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Ginkgo biloba L.
Van Beek T.A.; Bombardelli E.; Morazzoni P.
P. Morazzoni, Indena S.p.A., Scientific Department, Viale
Ortles 12, 20139 Milan Italy
Fitoterapia (Italy), 1998, 69/3 (195-244)
The chemistry, analysis, pharmacology and clinical
applications of extracts of the maidenhair tree (G. biloba)
are reviewed. This botanically unique tree contains some
unusual secondary metabolites, among others a number of highly
oxidised terpene trilactones (ginkgolides, bilobalide) which,
together with some flavonoids, are considered to be
responsible for the pharmacological activities of standardized
leaf extracts: vaso- and tissue-protective action,
cognition-enhancing and antiageing activity, including
stress-alleviating and neuroprotective/neurotrophic effects.
All these properties support the therapeutic applications
against cerebral insufficiency and impaired peripheral blood
circulation.
Antioxidant status and alpha1-antiproteinase
activity in subarachnoid hemorrhage patients.
Marzatico F, Gaetani P, Tartara F, Bertorelli L, Feletti F,
Adinolfi D, Tancioni F, Rodriguez y Baena R
Institute of Pharmacology, IRCCS Policlinico S. Matteo,
University of Pavia, Italy.
Life Sci 1998;63(10):821-6
The antiproteasic activity of alpha1-antitrypsin
(alpha1-AT) is reduced in cases of subarachnoid hemorrhage
from ruptured intracranial aneurysm and particularly in
patients currently smoking; alpha1-AT is very sensitive to
oxidant agents. About 50% of physiological anti-oxidant
systemic capacity is represented by Vitamin A, E and C.
Plasmatic amounts of alpha1-AT, alpha1-AT Collagenase
Inhibitory Capacity (CIC) and levels of vitamin A, vitamin E
and vitamin C were analyzed in 39 patients, 26 women and 13
men, operated for intracranial aneurysm; 11 patients with
unruptured intracranial aneurysm were considered as controls
while 28 patients were included within 12 hours from
subarachnoid hemorrhage (SAH). Plasmatic levels of vitamin A
and vitamin E were significantly lower (p=0.038 and p=0.0158)
in patients suffering SAH than in controls, while no
statistically significant differences were found in mean
plasmatic vitamin C levels. Level of alpha1-AT was not
statistically different in controls and in patients with SAH;
however, the activity of alpha1-AT, evaluated as CIC, is
significantly reduced in patients with SAH (p=0.019). We have
observed that systemic plasmatic levels of vitamins did not
significantly differ in relation to smoking habit. Vitamin A
and E represent an important defensive system against free
radicals reactions. Particularly, vitamin E acts as an
antioxidant by scavenging free-radicals. A reduced
anti-oxidant status might be related to the higher sensibility
of alpha1-AT to oxidative reactions and the activity of
alpha1-AT is dependent on the antioxidant capacity of
liposoluble vitamins. We can speculate that an acute systemic
oxidative stress condition might influence the rupture of
intracranial aneurysms.
Recent insights into the regulation of cerebral
circulation
Brian Jr. J.E.; Faraci F.M.; Heistad D.D.
Department of Anesthesia, University of Iowa Coll. of
Medicine, Iowa City, IA 52242 USA
Clinical and Experimental Pharmacology and Physiology
(Australia), 1996, 23/6-7 (449-457)
1. Mechanisms that regulate the cerebral circulation have
been intensively investigated in recent years. The role of
several vasodilator mechanisms has been examined in the
cerebral circulation, including nitric oxide (NO), trigeminal
peptides and potassium channels, as well as the potent
vasoconstrictor endothelin. These mediators appear to play a
role in physiological and pathophysiological responses of the
cerebral circulation. In the present review, we will focus on
some recent developments in each of these areas.
2. Nitric oxide is an important regulator of cerebral
vascular tone. Tonic production of NO maintains the cerebral
vasculature in a dilated state. NO appears to be an important
vasodilator during activation of neurons by excitatory amino
acids, somatosensory stimulation and cortical spreading
depression. Tonic production of NO appears to be critical in
vasodilatation during hypercapnia, although NO may not
directly mediate vasodilatation. NO produced by immunological
NO-synthase appears to be important in dilatation following
exposure to bacterial endotoxin.
