UvA-DARE (Digital Academic Repository)
Organ protection by the noble gas helium
Smit, K.F.
Link to publication
Citation for published version (APA):
Smit, K. F. (2017). Organ protection by the noble gas helium
General rights
It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s),
other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).
Disclaimer/Complaints regulations
If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating
your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask
the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam,
The Netherlands. You will be contacted as soon as possible.
UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl)
Download date: 17 Jun 2017
Chapter 3
Targets involved in cardioprotection by the nonanesthetic noble gas helium
Nina C. Weber
Kirsten F. Smit
Markus W. Hollmann
Benedikt Preckel
Current Drug Targets 2015;16:786-92.
ABSTRACT
‡•‡ƒ”…Š †ƒ–ƒ ˆ”‘ –Š‡ ’ƒ•– †‡…ƒ†‡ ‹†‹…ƒ–‡ –Šƒ– ‘„Ž‡ ‰ƒ•‡• Ž‹‡ š‡‘ ƒ† Š‡Ž‹— ‡š‡”–
profound cardioprotection when applied before, during or after organ ischemia. Of all noble
gases, especially helium has gained interest in the past years because it does not have an
ƒ‡•–Š‡–‹…Dz•‹†‡‡ơ‡…–dzŽ‹‡š‡‘ǡƒŽŽ‘™‹‰ƒ’’Ž‹…ƒ–‹‘‘ˆ–Š‹••’‡…‹Ƥ…‰ƒ•‹—‡”‘—•…Ž‹‹cal ischemia/reperfusion situations. Because helium has several unique characteristics and no
Š‡‘†›ƒ‹…•‹†‡‡ơ‡…–•ǡŠ‡Ž‹—…‘—Ž†„‡ƒ†‹‹•–‡”‡†‹•‡˜‡”‡Ž›‹ŽŽ’ƒ–‹‡–•Ǥ
Investigations in animals as well as in humans have proven that this noble gas is not
…‘’Ž‡–‡Ž›‹‡”–ƒ†…ƒ‹†—…‡•‡˜‡”ƒŽ„‹‘Ž‘‰‹…ƒŽ‡ơ‡…–•ǤŠ‘—‰Š–Š‡—†‡”Ž›‹‰‘Ž‡…—Žƒ”
mechanisms of helium-induced cardiac protection are still not yet fully understood, recently
†‹ơ‡”‡–•‹‰ƒŽ‹‰’ƒ–Š™ƒ›•Šƒ˜‡„‡‡‡Ž—…‹†ƒ–‡†Ǥ
40
Chapter 3 : Mechanisms of helium conditioning
INTRODUCTION
Helium belongs, next to neon, krypton, xenon, and the radioactive radon, to the group of
‘„Ž‡‰ƒ•‡•Ǥ‹–Š‹–Š‹•‰”‘—’–Š‡…Š‡‹…ƒŽ‡Ž‡‡–•ƒ”‡ƒŽŽ…Šƒ”ƒ…–‡”‹œ‡†„›ƤŽŽ‡†˜ƒŽ‡…‡
orbitals, carrying a maximum amount of electrons in the outer shell of the atom. These prop‡”–‹‡••—‰‰‡•–•–Šƒ–Š‡Ž‹—‹•Ǯ‹‡”–ǯƒ†Šƒ•ƒ˜‡”›Ž‘™…Š‡‹…ƒŽ”‡ƒ…–‹˜‹–›Ǥ†‡”•–ƒ†ƒ”†
conditions, the noble gases are odorless, tasteless, colorless monatomic gases.
In contrast to xenon, helium has no anesthetic properties.1 The application of 80-90 atmospheres of helium pressure was shown to increase the minimum alveolar concentration
ˆ‘” ˜‘Žƒ–‹Ž‡ ƒ‡•–Š‡–‹…•ǤŠ‹• ‡ƒ• –Šƒ– Š‡Ž‹— …‘—–‡”ƒ…–• –Š‡ ƒ‡•–Š‡–‹… ‡ơ‡…–• ‘ˆ ‘–Š‡”
‹ŠƒŽƒ–‹‘ƒŽƒ‡•–Š‡–‹…•Ǥ‡Ž‹—‹•–Š‡”‡ˆ‘”‡†‡Ƥ‡†ƒ•ƒǮ‘Ǧ‹‘„‹Ž‹œ‡”ǯǡ†‡•…”‹„‹‰ƒ‰ƒ•
–Šƒ–†‘‡•‘–‹†—…‡ƒ‡•–Š‡•‹ƒȋ‹‘„‹Ž‹œ‡Ȍ„—––Šƒ–’”‘„ƒ„Ž›Šƒ•‘–Š‡”„‡Šƒ˜‹‘”ƒŽ‡ơ‡…–•Ǥ2
In the last decade, another property of helium has become center of several experimental and
…Ž‹‹…ƒŽ ‹˜‡•–‹‰ƒ–‹‘•ǣ ‹– Šƒ• „‡‡ †‡‘•–”ƒ–‡† –Šƒ–ǡ ƒŽ–Š‘—‰Š Ǯ‹‡”–ǯ ƒ† ‘Ǧƒ‡•–Š‡–‹…ǡ
Š‡Ž‹—‡š‡”–•‹˜‹˜‘ƒ†‹˜‹–”‘‡ơ‡…–•‘ƒ…‡ŽŽ—Žƒ”Ž‡˜‡ŽǤ‡Ž‹—‹•ƒ„Ž‡–‘”‡†—…‡‹•…Š‡‹ƒȀ
reperfusion damage in cardiac tissue.3‡…ƒ—•‡Š‡Ž‹—ƒŽ•‘Šƒ•‘Š‡‘†›ƒ‹…•‹†‡‡ơ‡…–•
when clinically applied, it might be useful for organ protection in critically ill patients. This
review will summarize and discuss the underling pathways of helium conditioning and will
ˆ‘…—•‘–Š‡…‡ŽŽ—Žƒ”‡ơ‡…–•‘ˆŠ‡Ž‹—‹–Š‡Š‡ƒ”–Ǥ†‡”•–ƒ†‹‰ƒ†‡š’Ž‘”‹‰–Š‡•‡‡ơ‡…–•
‹‰Š–ƤƒŽŽ›Ž‡ƒ†–‘‡™•–”ƒ–‡‰‹‡•‘ˆ–‹••—‡”‡’ƒ‹”–Šƒ–…ƒ„‡‡’Ž‘›‡†‹…Ž‹‹…ƒŽ›‘…ƒ”†‹ƒŽ
ischemia/reperfusion situations.
Pre- and postconditioning
Š‡Ƥ”•–†‡•…”‹„‡†ˆ‘”‘ˆDz…‘†‹–‹‘‹‰dz‹•‹•…Š‡‹…pre-conditioning, which was described
in animals more than 20 years ago.4, 5 This phenomenon has been described in most living cells
and in all mammalian species. Conditioning the heart can be important in situations where a
„”‹‡ˆ‹–‡””—’–‹‘‘ˆ„Ž‘‘†ƪ‘™–‘ƒ‘”‰ƒ‘……—”•ǤŠ‹•‹•–Š‡…ƒ•‡†—”‹‰‘”‰ƒ–”ƒ•’Žƒ–ƒtion, surgery, acute myocardial infarction and percutaneous coronary interventions (PCI).
Most intensively investigated is myocardial pre-conditioning, which refers to an application of short periods of ischemia before a subsequent longer ischemic period. Preconditioning
can be divided into an early ȋ‹‡†‹ƒ–‡ ‡ơ‡…–ǡ Žƒ•–‹‰ ˆ‘” ͚Ǧ͛ Š‘—”•Ȍ ƒ† late phase of preconditioning (protection reappears after 24 hours lasting for 2-4 days).6
‡…‡–”‡•‡ƒ”…ŠƒŽ•‘ˆ‘…—•‡†‘post-conditioning, which is achieved by application of short
repetitive cycles of ischaemia directly at the onset of reperfusion.7 Another very recent concept
of conditioning is remote pre-/per- or postǦ…‘†‹–‹‘‹‰ǡ™Š‹…Š‹•†‡Ƥ‡†„›–Š‡ƒ’’Ž‹…ƒ–‹‘‘ˆ
sublethal ischemia to an organ that is located distant from the target organ.8, 9 The obvious
advantage of remote conditioning is that no additional manipulation on the threatened organ
itself has to be performed.
41
As applying ischemia to an organ yields a high risk of complications for the patient, the
•‡ƒ”…Šˆ‘”ƒŽ–‡”ƒ–‹˜‡‘’–‹‘•–‘‹‹…‹•…Š‡‹……‘†‹–‹‘‹‰“—‹…Ž›•Š‘™‡†–Šƒ–†‹ơ‡”‡–
’Šƒ”ƒ…‘Ž‘‰‹……‘’‘—†•ƒ…–‹˜ƒ–‹‰ƒ†‡‘•‹‡ǡ—•…ƒ”‹‹…ǡȽǦƒ†”‡‡”‰‹…ǡ‘’‹‘‹†‘”„”ƒ†›kinin receptors also contributed to organ protection.6 Among these substances, halogenated
ƪ—‘”‘…ƒ”„‘•Ž‹‡‹•‘ƪ—”ƒ‡ǡ†‡•ƪ—”ƒ‡ƒ†•‡˜‘ƪ—”ƒ‡ǡƒ•™‡ŽŽƒ•–Š‡‘„Ž‡‰ƒ•‡•ƒ”‡‡ƒ™Š‹Ž‡™‡ŽŽ‘™–‘‹†—…‡…ƒ”†‹‘’”‘–‡…–‹˜‡‡ơ‡…–•Ǥ10-12
Physical, chemical and molecular properties of helium
In order to get a better overview of the unique properties of the noble gas helium we will sumƒ”‹œ‡–Š‡‘•–”‡Ž‡˜ƒ–’Š›•‹…ƒŽǡ…Š‡‹…ƒŽƒ†ƒŽ•‘‘Ž‡…—Žƒ”‡ơ‡…–•‘ˆ‘„Ž‡‰ƒ•‡•–Šƒ–ƒ”‡
•—’’‘•‡†–‘„‡ƒ–Ž‡ƒ•–‹’ƒ”–”‡•’‘•‹„Ž‡ˆ‘”‡†‹ƒ–‹‰ƒ›’Šƒ”ƒ…‘Ž‘‰‹…ƒŽ‡ơ‡…–Ǥ‘‰
all noble gases, helium has a molecular weight of only 4 g/mol and has the lowest melting
and boiling points of all elements.13 In contrast to oxygen, which has a density of 1.43 g/m3,
helium has a very low density of 0.179 g/m3. The absolute viscosity of helium is 201.8 m poise,
which is lower compared to oxygen (viscosity of 211.4 m poise) and normal air (188.5 m poise).
