J. D. Pickard

Role of Prostaglandins and Arachidonic Acid Derivatives in the Coupling of Cerebral Blood Flow to Cerebral Metabolism

What normally provides tone in the cerebral circulation? What adjusts cerebral blood flow to cexad rebral metabolism? Why invoke arachidonic acid and its metabolites? The derivatives of arachidonic acid form an exxad traordinary and bewildering array of compounds of widely differing propertie s. Von Euler ( 1 93 6) created the term prostaglandin to christen the depressor, smooth-muscle-stimulating acidic lipid that he and Goldblatt had demonstrated in human seminal plasma. Bergstrom began to determine the structure of this group of compounds in 1 947 with publication in the early 1 960s (for review , see Bergstrom et aI. , 1 968). Prostaglandins are biosynxad the sized fro m arachidonic acid and dihomo-yxad linolenic acid , both of which are derived from the essential unsaturated long-chain dietary fatty acids. Arachidonic acid is the predominant substrate for prostaglandin synthesis in the brain. Following the isolation and description of the effects of the prixad mary and relatively stable prostaglandins (PGF2a , PGE1 , PGE2, PGD2, etc.) came the discovery that prostaglandin synthe s i s was inhibited by the nonsteroidal antiinflammatory age nts such as indomethacin and aspirin (Vane , 1 97 1). Certain disxad crepancies became apparent in the period 1 970-76 between the effects of prostaglandin synthesis inhixad bition and the effects of the known endogenous prostaglandins. Then , in rapid succession , came the description of the short-lived derivatives of arachi-

Local cerebral blood flow in rats with congenital hydrocephalus.

Local cerebral blood flow (LCBF) has been measured by [14C]iodoantipyrine quantitative autoradiography in H-Tx rats with inherited congenital hydrocephalus at 10, 21, and 30 days after birth. LCBF at 10 days was uniformly low in all ten brain regions studied and not significantly different between hydrocephalic and age-matched control rats. By 21 days LCBF had increased significantly in control rats. LCBF was significantly lower (<69%) in the hydrocephalics in all cortical regions and in the inferior colliculus LCBF at both 21 and 30 days. The cerebellar cortex, pons, and caudate were not significantly affected. At 30 days LCBF ranged from 55 to 115 ml 100 g−1 min−1 for hydrocephalics and from 100 to 183 ml 100 g−1 min−1 for controls.

Are the Vascular Effects of Naloxone Attributable to the Preservatives Methyl- and Propylparaben?

In vitro, the Nalonee® preparation of naloxone caused a concentration-dependent relaxation of human pial cortical arteries contracted by potassium, noradrenaline, serotonin, prostaglandin F2α (PGF2α), and haemorrhagic cerebrospinal fluid, or inhibited contractions elicited by these agents. However, the preservatives in the Nalonee preparation, methyl- and propylparaben, had similar effects. Pure naloxone alone had no effect on potassium or PGF2α-induced contractions. It is suggested that the relaxant effects on vascular smooth muscle of Nalonee can be attributed to the alkylparabens rather than to naloxone. The pronounced relaxations induced by the alkylparabens had a rapid onset, and they were stable and could easily be cleared after rinsing.

Prostaglandins, Thromboxane, Leukotrienes and the Cerebral Circulation in Health and Disease