3. Calcitonin gene-related peptide (CGRP), released from
trigeminal perivascular sensory nerves in the brain, is an
extremely potent dilator of brain vessels. CGRP may limit
noradrenaline- induced constriction of cerebral vessels and
contribute to dilatation during hypotension (autoregulation),
reactive hyperaemia, seizures and cortical spreading
depression.
4. Activation of potassium channels leads to
hyperpolarization of cerebral vascular smooth muscle and
appears to be a major mechanism for dilatation of cerebral
arteries. Agents that increase the intracellular concentration
of cyclic 3' 5'-adenosine monophosphate (cAMP) produce
vasodilatation in part by activation of large conductance
calcium- activated potassium channels (BK(Ca)) and
ATP-sensitive potassium channels (K(ATP)). Activation of both
K(ATP) and BK(Ca) channels also appears to contribute to
vasodilatation during hypoxia. In contrast to K(ATP) channels,
BK(Ca) channels appears to be active under basal conditions,
contributing to tonic dilatation of cerebral blood
vessels.
5. Endothelin is produced in the brain, but its role in the
physiological regulation of cerebral blood flow is not known.
Endothelin may contribute to the spasm of cerebral arteries
following subarachnoid haemorrhage.
Effects of hypertension on cerebral blood
vessels
Heistad D.D.; Baumbach G.L.; Kitazono T.; Faraci F.M.
Department of Internal Medicine, University of Iowa, College
of Medicine, Iowa City, IA 52242-1081 USA
Hypertens. Res. Clin. Exp. (Japan), 1993, 16/4
(225-231)
There have been major advances in our understanding of
regulation of cerebral circulation under normal conditions,
and of cerebral vascular changes during hypertension. In
relation to physiological mechanisms, nitric oxide (NO), or an
NO-containing substance, appears to play an important role in
regulation of cerebral blood flow, including coupling of
metabolism and blood flow. ATP-sensitive potassium channels
are a major mechanism that mediates cerebral vasodilatation
during several pharmacological and physiological stimuli,
including hypoxia. In relation to hypertension, potent
mechanisms protect the cerebral circulation during chronic
hypertension. Vascular hypertrophy also protects cerebral
vessels during hypertension by reducing wall stress and by
attenuation of increases in pressure in the microcirculation.
Vascular remodelling, which results in reduction in external
diameter of cerebral vessels, appears to be the dominant
structural change in cerebral arterioles during hypertension.
Endothelial dysfunction may play a key role in cerebral
vascular complications of hypertension. It is now thought that
hypertensive encephalopathy is produced by dysfunction of the
endothelial blood-brain barrier. Endothelial dysfunction in
chronic hypertension also results in abnormal vasomotor
regulation. Cerebral vascular muscle also may be dysfunctional
in hypertension, as responses to activation of ATP-sensitive
potassium channels appear to be impaired. Several mechanisms
may predispose to stroke as a complication of hypertension.
Endothelial dysfunction may lead to vasospasm, for example,
when platelets are activated. Collateral circulation in the
cerebrum is impaired by hypertension. Mean pressure is higher
in arterioles in the brain stem than in cerebral cortex, which
may predispose to hemorrhage in the brain stem.
Vasomotor effects of dimethyl sulfoxide on cat
cerebral arteries in vitro and in vivo
Pitts L.H.; Young A.R.; McCulloch J.; MacKenzie E.
Department of Neurological Surgery, School of Medicine,
University of California, San Francisco, CA 94122 USA
Stroke (USA), 1986, 17/3 (483-487)
We studied the direct vascular effects of dimethyl
sulfoxide (DMSO) in isolated middle cerebral arteries and on
pial arteriolar caliber after subarachnoid perivascular
microinjection in chloralose-anesthetized cats, and on brain
retraction in cats given DMSO intravenously. DMSO did not
constrict isolated cerebral arteries at any of the
concentrations studied (10sup -sup 1sup 0 to 4 x 10sup -sup 1
M). In middle cerebral arteries precontracted with potassium,
5-hydroxytryptamine, prostaglandin Fsub 2(alpha), or with
mechanically raised tone, DMSO at concentrations of 10sup -sup
1sup 0 to 10sup -sup 2 M had no significant effects; at
concentrations greater than 10sup -sup 2 M, DMSO consistently
relaxed the arteries, probably because of the hyperosmolarity
of the bathing solution. Microapplication of DMSO (10sup -sup
6 to 10sup -sup 2 M) around pial arterioles on the cortical
surface did not change arteriolar caliber significantly.
