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Among the various calcium-induced biologic events occurring in hypoxic neurons, activation of the calcium-activated neutral proteinase (calpain) is a likely mediator of neuronal degeneration. In this study, we assessed the protective effects of a calpain inhibitor (Cbz-Val-Phe-H) against hypoxic damage to the neocortex. An in vitro neocortical slice model from gerbils was used to study the delay to hypoxic depolarization during hypoxia and the recovery of synaptic responses after hypoxia. These responses were examined in control slices and slices treated with Cbz-Val-Phe-H. The delay to hypoxic depolarization did not differ between treated and control groups. In contrast, synaptic recovery after a fixed period of hypoxia (15 minutes) was significantly improved in the Cbz-Val-Phe-H-treated slices (P < .01). Concentrations of Cbz-Val-Phe-H of 50 mumol/L or greater were significantly more protective than a concentration of 20 mumol/L (P < .01). The data indicate that calcium-activated proteolysis plays a critical role in hypoxic damage to the neocortex and that calpain inhibitors may be useful therapeutic agents.

An impairment of endothelial function is associated with vasospasm after subarachnoid hemorrhage. Oxyhemoglobin is considered to be a critical trigger in the pathogenesis of vasospasm. The present studies examined the direct effects of oxyhemoglobin on cultured endothelial cells from bovine carotid artery. Confluent endothelial cells were treated with oxyhemoglobin, and the following were studied: 1) cell morphology, 2) cell density, and 3) the release of radiolabel from [3H]arachidonic acid-treated cells. Endothelial cells exposed to oxyhemoglobin exhibited detachment vacuoles, and cell density was significantly decreased in time- and dose-dependent manners. Superoxide dismutase, a free radical scavenger, provided partial protection against the cytotoxic effects of oxyhemoglobin. The release of radiolabel from [3H]arachidonic acid-treated cells was increased by oxyhemoglobin in time- and dose-dependent manners. Treatment with an inhibitor of phospholipase A2 or a calcium chelator inhibited the effects of oxyhemoglobin on arachidonic acid release and cellular viability. Oxyhemoglobin exerts a direct cytotoxic effect on cultured endothelial cells, and this effect is associated with increased release from [3H]arachidonic acid-labeled cells. Phospholipase A2 and free radicals appear to participate in the pathogenesis of endothelial cell damage. Oxyhemoglobin-induced compromise of endothelial cells may contribute to cerebrovascular pathology.

The timing of aneurysm surgery after subarachnoid hemorrhage is a major neurosurgical controversy addressed by the International Cooperative Study on the Timing of Aneurysm Surgery (1980-1983). The present report examines the results of this trial in the subgroup of patients admitted to North American centers. The method of study was a large, multicenter, prospective, epidemiological survey. Neurosurgeons were required to indicate prospectively the interval to planned aneurysm surgery at the time of patient admission. Outcome at 6 months was determined by a blinded evaluator, and overall management results were analyzed by the planned surgical interval. Seven hundred seventy-two (21.9% of the total study population) patients admitted from days 0 to 3 after subarachnoid hemorrhage were accrued in North American centers. Overall outcome in patients planned for surgery in days 0-3 was equivalent in terms of mortality (after adjustment for prognostic variables) to patients planned for days 11-32, but the early patients had significantly improved rates of good recovery (70.9% versus 61.7%, p less than 0.01). Patients planned for surgery during the days 7-10 interval had nearly twice the mortality of patients in the other intervals. In contrast to the results from the overall trial, which found no difference between early and delayed surgery, results were best in North American centers when surgery was planned between days 0 and 3 after subarachnoid hemorrhage. These findings argue strongly for early diagnosis and referral for surgical intervention of North American patients suspected of having a ruptured cerebral aneurysm.

Vasospasm is a serious complication associated with subarachnoid hemorrhage. Successful management of vasospasm will ultimately depend on a clear understanding of the scope of this phenomenon, including whether arterial elements of different calibers are equally affected. We therefore examined the responses to subarachnoid hemorrhage in rabbit basilar arteries, small pial arteries, and arterioles. We compared the brain stem pial arteries of 10 perfusion-fixed male New Zealand White rabbits after experimental subarachnoid hemorrhage to those of five control rabbits using morphological analysis of cross-sections of plastic-embedded vessels. After subarachnoid hemorrhage, the internal elastic lamina was highly corrugated in all basilar arteries (mean diameter 319 +/- 51 microns). These arteries were severely constricted in comparison with the control group, in which the mean diameter was 691 +/- 17 microns, and corrugation of the internal elastic lamina was not present. In contrast, small pial arteries and arterioles very rarely demonstrated a vasoconstrictive configuration after subarachnoid hemorrhage. The contractility of the smaller vessels was confirmed by injecting 2 mg/kg BaCl2 intracisternally. Following BaCl2 injection, corrugation of the internal elastic lamina was detected in the small arteries and arterioles as well as the basilar arteries. We conclude that experimental chronic vasospasm after subarachnoid hemorrhage in rabbits tends to occur in large conducting arteries rather than in smaller pial arteries and arterioles.

