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Biomedical subjects

E T MacKenzie

Publications and source records attributed to E T MacKenzie.

At least 109 records · Page 6Linked to original sources
PubMed1983

Influence of extracellular calcium and calcium antagonists on contractions induced by potassium and prostaglandin F2 alpha in isolated cerebral and mesenteric arteries of the cat.

1 The effects of a number of calcium antagonists (diltiazem, nifedipine, nimodipine and verapamil) have been studied on feline isolated pial arteries contracted by potassium (127 mM) or prostaglandin F2 alpha (PGF2 alpha, 2.5 microM) and mesenteric arteries contracted by potassium (127 mM). 2 Withdrawal of Ca2+ from the extracellular medium for 30 min reduced the contractile response to potassium in cerebral vessels by 92% and in mesenteric vessels by 96%. Subsequent addition of Ca2+ caused reproducible contractions which were inhibited by both nifedipine and nimodipine. 3 The four calcium antagonists relaxed the isolated middle cerebral artery contracted either by potassium or PGF2 alpha, and mesenteric arteries contracted by potassium, in the following order of potency: nimodipine greater than nifedipine greater than verapamil greater than diltiazem. 4 Nimodipine was more potent than nifedipine in cerebral arteries, and more potent in cerebral than in mesenteric arteries. Otherwise, the potassium-contracted cerebral and mesenteric vessels showed no major differences in sensitivity to calcium antagonists.

Animals↗
PubMed1983

Calcium antagonists: effects on cerebral blood flow and blood-brain barrier permeability in the rat.

1 Because they affect isolated cerebral arteries, some calcium antagonists have been studied on the intact cerebral circulation of the rat.2 Global cerebral blood flow ((133)Xe clearance technique) was measured in anaesthetized rats. Neither perhexiline (0.1 mug/kg to 1.0 mg/kg, i.v.) nor diltiazem (0.06-0.6 mg/kg, i.v.) had any significant effect on resting cerebral blood flow when measured 5 min after each dose. A high dose of nifedipine (1.0 mg/kg, i.v.) was administered during induced hypocapnia. Nifedipine failed to modify the hypocapnic vasoconstriction of the cerebral vasculature when compared to vehicle-treated rats.3 The possibility of discrete changes in regional cerebral blood flow was investigated. Local cerebral blood flow was measured in a number of brain regions by the [(14)C]-ethanol technique 15 min after the administration of nifedipine (20 or 100 mug/kg, i.v.). Nifedipine had no apparent effect on regional blood flow in the rat brain.4 Acute arterial hypertension increases protein leakage into the brain, a phenomenon susceptible to drugs that act on endothelial pinocytosis which is known to be calcium-dependent. The increase in protein extravasation, induced by the intravenous administration of either angiotensin II or adrenaline, was unchanged in rats previously treated with either nimodipine (20 mug/kg, i.v.) or nifedipine (50 mug/kg, i.v.) when dissolved in ethanol alone. However, nifedipine (20 mug/kg, i.v.) when dissolved in a solution of polyethylene glycol and ethanol further enhanced the hypertension-induced increase in brain albumin permeability.5 In conclusion, we have been unable to demonstrate any apparent effects of various calcium antagonists on the intact cerebral circulation of the rat, despite the number of different experimental models used.

Animals↗
PubMed1983

Cerebro-circulatory effects of so-called 'vasodilators' in the anaesthetised rat.

The cerebro-vascular effects of various agents used in the treatment of cerebral disorders (dihydroergotoxine, ifenprodil, naftidrofuryl, nicardipine, nicergoline, papaverine and vincamine) were studied in the anaesthetised rat. The agents effected an increase in global cerebral blood flow, each to a different magnitude, in a dose-related manner. The changes in flow induced in the normal brain are unlikely to be of much relevance to the use of these compounds in the treatment of focal cerebral ischaemia.

Anesthetics↗
PubMed1982

Effects of agents used in the pharmacotherapy of cerebrovascular disease on the oxygen consumption of isolated cerebral mitochondria.