Higher concentrations of DMSO (1%) increased arteriolar
caliber by 56 + or - 4% (p < 0.001), probably as a
consequence of solution hypertonicity. DMSO did not modify in
vivo cerebrovascular responses to alterations in perivascular
potassium ion concentrations. Intravenous administration of
DMSO did cause obvious brain shrinkage. These data provide no
support for the view that direct cerebral vascular effects
play a major role in the clinical efficacy of DMSO, but are
consistent with the hypothesis that DMSO's ability to lower
intracranial pressure derives from its osmotic effect on
cerebral issue.
Role of magnesium and calcium in alcohol-induced
hypertension and strokes as probed by in vivo television
microscopy, digital image microscopy, optical spectroscopy,
31P-NMR, spectroscopy and a unique magnesium ion-selective
electrode
Altura B.M.; Altura B.T.
Health Science Center, State University of New York, Box 31,
450 Clarkson Avenue, Brooklyn, NY 11203 USA
Alcohol. Clin. Exp. Res. (USA), 1994, 18/5
(1057-1068)
It is not known why alcohol ingestion poses a risk for
development of hypertension, stroke and sudden death. Of all
drugs, which result in body depletion of magnesium (Mg),
alcohol is now known to be the most notorious cause of
Mg-wasting. Recent data obtained through the use of
biophysical (and noninvasive) technology suggest that alcohol
may induce hypertension, stroke, and sudden death via its
effects on intracellular free Mg2+ ((Mg2+)(i)), which in turn
alter cellular and subcellular bioenergetics and promote
calcium ion (Ca2+) overload. Evidence is reviewed that
demonstrates that the dietary intake of Mg modulates the
hypertensive actions of alcohol. Experiments with intact rate
indicates that chronic ethanol ingestion results in both
structural and hemodynamic alterations in the
microcirculation, which, in themselves, could account for
increased vascular resistance. Chronic ethanol increases the
reactivity of intact microvessels to vasoconstrictors and
results in decreased reactivity to vasodilators. Chronic
ethanol ingestion clearly results in vascular smooth muscle
cells that exhibit a progressive increase in exchangeable and
cellular Ca2+ concomitant with a progressive reduction in Mg
content. Use of 31P-NMR spectroscopy coupled with
optical-backscatter reflectance spectroscopy revealed that
acute ethanol administration to rats results in dose-dependent
deficits in phosphocreatine (PCr), the (PCr)/(ATP) ratio,
intracellular pH (pH(i)), oxyhemoglobin, and the mitochondrial
level of oxidized cytochrome oxidase aa3, concomitant with a
rise in brain-blood volume and inorganic phosphate. Temporal
studies performed in vivo, on the intact brain, indicate that
(Mg2+)(i) is depleted before any of the bioenergetic changes.
Pretreatment of animals with Mg2+ prevents ethanol from
inducing stroke and prevents all of the adverse bioenergetic
changes from taking place. Use of quantitative digital imaging
microscopy, and mag-fura-2, on single-cultured canine cerebral
vascular smooth muscle, human endothelial, and rat astrocyte
cells reveals that alcohol induces rapid
concentration-dependent depletion of (Mg2+)(i). These cellular
deficits in (Mg2+)(i) seem to precipitate cellular and
subcellular disturbances in cytoplasmic and mitochondrial
bioenergetic pathways leading to Ca2+ overload and ischemia. A
role for ethanol-induced alterations in (Mg2+)(i) should also
be considered in the well-known behavioral actions of
alcohol.
Different effects of Mg2+ on endothelin-1- and
5-hydroxytryptamine- elicited responses in goat
cerebrovascular bed
Torregrosa G.; Perales A.J.; Salom J.B.; Miranda F.J.;
Barbera M.D.; Alborch E.