Major cerebral collateral arteries enlarge following bilateral ligation of the common and internal carotid arteries. The purpose of this investigation was to determine the relative contribution of cellular hypertrophy versus cellular hyperplasia to this vessel change in a morphometric analysis as well as the functional properties of remodeled vessels in an in vitro study. We assessed cell number and vessel dimensions by morphometric analysis of 16 perfusion-fixed rabbit basilar arteries. Results demonstrated significant increases in luminal diameter from 761 to 946 microns (p less than 0.01), medial cross-sectional area from 5.1 x 10(4) to 7.6 x 10(4) micron2 (p less than 0.005), smooth muscle cell volume from 9.19 x 10(5) to 1.44 x 10(6) micron3 (p less than 0.0005), and overall arterial length from 17.41 to 20.36 mm (p less than 0.005) in basilar arteries from the eight ligated rabbits compared with the eight sham-operated controls. Smooth muscle cell volume fraction and cell numerical density were unchanged whereas the number of cells per unit length of artery was increased significantly from 21.5 to 31.0 cells/micron (p less than 0.05). These data indicate that smooth muscle cell hyperplasia rather than hypertrophy contributes to increases in vessel mass. Functional properties of the basilar arteries from 10 ligated and 10 normal control rabbits were analyzed in vitro. Results showed increased contraction to potassium chloride (approximately 74%) (p less than 0.01) and increased sensitivity of smooth muscle to acetylcholine (p less than 0.05) while maximal relaxation was the same as control in the ligated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied disruption of the blood-brain barrier after experimental subarachnoid hemorrhage induced by an injection of 4 ml autologous arterial blood into the cisterna magna of rabbits. The animals were killed at 40 minutes, 6 hours, 1 day, 2 days, 4 days, or 6 days after subarachnoid hemorrhage. We assessed the integrity of the barrier function of intraparenchymal vessels in the ventral brain stem and cerebral hemispheres morphologically with transmission electron microscopy, using horseradish peroxidase as a tracer. In the ventral brain stem, which was in direct contact with the cisternal clots, markedly increased peroxidase staining toward the core of the brain stem was observed on the first day after subarachnoid hemorrhage. In an area of the cerebral hemispheres distant from the clots, barrier disturbance was prominent in the 6-hour specimens, and permeation of the tracer was spotty. From the distribution and morphological findings of these lesions, permeability changes in the ventral brain stem may have been caused by a direct effect of the cisternal clots; in the cerebral hemispheres, hemodynamic factors and changes in intracranial pressure associated with the elderly stages of subarachnoid hemorrhage seemed to be responsible. These results suggest that barrier disturbance associated with subarachnoid hemorrhage may be multifactorial in time course and location.

Anticoagulation with heparin is frequently recommended for patients with progressing ischemic cerebral infarction, yet little data is available detailing the acute results of treatment with this agent. We report the results of continuous intravenous heparin treatment in 36 consecutive patients admitted with progressing ischemic infarction, all of whom had computed tomography scans to exclude the diagnosis of hemorrhage prior to treatment. Overall, 18 of 36 (50%) had continued neurologic worsening despite treatment. The incidence of further worsening was greater in carotid territory infarctions (14 of 19, 74%) than in either vertebrobasilar (2 of 8, 25%) or lacunar (2 of 9, 22%) infarctions (p less than 0.05, Fisher's exact test). These observations suggest that additional controlled studies of the efficacy of heparin in progressing ischemic infarction are warranted.

Aneurysmal subarachnoid hemorrhage is a neurosurgical emergency. Early medical intervention is axiomatic for minimizing rebleeding and ischemia from vasospasm and achieving optimum results. The purpose of this study was to document the length and causes of the delay in referral which occur in patients following aneurysmal subarachnoid hemorrhage. The case histories of 150 consecutive patients admitted to The University of Iowa with proven ruptured aneurysms were studied. Medical records from The University of Iowa and referring hospitals were reviewed, and patients, families, and referring physicians interviewed. Overall, only 36% were referred within 48 hours of their first clear cut, recognizable sign or symptom of subarachnoid hemorrhage. Median time to referral was 3.6 days. Delay was due to physician diagnostic problems in 37%, delayed referral policy in 23%, unstable patient condition in 7%, failure of patients to recognize severity of illness in 8%, and logistical reasons in 12%. These data suggest that a large proportion of patients have a delay in achieving definitive neurosurgical care following aneurysm rupture, and that for the most part this delay is avoidable. More emphasis must be placed on public health and primary physician education regarding subarachnoid hemorrhage.