‡…ƒ—•‡–Š‡ƪ‘™‘ˆƒ‰ƒ•†‡’‡†•‘–Š‡†‡•‹–›ƒ†˜‹•…‘•‹–›‘ˆ‡ƒ…Š‡Ž‡‡––Šƒ–‹•’”‡•‡–
‹–Š‡”‡•’‡…–‹˜‡‰ƒ•‹š–—”‡ǡƒ‹”ƪ‘™–Š”‘—‰Š–Š‡Ž—‰•‹•†‡’‡†‹‰‘–Š‡‰ƒ•‹š–—”‡–Šƒ–
is inhaled. Due to the low density of helium, inhalation of this gas reduces work of breathing
and helium is hence available for clinical use in patients with obstructive airway diseases.13, 14
Ventilators that allow administration of helium by invasive and non-invasive ventilation have
been invented and helium can be used during heart, vascular or transplantation surgery, all
typical clinical ischemia/reperfusion situations occurring on a daily basis.
The anesthetic potency of a substance is almost linearly correlated with its oil/water parti–‹‘…‘‡ƥ…‹‡–Ǥ15 The low fat solubility of helium determines the low partial pressure of helium
in the central nervous system. It was shown that helium administrated in supra-atmospheric
levels induced tremors and convulsions in rats that had been exposed to 84.6 ± 22.2 atmospheres of helium. These results suggest that helium activates the central nervous system
rather than depressing the neural cell activity.2, 16
Cardioprotection induced by helium-what do we know?
 ͚͘͘͟ǡ ƒ‰‡Ž ƒ† …‘Ǧ™‘”‡”• ™‡”‡ –Š‡ Ƥ”•– –‘ •Š‘™ –Šƒ– –Š”‡‡ –‹‡• ͝ ‹—–‡• ‹ŠƒŽƒ–‹‘
administration of 70% helium before a coronary artery occlusion for 30 minutes followed by 3
Š‘—”•‘ˆ”‡’‡”ˆ—•‹‘•‹‰‹Ƥ…ƒ–Ž›”‡†—…‡†‹ˆƒ”…–•‹œ‡‹”ƒ„„‹–Š‡ƒ”–•Ǥ17Š‹•™ƒ•–Š‡Ƥ”•–’”‘‘ˆ
that helium is capable of inducing preconditioning of the heart.
–Š‹••–—†›ǡ–Š‡ƒ—–Š‘”•—•‡†•‡˜‡”ƒŽ†‹ơ‡”‡–‹Š‹„‹–‘”•‹‘”†‡”–‘„Ž‘…‡œ›‡•‘ˆ–Š‡
•‘…ƒŽŽ‡†Dz”‡’‡”ˆ—•‹‘‹Œ—”›•ƒŽ˜ƒ‰‡‹ƒ•‡ȋȌ’ƒ–Š™ƒ›dzǤŠ‡›•Š‘™‡†–Šƒ–ƒ†‹‹•–”ƒ–‹‘
of a phosphatidylinositol-3-kinase (PI3K) antagonist, a mitogen/extracellular signal-related
kinase 1 (MEK-1) inhibitor and an inhibitor of the 70-kDa ribosomal protein s6 kinase (p70s6kinase) all were capable to block helium induced cardioprotection in the ischemic rat heart.17
42
Chapter 3 : Mechanisms of helium conditioning
ƒ‹–‡”‡•–‹‰•‡–‘ˆ•—„•‡“—‡–•–—†‹‡•ǡ–Š‡•ƒ‡ƒ—–Š‘”•‹†‡–‹Ƥ‡†•‡˜‡”ƒŽ’‘–‡–‹ƒŽ‡›
players in the mechanism underlying helium induced preconditioning. Pro-survival kinases
ˆ”‘–Š‡’ƒ–Š™ƒ›‹Š‹„‹–‰Ž›…‘‰‡•›–Šƒ•‡‹ƒ•‡Ǧ͛„‡–ƒȋ
Ǧ͛ȾȌƒ…–‹˜‹–›ƒ†•–‹—Žƒ–‡
apoptotic protein p53 degradation. To evaluate whether these two pathways would probably
also play a role in helium induced cardioprotection, Pagel and co-workers investigated if a
’Šƒ”ƒ…‘Ž‘‰‹…ƒŽ‹Š‹„‹–‹‘‘ˆ
Ǧ͛Ⱦƒ†’͛͝™‘—Ž†Ž‘™‡”–Š‡–Š”‡•Š‘Ž†‘ˆŠ‡Ž‹—Ǧ‹†—…‡†
protection.18 Employing the mitochondrial permeability transition pore (mPTP) opener atrac–›Ž‘•‹†‡‹–Š‡‹”‹˜‹˜‘•‡––‹‰ǡ–Š‡ƒ—–Š‘”•…‘—Ž†•Š‘™–Šƒ–‹Š‹„‹–‹‘‘ˆ
Ǧ͛Ⱦ‘”’͛͝Ž‘™‡”•
the threshold of helium-induced preconditioning via a mPTP-dependent mechanism.18
A similar result was achieved by the use of morphine (0.1 mg/kg) in combination with
helium-preconditioning in rabbits.19 These data suggest that helium preconditioning involves
ƒ ‘’‹‘‹†Ǧ”‡…‡’–‘” ‡†‹ƒ–‡† ‡…Šƒ‹•Ǥ Š‹• …‘—Ž† Šƒ˜‡ •‹‰‹Ƥ…ƒ– ‹’Ž‹…ƒ–‹‘• ‹ –Š‡
clinical scenario, as morphine is a routinely used opioid analgesic applied in patients with
ischemia-reperfusion problems, e.g. in patients with acute myocardial infarction. The above
‡–‹‘‡†’”‘Ǧ•—”˜‹˜ƒŽ‹ƒ•‡•͛ǡ͙Ȁ͚ƒ†–Š‡‹”†‘™•–”‡ƒ–ƒ”‰‡–•ǣ‡†‘–Š‡Ž‹ƒŽ‹–”‹…
‘š‹†‡•›–Šƒ•‡ȋ‡Ȍǡ’͛͝ƒ†
Ǧ͛ȾǡƒŽŽŠƒ˜‡„‡‡•Š‘™–‘’”‡˜‡–‘’‡‹‰‘ˆ–Š‡
in ischemic preconditioning.20
Mitochondria are the source of cellular energy deliver and determine the life or death fate
‘ˆ‹†‹˜‹†—ƒŽ…‡ŽŽ•ǡ™Š‘Ž‡‘”‰ƒ•ǡƒ†ƤƒŽŽ›–Š‡‡–‹”‡‘”‰ƒ‹•ǤŠ‡–Š”‡‡ƒ‹‹–‘…Š‘drial phenomena: 1) opening of mitochondrial adenosine triphosphate-regulated potassium
…Šƒ‡Ž ȋ‹–‘Ȍǡ ͚Ȍ ‰‡‡”ƒ–‹‘ ‘ˆ ƒ •ƒŽŽ ”‡ƒ…–‹˜‡ ‘š›‰‡ •’‡…‹‡• ȋȌ „—”•–ǡ ƒ† ͛Ȍ
ƒ‹–‡ƒ…‡ ‘ˆ –Š‡  Šƒ˜‡ „‡‡ Ž‹‡† –‘ …ƒ”†‹‘’”‘–‡…–‹˜‡ ‡ơ‡…–•ǡ ƒ† –Š‡› ƒ”‡ Ž‹‡Ž›
not mutually exclusive. The opening of the mPTP causes mitochondrial dysfunction, and preconditioning is considered might be protective by preserving cardiac mitochondrial function,
thereby reducing tissue damage.
