.8% (6) and 74.3±9.7% (8) (means±S.E. ( n)), respectively, consistent with the endothelin-1 dependency of the constriction. BQ610, BQ788, and RES-701-1 relaxed the isocapnic alkaline suffusate constriction by 74.9±6.7% (5), 65.5±6.4% (5), and 78.0±6.5% (4) (means±S.E. ( n)), respectively. Thus, the relaxation profile to the selective endothelin receptor antagonists in isocapnic alkaline constricted vessels more closely approximated the relaxation profile observed in hypocapnic constricted as compared to endothelin-1-constricted vessels. Hypocapnia did not alter the 5 nM endothelin-1 constriction. These results suggest that, under conditions of acute metabolic alkalosis and accompanying compensatory hypercapnia, subsequent hypocapnic constriction is endothelin mediated. Both ET A and ET B receptor activation may mediate the hypocapnic constriction. The hypocapnic constriction is not due to enhanced endothelin-1 constriction and, thus, is due to the release of endothelin-1 and/or additional endothelins.

Reversal of hypercapnia induces K ATP channel and NO-independent constriction of basilar artery in rabbits with acute metabolic alkalosis

The mechanism of hypocapnic constriction of the cerebral vasculature under conditions of altered acid–base balance has not been investigated. As K ATP channels and NO have been implicated in hypocapnic constriction, this study investigated their roles in the constriction due to lowered pCO 2 in hypercapnic rabbits with acute metabolic alkalosis. Metabolic alkalosis was induced acutely following ketamine/xylazine injection. Lowering blood pCO 2 from initial baseline hypercapnic levels to near normocapnic and hypocapnic levels constricted basilar artery by 10.2±0.8% (4) and 16.2±0.6% (44), respectively (means±S.E., n), as determined in an in situ cranial window preparation. The constrictions were maintained for 4–5 h and return of pCO 2 to hypercapnic levels relaxed the constriction. Changing the suffusate pH to either the pH of the cerebral spinal fluid observed during initial baseline hypercapnia or following lowered pCO 2 did not alter the magnitude of constriction due to lowered pCO 2. Neither 0.3 mM N G-monomethyl- l-arginine monoacetate, an NO synthase inhibitor, nor 10 μM glibenclamide, a K ATP channel blocker, altered the magnitude of hypocapnic constriction. These results demonstrated that under conditions of acute metabolic alkalosis and accompanying compensatory hypercapnia, subsequent pCO 2 reduction induces prolonged constriction of the basilar artery that is independent of (1) cerebral spinal fluid pH over a physiologic range, and (2) NO and K ATP channels.

Anticardiolipin antibody aggravates cerebral vasospasm after subarachnoid hemorrhage in rabbits.

We previously reported that patients with antiphospholipid antibodies (aPLs) frequently demonstrate cerebral infarction due to cerebral vasospasm after subarachnoid hemorrhage (SAH). To examine the participation of aPLs in the pathogenesis of vasospasm after SAH, we studied the relationships of aPLs and SAH in an animal model. SAH was produced in 34 rabbits that received two subarachnoid injections of autologous arterial blood. The animals were divided into four experimental groups: SAH was induced in group A (n=9), intracutaneous injection of cardiolipin (CL) was performed before the induction of SAH in group B (n=5), intravenous injection of CL was performed before SAH in group C (n=12), and cyclosporin A was infused intravenously after the intravenous injection of CL and induction of SAH in group D (n=8). Enzyme-linked immunosorbent assay identifying the titer of IgG CL antibodies, neurological evaluation, cerebral angiography, and histological examination were performed in all four groups. A significant elevation of anti-CL antibodies, aggravation of neurological deficit, and reduction of caliber of the basilar artery were observed in rabbits that received the intravenous immunization of CL (group C). The administration of cyclosporin A reduced the titer of anti-CL antibody, aggravation of neurological deficit, constriction of basilar artery, and the incidence of cerebral infarction (group D). Anti-CL antibodies may therefore be involved in the deterioration of cerebral vasospasm after SAH.

Prevention of cerebrovasospasm following subarachnoid hemorrhage in rabbits by the platelet-activating factor antagonist, E5880.

Recently, an important role of platelet-activating factor (PAF), an inflammation mediator, has been demonstrated in the genesis of cerebral vasospasm following subarachnoid hemorrhage (SAH). In the current study, the authors examined whether intravenous administration of the novel PAF antagonist, E5880, can prevent vasospasm following SAH in rabbits. A vasospasm model was produced in three groups of rabbits using two subarachnoid injections of autologous arterial blood, followed by intravenous administration of distilled water (control), a low dose of E5880 (0.1 mg/kg in distilled water), or a high dose of E5880 (0.5 mg/kg in distilled water). Neurological deterioration was largely prevented in the rabbits that received E5880. Basilar artery constriction was also reduced by both doses of E5880. Histological examination at autopsy predominantly showed ischemic changes in the brain. Animals in each E5880-treated group exhibited ischemic changes less frequently than those in the control group. Plasma thromboxane B2 concentrations were reduced in rabbits treated with E5880. Platelet-activating factor was immunolocalized in the intima and media of the basilar artery in the control group. The PAF immunoreactivity demonstrated in the basilar artery was decreased in the E5880 groups in a dose-dependent manner. Thus, this study provides evidence that PAF may play a role in the pathogenesis of vasospasm after SAH and that intravenous administration of E5880 is a promising approach in preventing vasospasm.

Failure of FK-506, a new immunosuppressant, to prevent cerebral vasospasm in a canine two-hemorrhage model.

