David A. Cook

MECHANISMS OF CEREBRAL VASOSPASM IN SUBARACHNOID HAEMORRHAGE

Cerebrovascular spasm is a slowly developing constriction of the cerebral arteries, which frequently follows subarachnoid haemorrhage and is associated with considerable morbidity and mortality. The condition has been studied by use of models of subarachnoid haemorrhage in the whole animal and examination of isolated blood vessels or vascular smooth muscle cells in culture. The condition probably arises from the action of haemoglobin released from erythrocytes trapped in the subarachnoid clots, although the mechanism of action of haemoglobin remains uncertain. Systemic pharmacotherapy to avert or reverse vasospasm is still experimental.

Models of interprofessional learning in Canada.

This article provides an overview of interprofessional education in Canada, with a view to defining programs at all levels in terms of what models have been employed. The available information implies that the lack of convincing evidence of the effectiveness of existing programs is probably the most serious problem for the expansion of interprofessional education. The objectives of the programs are both to increase the knowledge about the other professions and their scope of practice, and to improve team function, and there are a number of well-established interprofessional programs in Canada that are designed to achieve these objectives, and many other examples of programs that are partial or planned. Despite this, the present interprofessional education initiatives tend to involve only a small proportion of the total health work trainees. There is a need for programs that are more widespread. The most frequent model involves a mandatory experience, which is case-based, involves all the students registered in Health Faculties, and where the students form interprofessional student teams. In addition to examining believable cases, the students also learn some specific information about interacting with the other professions and gain knowledge about the roles, knowledge and contributions that can be made by professions other than their own.

Nimodipine and Chronic Vasospasm in Monkeys: Part 1 Clinical and Radiological Findings

The efficacy of the calcium channel blocker nimodipine in the prevention of chronic cerebral vasospasm (VSP) and delayed ischemia after subarachnoid hemorrhage (SAH) in monkeys was examined in a blind, randomized, placebo-controlled trial. The primate model developed in this laboratory reliably induces chronic cerebral vasospasm and can induce pathologically proven delayed ischemic neurological deficits (DINDs). With standard microsurgical procedures, an average 6.4-ml autologous hematoma was placed directly against the major anterior cerebral vessels in the right basal subarachnoid spaces of 24 monkeys. The monkeys were randomized to one of four groups and were treated orally q8h for 7 days with nimodipine (3, 6, or 12mg/kg)or placebo. An additional 2 monkeys underwent the surgical procedure without clot placement. Drug administration began between 14 and 20 hours after clot placement. Indices monitored before and after SAH included neurological status, angiographic cerebral vessel caliber, and cerebral blood flow. Significant VSP (25 to 100% reduction in vessel caliber) was present on Day 7 on the clot side in 83% of the animals (P less than or equal to 0.001). There was no significant difference (P greater than 0.05) in the incidence of VSP among the four groups. Similarly, there was no significant difference (P greater than 0.05) in the mean vessel caliber reduction after SAH among the four treatment groups. There was no VSP present on Day 7 in the sham-operated animals. One animal receiving high dose nimodipine (12 mg/kg p.o. q8h) developed a DIND on Day 5 after SAH. A second animal in the 12-mg/kg group developed a transient neurological deficit between Days 4 and 7.

Detection of endothelium in cerebral blood vessels

An increasing body of evidence implies that the results of pharmacological studies of blood vessels may depend on the presence of an intact layer of endothelial cells inside the blood vessels. This is often inadvertently removed during the early part of the experiment and it is thus necessary to have some means of determining whether the endothelium is intact or has suffered extensive damage. Previous reports describe a stain that will enable the endothelial cells to be visualized, however we find that in the cerebral vasculature this approach is unsatisfactory in that it provides a gross underestimate of the amount of intact endothelium. A modification of the original procedure is described that provides results that correspond well with those of scanning or transmission electron microscopy.

Effects of Vasospasm on Levels of Prostacyclin and Thromboxane A2 in Cerebral Arteries of the Monkey

To determine whether cerebral arteries in spasm have an altered capacity to synthesize the vasoactive substances prostacyclin and thromboxane A2, we measured levels of these arachidonic acid metabolites using a primate model of vasospasm. Twenty-four cynomolgus monkeys were assigned at random to one of three groups designated sham, clot, or clot-removal. All animals underwent base line cerebral angiography and bilateral dissection of the major cerebral arteries from the arachnoid. The clot and clot-removal groups had autologous hematomas placed around the vessels to simulate subarachnoid hemorrhages. The sham group had a similar volume of saline instilled into the subarachnoid space. Twenty-four hours later, the clot-removal group underwent a second craniotomy to remove the hematomas. Seven days after the initial operation, angiography was repeated on all animals. The animals were then killed, and the cerebral arteries were removed. Basal levels of prostacyclin and thromboxane in the cerebral vessels were measured after incubation in vitro by radioimmunoassay. No detectable leukotriene C4 release by these arteries was measurable using radioimmunoassay. Angiography revealed severe cerebral vasospasm in the clot group, but not in the clot-removal or sham groups. There were no statistical differences among the groups in thromboxane release, but prostacyclin levels were significantly lower in the clot group than in the clot-removal group (P less than 0.05). It thus seems that, if an imbalance in constrictor and dilator eicosanoids occurs in association with vasospasm, this is more likely to arise from a relative lack of the vasodilator component prostacyclin than from a surplus of the vasoconstrictor thromboxane.(ABSTRACT TRUNCATED AT 250 WORDS)