The opening of the mPTP during reperfusion is enhanced by normalization of acidic pH after
–Š‡„Ž‘‘†ƪ‘™Šƒ•„‡‡”‡•–‘”‡†Ǥ21‘”†‡”–‘‡š–‡†–Š‡‹”Ƥ†‹‰–Šƒ–Š‡Ž‹—‹†—…‡•’”‡conditioning via preventing mPTP opening, Pagel and coworkers applied transient alkalosis
during the early reperfusion phase and showed that helium-induced cardio-protection was
abolished.22 However, the mPTP inhibitor Cyclosporine A could restore the cardioprotection
in the presence of alkalosis.22 These data indicate that helium inhibits mPTP opening by
ƒ‹–ƒ‹‹‰ ‹–”ƒ…‡ŽŽ—Žƒ” ƒ…‹†‘•‹• †—”‹‰ ‡ƒ”Ž› ”‡’‡”ˆ—•‹‘Ǥ ‡‰ƒ”†‹‰ –Š‡ ”‘Ž‡ ‘ˆ ƒ†
–Š‡‹–‘…Š‘†”‹ƒŽǦ…Šƒ‡Ž‹Š‡Ž‹—’”‡…‘†‹–‹‘‹‰‹–™ƒ••Š‘™–Šƒ––Š‡•…ƒ˜engers N-Acetylcysteine and N-2-mercaptopropionyl glycine or the K-ATP-channel blocker
5-hydroxydecanoate completely abolished helium induced preconditioning in rabbits.23
In a study of our own laboratory we analyzed cardiac mitochondrial function by measuring the rate of oxygen consumption in isolated mitochondria in rats.24 The rate of oxygen
consumption of isolated mitochondria after administration of a complex 2 substrate (state
2), adenosine diphosphate (state 3), and after complete phosphorylation of adenosine diphos43
’Šƒ–‡–‘ƒ†‡‘•‹‡–”‹’Š‘•’Šƒ–‡ȋ•–ƒ–‡͜Ȍ™ƒ•—•‡†–‘‡Žƒ„‘”ƒ–‡ƒ†‹”‡…–‡ơ‡…–‘ˆŠ‡Ž‹—…‘ditioning on mitochondrial function.24 The results showed a mild mitochondrial uncoupling,
as helium-induced preconditioning increased state 4 respiration (state 3 respiration was not
changed), thus reducing the respiratory control index (state 3/state 4). 24 Infarct size reduction
after helium preconditioning was blocked by Iberotoxin, a mitochondrial calcium sensitive potassium (mKCa) channel blocker.24ƒ•–—†›‹˜‡•–‹‰ƒ–‹‰–Š‡†‹ơ‡”‡…‡•„‡–™‡‡›‘—‰ƒ†
aged myocardium, infarct size reduction by helium was completely abolished by the protein
kinase A (PKA) blocker H-89.25 In the same study it could be shown that also activation of mKCa
channels by NS1619 reduced infarct size in young and aged rats.25 Interestingly, the adenylyl
…›…Žƒ•‡ƒ…–‹˜ƒ–‘”ˆ‘”•‘Ž‹ȋ‹ƒ…‘…‡–”ƒ–‹‘‘ˆ͛͘͘Ɋ‰Ȁ‰Ȍ”‡†—…‡†‹ˆƒ”…–•‹œ‡‘Ž›‹›‘—‰
animals.25Š‹‰Š‡”†‘•‡‘ˆˆ‘”•‘Ž‹ȋ͙͘͘͘Ɋ‰Ȁ‰ȌǡŠ‘™‡˜‡”ǡ”‡†—…‡†‹ˆƒ”…–•‹œ‡ƒŽ•‘‹ƒ‰‡†
rats. It is therefore suggested that helium preconditioning involves and is partly mediated by
activation of PKA and that changes in PKA regulation could explain the age-dependent loss of
tissue protection by preconditioning.25
Next to the above-mentioned enzymes, also nitric oxide synthase (NOS) has been implicated in helium-induced preconditioning in rabbits.26 The non-selective NOS inhibitor
N-nitro-L-arginine methyl ester was infused during the helium preconditioning protocol and
completely abrogated cardioprotection. In contrast, the selective inducible NOS inhibitor or a
•‡Ž‡…–‹˜‡‡—”‘ƒŽ‹Š‹„‹–‘”†‹†‘–ƒơ‡…–Š‡Ž‹—Ǧ‹†—…‡†’”‡…‘†‹–‹‘‹‰Ǥ26 These data
show that NO might be generated by NOS during helium preconditioning.26
‡‰ƒ”†‹‰–Š‡—•‡‘ˆ†‹ơ‡”‡–Š‡Ž‹—…‘…‡–”ƒ–‹‘‹”ƒ–•ǡ—Š‡–ƒŽǤ‹†—…‡†Žƒ–‡’”‡…‘ditioning by a 15 minute administration of 70%, 50%, 30%, and 10% helium in a time window
24 hours before ischemia/reperfusion.27 A helium concentration of 30% was still protective
but a concentration of 10% was not,27 indicating that there is a threshold for a certain con…‡–”ƒ–‹‘ ‘ˆ –Š‡ ‘„Ž‡ ‰ƒ•ǤŠ‹• –Š”‡•Š‘Ž† ‹• “—‹–‡ Ž‘™ǡ ƒŽŽ‘™‹‰ ƒŽ•‘ ‹ŠƒŽ‹‰ ƒ •‹‰‹Ƥ…ƒ–
amount of oxygen, a fact that might play a critical role when the noble gas is used in clinical ischemia-reperfusion situations. In additional experiments, Huhn et al. showed that the
COX-2 inhibitor NS-398 blocked helium induced late preconditioning.27 Most of the described
‡…Šƒ‹••Šƒ˜‡„‡‡‹˜‡•–‹‰ƒ–‡†„›†‹ơ‡”‡–’Šƒ”ƒ…‘Ž‘‰‹…ƒŽ‹–‡”˜‡–‹‘•”ƒ–Š‡”–Šƒ
by direct biochemical methods. HowŠ‡Ž‹—‹‰Š–ƒơ‡…––Š‡•‡’”‘Ǧ•—”˜‹˜ƒŽ‹ƒ•‡•ƒ†–Š—•
mediate cardioprotection is yet completely unknown.
ƒ†‹ơ‡”‡–ƒ’’”‘ƒ…Šǡ‘–—•‹‰ƒ›’Šƒ”ƒ…‘Ž‘‰‹…ƒŽ„Ž‘…ƒ†‡„—–”ƒ–Š‡”ƒ‰‡‡‡š’”‡•sion screening along with histology scores, we got more detailed information on target genes
that are regulated by helium induced postconditioning.28 ƒ–• ™‡”‡ •—„Œ‡…–‡† –‘ ͚͝ ‹ ‘ˆ
ischemia and 5, 15, or 30 min of helium postconditioning. Semi-quantitative histological
analysis revealed that 15 min of helium postconditioning reduced the extent of ischaemia/
”‡’‡”ˆ—•‹‘Ǧ‹†—…‡†…‡ŽŽ†ƒƒ‰‡ǡ„—––Š‹•‡ơ‡…–™ƒ•‘–‘„•‡”˜‡†ƒˆ–‡”͝ƒ†͛͘‹‘ˆŠ‡Ž‹—
postconditioning.28 The protective 15 min helium-postconditioning stimulus resulted in upregulation of 17 of 23 genes involved in necrosis, and in 18 of 25 genes involved in pro-apoptosis.
44
Chapter 3 : Mechanisms of helium conditioning
On the other hand, 4 of 23 (necrosis) and 7 of 25 genes (pro-apoptosis) were down-regulated.
”‘–Š‡ƒ–‹Ǧƒ’‘’–‘–‹…‰‡‡•ǡ͡‘ˆ͙͙ƒ†ˆ”‘‰‡‡•‹˜‘Ž˜‡†‹ƒ—–‘’Šƒ‰›ǡ͚͜‘ˆ͚͛™‡”‡
up-regulated after helium postconditioning.28 Taken together, these data indicate that helium
postconditioning at least partly is mediated by alterations in the cell death program.28
Interestingly, other noble gases were proven to disrupt conformational changes of the
proteins urate oxidase, an intracellular globular protein composed of large hydrophobic cavities and Annexin V, a protein with a hydrophilic pore inside known to bind to cell membranes
by a calcium-dependent action.29 ‹ơ‡”‡– …‡ŽŽ ‡„”ƒ‡ ”‡…‡’–‘”•ǡ ‡Ǥ‰Ǥ –Š‡ Ǧ‡–Š›ŽǦǦ
aspartate receptors,30–Š‡–™‘Ǧ’‘”‡†‘ƒ‹’‘–ƒ••‹—…Šƒ‡ŽǦ͙ǡ31 the plasmalemmal
ATP-sensitive potassium (KATP) channel,32 the nicotinic acetylcholine receptor33 as well as the
5-hydroxytryptamine type 3 receptor, 34Šƒ˜‡„‡‡•Š‘™–‘„‡ƒơ‡…–‡†„›‘„Ž‡‰ƒ•‡•Ǥ–Šƒ•
to be mentioned that these investigations were mostly performed in neuronal cells and for
†‹ơ‡”‡–‘„Ž‡‰ƒ•‡•–ŠƒŠ‡Ž‹—ǤŠƒ––Š‡•‡…‡ŽŽ—Žƒ”‡ơ‡…–•ƒ”‡ƒŽ•‘‹˜‘Ž˜‡†‹…ƒ”†‹ƒ…’”‘tection by helium is therefore speculation. However, it is worth mentioning that they clearly
link noble gas action to membrane structures.
A role for membrane proteins “caveolins” in helium induced cardioprotection
As helium is an inert gas with a lower activity to react with other compounds or receptors, but
nevertheless has been show to induce biological changes, membrane structures and membrane proteins might be important in helium-induced cardioprotection.