We investigated the effect of adenosine on neurogenic contraction of the canine cavernous carotid artery, using an isometric tension recording device and transmural nerve stimulation. Adenosine, in concentrations under 10(-5)M, had no relaxing effect on the contractions produced by high [K]o solution or 10(-5)M norepinephrine. Transmural nerve stimulation (stimulus: 1 msec duration, 100V intensity) evoked a frequency-dependent contraction, which was abolished by 3 X 10(-7)M tetrodotoxin. Adenosine in concentrations of 10(-6)M and 10(-5)M, inhibited the neurogenic contraction at each frequency, more so in the low frequency range. This inhibitory effect of adenosine was significantly antagonized by 10(-5)M theophylline. Pretreatment with 2 X 10(-8)M dipyridamole had no effect on neurogenic contractions, but augmented the inhibitory effect of adenosine. 10(-5)M theophylline did not augment the neurogenic contractions. The findings that both dipyridamole and theophylline failed to affect the neurogenic contractions in the absence of adenosine suggests that the presynaptic autoinhibition mechanism of adenosine may not be involved in neuromuscular transmission in this tissue. These results suggest that there is a presynaptic adenosine receptor in the nerve terminal which inhibits the release of neurotransmitter in canine cavernous carotid artery. It is also probable that the vasodilating effect of adenosine in the cavernous carotid artery is mainly due to its inhibitory effect on neurotransmission rather than to a direct relaxing effect on smooth muscle.

An isometric tension measurement of ring segments was performed in the rabbit basilar and common carotid arteries in vitro to investigate the regional differences in the calcitonin gene-related peptide (CGRP)-induced vasodilation and the effect of subarachnoid hemorrhage on CGRP-induced vasodilation. CGRP elicited vasodilation of the rabbit basilar artery in a dose-dependent fashion when the artery was precontracted by 10(-5) M 5-hydroxytryptamine, whereas almost no relaxation occurred in the rabbit common carotid artery. The relaxation of the basilar artery was 64.03 +/- 1.85% at 3 x 10(-8) M CGRP, with an EC50 of 8.46 +/- 0.08. Two days after experimental subarachnoid hemorrhage, CGRP-induced relaxation of the rabbit basilar artery was 53.96 +/- 8.08% of the 10(-5) M 5-hydroxytryptamine-induced contraction, not significantly different from that of the basilar artery of the control rabbit. Our findings suggest that CGRP induces potent vasodilation in the rabbit basilar artery and that no impairment of vasodilation occurred after experimental subarachnoid hemorrhage. We speculate that CGRP may have therapeutic potential in cerebrovascular disease such as vasospasm after subarachnoid hemorrhage.

Cerebral vasospasm following aneurysmal subarachnoid hemorrhage is one of the most important causes of cerebral ischemia, and is the leading cause of death and disability after aneurysm rupture. There are two definitions of cerebral vasospasm: angiographic and clinical. Care must be exercised to be certain that it is clear which entity is being addressed. The diagnosis of the clinical syndrome is one of exclusion and can rarely be made with absolute certainty. The pathogenesis of cerebral vasospasm is poorly understood. Most current theories focus on the release of factors from the subarachnoid clot. More attention must be given to the role of endothelial damage and alterations in the blood-arterial wall barrier. The application of modern techniques for studying vascular smooth muscle which have been developed as a result of research in the areas of hypertension and atherosclerosis must be applied to the problem of cerebral vasospasm. A stress test to select patients with angiographic arterial narrowing who have adequate cerebral vascular reserve to undergo surgery should be developed. The optimal treatment of vasospasm awaits development of agents for blocking or inactivating spasmogenic substances or blocking arterial smooth muscle contraction. Rheological or hemodynamic manipulations to prevent or reverse ischemic consequences of vasospasm are relatively effective, but complicated and hazardous, and should be viewed principally as interim measures awaiting development of more specific therapies for the arterial narrowing.