Centro de Investigacion, Hospital Universitario 'La Fe',
Avda. Campanar 21, E-46009 Valencia Spain
J. Cardiovasc. Pharmacol. (USA), 1994, 23/6
(1004-1010)
Mg2+ influences the response of cerebral arteries to
several agonists, but until now its effects on endothelin-1
(ET-1) had not been studied. We recorded and compared the
responses of goat cerebrovascular bed to ET-1 and
5-hydroxytryptamine (5-HT) during various Mg2+ treatments. We
performed experiments in vitro by recording isometric tension
in isolated goat middle cerebral arteries and in vivo by
recording cerebral blood flow (CBF) and other physiologic
parameters in conscious goats. Cumulative addition of ET-1
(10-101-3 x 10-8M) and 5-HT (10-9-10-5M) contracted cerebral
arteries concentration dependently in bath media containing 0
(Mg2+ free medium), 1 (control), and 10 mM Mg2+, but the
influence of Mg2+ was different: Mg2+ deprivation increased
sensitivity (EC50) and Mg2+ overload reduced contractility
(E(max)) of cerebral arteries to 5-HT, whereas the ET-1
response did not change in these conditions. Cumulative
addition of Mg2+ (10-4-3 x 10-2M) at the active tone induced
by ET-1 (10-9M) and 5-HT (10-5M) elicited
concentration-dependent relaxations of cerebral arteries, but
the relaxant response was lower at the ET-1 precontraction.
Infusions of ET-1 (0.1 nmol/min) and 5-HT (10 microg/min)
directly into the cerebroarterial supply of the unanesthetized
goats elicited a sustained decrease in CBF and an increase in
cerebral vascular resistance. Magnesium sulfate, administered
as increasing doses (10-300 mg) in the same way increased CBF
and decreased cerebral vascular resistance, although this
effect was less on ET-1-induced than on 5-HT-induced cerebral
vasoconstriction. When infused intravenously (i.v.; 3 g/15
min), magnesium sulfate had no effect on the ET-1-induced
cerebral vasoconstriction, but increased 5-HT-reduced CBF.
ET-1 is a relatively Mg2+-resistant contractile stimulus in
the cerebrovascular bed. This should be taken into account in
consideration of the therapeutic potential of Mg2+ in
cerebrovascular disorders in which ET-1 might be involved.
Ethanol-induced contraction of cerebral arteries in
diverse mammals and its mechanism of action
Zhang A.; Altura B.T.; Altura B.M.
Department of Physiology, Box 31, SUNY, Health Sciences
Center, 450 Clarkson Avenue, Brooklyn, NY 11203 USA
Eur. J. Pharmacol. Environ. Toxicol. Pharmacol. Sect.
(Netherlands), 41993, 248/3 (229-236)
Acute ethanol exposure (8-570 mM) induced potent
contractile responses of rings in both basilar and middle
cerebral arteries, from dogs, sheep, piglets and baboons, in a
dose-dependent manner. The contractions were reproducible and
not tachyphylactic. The middle cerebral arteries were found to
be more sensitive to ethanol than the basilar arteries. No
known pharmacological antagonist, tested, exerted any effects
on ethanol-induced contractions. No differences in
responsiveness to ethanol in canine arteries were found
between male and female animals or between the presence and
the absence of endothelial cells. Removal of extracellular
Ca2+ ((Ca2+)0) partially attenuated ethanol-induced
contractions, while withdrawal of extracellular Mg2+ ((Mg2+)0)
potentiated such contractions. In the complete absence of
(Ca2+)0, caffeine and ethanol induced similar, transient
contractions followed by relaxation in K+-depolarized cerebral
vascular tissue. Ethanol-induced contractions were completely
abolished by pretreatment of tissues with caffeine. Our
results suggest that:
(a) acute ethanol intoxication can induce direct contractions
(independent of amine, prostanoid or opioid mediation) of
diverse mammalian cerebral vascular tissues, including those
from primates;
(b) these contractile responses are heterogeneous along the
cerebrovascular tree and independent of endothelial
cells;
(c) in addition to a need for (Ca2+)0, an intracellular
release of Ca2+ is needed for ethanol to induce contractions;
and
(d) hypomagnesemia or Mg deficiency potentiates the
contractile effects of ethanol on brain vessels and may be a
risk factor for ethanol-related, ischemic stroke events.
Calcium antagonist activity of vinpocetine and
vincamine in several models of cerebral ischaemia
Lamar J.-C.; Poignet H.; Beaughard M.; Dureng G.