ƒ˜‡‘Žƒ‡ǡ ƒŽ•‘ ƒ‡† DzŽ‹––Ž‡ …ƒ˜‡•dzǡ ƒ”‡ …Š‘Ž‡•–‡”‘ŽǦ ƒ† •’Š‹‰‘Ž‹’‹†Ǧ‡”‹…Š‡† ‹˜ƒ‰‹ƒtions of the plasma membrane. These little caves are c considered a subset of lipid rafts.35
The important structural proteins that are essential for the formation of Caveolae are called
Caveolin. Caveolins exist in three isoforms.36, 37 Caveolins are critically involved in ischemic as
™‡ŽŽƒ•‹•‘ƪ—”ƒ‡Ǧ‹†—…‡†…‘†‹–‹‘‹‰Ǥ38-40ƒ˜‡‘Ž‹•Šƒ˜‡•…ƒơ‘Ž†‹‰†‘ƒ‹•–Šƒ–ƒ…Š‘”
and regulate proteins.41 The isoforms Caveolin-1 and -2 have been shown to be expressed
in multiple cell types, while caveolin-3 is mostly expressed in striated (skeletal and cardiac)
muscle and certain smooth muscle cells.42 Caveolins regulate multiple cellular processes,
including vesicular transport, cholesterol and calcium homeostasis, as well as inter- and
intracellular signal transduction. Most importantly, caveolins have recently been detected in
mitochondria.43, 44†‡” –Š‡ ‹–”ƒ…‡ŽŽ—Žƒ” …‘–”‘Ž ‘ˆƒ˜‡‘Ž‹• †‹ơ‡”‡– •‹‰ƒŽ‹‰ ‘Ž‡…—Ž‡•
are recruited to the Caveolae, where they induce a direct temporal and spatial regulation of
signal transduction.45
‡…‡–‡˜‹†‡…‡ˆ”‘”‡•‡ƒ”…Š•Š‘™•–Šƒ–•‡˜‡”ƒŽ•‹‰ƒŽ‹‰‘Ž‡…—Ž‡•‹‰Š–‡š‹•–ƒ•—Ž–‹’”‘–‡‹…‘’Ž‡š‡•ǤŠ‡•‡…‘’Ž‡š‡•ƒ”‡…ƒŽŽ‡†Dz•‹‰ƒŽ‘•‘‡•dzǤŠ‡›…‘–‹—‘—•Ž›…Šƒ‰‡”
their form and dissociate under basal or stimulated conditions. Caveolins are suggested to
’Žƒ›ƒ•‹‰‹Ƥ…ƒ–”‘Ž‡‹–Š‡†›ƒ‹…•‘ˆ–Š‡•‡—Ž–‹’”‘–‡‹…‘’Ž‡š‡•Ǥ 46’‡…‹Ƥ…ƒŽŽ›ǡ‹”‡gard to signaling molecules involved in cardiac protection, many G–protein coupled receptors
ȋ
Ȍ‹…Ž—†‹‰‘’‹‘‹†47 and adenosine receptors48 localize to caveolae. Additionally, many
45
of the signaling molecules involved in cardiac protection, including the G-alpha subunit of heterotrimeric G-proteins, Src kinases, PI3ǡ‡ǡ‹•‘ˆ‘”•ƒ†ǡƒŽŽŠƒ˜‡„‡‡Ž‹‡†–‘
…ƒ”†‹‘’”‘–‡…–‹‘ƒ†ƒ”‡‘™–‘„‹†–Š‡•…ƒơ‘Ž†‹‰†‘ƒ‹‘ˆ…ƒ˜‡‘Ž‹Ǥ49, 50 Additionally,
caveolins have recently been shown to modulate mitochondrial function.51, 52
‹”•– ‹˜‡•–‹‰ƒ–‹‘• ƒ‹‹‰ –‘ ‡Ž—…‹†ƒ–‡ ƒ ’‘••‹„Ž‡ …‘‡…–‹‘ ‘ˆ Š‡Ž‹— ™‹–Š …ƒ˜‡‘Ž‹• ‹
ˆƒ…– •Š‘™‡† –Šƒ– Š‡Ž‹— ‹ŠƒŽƒ–‹‘ ƒơ‡…–• …ƒ˜‡‘Ž‹Ǧ͙Ȁ͛ ‡š’”‡••‹‘ ‹ ‹…‡ Š‡ƒ”–Ǥ53 In this
study, mice inhaled either helium (70%) or oxygen (30%) for 20 min. Thirty minutes or 24
hours after inhalation hearts were excised and blood was withdrawn in order to obtain serum
ˆ”‘ –Š‡ ‹…‡Ǥ ‡•—Ž–• •Š‘™‡† –Šƒ– Š‡Ž‹— ‹ŠƒŽƒ–‹‘ †‡…”‡ƒ•‡† …ƒ˜‡‘Ž‹Ǧ͙ ƒ† …ƒ˜‡‘Ž‹Ǧ͛
‡š’”‡••‹‘‹–Š‡Š‡ƒ”–ƒˆ–‡”͚͜Š‘—”•ǤŠ‹•™ƒ•…‘Ƥ”‡†„›ƒƒŽ›•‡•‘ˆ–Š‡„—‘›ƒ–…ƒ˜‡‘Ž‹
enriched fractions also showing lower caveolin levels. In addition, caveolin-1/-3 levels were
elevated in serum of mice. These results suggest that circulating factors in the bloodstream
ƒ›„‡’ƒ”–‘ˆ–Š‡‡…Šƒ‹•–Šƒ–‡†‹ƒ–‡•’”‘–‡…–‹‘‹†‹ơ‡”‡–ˆ‘”•‘ˆ…‘†‹–‹‘‹‰Ǥ
The summarized experimental data for helium induced conditioning are depictured in Ƥ‰—”‡͙.
Helium in diseased animal models
A limitation of most of the above described studies is that they were performed in healthy
ƒ‹ƒŽ‘†‡Ž•Ǥ‘™‡˜‡”ǡ‹–Šƒ•„‡‡•Š‘™–Šƒ–†‹ơ‡”‡–…‘Ǧ‘”„‹†‹–‹‡•Ž‹‡ǡ†‹ƒ„‡–‡•ǡƒ‰‹‰
and hypertension block conditioning.54 This fact clearly indicates the need of further research
‹†‹•‡ƒ•‡†‘†‡Ž•–Šƒ–‘”‡”‡Ž‹ƒ„Ž›”‡ƪ‡…––Š‡”‡ƒŽ’ƒ–‹‡–ǤŽ›–”ƒ•Žƒ–‹‘‘ˆ‡š’‡”‹‡–ƒŽ
data in diseased animals enables us to develop clinical strategies of tissue repair in patients
•—ơ‡”‹‰ ˆ”‘ ‹•…Š‡‹ƒȀ”‡’‡”ˆ—•‹‘ •‹–—ƒ–‹‘• ‘ˆ –Š‡ Š‡ƒ”–Ǥ ‡‰ƒ”†‹‰ •—…Š ‹˜‡•–‹‰ƒ–‹‘•ǡ
only a few studies have been performed in animals. In one study, healthy Wistar Kyoto rats
and spontaneous hypertensive rats were subjected to 25 min of myocardial ischaemia and
120 min reperfusion. The animals inhaled 70% helium for 15 min after the index ischaemia
(helium post-conditioning), combined with 15 min helium inhalation 24 hours prior to index
ischaemia (helium late pre-conditioning) or a triple intervention containing 3 additional
cycles of 5 min helium inhalation shortly before ischemia (helium early preconditioning.55 In
hypertensive animals, the helium triple intervention by pre-/post- and late conditioning was
able to induce cardioprotection, a single intervention by helium postconditioning alone was
however not protective.55˜‡•–‹‰ƒ–‹‘•‘–Š‡’Š‘•’Š‘”›Žƒ–‹‘‘ˆ
Ǧ͛Ⱦƒ†Ǧɂ‹–Š‹•
‡š’‡”‹‡–ƒŽ•‡––‹‰”‡˜‡ƒŽ‡†–Šƒ–Š‡Ž‹—…‘†‹–‹‘‹‰†‘‡•‘–‹˜‘Ž˜‡
Ǧ͛Ⱦƒ†Ǧɂ
related mechanisms.55
In pre-diabetic Zucker obese rats,56 helium induced cardioprotection was blocked. In this
study in Zucker lean rats but not in Zucker obese rats helium was capable to induce mild
mitochondrial uncoupling.56‘”‡‘˜‡”ǡ›‘…ƒ”†‹ƒŽ͙Ȁ͚ƒ†–’Š‘•’Š‘”›Žƒ–‹‘™‡”‡‘–
ƒơ‡…–‡†„›Š‡Ž‹—‹„‘–Šƒ‹ƒŽ•–›’‡•Ǥ‘™‡˜‡”ǡ
Ǧ͛Ⱦ’Š‘•’Š‘”›Žƒ–‹‘™ƒ•”‡†—…‡†‹
the heart only in Zucker lean animals but not in the obese rats.56
46
Chapter 3 : Mechanisms of helium conditioning
He
Caveolae/
Caveolin
MEKͲ1
Apoptotic
proteins
Erk1/2
He
He
GͲproteinͲ
coupled
receptor
IP3/DAG
PKCͲɸ
FͲactin
Atractyloside
јCa2+
јROS
јPi
He
GSKͲ3ɴ
p70s6K
mTOR
He
PI3K
PDK1
mPTP
AKT/PKB
ĐůŽƐĞĚ
P53
ĂƌĚŝŽƉƌŽƚĞĐƚŝŽŶ
He
Bax,Bad,Bim,
Caspases
He
PKA
eNOS
NO
LͲNAME
mKCA
љpH
Mito KATP
ATP/ADP
Mg2+
Cyclosporin A
He
Figure 1: Mechanisms involved in helium-induced cardioprotection
Š‹• Ƥ‰—”‡ •—ƒ”‹œ‡• –Š‡ ‘™ ‡…Šƒ‹•• ‹ Š‡Ž‹—Ǧ‹†—…‡† …ƒ”†‹‘’”‘–‡…–‹‘ǡ ƒ‹Ž› ˜‹ƒ –Š‡ ’ƒ–Š™ƒ›Ǥ‡Ž‹—‹•†‡’‹…–‡†ƒ•ƒ›‡ŽŽ‘™…‹”…Ž‡ȋ‡ȌǤ””‘™•‹†‹…ƒ–‡ƒƒ…–‹˜ƒ–‹‰‘”—’Ǧ”‡‰—Žƒ–‘”›‡ơ‡…–ǡ
•“—ƒ”‡•‹†‹…ƒ–‡ƒ•—’’”‡••‹˜‡‘”†‘™Ǧ”‡‰—Žƒ–‘”›‡ơ‡…–Ǥ”‡˜‡–‹‰–Š‡ˆ”‘‘’‡‹‰‹†‹…ƒ–‡•…ƒ”dioprotection.
Ǧ͙ 㠏‹–‘‰‡Ǧƒ…–‹˜ƒ–‡† ’”‘–‡‹ ‹ƒ•‡Ǧ‡š–”ƒ…‡ŽŽ—Žƒ” •‹‰ƒŽǦ”‡‰—Žƒ–‡† ‹ƒ•‡Ǧ͙Ǣ ͙Ȁ͚ 㠚–”ƒ…‡ŽŽ—Žƒ”
•‹‰ƒŽǦ”‡‰—Žƒ–‡†‹ƒ•‡͙Ȁ͚Ǣ͛㋐‘•‹–‘Ž–”‹’Š‘•’Šƒ–‡Ǧ͛Ǣ
ㆋƒ…›Ž‰Ž›…‡”‘ŽǢǦɂγ’”‘–‡‹‹ƒ•‡‡’•‹Ž‘Ǣ
͛Ⱦγ
Ž›…‘‰‡•›–Šƒ•‡‹ƒ•‡͛ȾǢ͛γŠ‘•’Šƒ–‹†›Ž‹‘•‹–‘ŽǦ͛Ǧ‹ƒ•‡ǡǦ͙γ’Š‘•’Š‘‹‘•‹–‹†‡Ǧ†‡’‡†‡–’”‘–‡‹‹ƒ•‡Ǧ͙Ǣγ’”‘–‡‹‹ƒ•‡ǢγƒƒŽ‹ƒ–ƒ”‰‡–‘ˆ”ƒ’ƒ›…‹Ǣ͛͝γ
—‘”’”‘–‡‹͛͝Ǣ‹–‘…Š‘†”‹ƒŽ’‡”‡ƒ„‹Ž‹–›–”ƒ•‹–‹‘’‘”‡Ǣ‡γ‡†‘–Š‡Ž‹ƒŽ‹–”‹…‘š‹†‡•›–Šƒ•‡Ǣ㐋–”‹…‘š‹†‡ǢǦγǦ
Ǧ‹–”‘ƒ”‰‹‹‡‡–Š›Ž‡•–Š‡”Ǣγ’”‘–‡‹‹ƒ•‡Ǣƒγ‹–‘…Š‘†”‹ƒŽ…ƒŽ…‹—Ǧ•‡•‹–‹˜‡’‘–ƒ••‹—…Šƒ‡ŽǢ㔇ƒ…–‹˜‡‘š›‰‡•’‡…‹‡•Ǣ‹γ‹‘”‰ƒ‹…’Š‘•’Šƒ–‡Ǣ
テ‡‘•‹‡–”‹’Š‘•’Šƒ–‡Ǣテ‡‘•‹‡†‹’Š‘•’Šƒ–‡Ǥ
In the senescent myocardium, Heinen et al. demonstrated that administration of helium
in a preconditioning manner did not lower infarct size. 24 Moreover, the above described mild
mitochondrial uncoupling after helium inhalation could only be found in young but not in old
animals.24 In a second study in aged animals infarct size was reduced by activation of mKCa
channels using in young and aged rats.25
47
Helium used in clinical situations: are we yet so far?