Arachidonic acid is ubiquitously distributed throughout the body and its derivatives form an extraordinary and bewildering array of compounds of widely differing properties. It is most unwise to generalize about how a given cell or tissue will utilize each pathway. This system responds to both physiological and pathological stimuli but the respective roles of the various products can be very difficult to unravel as will become all too apparent. The recent British Medical Bulletin (1983) provides an excellent overview of the subject. Von Euler (1936) created the term “prostaglandin” to christen the depressor, smooth muscle–stimulating acidic lipid that he and Goldblatt had demonstrated in human seminal plasma. Bergstrom began to determine the structure of this group of compounds in 1947 with publication in the early 1960s (for review, see Bergstrom et al. 1968). Following the isolation and description of the effects of the primary and relatively stable prostaglandins (PGF2 α, PGE1,PGE2, PGD2, etc.) came the discovery that prostaglandin synthesis was inhibited by the non–steroidal antiinflammatory agents such as indomethacin and aspirin (Vane 1971). Certain discrepancies became apparent in the period 1970–1976 between the effects of prostaglandin synthesis inhibition and the effects of the known endogenous prostaglandins. Then, in rapid succession, came the description of the short-lived derivatives of arachidonic acid metabolism, including rabbit aortacontracting substance (Palmer et al. 1973), the cyclic endoperoxides, PGG2 and PGH2, and thromboxane A2 and its inactive metabolite thromboxane B2 (Samuelsson et al. 1978, for review).

Spectrum of Altered Reactivity of Isolated Cerebral Arteries following Subarachnoid Haemorrhage—Response to Potassium, pH, Noradrenaline, 5-Hydroxytryptamine, and Sodium Loading

The circular contractile responses to various stimuli have been measured in segments of cerebral arteries (both middle cerebral and basilar) taken from dogs either 3 or 7 days following the cisternal injection of autologous blood under anaesthesia. The maximum contractile response to 5-hydroxytryptamine was increased significantly 7 days following subarachnoid haemorrhage; the response to noradrenaline also increased but not significantly at 7 days. The contractile response to a raised extracellular potassium concentration (25 and 100 mM) was slightly depressed by 7 days, and the response to a fall in extracellular pH was depressed by 43% both 3 and 7 days following subarachnoid haemorrhage. The ability of these arteries to handle a sodium load was also assessed. The arteries were sodium loaded for various periods of time in mock cerebrospinal fluid with a zero potassium concentration. On transfer to 25 mM potassium solution, the duration but not the magnitude of the initial relaxation phase prior to a final contraction was greater with increasing time spent in the zero potassium solution. Both the magnitude and the duration of this relaxation phase, which reflect in part the ability of the vascular smooth muscle to extrude the sodium load, were increased in arteries following subarachnoid haemorrhage when compared with control arteries. These results demonstrate that the altered reactivity of cerebrovascular smooth muscle following subarachnoid haemorrhage persists in vitro and is more than simply an enhanced response to biogenic amines.

Adult communicating hydrocephalus

In patients with the triad of gait disorder, dementia, and incontinence and, in addition, a predisposing cause for the ventriculomegaly demonstrated on a CT scan and no mass, a shunt should be carried out. In cases in which there is no known aetiology for the ventricular enlargement, the cerebral sulci are widened, or the complete triad is not present, I would monitor intracranial pressure for 24--48 hours. It remains to be seen whether further quantification of the CT scan will supplant the need for intracranial pressure monitoring. Brain biopsy is not routinely performed. Many basic as well as clinical questions remain to be answered. For example, it is by no means certain that the natural history of NPH is one of progressive deterioration--some patients appear to remain stable (Hughes et al, 1978). An offer to carry out a shunt is made immediately on diagnosis in the belief that any deterioration that occurs through delay may not be reversible. Furthermore, how can patients with NPH who present with an atypical picture be identified (Crowell et al, 1973; Rice and Gendelman, 1973; Sypert et al, 1973)? Unfortunately, more liberal provision of CT scanning services will be required to tackle these problems. For the present we must be content with more detailed clinical analysis of these patients and a controlled trial to determine the best method of carrying out shunts.

Association of hypovolemia after subarachnoid hemorrhage with computed tomographic scan evidence of raised intracranial pressure.