A number of drugs used in the pharmacotherapy of cerebral metabolic and vascular disease have been studied for their effects on the respiration of mitochondria isolated from the rat brain. Some of these agents increased the respiratory control ratio by more than 5% from base-line values (at p less than 0.05), namely, aminophylline, dihydroergotoxine, ifenprodil, nicergoline, raubasine, and vincamine. The ability of these agents to increase the efficiency of mitochondrial respiration could be correlated with two other attributes peculiar to these five drugs: their ability to contract cerebrovascular smooth muscle when studied in vitro and their ability to decrease the volume of infarcted brain tissue following experimental occlusion of the middle cerebral artery in the cat. Papaverine and its derivatives (naftidrofuryl, viquidil, YC-93) decreased respiratory control, an effect that might correlate with their capacity to effect a vasodilatation of the cerebral vessels and their inefficacy in models of acute cerebral infarction. There is a considerable body of evidence suggesting that one of the earliest and most fundamental perturbations of cerebral ischaemia is a loss of respiratory control. Ifenprodil, vincamine, and some related "anti-ischaemic" compounds are capable of increasing respiratory control in normal cerebral mitochondria, and this capacity might well help to explain their therapeutic potential in cerebrovascular disorders in which energy supply to the brain is limited.

Animals↗
PubMed1982

Brain ischaemia, calcium and calcium antagonists.

There is a great similarity between the loss of respiratory activity of isolated cerebral mitochondria which have been submitted to ischaemia in vivo and the loss of activity following the incubation of normal cerebral mitochondria in the presence of Ca2+. These observations may imply that Ca2+ could play an important role in the pathogenesis of the cellular changes which accompany ischaemia. Studies in vitro with Ca2+ antagonists (diltiazem, nifedipine, perhexiline and verapamil) have shown these agents to possess a powerful vasodilatatory action but to be incapable of reversing the loss of functional activity of isolated mitochondria from the ischaemic brain. Although the treatment of a primary focal cerebral ischaemia by Ca2+ antagonists does not seem promising, these agents may be of considerable interest in the therapy of cerebral ischaemia secondary to vasospasm.

Animals↗
PubMed1981

Various indices of brain metabolism and activity in a model of chronic neurological dysfunction: triethyl tin intoxication in the rat.

A number of pathological agents of interest in the therapy of cerebrovascular disease can retard the development of the neurologic deficit induced by triethyl tin. Locomotor activity was decreased at a time when no evidence of neurologic deficit could be detected. Conduction velocity in the peripheral as well as assessed from measurement of cerebral blood flow, local cerebral glucose utilization, brain water and electrolyte content as well as neuropathology were measured before and frank deficit could be clinically detected.

Animals↗
PubMed1981

Correlation of local blood flow, glucose consumption and probability of necrosis following a middle cerebral artery occlusion in the cat.

At defined coronal sections, the surface area of infarcted tissue was measured 4 days after the occlusion of the middle artery in 11 cats. In groups of cats treated with ifenprodil (5.6 and 16.7 microgram/kg . min over 3 h. 5 min after the occlusion), the infarcted surface was significantly decreased. The topographic localization of the infarction was studied in control and treated cats. This established necrosis was correlated with measures of focal cerebral blood flow and glucose consumption 3.5 h after the middle cerebral artery occlusion. Grey matter blood flow was universally low in untreated cats, but in cats treated with ifenprodil (5.6 microgram/kg . min) cortical and caudate nucleus blood flow was 2-3 times greater, even in those regions that were later infarcted in the treated cats. Glucose consumption was similarly reduced in untreated cats but there was little difference between the control and drug-treated cats except in some areas where drug treatment appeared to further reduce the values for focal glucose consumption. These regions correlated with those in which infarction was later found in the cats treated with ifenprodil. It is hoped that such correlations between pathology. flow and metabolism could help the search for effective pharmacotherapy of cerebrovascular disease.

Animals↗
PubMed1979

Histofluorescence study on monoamine entry into the brain before and after opening of the blood-brain barrier by various mechanisms.