Department of Pharmacology, Riom Laboratories-Cerm, F-63203
Riom Cedex France
Drug Dev. Res. (USA), 1988, 14/3-4 (297-304)
The potency and selectivity (i.e., the central vs.
peripheral vascular smooth muscle activity) of the calcium
antagonist (CA) effects of vinpocetine and vincamine have been
compared with those of the standard CAs: flunarizine,
verapamil, dilitazem, and nimodipine in rabbit basilar and
splenic artery preparations. The cerebral antiischemic
activity of these substances also was evaluated in five
well-documented in vivo models, i.e., hypobaric and normobaric
hypoxia, global cerebral ischemia to MgCl2, cytotoxic anoxia
with KCN, and cerebral edema induced by triethyl tin. Both
vinpocetine and vincamine possess only weak CA activity, the
potency order being: nimodipine > dilitazem > flunazine
= verapamil > vinpocetine > vincamine, with vinpocetine
and flunarizine, in contrast to other compounds, showing a
clear, 6- to 13-fold selectivity for cerebral vascular smooth
muscle. In the in vivo models, vinpocetine and flunarizine,
together with vincamine, proved most active and had a larger
spectrum of activity than the other CAs. These results suggest
that the cerebrally selective CA effects of vinpocetine are at
most only partly responsible for the effects of this compound
in the in vivo models of cerebral ischemia.
Mgsup 2sup +-Casup 2sup + interaction in
contractility of vascular smooth muscle: Mgsup 2sup + versus
organic calcium channel blockers on myogenic tone and
agonist-induced responsiveness of blood vessels
Altura BM, Altura BT, Carella A, Gebrewold A, Murakawa T,
Nishio A
Department of Physiology, State University of New York,
Health Science Center at Brooklyn, Brooklyn, NY 11203
USA
Can J Physiol Pharmacol 1987 Apr;65(4):729-45
Contractility of all types of invertebrate muscle is
dependent upon the actions and interactions of two divalent
cations, viz., calcium (Casup 2sup +) and magnesium (Mgsup
2sup +)ions. The data presented and reviewed herein contrast
the actions of several organic Casup 2sup + channel blockers
with the natural, physiologic (inorganic) Casup 2sup +
antagonist, Mgsup 2sup +, on microvascular and macrovascular
smooth muscles. Both direct in vivo studies on microscopic
arteriolar and venular smooth muscles and in vitro studies on
different types of blood vessels are presented. It is clear
from the studies done so far that of all Casup 2sup +
antagonists examined, only Mgsup 2sup + has the capability to
inhibit myogenic, basal, and hormonal-induced vascular tone in
all types of vascular smooth muscle. Data obtained with
verapamil, nimopidine, nitrendipine, and nisoldipine on the
microvasculature are suggestive of the probability that a
heterogeneity of Casup 2sup + channels, and of Casup 2sup +
binding sites, exists in different microvascular smooth
muscles; although some appear to be voltage operated and
others, receptor operated, they are probably heterogeneous in
composition from one vascular region to another. Mgsup 2sup +
appears to act on voltage-, receptor-, and leak-operated
membrane channels in vascular smooth muscle. The organic Casup
2sup + channel blockers do not have this uniform capability;
they demonstrate selectivity when compared with Mgsup 2sup +.
Mgsup 2sup + appears to be a special kind of Casup 2sup +
channel antagonist in vasular smooth muscle. At vascular
membranes it can
(i) block Casup 2sup + entry and exit,
(ii) lower peripheral and cerebral vascular resistance
(iii) relieve cerebral, coronary, and peripheral vasospasm,
and
(iv) lower arterial blood pressure.
At micromolar concentrations (i.e., 10-100 muM), Mgsup 2sup +
can cause significant vasodilatation of intact arterioles and
venules in all regional vasculatures so far examined. Although
Mgsup 2sup + is three to five orders of magnitude less potent
than the organic Casup 2sup + channel blockers, it possesses
unique and potentially useful Casup 2sup + antagonistic
properties.
The effect of hypertension on cerebral
atherosclerosis in the cynomolgus monkey
Hollander W.; Prusty S.; Kemper T.; Rosene D.L.; Moss M.B.;
Baumbach G.L.