Hypovolemic patients are more likely to suffer delayed cerebral ischemia and infarction after a subarachnoid hemorrhage (SAH). Prompt recognition and correction of hypovolemia may improve the outcome. We have identified computed tomographic (CT) scan findings that increase the probability of a patient presenting with hypovolemia soon after an SAH. The plasma volume (PV) of 25 patients admitted within 96 hours of an SAH was measured using radioiodinated serum albumin. The normal PVs were measured in an outpatient setting 6 months later or predicted from their total body water. Nine patients (36%) were found to be hypovolemic, defined as a fall in PV exceeding 10% of the normal PV (mean fall, 18 +/- 2%). Sixteen patients were normovolemic or hypervolemic (mean PV, +9 +/- 2%). The basal cisterns were compressed or obliterated on the CT scans of all hypovolemic patients compared with 12.5% of normovolemic patients (chi-square, 14.52; P less than 0.01). The probabilities of a patient being hypovolemic if the CT scan indicated raised intracranial pressure were high: hydrocephalus, P = 0.80; compression of the basal cisterns, P = 0.82; and compression of the basal cisterns associated with intracerebral hematoma or midline shift, P = 1.00. Patients with an SAH and radiological evidence of raised intracranial pressure should be considered at particular risk for systemic hypovolemia.

Recurrent Aneurysmal Subarachnoid Haemorrhage: Incidence, timing and effects. A re-appraisal in a surgical series

A series of 510 patients with proven aneurysmal subarachnoid haemorrhage (SAH) is reported. The incidence of recurrent haemorrhage during the period awaiting surgery was 13.7%. There was no significant difference in incidence between good and poor grade patients. Following rebleeding there was an immediate mortality of 34% in good grade patients and 52% in poor grade patients. In the long term only 44.4% of good grade and 8% of poor grade patients made a good recovery following a second bleed as compared to 70.6% and 52.8% respectively for those who did not rehaemorrhage.

A modification of the method for the measurement of cerebral blood flow using [14C]iodoantipyrine in small animals

We have modified the method for the measurement of cerebral blood flow using [14C]iodoantipyrine in small animals to overcome problems caused by rapid sequential arterial sampling. A second isotope, gamma-emitting [99mTc]pertechnetate, is infused together with [14C]iodoantipyrine. The 99mTc is counted externally by a detector placed over the chest. The arterial curve for [14C]iodoantipyrine can be reconstructed from a single arterial sample collected from the severed neck and the shape of the 99mTc chest curve. Because of the short half-life of 99mTc (6 h), all 14C measurements, including preparation of autoradiograms, may be made 3 days later.

The effects of hyponatraemia and subarachnoid haemorrhage on the cerebral vasomotor responses of the rabbit

Impairment of cerebral autoregulation and development of hyponatraemia are both implicated in the pathogenesis of delayed cerebral ischaemia and infarction following subarachnoid haemorrhage (SAH) but the pathophysiology and interactions involved are not fully understood. We have studied the effects of hyponatraemia and SAH on the cerebral vasomotor responses of the rabbit. Cerebrovascular reactivity to hypercapnia and cerebral autoregulation to trimetaphan-induced hypotension were determined in normal and hyponatraemic rabbits before and 6 days after experimental SAH produced by two intracisternal injections of autologous blood. Hyponatraemia (mean plasma sodium of 119 mM) was induced gradually over 48 h by administration of Desmopressin and intraperitoneal 5% dextrose. Sham animals received normal saline. The cerebrovascular reactivity (% change ±SD in cortical CBF/mm Hg PaCO2, measured by hydrogen clearance) of hyponatraemic (4.8 ± 3.0%) and SAH (1.3 ± 2.0%) animals was significantly less (p < 0.05) than control (11.6 ± 4.0%) and sham (8 ± 2.0%) animals, whereas the reactivity of hyponatraemic-SAH animals was preserved (9.8 ± 6.0%). Hyponatraemia and SAH alone each significantly impaired CBF autoregulation but their combined effects were not additive. Systemic hyponatraemia impairs normal cerebral vasomotor responses but does not augment the effects of experimental SAH in the rabbit.