The relationship between exogenous, circulating monoamines to the wall of cerebral microvessels, and the entrance of these amines into the cerebral parenchyma was studied by the formaldehyde histofluorescence technique in rats. No monoamine fluorescence could be detected in the wall tissue of the microvessels (pericytes and andothelial cells) unless either MAO or COMT were inhibited; these are integral to the blood-brain barrier mechanisms to monoamines. After transient opening of the morphologic blood-brain barrier by either a hypertonic of hypertensive insult, the amine fluorescence in the walls of the microvessels was intensified compared to that which was noted after monoamine oxidase inhibition by itself. Following opening of the structural blood-brain barrier, the circulating amines also passed through into the neuropil where they were concentrated within neurons, as demonstrated by prior depletion of endogenous monoamine transmitters by reserpine. Thus, both enzymatic and morphologic mechanisms in the blood-brain barrier ar involved in impeding the passage of monoamines into the cerebral parenchyma.

Animals↗
PubMed1979

Effects of increasing arterial pressure on cerebral blood flow in the baboon: influence of the sympathetic nervous system.

The influence of stimulation of the cervical sympathetic chain on the response of cerebral blood flow to hypertension induced by the intravenous infusion of angiotensin was studied in anaesthetised baboons. Cerebral blood flow was measured by the intracarotid 133Xenon injection technique. Possible lesions of the blood-brain barrier were studied by injecting Evans blue towards the end of the experiment and ischaemic brain damage was assessed following perfusion fixation. In a control group of five baboons blood flow increased by 53 +/- 9% (mean +/- S.E.) from the base line values in the arterial pressure range 130-159 mm Hg. In four baboons subjected to unilateral sympathetic stimulation flow increased by 16 +/- 4% in the same pressure range. In three baboons subjected to bilateral sympathetic stimulation there were no significant increases in flow until the arterial pressure had increased above 159 mm Hg. Disruption of the blood-brain barrier in the parietooccipital regions was only seen in the control animals but not in the stimulated baboons. Ischaemic brain damage was not observed with the exception of one small lesion in a single stimulated baboon. These findings provide strong support for the observations of Bill and Linder (1976) that activation of the cervical sympathetic can modify the level at which breakthrough of cerebral blood flow occurs in association with systemic hypertension.

Angiotensin II↗
PubMed1979

Effect of adenosine triphosphate and some derivatives on cerebral blood flow and metabolism.

1. Responses of cerebral blood vessels to peri- and intravascular doses of ATP (adenosine triphosphate) and some derivatives were studied in cat and baboon. 2. Perivascular application of ATP to cat pial arterioles gave a threshold dilatory effect at a concentration of 10(-11) M. This figure is comparable to the amount of ATP calculated to be released from electrically stimulated brain slices. 3. It is concluded that adenine nucleotides have a major role to play in the local control of cerebral blood flow. 4. Intracarotid injection of ATP showed a calculated threshold effect at 4 x 10(8) M in the cat and 4 x 10(-9) M in the baboon. 5. The threshold response of the vasculature to intracarotid adenosine lay between 4 x 10(-7) M and 4 x 10(-6) M in the baboon. Little effect was produced with AMP, pyrophosphate and inorganic phosphate. 6. Intracarotid ATP increased the oxygen consumption of the baboon brain parenchyma. This effect was attributed in part to an elevation of the cellular cyclic AMP levels. 7. Osmotic disruption of the blood-brain barrier in baboon did not affect the vasodilatory or metabolic effect of intracarotid ATP. 8. It is postulated that circulating purine compounds mediate a form of metabolic communication inthe body. Also, release of purine compounds from active local nerves might influence cerebral blood flow.

Adenosine Triphosphate↗
PubMed1979

Effects of nifedipine of pial arteriolar calibre: an in vivo study.