The effect of subarachnoid hemorrhage on metabolic rates in rabbit cerebral arteries was investigated by measuring adenosine triphosphate (ATP) content and L-lactate release. The mean +/- SEM ATP content was 0.38 +/- 0.02 mumol/g wet wt in control rabbit basilar arteries (n = 6). The ATP content decreased significantly to 0.17 +/- 0.02 mumol/g wet wt 2 days after experimental subarachnoid hemorrhage (n = 6), although only a slight decrease was detected in the basilar arteries 2 days after cisternal injection of the same amount of artificial cerebrospinal fluid. Hypoxia significantly decreased ATP content in the control basilar arteries to 0.26 +/- 0.04 mumol/g wet wt (n = 6). The same degree of hypoxia did not decrease ATP content in the basilar arteries after subarachnoid hemorrhage. Release of L-lactate was significantly higher from the arteries after subarachnoid hemorrhage than from the control arteries under both aerobic and hypoxic conditions. Our results indicate that subarachnoid hemorrhage induced an alteration of metabolic rates in rabbit cerebral arteries. The oxygen-requiring pathways to synthesize ATP may be important in control cerebral arteries; however, after experimental subarachnoid hemorrhage, the main pathway in the cerebral arteries may shift from oxygen-requiring pathways to an anaerobic glycolytic pathway.

The effect of intra-arterial adenosine on cerebral blood flow was studied in 11 anesthetized dogs. In a first group of 6 dogs, adenosine was infused into a vertebral artery for 40 minutes at a dose of 0.3 to 0.5 mg/kg/min. Blood flow was determined before, during and after the adenosine infusion using the radioactive microsphere technique. In a second group of 5 dogs, adenosine (3 +/- 1 mcg/kg/min) was infused in a similar manner after potentiating its effect with intravenous dipyridamole, and measurements before and after the intravenous dipyridamole and during and after the adenosine infusion were performed. Systemic arterial pressure and blood gases were unchanged throughout the experiment in both groups of dogs. Blood flow to the cerebral hemispheres, cerebellum, brain stem, paraspinous and temporalis muscles remained unchanged during the adenosine infusion in both groups of dogs. Adenosine has been implicated as an active agent in the vasodilatory component of cerebral autoregulation. A controversy exists as to whether intervascular or only interstitial adenosine is of physiologic importance. These findings suggest that intra-arterial adenosine does not play a significant role in the regulation of cerebral blood flow.

The purpose of the present study was to evaluate the dependence of the arterial contractions induced by different vasoactive agents upon intracellularly stored calcium in canine versus monkey cerebral arteries. The potency for inducing contractions in Ca++-free media was in the order of 9,11-epithio-11,12-metano-thromboxane A2 (STXA2) greater than prostaglandin F2 alpha (PGF2 alpha) much greater than serotonin greater than K+ in canine basilar arteries, and STXA2 greater than PGF2 alpha much greater than serotonin = K+ in monkey basilar arteries.

The timing of aneurysm surgery is one of the major controversies in the management of subarachnoid hemorrhage. The Cooperative Aneurysm Study is conducting an international epidemiological study to determine mortality and morbidity related to timing of surgery. From January, 1981 to July, 1983 over 3,500 patients have been registered from 68 centers. This preliminary report updates the progress of the study, describes the patient population, and presents overall outcome results.

In 7 dogs anesthetized with halothane and nitrous oxide, dipyridamole was administered in a loading dose of 1 mg/kg supplemented with 0.5 mg/kg every 30 minutes. Cardiovascular parameters and organ blood flows (using the radioactive microsphere technique) were measured before and at 30 minute intervals after each administration of dipyridamole, for a total of 105 minutes. The administration of dipyridamole was associated with a 20% reduction in systemic arterial pressure, a 31% reduction in peripheral vascular resistance, and a 13% increase in cardiac index. Cerebrovascular resistance decreased 21%, but regional cerebral blood flow and metabolism were unchanged. Blood flow to the heart increased 355% in the right ventricle and 213% in the left ventricle. Blood flow to the jejunum decreased 52% while blood flow to the kidney and liver decreased slightly. The circulatory effects of dipyridamole are probably related to its interference with the inactivation of endogenous adenosine. The differential effects of dipyridamole on organ flow are similar to those seen following the IV infusion of adenosine.

The effect of subarachnoid hemorrhage (SAH) on endothelium-dependent vasodilation of isolated rabbit basilar artery was examined using an isometric tension recording method. Thirty-five rabbits that had 2 successive blood injections were divided into 3 groups: normal animals (control), 4 days, and 3 weeks after the first SAH. Acetylcholine (ACh) (10(-6)-10(-4) M) and adenosine triphosphate (ATP) (10(-6)-10(-4) M) were used to evoke dose-dependent vasodilation of isolated arterial rings previously contracted by 10(-6) M serotonin. In the animals killed 4 days after the first SAH, both ACh- and ATP-induced relaxation were suppressed, and the degree of relaxation of this group was 38 +/- 4.5% (mean +/- SEM) and 22 +/- 3.9% of the initial contractile tone in response to 10(-4) M ACh and 10(-4) M ATP, respectively. Suppression of the relaxation induced by ATP was seen even in the animals killed 3 weeks after the first SAH. Moreover, pretreatment with hemoglobin (10(-6) and 10(-5) M) inhibited endothelium-dependent vasodilation induced by ACh in the arterial rings from the animals killed 4 days after the first SAH. The present experiments suggest that impairment of the endothelium-dependent vasodilation following SAH may be involved in the pathogenesis of cerebral vasospasm.

