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Flashcards in Oxygen Sensing Deck (28)
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What is the effect of location of the level of "normoxia" ?

Oxygen cascade to mitochrondria, due to metabolic processes consuming oxygen. Large drop air -> alveoli due to dead space


Why is oxygen sensing necessary?

Adapting tissues to high low PaO2 - normal homeostasis, birth, disease, altitude

VQ matching

Matching ventilation to metabolic needs


Which cell types display the ability to sense oxygen?

Pulmonary circulation - HPV
Carotid body glomus - control of ventilation
Neuroepithelial cells
Kidney - EPO
Adrenal medulla - fetal adrenal chromaffin cells (release catecholamines ? needed for adaptation to birth)
Vascular system - angiogenesis (VEGF)


Cellular targets following sensing of hypoxia?

Protective proteins, eg haemoxygenase and SOD
Angiogenesis and VEGF
Ion channels (direct and indirect)
Ca2+ handling mechanisms (eg SR release)


What is the response of the carortid body glomus cells to hypoxia?

Type 1 cells inhibit K+ channels, depolarisaing and activating VGCC, release of NTs ATP, Ach, dopamine


What are glomus type II cells?

Sheath of the carotid body


When is hypoxic pulmonary vasoconstriction a problem?

In chronic hypoxia, entire lung becomes vasoconstricted


What is the function of neuroepithelial cells?

Located at bifurcation of the small airways

Sense airway hpoxia and act in concert with HPV and CB especially during transition to air breathing in parturition


Function adrenomedullary chromaffin cells?

In fetus and neonate, hypoxia causes the release of catecholamines.

Probably a protective function to support cardiac function during birth and transformation of airway epithelium for breathing air.


Describe the function of HIF

Leads to transcription EPO and VEGF

Hydroxylation of proline residues by prolyl-hydroxylases labels HIF for degradation by von Hippel Lindau tumour suppressor. Action of HIF also inhibited by FIH.

Hypoxia inhibits PHDs as they use O2 as a co-substrate.


What is the effector mechanism in the pulmonary artery after sensing hypoxia?

Release Ca2+ from ryanodine sensitive stores and Rho kinase mediated Ca2+ sensitisation.

MLCP is inhibited by Rho kinase. MLCP inhibits contraction.


What is the mechanism of smooth muscle contraction?

Ca2+ binds to calmodulin which phosphorylates MLC to allow contraction.


What is the effect on HPV of blocking Rho kinase?

Prevents the sustained vasoconstriction seen in control


Effect of hypoxia on VGCC?

Inhibits K+ channels -> opening VGCCs

But HPV still seen to occur when L-type Ca channels blocked, RyR sensitive channels critical as are Ca sensitisation mechanisms

Other K+ channels may be involved in glomus cells - eg two-pore domain K+ channels (TASK)


4 main hypotheses for hypoxia sensing?

1 - Mitochondria. ATP production/energy state. Redox hypothesis. Increased ROS hypothesis.

2. NADPH oxidases - Increase ROS. Decrease ROS.

3. Haemoxygenase2 - CO and K+ channels

4. Hydrogen sulphide - increases in hypoxia due to decreased oxidation

Each mechanism has a varying sensitivity.


What is the effect of a mitochondrial inhibitor?

Mimics hypoxia in glomus cells


Theories why inhibition of mitochondrial function might be linked to effectors?

1 - Redox and ROS hypotheses
2 - Altered energy state, the AMPK hypothesis


What is hydrogen sulphide?

An endogenously produced gaseous signalling molecule which dilates the systemic, but constrict the pulmonary vasculature. Appears to mimic hypoxia.

Inhibits mitochondrial ETC.

Acts in similar manner to CO and NO

? not sensor for HPV


What is haemoygenase-2?

HO-2 is co-located with BK channels in glomus cells. In normoxia, CO from HO-2 keeps channel open. Lack of O2 removes this so channels close, membrane depolarise and VGCC open -> Ca entry


Evidence against HO-2 mechanism?

HO-2 KO mice do not lose hypoxia sensiong.

BK channels not involved in HPV and controversial in glomus cells.


What does HO-2 produce?

Heme -> Biliverdin, Fe, CO


What switches on AMPK?



Evidence for AMPK hypothesis?

Inhibition of mitochondrial function increases ration AMP:ATP, activating aMPK which then regulated BKCa and TASK-3 through potentially direct phosphorylation -> depolarisation -> Ca release


What is the redox hypothesis of HPV?

Hypoxia inhibits the mitochondria to reduce ROS, increase NADH and GSH. This inhibits Kv channels leading to depolarisation which then activates L-type Ca channels -> constriction


What is the energy state and AMPK hypothesis?

Inhibition of mitochondrial oxidative phosphorylation. Increased ROS and decreased ATP production. Ros activates AMPK. Reduced ATP activated AMPK. AMPK leads to Ca2+ release from SR (RyR receptors) via cADPR. It also inhibits Kv channels -> depolarisation -> Ca release


What is the elevate ROS hypothesis?

Inhibition of mitochondrial oxidate phosphorylation -> increased generation of SO from complex III -> Ca release from SR via AMPK/cADPR, activation NSCCs, Rho Kinase mediated Ca sensitisation, release from RyR sensitive stores


What evidence is there againstREDOC and AMPK hypothesis?

Mitochondrial inhibitors should mimic hypoxia, but they actually block it


Evidence for increased ROS hypothesis?

Antioxidants block HPV/elevation in Ca2+