In cats the response of individual pial arterioles to perivascular microapplication of the Ca++-antagonistic drug nifedipine was studied using the image-splitting technique developed by Baez. It has previously been shown that the coefficient of variation for repeated measurements of pial vessel diameter using this system is 1%, under conditions of steady arterial pressure and blood gas tensions. All investigated pial arterioles invariably responded with a dilatation at an injected nifedipine concentration of 10 microM. The dilatatory response was inversely proportional to the resting vessel calibre, i.e., arterioles less tham 70 microns responded with a significantly stronger dilatation as compared with arterioles greater than 100 microns in diameter. In experiments where a minor subarachnoid hemorrhage was made by the injection micropipette injuring capillaries just before the perivascular microapplication of nifedipine, a dilatatory response invariably ensued in spite of the perivascular blood which in itself constricted the arterioles under examination.

Animals↗
PubMed1978

Anaesthesia for studies of the cerebral circulation: a comparison of phencyclidine and althesin in the baboon.

The effects of phencyclidine on cerebral blood flow, cerebral metabolic rate for oxygen and carbon dioxide reactivity were compared with those of Althesin in six baboons. Under similar and stable levels (Stage 1) of electroencephalographic activity cerebral blood flow and the cerebral metabolic rate for oxygen were significantly less during the infusion of Althesin when compared with the values obtained during the infusion of phencyclidine. Reactivity to carbon dioxide was present and similar during the infusion of either drug.

Alfaxalone Alfadolone Mixture↗
PubMed1978

Effects of hypotension induced by halothane, on the cerebral circulation in baboons with experimental renovascular hypertension.

The effect of graded, progressive hypotension on the autoregulation of cerebral blood flow was studied in anaesthetized baboons with experimental renovascular hypertension. Graded hypotension was induced over a period of 5-6 h by the administration of increasing concentrations of halothane. In these chronically hypertensive animals cerebral blood flow remained constant until the mean arterial pressure had decreased to approximately 90 mm Hg. At mean arterial pressures of less than this value cerebral blood flow was pressure passive. At the completion of the investigation the brains were fixed by perfusion and submitted to neuropathological examination. Evidence of chronic hypertension and of ischaemic brain damage was found in every animal.

Animals↗
PubMed1978

Effect of exogenous noradrenaline on local cerebral blood flow after osmotic opening of the blood-brain barrier in the rat.

1. The regional penetration into the brain of exogenous labelled noradrenaline (following unilateral injection into the internal carotid artery) was correlated with the effect of this amine on regional cerebral blood flow as measured by the [14C]ethanol technique in anaesthetized rats. 2. A hyperosmolar solution of urea was injected into the ipsilateral internal carotid artery to induce osmotic opening of the blood-brain barrier. 3. The extent of the blood-brain barrier damage was followed by macroscopic and fluorescence microscopic visualization of systemically injected Evans blue, and by the determination of the brain uptake index for noradrenaline. 4. The extravasation of Evans blue was restricted to the brain areas nourished by the internal carotid artery on the same side as the injection. 5. The normally low penetration of noradrenaline into the brain was enhanced fourfold in those brain regions that showed Evans blue extravasation following the administration of hypertonic urea. 6. In the same regions, the systemic administration of noradrenaline markedly increased local cerebral blood flow, compared to the contralateral hemisphere that was unaffected by the injection of urea. This effect on regional cerebral blood flow was blocked by the beta-receptor antagonist, propranolol.

Animals↗
PubMed1977

Migraine and the blood-brain barrier.

The prodromal (cerebral) symptoms of migraine are associated with a fall in cerebral blood-flow (C.B.F.). The suggestion that various circulating vasoactive agents might be the cause of this fall in C.B.F. ignores the contradictory findings that the cerebral vascular bed is normally unresponsive to such agents; but if the blood-barrier is disrupted, systemically administered monoamines and prostaglandins elicit pronounced changes in cerebral-tissue perfusion and metabolism. A defect in the blood-brain barrier of migraine patients (particularly those in whom an item of diet may trigger an attack) would make the cerebral circulation vulnerable to variations in circulating levels of vasoactive substances. Alternatively, the barrier could be intact in non-dietary patients, but release of monoamines or prostaglandins from the brain itself could account for the observed changes in the cerebral circulation.

Blood-Brain Barrier↗