Dichloroacetate (DCA) is known to prevent the phosphorylation of the pyruvate dehydrogenase complex (PDHC) by blocking the action of PDH kinase. This action allows the active PDHC to exert its effect on the metabolism of glucose, lactate and alanine to acetyl CoA. DCA has been shown to reduce serum lactate levels in humans and animals in such conditions as diabetes, phenformin-induced hepatic failure, exercise, and endotoxin-induced shock. Lactic acidosis in the brain has often been postulated as a cause of neuronal damage following ischemia and hypoxia. Therefore, we examined the effect of intravenously administered DCA (100 mg/kg) in rats that were rendered hyperglycemic by intravenous glucose (2 g/kg), and then made to undergo 15 minutes of incomplete cerebral ischemia by bilateral carotid ligation and systemic hypotension (mean arterial pressure of 50 mm Hg). DCA significantly reduced serum lactate levels pre-ischemia, but had no effect on serum lactate levels after ischemia induction. Brain levels of lactate, ATP and PCr after 15 minutes of incomplete ischemia were unaffected by DCA. We conclude that in this in-vivo model the control of PDHC activity in the brain may be different than that in the periphery, and that DCA was not effective in reducing brain tissue lactate levels.

We evaluated the effects of aging and hypertension on endothelium-dependent relaxation of rat common carotid arteries using 14-week-old (young) and 11-month-old (old) Wistar-Kyoto rats (WKY) and age-matched spontaneously hypertensive rats (SHR). Isometric tension of common carotid artery ring segments was measured. With a resting tension of 2.0 g determined from the baseline tension-contraction curves, precontraction was induced by 10(-5) M 5-hydroxytryptamine and endothelium-dependent relaxation was measured by application of either acetylcholine or adenosine 5'-triphosphate (ATP). Mean arterial blood pressure was 73.1 +/- 3.0 mm Hg in WKY and 110.0 +/- 3.1 mm Hg in SHR. These baseline values were significantly different. Acetylcholine-induced maximal relaxations were 70.1 +/- 2.6% of the 5-hydroxytryptamine-induced contraction in young WKY, 45.6 +/- 2.1% in old WKY, 35.1 +/- 1.8% in young SHR, and 21.4 +/- 2.5% in old SHR. On the other hand, ATP-induced relaxations were 52.0 +/- 3.2%, 35.7 +/- 3.8%, 21.7 +/- 3.5%, and 17.0 +/- 1.8% in the groups, respectively. Acetylcholine-induced relaxations were significantly different between WKY and SHR, young and old, independently. On the other hand, ATP-induced relaxations were also significantly different between young and old WKY, although no significant difference was observed between young and old SHR. The fact that endothelium-dependent relaxation of a cephalic artery is impaired in old rats and in hypertensive rats suggests that aging and hypertension are risk factors that may augment the disturbance of the cerebral circulation in pathologic conditions.

Prolonged normoxic hypercapnia initially caused an increase in canine cerebral blood flow, as measured by the radioactive microsphere technique, accompanied by a decrease in cerebrovascular resistance. These effects persisted for 3 hours. An adaptive decrease in cerebral blood flow and increase in cerebrovascular resistance were seen when hypercapnia was maintained for an additional 3 hours. Regional variations occurred; those areas with the greatest initial hypercapnic blood flow (cortex, caudate nucleus) showed a greater rate of decay of flow over time. Cerebrospinal fluid pH, initially acidotic during hypercapnia, increased over the subsequent 5 hours from 6.99 +/- 0.02 to 7.13 +/- 0.02. This was accompanied by an increase in the cerebrospinal fluid bicarbonate ion concentration from a normocapnic baseline of 19.6 +/- 0.6 to 26.2 +/- 4 mEq/l. Total and regional cerebral blood flow were linearly related to cerebrospinal fluid pH (R2 = 0.97). Extrapolation of a full adaptive return of flow to baseline indicated a shift in the cerebrovascular sensitivity to extracellular hydrogen ion concentration during prolonged hypercapnia.