Even though helium has been applied successfully in patients with respiratory diseases for
decades, the enormous amount of research on helium induced cardiac protection could not
yet be translated to the clinical situation.
‡‰ƒ”†‹‰…Ž‹‹…ƒŽ•–—†‹‡•ǡ•‘ˆƒ”‘Ž›‘‡•–—†›‹’ƒ–‹‡–•–Šƒ–™‡”‡•—„Œ‡…–‡†–‘ƒ…‘”‘ƒ”›
artery bypass grafting surgery exists.57 These patients inhaled helium (70%) for 3 x 5 minutes
before start of the cardiopulmonary bypass (helium pre-conditioning) or at the point when the
coronary artery reperfusion was started by declamping of the aorta. Surprisingly, both applied
conditioning protocols alone, and even the combination of pre- and postconditioning did not
•Š‘™’”‘–‡…–‹˜‡‡ơ‡…–•‘–Š‡’‘•–Ǧ‘’‡”ƒ–‹˜‡–”‘’‘‹”‡Ž‡ƒ•‡Ǥ57
‡‰ƒ”†‹‰’”‘–‡…–‹‘‘ˆ‘–Š‡”‘”‰ƒ•–Šƒ–Š‡Š‡ƒ”–„›Š‡Ž‹—ǡ‘”‡’”‘‰”‡••™ƒ•ƒ†‡‹
human tissue. Helium protects the human endothelium against ischemia/reperfusion damage
‹ƒˆ‘”‡ƒ”„Ž‘‘†ƪ‘™‘†‡Ž‘ˆŠ‡ƒŽ–Š›˜‘Ž—–‡‡”•Ǥ58 After a 20 minute forearm ischemia/
reperfusion period endothelial function was measured by response to acetylcholine. 58 Venous
‘……Ž—•‹‘’Ž‡–Š›•‘‰”ƒ’Š›‡ƒ•—”‡‡–‘ˆ–Š‡ˆ‘”‡ƒ”„Ž‘‘†ƪ‘™•Š‘™‡†–Šƒ–‹ŠƒŽƒ–‹‘
of 3 x 5 minutes of 79% helium inhalation prevented post-ischemic endothelial dysfunction.58
‘™‡˜‡”ǡ Š‡Ž‹— ’”‡…‘†‹–‹‘‹‰ †‹† ‘– ƒơ‡…– ’Žƒ•ƒ Ž‡˜‡Ž• ‘ˆ …›–‘‹‡•ǡ ƒ†Š‡•‹‘ ‘Ž‡cules, or microparticles.58 In this study, the endothelium was also protected 24 hours after the
Š‡Ž‹—‹ŠƒŽƒ–‹‘ǡ•—‰‰‡•–‹‰ƒŽƒ–‡‡†‘–Š‡Ž‹ƒŽ’”‡…‘†‹–‹‘‹‰‡ơ‡…–‘–Š‡‡†‘–Š‡Ž‹—„›
helium inhalation.58 Interestingly, in this volunteer study an involvement of NOS, which was
previously found by Pagel and co-workers26‹”ƒ„„‹–•ǡ…‘—Ž†‘–„‡…‘Ƥ”‡†ǡ58 once again
•Š‘™‹‰†‹ơ‡”‹‰”‡•—Ž–•‘ˆŠ‡Ž‹—‹†—…‡†‘”‰ƒ’”‘–‡…–‹‘‹ƒ‹ƒŽƒ†Š—ƒ–‹••—‡Ǥ
Another study in human healthy volunteers inhaling 50% helium before, during and after
ischemia used post-ischemic reactive hyperemia to determine endothelial function. In this
study endothelial function was measured before and after 15 min of forearm ischaemia.59
There we no changes in the post-occlusive hyperemic reaction detected, but th e authors
ˆ‘—†ƒ‹…”‡ƒ•‡†Ž‡˜‡Ž‘ˆ–Š‡’”‘Ǧ‹ƪƒƒ–‘”›ƒ”‡”͙͙„ƒ†Ǧ͙‘Ž‡—‘…›–‡•Ǥ
In contrast, the expression of the pro-coagulant markers CD42b and PSGL-1 on platelets was
decreased.59Š‡•‡†ƒ–ƒ•—‰‰‡•–ƒ‹Ž†ƒ–‹Ǧ‹ƪƒƒ–‘”›’”‘’‡”–›‘ˆŠ‡Ž‹—‹Š—ƒ•Ǥ
In a study of Oei et al.male healthy volunteers inhaled 30 minutes if heliox (79% He / 21%O2)
or air respectively. In this study in a whole blood ex vivo ‘†‡Ž –Š‡ ‡ơ‡…– ‘ˆ Š‡Ž‹— ‘ –Š‡
”‡•’‘•‹˜‡‡••‘ˆ–Š‡Š—ƒ‹—‡”‡•’‘•‡™ƒ•–‡•–‡†ǤŽ‘‘†™ƒ•™‹–Š†”ƒ™ƒ–†‹ơ‡”ent time points after helium inhalation and then incubated with lipopolysaccharide (LPS),
lipoteichoic acid, T-cell stimuli anti-CD3/ anti-CD28 or pure media for 0, 2, 4 and 24 hours.
–Š‹••–—†›ǡ–—‘”‡…”‘•‹•ˆƒ…–‘”ǦƒŽ’ŠƒȋǦƒŽ’ŠƒȌǡ‹–‡”Ž‡—‹Ǧ͙„‡–ƒȋǦ͙„‡–ƒȌǡ‹–‡”Ž‡—kin-6 (IL-6), interleukin-8 (IL-8), interferon-gamma and interleukin-2 (IL-2) were analysed by
cytometric bead arrays.60‡Ž‹—‹ŠƒŽƒ–‹‘†‹†‘–ƒơ‡…–Ž‡˜‡Ž•‘ˆǦƒŽ’ŠƒǡǦ͙„‡–ƒǡǦ͞ǡ
Ǧ͠ǡǦ‰ƒƒƒ†Ǧ͚‹…‘’ƒ”‹•‘–‘ƒ‹”‹ŠƒŽƒ–‹‘Ǥ††‹–‹‘ƒŽŽ›ǡƒ‰”‘—’‘ˆ˜‘Ž—–‡‡”•
‹ŠƒŽ‹‰Š‡Ž‹—ˆ‘”–Š‡‡š–‡†‡†’‡”‹‘†‘ˆ͘͞‹†‹†‘–•Š‘™†‹ơ‡”‡…‡•‹…›–‘‹‡’”‘†—…48
Chapter 3 : Mechanisms of helium conditioning
tion after LPS stimulation of whole blood. Thus, in contrast to the study of Lucchinetti and
…‘Ǧ™‘”‡”•ǡ‹–Š‡•–—†›‘ˆ‡‹‡–ƒŽǤŠ‡Ž‹—Šƒ†‘‡ơ‡…–‘–Š‡”‡•’‘•‹˜‡‡••‘ˆ–Š‡‹ƒ–‡
and early adaptive immune system.60
SUMMARY AND CONCLUSION:
Taking together, cardioprotective and anesthetic properties of gases often coexist, as is the
case for the volatile anesthetics and xenon but not for helium making it unique between these
substances.
Š‹• •—‰‰‡•–• –Šƒ– ‰ƒ•‡‘—• ’”‘’‡”–‹‡• ƒ† ’”‘–‡…–‹˜‡ ‡ơ‡…–• ƒ”‡ …‘‡…–‡† ƒ† •Šƒ”‡
parts of a common pharmacologic mechanism. So far, a complete overview of the underlying
molecular mechanisms of preconditioning by gaseous agents still cannot be drawn. However,
molecular targets like the mitochondrial permeability transition pore (mPTP), mitogen acti˜ƒ–‡†’”‘–‡‹‹ƒ•‡•ȋȌǡ’”‘–‡‹‹ƒ•‡ǡƒ†ˆ‘”Š‡Ž‹—ǡ–Š‡’ƒ–Š™ƒ›ȋȀ
PI3K) and Caveolins are reported to be involved.
Summarizing all experimental data published so far, we suggest that the noble gas helium
might become a very promising agent not only in patients with ventilation disorders but also
in those patients undergoing critical acute ischemic events of the heart. However, this review
clearly demonstrates the need to translate the experimental data to the clinical situation, as
studies on cardioprotection by helium in patients are very limited.