Department of Biochemistry, Boston University School of
Medicine, 80 E Concord St, Boston, MA 02118 USA
Stroke (USA), 1993, 24/8 (1218-1227)
Background and Purpose: There is substantial clinical,
pathological, and experimental evidence that hypertension
aggravates atherosclerosis of the extracranial vessels. The
present study assesses the effects of hypertension on the
development of cerebral atherosclerosis in nonhuman primates
fed an atherogenic diet.
Methods: The extent and severity of cerebral
atherosclerosis were evaluated morphologically,
morphometrically, and biochemically in atherosclerotic monkeys
with and without hypertension. Atherosclerosis was induced by
feeding a hypercholesterolemic diet for 12 months;
hypertension was produced by surgical coarctation of the
thoracic aorta.
Results: At autopsy, gross atherosclerotic lesions of the
major cerebral arteries were observed in 15 of 16
atherosclerotic monkeys with hypertension compared with 5 of
16 atherosclerotic animals without hypertension. In the
hypertensive-atherosclerotic group, 38.5% of the vessels
examined showed gross involvement compared with only 3.4% of
the vessels involved in the atherosclerotic group (P<.001).
The lesions in the atherosclerotic group were generally mild,
whereas those in the hypertensive- atherosclerotic group were
severe and resulted in significant luminal narrowing and
occlusion of vessels (P<.001). The small branches of the
cerebral arteries also showed severe disease with luminal
obstruction in the hypertensive-atherosclerotic group. The
extent and severity of cerebral atherosclerosis were
significantly related to the severity of the hypertension
(P<.05).
Conclusions: Hypertension is an important factor in
cerebral atherosclerosis because of its accelerating effect on
the disease. Nonhuman primate models may be useful in
clarifying the role of hypertension and atherosclerosis in
cerebral vascular disease.
The case for intravenous magnesium treatment of
arterial disease in general practice: Review of 34 years of
experience
Browne S.E.
17 The Close, Wilmington, Dartford, Kent DA2 7ES United
Kingdom
J. Nutr. Med. (United Kingdom), 1994, 4/2
(169-177)
Magnesium sulphate (MgSO4) in a 50% solution was injected
initially intramuscularly and later intravenously into
patients with peripheral vascular disease (including gangrene,
claudication, leg ulcers and thrombophlebitis), angina, acute
myocardial infarction (AMI), non-haemorrhagic cerebral
vascular disease and congestive cardiac failure. A powerful
vasodilator effect with marked flushing was noted after
intravenous (IV) injection of 4-12 mmol of magnesium (Mg) and
excellent therapeutic results were noted in all forms of
arterial disease. This technique of rapidly securing very high
initial blood levels of MgSO4 produces results in arterial
disease which cannot be equalled by oral vasodilators or
intramuscular (IM) or IV infusion therapy. It is suggested
that the most important action of MgSO4 in AMI is to open up
collateral circulation and relieve ischaemia thus reducing
infarct size and mortality rates. Prophylactic use of MgSO4
and its effect on serum lipid, fibrinogen, urea and creatinine
levels are discussed.
Neuropsychiatric complications of cardiac
surgery
Nussmeier N.A.
Mercy Medical Center, Redding, CA 96049-6009 USA
J. Cardiothorac. Vasc. Anesth. (USA), 1994, 8/1 Suppl. 1
(13-18)
Historically, intracardiac operations have carried a higher
risk of neurologic complications than coronary artery bypass
grafting (CABG) procedures, although the incidence of such
complications has been increasing after CABG in recent years.
In both intracardiac and extracardiac surgery, macroemboli
from the surgical field cause most neurologic complications.
The periods of highest risk for emboli are during aortic
cannulation, onset of bypass, and weaning from bypass. Risk
factors include atherosclerosis of the ascending aorta,
advanced age, presence of concomitant cerebral vascular
disease, previous neurologic abnormality, duration of surgery,
diabetes, and history of failure of the native circulation.
Although hypothermia is beneficial in elective circulatory
arrest, its usefulness in reducing postoperative central
nervous system deficits during routine cardiac operations may
be limited. Studies suggest a role for barbiturate protection
in intracardiac but not in extracardiac surgery. Studies have
not shown better neurologic or neuropsychological outcome with
the use of membrane oxygenation and arterial filtration.
Recent studies suggest no correlation of neurologic injury
with serum glucose levels during CABG, with either duration or
severity of hypotension during hypothermic CABG, or with blood
gas management during hypothermic CABG.
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