N3 OS Flashcards

1
Q

which of nitrogen forms in the key regulator of vascular tone?

A

Nitric oxide (NO)

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2
Q

in which of the clinical conditions is diminished NO production observed?

A
  1. hypertension
  2. hyperlipidemia
  3. chronic kidney disease
  4. T2D
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3
Q

what are the three NOS isoforms?

A
  1. eNOS - endothelial NOS
  2. nNOS - neuronal NOS, NO is used as a signalling molecule in the nervous system
  3. iNOS - inducible NOS, in response to infection and inflammation your WBC regulate NO, very damaging free radical as they release ROS during phagocytosis
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4
Q

what does the oxidation of nitric oxide generates?

A

generates nitrate from oxidation of NO from L-arginine NOS pathway

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5
Q

how much nitrate is produced per day from the NOS pathway?

A

1mmol nitrate/day

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6
Q

how much nitrate per day is obtained from typical western diet?

A

1-2mmol/day

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7
Q

what are the primary source of storage of NO?

A

nitrate and nitrite

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8
Q

where is nitrite (NO3-), nitrate (NO2-) and nitric oxide (NO) obtained from?

A
nitrite and nitrate (NO2- and NO3-) - diet 
nitric oxide (NO) - NOS
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9
Q

outline the steps of circulation of dietary nitrate (NO3-)

A
  1. nitrate (NO3-) derived from diet is swallowed
    2a. 25% of nitrate (NO3-) concentrated in the salivary glands
    2b. and the rest is secreted into the mouth where it is reduced to nitrite (NO2-) by facultative anaerobes on the dorsal of tongue
  2. rapid and complete absorption of nitrate (NO3-) in upper gastrointestinal tract
  3. some of the nitrite (NO2-) undergoes acidic reduction to NO in stomach with remaining getting absorbed in blood
  4. 60% of ingested nitrate (NO3-) is lost/secreted in urine within 48h
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10
Q

what are the ways for nitrite (NO2-) reduction to nitric oxide (NO)

A
  1. acid catalysation
  2. xanthine oxidoreductase
  3. deoxyheamoglobin and other haem proteins
  4. nitric oxide synthase
  5. vitamin D
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11
Q

how does vitamin D mediate the NO2- conversion to NO?

A

in sunlight nitrite and other nitrogen species in skin and the UV radiation can liberate NO from the stores

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12
Q

what are the mechanisms of impaired bioavailability?

A
  1. oxdiative stress - increased ROS
  2. substrate/cofactor availability - arginine is nitrogen donor molecule for NO but enough oxygen required as well
  3. retention by altered haemoglobin - glycated hb (Diabetes)
  4. increased expression of intracellular inhibitor of eNOS - Caveolin-1
  5. increased concentration of NOS inhibitors - ADMA
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13
Q

what are the characterstics of organic nitrates (NO donors) when used as treatments and it used for which treatments?

A
its characterstics are:
1. rapid onset 
2. lowers systemic BP
3. inhibits platelet aggregation 
it is used treat: 
1. angina 
2. heart failure 
Also used as 
1. explosives 
2. potent vasodilator
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14
Q

what are the limitations of organic nitrate (NO donors) usage?

A
  1. development of tolerance - due p45 down regulation and ROS generation
  2. endothelial dysfunction
  3. extensive first pass metabolism
  4. high variability for bioavailability when taken orally
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15
Q

what are the advantages of nitrate supplementation?

A
  1. reduces systolic blood pressure and increases plasma nitrite concentration
  2. protection against IR (ischemic reperfusion) injury - by inhibiting superoxide dioxide in mitochondria
  3. improved exercise efficiency - reduces the amount of oxygen required for maximal exercise
  4. protection against metabolic syndrome like diabetes and heart diseases
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16
Q

what are the harmful effects of supplementary nitrate?

A
  1. association with cancer

2. blue baby syndrome

17
Q

how do we know that supplementary nitrate provide protection against metabolic syndrome?

A
  1. MS like diabetes and heart disease – obesity, high lipid, hypertension - took some
  2. eNOS knock out mice – they end up heavier than their WT
  3. they have dysregulated glucose homeostasis
18
Q

what is blue baby syndrome?

A
  • Blue baby syndrome caused by nitrates in drinking water leading to methemoglobinemia (metHb)
  • Nitrates from polluted drinking water form compounds in the body that change haemoglobin to methemoglobin, decreasing the ability of blood to carry oxygen.
  • In infants, the condition can be fatal
19
Q

how does NO effect Ca2+ causing vasodilation?

A
Activate sGC (soluble guanylyl cyclase), generation cGMP, inhibition of Ca2+ influx into cells.  
Ca2+ influx causes smooth muscle contraction in vasculature thereby, inhibiting vasoconstriction