The Pharmacology of Cerebral Vasospasm

About 3 days after subarachnoid hemorrhage the cerebral blood vessels often undergo a sustained constriction (cerebral vasospasm) which is associated with increased morbidity and mortality. Examination of the literature suggests that interactions of hemoglobin, various prostaglandins, and perhaps some other agents are responsible for this condition, which is apparently associated with endothelial damage or other structural changes. The most promising therapy involves treatment with calcium antagonists.

Changes in vasoactive properties of blood products with time and attempted identification of the spasmogens.

The contractile activity of various fresh, or incubated blood fractions was studied in vitro using the isolated canine basilar artery. Significantly greater contraction was induced by fresh platelet rich plasma (PRP) and serum compared to red blood cells (RBC). Following incubation, the contractile activity of RBC increased, reaching a plateau at day-3 and it was maintained for at least 14 days, while both PRP and serum lost most of their activity after 24 h of incubation. The contractions induced by fresh blood fractions were only partially blocked by desensitization of 5-hydroxytryptamine (5-HT) receptors or by the 5-HT antagonist methysergide. D-600 effectively antagonized the response to all blood fractions. Biochemical analysis of the incubated RBC by means of Sephacryl S-200 column chromatography and SDS-urea polyacrylamide gel electrophoresis revealed that the contractile substance possessed a molecular weight of about 60,000 daltons. Vasoactivity was only present in one peak of the chromatographically eluted fractions which was shown to possess a similar absorption spectrum to that of hemoglobin. Hemoglobin concentration was highest in day 3, 7, and 14 fractions and may be correlated with the contractile activity of incubated samples.

Inhibition of purine metabolism--computer-assisted analysis of drug effects.

Abstract Procedures are described by which the apparent rates of eight enzymes and three other parameters of purine ribonucleotide metabolism can be calculated from data obtained using intact cells, and the effects of drugs on each separately determined. An APL/360 computer program is used.

Time course of changes in concentration of intracellular free calcium in cultured cerebrovascular smooth muscle cells exposed to oxyhemoglobin.

A culture of smooth muscle cells obtained from monkey middle cerebral arteries was developed to allow quantitative assessment of intracellular calcium and immunofluorescence analysis after various periods of exposure to oxyhemoglobin. Intracellular calcium concentration was examined for up to 7 days after a single exposure to oxyhemoglobin. Intracellular calcium concentrations were measured with the fluorescent dye fura-2 and were significantly elevated for 7 days after exposure to oxyhemoglobin (P less than 0.01). Less than 2 minutes after application of oxyhemoglobin, there was marked elevation of intracellular calcium from the control value of 75 +/- 2 nmol/L to 240 +/- 28 nmol/L (P less than 0.01 by analysis of variance). Intracellular calcium concentration of cells exposed for 24 hours to oxyhemoglobin and then grown in normal oxyhemoglobin-free medium fell close to normal levels on Days 3 and 7. On Day 3, the increase in intracellular calcium that followed repeated daily exposure to oxyhemoglobin was greater than that resulting from a single application of oxyhemoglobin (P less than 0.01 by Students t test), but by Day 7 the elevation produced by these different approaches was similar. Smooth muscle cells exposed to oxyhemoglobin showed a reduction in immunoreactivity to alpha-actin. These data support the hypothesis that disruption of intracellular calcium regulation and calcium overloading may be important in the process of cell injury, which results in vasoconstriction and sometimes cell death, after exposure to oxyhemoglobin.

Glibenclamide relaxes vascular smooth muscle constriction produced by prostaglandin F2α

The present study has demonstrated: (1) glibenclamide can reduce resting tension in canine cerebral arteries but has no effect on resting tension in the rat aorta; (2) glibenclamide can relax prostaglandin F2 alpha-induced contractions in the rat aorta, and in canine femoral, mesenteric, renal, coronary, basilar and middle cerebral arteries; (3) the relaxation produced by glibenclamide in rat aorta is comparable to that of glyceryl trinitrate and stronger than that of papaverine; (4) canine femoral arteries are less sensitive to glibenclamide than the other arteries; (5) in cerebral arteries glibenclamide was as effective as papaverine, but less effective than glyceryl trinitrate; (6) the actions of glibenclamide on cerebral arteries are not mediated by cGMP as they were not blocked by methylene blue, an inhibitor of guanylate cyclase; (7) the effects of glibenclamide are not endothelium-dependent. The mechanism by which glibenclamide produces relaxation is not clear; while the drug is known to block ATP-dependent potassium channels, in vascular smooth muscle this would cause contraction, not dilation. The action of glibenclamide may be at the level of the receptor or the signal transduction process.