49
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
50
ƒ‰‘ǡ‘”Žƒ†ƒ†”—„ƒǤ‹ơ—•‹‘…‘‡ƥ…‹‡–•ƒ†•‘Ž—„‹Ž‹–›…‘‡ƥ…‹‡–•ˆ‘”‰ƒ•‡•‹
„‹‘Ž‘‰‹…ƒŽƪ—‹†•ƒ†–‹••—‡•ǣƒ”‡˜‹‡™ǤUndersea Hyperb MedǤ͙͡͡͞Ǣ͚͛ǣ͚͜͟Ǧ͚͟Ǥ
‘„Ž‹ǡƒ‰ǡ‰‡”ǡ͚†ǡƒ•–‡”ǡ
‘‰ǡ‘‡•…—ǡƒŽ•‡›ƒ†”—†‡ŽŽǤ‹‹—
ƒŽ˜‡‘Žƒ”…‘…‡–”ƒ–‹‘•‘ˆ‘„Ž‡‰ƒ•‡•ǡ‹–”‘‰‡ǡƒ†•—Žˆ—”Š‡šƒƪ—‘”‹†‡‹”ƒ–•ǣŠ‡Ž‹—ƒ†‡‘
as nonimmobilizers (nonanesthetics). Anesth AnalgǤ͙͡͡͠Ǣ͟͠ǣ͙͜͡Ǧ͚͜Ǥ
‡‹
ǡ‡„‡” ǡ ‘ŽŽƒ ƒ† ”‡…‡Ž Ǥ‡ŽŽ—Žƒ” ‡ơ‡…–• ‘ˆ Š‡Ž‹— ‹ †‹ơ‡”‡– ‘”‰ƒ•Ǥ
AnesthesiologyǤ͚͙͘͘Ǣ͙͙͚ǣ͙͛͘͝Ǧ͙͘Ǥ
—””›ǡ‡‹‰•ƒ†‡‹‡”Ǥ”‡…‘†‹–‹‘‹‰™‹–Š‹•…Š‡‹ƒǣƒ†‡Žƒ›‘ˆŽ‡–ŠƒŽ…‡ŽŽ‹Œ—”›
in ischemic myocardium. CirculationǤ͙͡͠͞Ǣ͟͜ǣ͙͙͚͜Ǧ͛͞Ǥ
‡‹‡” ǡ —””› ǡƒƒ•ƒ™ƒ ǡ ‹ŽŽ ƒ† ‡‹‰• Ǥ ‘—” „”‹‡ˆ ’‡”‹‘†• ‘ˆ ›‘…ƒ”†‹ƒŽ
ischemia cause no cumulative ATP loss or necrosis. Am J PhysiolǤ͙͡͠͞Ǣ͚͙͝ǣ͙͛͘͞Ǧ͙͝Ǥ
‡ŽŽ‘ƒ†‘™‡›Ǥ”‡…‘†‹–‹‘‹‰–Š‡›‘…ƒ”†‹—ǣˆ”‘…‡ŽŽ—Žƒ”’Š›•‹‘Ž‘‰›–‘…Ž‹‹…ƒŽ
cardiology. Physiol RevǤ͚͛͘͘Ǣ͛͠ǣ͙͙͙͛Ǧ͙͝Ǥ
‹–‡Ǧ‘Šƒ•‡ǡ‡ŽŽ‘ƒ†’‹‡Ǥ‘•–…‘†‹–‹‘‹‰ǣƒ•‹’Ž‡ǡ…Ž‹‹…ƒŽŽ›ƒ’’Ž‹…ƒ„Ž‡’”‘…‡dure to improve revascularization in acute myocardial infarction. CirculationǤ͚͘͘͝Ǣ͙͙͚ǣ͚͘͠͝Ǧ͠Ǥ
Hausenloy DJ, Mwamure PK, Venugopal V, Harris J, Barnard M, Grundy E, Ashley E, Vichare S, Di
ƒŽ˜‘ǡ‘Ž˜‡ƒ”ǡƒ›™ƒ”†ǡ‡‘‰Šǡƒ…ŽŽ‹•–‡”ƒ†‡ŽŽ‘Ǥơ‡…–‘ˆ”‡‘–‡‹•…Šaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft
surgery: a randomised controlled trial. LancetǤ͚͘͘͟Ǣ͛͘͟ǣ͟͝͝Ǧ͡Ǥ
”œ›Ž‡ƒ†Š‹––ƒ‡”Ǥ
‡‡•‹•‘ˆ”‡‘–‡…‘†‹–‹‘‹‰ǣƒ…–‹‘ƒ–ƒ†‹•–ƒ…‡ǦǦǯŠ›’‘–Š‡•‡•
‘Ƥ‰‘ǯǫJ Cardiovasc MedǤ͚͙͛͘Ǣ͙͜ǣ͙͘͠Ǧ͞Ǥ
—–‡ƒǡ”†‘†‹ǡ‡””‡”ƒƒ†‰‘—Ž˜ƒ–Ǥ‘Žƒ–‹Ž‡ƒƒ‡•–Š‡–‹…•ƒ†…ƒ”†‹‘’”‘–‡…–‹‘ǣ
lessons from animal studies. Fundam Clin PharmacolǤ͚͙͛͘Ǣ͚͟ǣ͚͙Ǧ͛͜Ǥ
Pagel PS. Myocardial protection by volatile anesthetics in patients undergoing cardiac surgery: a
critical review of the laboratory and clinical evidence. J Cardiothorac Vasc AnesthǤ͚͙͛͘Ǣ͚͟ǣ͚͟͡Ǧ͚͠Ǥ
Weber NC and Schlack W. Inhalational anaesthetics and cardioprotection. 1. HandbExpPharmacol.
2008:187-207.
ƒ””‹• ƒ† ƒ”‡• ǤŠ‡ —•‡• ‘ˆ Š‡Ž‹— ƒ† š‡‘ ‹ …—””‡– …Ž‹‹…ƒŽ ’”ƒ…–‹…‡Ǥ Anaesthesia.
͚͘͘͠Ǣ͛͞ǣ͚͜͠Ǧ͛͡Ǥ
Berganza CJ and Zhang JH. The role of helium gas in medicine. Med Gas ResǤ͚͙͛͘Ǣ͛ǣ͙͠Ǥ
Little HJ. How has molecular pharmacology contributed to our understanding of the mechanism(s)
of general anesthesia? Pharmacol TherǤ͙͡͡͞Ǣ͞͡ǣ͛͟Ǧ͝͠Ǥ
”ƒ—‡”ǡ‘‰ƒǡ—‰‘ǡƒ…†‘ƒŽ†
ƒ†‹ŽŽ‡”Ǥƒ––‡”•‘ˆ‹–‡”ƒ…–‹‘‘ˆ‡ơ‡…–•
of light metabolically inert gases with those of hydrostatic pressure as such--a review. Undersea
Biomed ResǤ͙͚͡͠Ǣ͡ǣ͛͛͝Ǧ͡͞Ǥ
ƒ‰‡Žǡ”‘Ž‹‘™•‹
ǡŠ‹ǡ‡ƒ–ƒ’—”ƒǡ‡”•–‡ǡ‡‹Š”ƒ—…Šǡƒ”Ž–‹‡”ƒ†
”ƒ––ǡ”Ǥ‘„Ž‡‰ƒ•‡•™‹–Š‘—–ƒ‡•–Š‡–‹…’”‘’‡”–‹‡•’”‘–‡…–›‘…ƒ”†‹—ƒ‰ƒ‹•–‹ˆƒ”…–‹‘„›
activating prosurvival signaling kinases and inhibiting mitochondrial permeability transition in
vivo. Anesth AnalgǤ͚͘͘͟Ǣ͙͘͝ǣ͚͝͞Ǧ͡Ǥ
ƒ‰‡Žǡ”‘Ž‹‘™•‹
ǡ”ƒ––ǡ”ǤǡŠ‹ǡ‘—”ǡƒ”Ž–‹‡”ƒ†‡‹Š”ƒ—…ŠǤŠ‹„‹–‹‘
of glycogen synthase kinase or the apoptotic protein p53 lowers the threshold of helium cardioprotection in vivo: the role of mitochondrial permeability transition. Anesth AnalgǤ͚͘͘͠Ǣ͙͘͟ǣ͟͞͡Ǧ
75.
Chapter 3 : Mechanisms of helium conditioning
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
Pagel PS, Krolikowski JG, Amour J, Warltier DC and Weihrauch D. Morphine reduces the threshold
of helium preconditioning against myocardial infarction: the role of opioid receptors in rabbits. J
Cardiothorac Vasc AnesthǤ͚͘͘͡Ǣ͚͛ǣ͙͞͡Ǧ͚͜Ǥ
ƒ—•‡Ž‘›ǡ‰ƒ†‡ŽŽ‘ǤŠ‡‹–‘…Š‘†”‹ƒŽ’‡”‡ƒ„‹Ž‹–›–”ƒ•‹–‹‘’‘”‡ƒ•ƒ–ƒ”‰‡–
for preconditioning and postconditioning. Basic Res CardiolǤ͚͘͘͡Ǣ͙͘͜ǣ͙͠͡Ǧ͚͚͘Ǥ
‘Š‡ǡƒ‰ƒ†‘™‡›ǤŠ‡’Š›’‘–Š‡•‹•‘ˆ’‘•–…‘†‹–‹‘‹‰ǣ•–ƒ……ƒ–‘”‡’‡”ˆ—•‹‘
reintroduces oxygen and perpetuates myocardial acidosis. CirculationǤ͚͘͘͟Ǣ͙͙͝ǣ͙͠͡͝Ǧ͛͘͡Ǥ
Pagel PS and Krolikowski JG. Transient metabolic alkalosis during early reperfusion abolishes helium preconditioning against myocardial infarction: restoration of cardioprotection by cyclosporin
A in rabbits. Anesth AnalgǤ͚͘͘͡Ǣ͙͘͠ǣ͙͘͟͞Ǧ͚͠Ǥ
ƒ‰‡Žǡ”‘Ž‹‘™•‹
ǡ”ƒ––ǡ”ǤǡŠ‹ǡ‘—”ǡƒ”Ž–‹‡”ƒ†‡‹Š”ƒ—…ŠǤ‡ƒ…–‹˜‡
oxygen species and mitochondrial adenosine triphosphate-regulated potassium channels mediate
helium-induced preconditioning against myocardial infarction in vivo. J Cardiothorac Vasc Anesth.