In order to clarify the possible role of immunological reaction in the pathogenesis of cerebral vasospasm, the authors examined the prophylactic effect of the immunosuppressant agents FK-506 and cyclosporin A on chronic vasospasm in a canine two-hemorrhage model. While a mean constriction of the basilar artery to 81.0% +/- 4.0% (+/- standard error of the mean) occurred on Day 2 and to 63.8% +/- 3.5% on Day 7 in the untreated group, constriction to 77.9% +/- 3.4% on Day 2 and 62.8% +/- 3.0% on Day 7 was demonstrated in the FK-506-treated group (difference not significant). This tendency was also noted in the cyclosporin A-treated group, with basilar artery constriction to 81.8% +/- 3.7% and 56.3% +/- 2.7%, respectively (difference not significant). The histological changes of the basilar artery, including corrugation of the elastic lamina, detachment of endothelial cells, and vacuolar formation in the smooth-muscle layer were not different in the two treated groups and the one control group. Since these immunosuppressant agents are known to inhibit the release of interleukin-2 (IL-2), the level of IL-2 was examined in the cerebrospinal fluid of patients with cerebral vasospasm. While interleukin-1 gradually increased in level as time passed, the level of IL-2 was consistently low during the course of the study, indicating less participation of IL-2 in the pathogenesis of cerebral vasospasm. This clinical observation matched the experimental results. The authors conclude that cell-mediated immunoreaction, initiated mainly by IL-2, plays little role in the pathogenesis of cerebral vasospasm.

Platelet-activating factor and cerebral vasospasm following subarachnoid hemorrhage

This study examines whether platelet-activating factor (PAF) is involved in the occurrence of vasospasm after subarachnoid hemorrhage (SAH). A vasospasm model was produced in rabbits, with animals in six experimental groups receiving two subarachnoid injections of autologous arterial blood with the addition of one of the following; saline (Control Group 1), 25% dimethyl sulfoxide (Control Group 2), PAF (1, 2.5, 5, or 10 micrograms), CV6209 (10 or 100 micrograms), BN52021 (10 or 100 micrograms), or anti-PAF immunoglobulin G (IgG, 50 or 500 micrograms). No significant differences were detected between Control Groups 1 and 2 with regard to neurological deterioration and basilar artery constriction after SAH was induced. Administration of PAF together with autologous blood aggravated neurological deficits in a dose-dependent manner (r = 0.724, p < 0.001) and produced basilar artery constriction at two doses each of 2.5 micrograms (p < 0.05), 5 micrograms (p < 0.01), and 10 micrograms (p < 0.01). Neurological deterioration was prevented in rabbits receiving an intracisternal administration of either PAF antagonist CV6209 or BN52021 or anti-PAF IgG (p < 0.01 at a total dose of 20 micrograms and p < 0.05 at a total dose of 200 micrograms CV6209, p < 0.01 at total doses of 20 and 200 micrograms BN52021, and p < 0.01 at total doses of 100 and 1000 micrograms anti-PAF IgG). A reduction in basilar artery constriction was achieved by the injection of anti-PAF IgG (p < 0.05 at total doses of 100 and 1000 micrograms). Histological examination at autopsy on Days 14 to 21 showed mainly ischemic changes in the brain, including selective neuronal necrosis and cerebral infarction. The control and PAF groups showed marked ischemic changes. On the other hand, no ischemic changes were noted in the anti-PAF IgG group, and only 9% of animals in the CV6209 group and 25% in the BN52021 group demonstrated selective neuronal necrosis or infarction. This study thus provides evidence to support the role of PAF in the pathogenesis of vasospasm after SAH.

Effect of protein kinase C inhibitors on endothelin- and vasopressin-induced constriction of the rat basilar artery.

The goal of this study was to determine whether inhibitors of protein kinase C (PKC) attenuate constrictor responses of the basilar artery in vivo to endothelin and arginine vasopressin. In anesthetized rats, the diameter of basilar arteries was measured through a cranial window [control diameter 218 +/- 3 (SE) microns]. Vessel diameter was measured during topical application of agonists and antagonists. Sphingosine (10(-6) M), a PKC inhibitor that binds to the regulatory site of PKC, attenuated vasoconstriction in response to endothelin (10(-9), 10(-8), and 10(-7) M) and vasopressin (10(-9) and 10(-8) M). H-7 (10(-9) M), a PKC inhibitor that binds to the catalytic site of PKC, also inhibited vasoconstriction in response to endothelin and vasopressin. Sphingosine and H-7 did not affect baseline diameter and did not attenuate vasoconstriction in response to prostaglandin (PG) F2 alpha. The V1 antagonist [d(CH2)5Tyr(Me)]arginine vasopressin (10(-8) M) significantly inhibited constriction in response to vasopressin (10(-9) and 10(-8) M) but not PGF2 alpha (10(-6) M). These observations suggest that activation of PKC may contribute to endothelin-induced constriction of the basilar artery in vivo and that PKC may also be a mediator of V1-receptor-mediated constriction of the basilar artery in response to vasopressin.

Biphasic constriction of rabbit basilar artery following experimental subarachnoid hemorrhage: A morphometric study

To assess the changes in arterial structure resulting from subarachnoid hemorrhage, morphometric analysis was performed on basilar arteries from rabbits that had received an experimental subarachnoid hemorrhage up to 6 days earlier. For morphometric determination, the crosssectional area of the media, the area of the lumen, and the length of the internal elastic lamina were measured planimetrically. The morphometric diameter of the lumen, the media-to-radius ratio, and several other morphometric parameters were also calculated. Subarachnoid hemorrhage induced significant biphasic constriction of the basilar artery without any changes in the cross-sectional area of the media. The relative amount of smooth muscle cell decreased significantly in the late stage of hemorrhage.