͚͘͘͠Ǣ͚͚ǣ͜͝͝Ǧ͡Ǥ
‡‹‡ǡ—Šǡ‡‡Ž‡ǡ——”„‹‡”ǡ…ŠŽƒ…ǡ”‡…‡Žǡ‡„‡”ƒ†‘ŽŽƒǤ
Helium-induced preconditioning in young and old rat heart: impact of mitochondrial Ca(2+) -sensitive potassium channel activation. AnesthesiologyǤ͚͘͘͠Ǣ͙͘͡ǣ͛͘͠Ǧ͞Ǥ
—Šǡ‡„‡”ǡ”‡…‡Žǡ…ŠŽƒ…ǡƒ—‡”ǡ‘ŽŽƒƒ†‡‹‡Ǥ‰‡Ǧ”‡Žƒ–‡†Ž‘••‘ˆ
cardiac preconditioning: impact of protein kinase A. Exp GerontolǤ͚͙͚͘Ǣ͜͟ǣ͙͙͞Ǧ͚͙Ǥ
ƒ‰‡Ž ǡ ”‘Ž‹‘™•‹ ǡ ”ƒ–– ǡ ”Ǥǡ Š‹ǡ ‘—” ǡ ƒ”Ž–‹‡” ƒ† ‡‹Š”ƒ—…Š ǤŠ‡
mechanism of helium-induced preconditioning: a direct role for nitric oxide in rabbits. Anesth
AnalgǤ͚͘͘͠Ǣ͙͘͟ǣ͚͟͞Ǧ͠Ǥ
—Šǡ‡‹‡ǡ‡„‡”ǡ‹‡„‡”ǡ‘ŽŽƒǡ…ŠŽƒ…ƒ†”‡…‡ŽǤ‡Ž‹—Ǧ‹†—…‡†
late preconditioning in the rat heart in vivo. BrJAnaesthǤ͚͘͘͡Ǣ͙͚͘ǣ͙͜͞Ǧ͙͡Ǥ
‡‹
ǡ‡‰‡”ǡƒ
‘Ž‡ǡŽŽ‡•ǡŽ‹…ǡƒ‡”ƒŽǡƒ
—Ž‹ǡ‘ŽŽƒǡ
”‡…‡Ž ƒ†‡„‡” Ǥ ‡†—…–‹‘ ‘ˆ …ƒ”†‹ƒ… …‡ŽŽ †‡ƒ–Š ƒˆ–‡” Š‡Ž‹— ’‘•–…‘†‹–‹‘‹‰ ‹ ”ƒ–•ǣ
transcriptional analysis of cell death and survival pathways. Mol MedǤ͚͙͘͜Ǣ͚͘ǣ͙͝͞Ǧ͚͞Ǥ
‘ŽŽ‘…ǯŠǡ‘’‘˜ƒǦ†‡Ž‹˜‡‹”ƒƒ–‘•ǡ‡–ƒ‹ŽŽ‡ƒ—ǡ‹˜ƒ”‡•ǡ‘‡–‡ǡƒ‰Ž‘‹•†ǯ•–ƒ‹–‘ǡ
ƒŽŽ‘‹•ǡ”‹••‘ǡ‹••‘ǡ‡ƒ‹”‡ǡ”ƒ‰‡ƒ†„”ƒ‹‹Ǥ”‘–‡‹…”›•–ƒŽŽ‘‰”ƒ’Š›—†‡”
xenon and nitrous oxide pressure: comparison with in vivo pharmacology studies and implications
for the mechanism of inhaled anesthetic action. Biophys JǤ͚͘͘͟Ǣ͚͡ǣ͚͙͟Ǧ͚͜Ǥ
”ƒ•ǡ‹…‹•‘ǡ†‡‘—•ƒǡƒŽŽƒ†‹‡„Ǥ‘™†‘‡•š‡‘’”‘†—…‡ƒƒ‡•–Š‡•‹ƒǫ
NatureǤ͙͡͡͠Ǣ͛͡͞ǣ͚͛͜Ǥ
”—••ǡ—•Š‡ŽŽǡ”‹‰Š–ǡ‹‡„ǡƒ–Š‹‡ƒ†”ƒ•Ǥ™‘Ǧ’‘”‡Ǧ†‘ƒ‹ή…Šƒ‡Ž•
are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane. Mol Pharmacol.
͚͘͘͜Ǣ͞͝ǣ͛͜͜Ǧ͚͝Ǥ
Bantel C, Maze M and Trapp S. Neuronal preconditioning by inhalational anesthetics: evidence for
the role of plasmalemmal adenosine triphosphate-sensitive potassium channels. Anesthesiology.
͚͘͘͡Ǣ͙͙͘ǣ͡͠͞Ǧ͡͝Ǥ
ƒƒ—”ƒƒ†ƒ””‹•Ǥơ‡…–•‘ˆ‰ƒ•‡‘—•ƒ‡•–Š‡–‹…•‹–”‘—•‘š‹†‡ƒ†š‡‘‘Ž‹‰ƒ†Ǧ‰ƒ–‡†
‹‘…Šƒ‡Ž•Ǥ‘’ƒ”‹•‘™‹–Š‹•‘ƪ—”ƒ‡ƒ†‡–Šƒ‘ŽǤAnesthesiologyǤ͚͘͘͘Ǣ͛͡ǣ͙͘͡͝Ǧ͙͙͘Ǥ
Suzuki T, Koyama H, Sugimoto M, Uchida I and Mashimo T. The diverse actions of volatile and
gaseous anesthetics on human-cloned 5-hydroxytryptamine3 receptors expressed in Xenopus
oocytes. AnesthesiologyǤ͚͚͘͘Ǣ͡͞ǣ͞͡͡Ǧ͘͟͜Ǥ
51
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52
‹‡ǡƒǡŠ—‰ƒ†
”‘••Ǥ‹’‹†”ƒˆ–•ƒ”‡‡”‹…Š‡†‹ƒ”ƒ…Š‹†‘‹…ƒ…‹†ƒ†’Žƒ•‡nylethanolamine and their composition is independent of caveolin-1 expression: a quantitative
electrospray ionization/mass spectrometric analysis. BiochemistryǤ͚͚͘͘Ǣ͙͜ǣ͚͘͟͝Ǧ͠͠Ǥ
Š—ǡ‹›ƒƒ‰‡ǡ‹•ƒ–‹ƒ†‘†‹•ŠǤ‹‰ƒŽ–”ƒ•†—…–‹‘‘ˆƒ
’”‘–‡‹Ǧ…‘—’Ž‡†”‡…‡’tor in caveolae: colocalization of endothelin and its receptor with caveolin. Proc Natl Acad Sci U S
AǤ͙͜͡͡Ǣ͙͡ǣ͙͙͚͟͠Ǧ͚͛Ǥ
ƒ”–‘
ǡƒ›ǡ‘”œ‹ƒ†–ƒ‰Ǥƒ˜‡‘Ž‹Ǧ͛ƒ••‘…‹ƒ–‡•™‹–Š†‡˜‡Ž‘’‹‰Ǧ–—„—Ž‡•†—”‹‰
—•…Ž‡†‹ơ‡”‡–‹ƒ–‹‘ǤJ Cell BiolǤ͙͟͡͡Ǣ͙͛͞ǣ͙͛͟Ǧ͜͝Ǥ
‘”‹ƒ™ƒǡƒ–‡Žǡ•—–•—‹ǡ‡‹‰•ǡ‹††ǡƒ‰‹™ƒ”ƒǡ•Š‹ƒ™ƒǡ•‡Žƒ†
‘–ŠǤƒ˜‡‘Ž‹Ǧ͛‡š’”‡••‹‘ƒ†…ƒ˜‡‘Žƒ‡ƒ”‡”‡“—‹”‡†ˆ‘”‹•‘ƪ—”ƒ‡Ǧ‹†—…‡†…ƒ”†‹ƒ…’”‘–‡…tion from hypoxia and ischemia/reperfusion injury. J Mol Cell CardiolǤ͚͘͘͠Ǣ͜͜ǣ͙͚͛Ǧ͛͘Ǥ
ƒ–‡Žǡ•—–•—‹ǡ‡ƒ†ǡ‹‡•ƒǡ‡‹‰•ǡ‘”‹ƒ™ƒǡ—ƒ‰ǡ‘”‡‘ǡƒ–‡Ž
ǡ•‡Žƒ†‘–ŠǤ‡…Šƒ‹••‘ˆ…ƒ”†‹ƒ…’”‘–‡…–‹‘ˆ”‘‹•…Š‡‹ƒȀ”‡’‡”ˆ—•‹‘‹Œ—”›ǣƒ
role for caveolae and caveolin-1. FASEB JǤ͚͘͘͟Ǣ͚͙ǣ͙͝͞͝Ǧ͟͜Ǥ
•—–•—‹ǡƒ™ƒ”ƒ‰—…Š‹ǡ‘”‹ƒ™ƒǡ‹‡•ƒǡ‹††ǡŠ‹Ǧ‡‡ǡ‡ƒ†ǡƒ–‡Žǡ
‘–Šƒ†ƒ–‡ŽǤ‘Ž‡‘ˆ…ƒ˜‡‘Ž‹Ǧ͛ƒ†‰Ž—…‘•‡–”ƒ•’‘”–‡”Ǧ͜‹‹•‘ƪ—”ƒ‡Ǧ‹†—…‡††‡Žƒ›‡†
cardiac protection. AnesthesiologyǤ͚͙͘͘Ǣ͙͙͚ǣ͙͙͛͞Ǧ͜͝Ǥ
Sargiacomo M, Scherer PE, Tang Z, Kubler E, Song KS, Sanders MC and Lisanti MP. Oligomeric
structure of caveolin: implications for caveolae membrane organization. Proc Natl Acad Sci U S A.
͙͡͡͝Ǣ͚͡ǣ͘͜͟͡Ǧ͙͙Ǥ
Song KS, Scherer PE, Tang Z, Okamoto T, Li S, Chafel M, Chu C, Kohtz DS and Lisanti MP. Expression of caveolin-3 in skeletal, cardiac, and smooth muscle cells. Caveolin-3 is a component of the
sarcolemma and co-fractionates with dystrophin and dystrophin-associated glycoproteins. J Biol
ChemǤ͙͡͡͞Ǣ͚͙͟ǣ͙͙͘͝͞Ǧ͝Ǥ
ƒ‡‡”•‡Ž˜ƒ ǡ ƒ–‡Ž ƒ† ‘–Š Ǥ ƒ˜‡‘Ž‹• ƒ† Š‡ƒ”– †‹•‡ƒ•‡•Ǥ Adv Exp Med Biol.
͚͙͚͘Ǣ͚͟͡ǣ͙͜͝Ǧ͝͞Ǥ
‹ǡ‹—ǡ‹Ž…Š‡”ƒ††‡”•‘
Ǥ‡ŽŽǦ•’‡…‹Ƥ…–ƒ”‰‡–‹‰‘ˆ…ƒ˜‡‘Ž‹Ǧ͙–‘…ƒ˜‡‘Žƒ‡ǡ•‡…”‡tory vesicles, cytoplasm or mitochondria. J Cell SciǤ͚͙͘͘Ǣ͙͙͜ǣ͙͛͟͡Ǧ͘͜͠Ǥ
Williams TM and Lisanti MP. The caveolin proteins. Genome BiolǤ͚͘͘͜Ǣ͝ǣ͚͙͜Ǥ
‡”‘ƒ†ƒŽŽ‹‰ƒ†Ǥƒ˜‡‘Ž‹•ƒ†–Š‡”‡‰—Žƒ–‹‘‘ˆ‡†‘–Š‡Ž‹ƒŽ‹–”‹…‘š‹†‡•›–Šƒ•‡‹–Š‡
heart. Cardiovasc ResǤ͚͘͘͞Ǣ͞͡ǣ͟͠͠Ǧ͟͡Ǥ
‡ƒ†ǡƒ–‡Žǡ‘–Šǡƒ‹ǡ‹‡•ƒǡƒ”“—Šƒ”
ƒ†•‡ŽǤ
Ǧ’”‘–‡‹Ǧ…‘—’Ž‡†”‡ceptor signaling components localize in both sarcolemmal and intracellular caveolin-3-associated
microdomains in adult cardiac myocytes. J Biol ChemǤ͚͘͘͝Ǣ͚͘͠ǣ͙͛͛͘͞Ǧ͜͜Ǥ
ƒ•Ž‡›ǡƒ”ƒ›ƒǡ‹––‡„‘‰ƒƒ”†ƒ†ƒ”–Ǥ…–‹˜ƒ–‡†…ƒ”†‹ƒ…ƒ†‡‘•‹‡ȋ͙Ȍ”‡…‡’–‘”•
translocate out of caveolae. J Biol ChemǤ͚͘͘͘Ǣ͚͟͝ǣ͙͜͜͟Ǧ͚͙Ǥ
ƒŽŽƒ”†Ǧ”‘ˆ–ǡ ‘…Žƒ”ǡ ”‹•–‘
ƒ† ƒ•Ž‡› Ǥ ‡‰‹‘ƒŽ ›‘…ƒ”†‹ƒŽ ‹•…Š‡‹ƒǦ‹†—…‡† ƒ…tivation of MAPKs is associated with subcellular redistribution of caveolin and cholesterol. Am J
Physiol Heart Circ PhysiolǤ͚͘͘͞Ǣ͚͙͡ǣ͞͝͠Ǧ͟͞Ǥ
Krajewska WM and Maslowska I. Caveolins: structure and function in signal transduction. Cell Mol
Biol LettǤ͚͘͘͜Ǣ͡ǣ͙͡͝Ǧ͚͚͘Ǥ
ƒ˜Ž‹†‡•ǡ•‹”‹‰‘•ǡ‡”ƒǡŽ‘‡„‡”‰ǡ”ƒ
ǡƒ•‹‹”‘ǡƒ‰ǡ‘”–‹ƒǡ††›ƒǡ
‡•–‡ŽŽ
ǡƒ”–‹‡œǦ—–•…Š‘‘”ǡ‘–‰‹ƒƒ†‹•ƒ–‹Ǥ‘••‘ˆ•–”‘ƒŽ…ƒ˜‡‘Ž‹Ǧ͙Ž‡ƒ†•–‘
‘š‹†ƒ–‹˜‡•–”‡••ǡ‹‹…•Š›’‘š‹ƒƒ††”‹˜‡•‹ƪƒƒ–‹‘‹–Š‡–—‘”‹…”‘‡˜‹”‘‡–ǡ…‘ˆ‡””‹‰–Š‡Dz”‡˜‡”•‡ƒ”„—”‰‡ơ‡…–dzǣƒ–”ƒ•…”‹’–‹‘ƒŽ‹ˆ‘”ƒ–‹…•ƒƒŽ›•‹•™‹–Š˜ƒŽ‹†ƒ–‹‘ǤCell Cycle.
͚͙͘͘Ǣ͡ǣ͚͚͙͘Ǧ͙͡Ǥ
Chapter 3 : Mechanisms of helium conditioning
52.
53.
54.
55.
56.
57.
58.
59.
60.
‘•…Š ǡ ƒ”‹ ǡ ‡”• ǡ ‡”ƒ†‡œ ǡ ƒŒƒ”†‘ ǡ ƒ••ƒ ǡ ‹”ƒŽ– ǡ ‘Ž‡ŽŽ ǡ ƒŽ‰‘ƒ ǡ
ƒ”„‡”‘ǡ
‘œƒŽ‡œǦ‘”‡‘ǡƒ–‹ƒ•ǡ‡„ƒ”ǡƒŽ•‹†‡ǡƒ’•ǡ”‹…Šǡ
”‘••ǡ
ƒ”…‹ƒǦ
—‹œǡ‡”‡œǦƒ˜ƒ””‘ǡ‡”ƒ†‡œǦŠ‡…ƒƒ†‘ŽǤƒ˜‡‘Ž‹Ǧ͙†‡Ƥ…‹‡…›…ƒ—•‡•…Š‘Ž‡•–‡”‘ŽǦ
dependent mitochondrial dysfunction and apoptotic susceptibility. Curr BiolǤ͚͙͙͘Ǣ͚͙ǣ͙͞͠Ǧ͞Ǥ
‡„‡”ǡ‹Ž‡›ǡ”˜‹‡ǡ‡ŽŽ‡”ŠƒŽ•ǡ‹‡•ƒǡ‘–Šǡ”‡…‡Žǡ‘ŽŽƒǡ
Patel HH. Helium inhalation induces caveolin secretion to blood. FASEB JǤ͚͙͛͘Ǣ͚͙͟Ǥ
‡”†‹ƒ†›ǡƒ—•‡Ž‘›ǡ‡—•…Š
ǡƒš–‡”
ƒ†…Š—ŽœǤ–‡”ƒ…–‹‘‘ˆ”‹•ˆƒ…–‘”•ǡ…‘‘”bidities, and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning. Pharmacol RevǤ͚͙͘͜Ǣ͞͞ǣ͙͙͚͜Ǧ͟͜Ǥ
‡‹ ǡ —Š ǡ ‡‹‡ ǡ ‘ŽŽƒ ǡ …ŠŽƒ… ǡ ”‡…‡Ž ƒ† ‡„‡” Ǥ ‡Ž‹—Ǧ
induced cardioprotection of healthy and hypertensive rat myocardium in vivo. Eur J Pharmacol.
͚͙͚͘Ǣ͜͞͠ǣ͙͚͝Ǧ͙͛Ǥ
—Šǡ‡‹‡ǡ‡„‡”ǡ‡”‹†‘‰‘ǡ‡‹
ǡ‘ŽŽƒǡ…ŠŽƒ…ƒ†”‡…‡ŽǤ
Helium-induced early preconditioning and postconditioning are abolished in obese Zucker rats in
vivo. J Pharmacol Exp TherǤ͚͘͘͡Ǣ͚͛͡ǣ͘͘͞Ǧ͟Ǥ
‹–ǡ”‡˜‘‘”†ǡ‡‡”–ǡ†‡‘Žǡ‡”‹†‘‰‘ǡ˜ƒ‹‡”‡ǡ…ŠŽƒ…ǡ‘ŽŽƒ
ǡ‡„‡” ƒ† ”‡…‡Ž Ǥ ơ‡…– ‘ˆ Š‡Ž‹— ’”‡Ǧ ‘” ’‘•–…‘†‹–‹‘‹‰ ‘ •‹‰ƒŽ –”ƒ•†—…–‹‘
kinases in patients undergoing coronary artery bypass graft surgery. J Transl MedǤ͚͙͘͞Ǣ͙͜ǣ͚͜͡Ǥ
‹– ǡ ‡‹ ǡ ”‡˜‘‘”† ǡ –”‘‡• ǡ ‹‡—™Žƒ† ǡ …ŠŽƒ…ǡ ‘ŽŽƒ ǡ‡„‡” and Preckel B. Helium induces preconditioning in human endothelium in vivo. Anesthesiology.
͚͙͛͘Ǣ͙͙͠ǣ͡͝Ǧ͙͘͜Ǥ
Lucchinetti E, Wacker J, Maurer C, Keel M, Harter L, Zaugg K and Zaugg M. Helium Breathing
”‘˜‹†‡•‘†‡•––‹‹ƪƒƒ–‘”›ǡ„—–‘†‘–Š‡Ž‹ƒŽ”‘–‡…–‹‘‰ƒ‹•–•…Š‡‹ƒǦ‡’‡”ˆ—•‹‘
Injury in Humans In Vivo. Anesthesia and AnalgesiaǤ͚͘͘͡Ǣ͙͘͡ǣ͙͙͘Ǧ͘͠Ǥ
‡‹ ǡ ‹– ǡ ˜† ‘†‡”˜‘‘”– ǡ ”‡˜‘‘”† ǡ ‘‘‰‡†‹Œ ǡ ‹‡Žƒ† ǡ ‘ŽŽƒ ǡ
”‡…‡Ž ƒ†‡„‡” Ǥ ơ‡…–• ‘ˆ Š‡Ž‹— ƒ† ƒ‹” ‹ŠƒŽƒ–‹‘ ‘ –Š‡ ‹ƒ–‡ ƒ† ‡ƒ”Ž› ƒ†ƒ’–‹˜‡
immune system in healthy volunteers ex vivo. J Transl MedǤ͚͙͚͘Ǣ͙͘ǣ͚͙͘Ǥ
53