which of nitrogen forms in the key regulator of vascular tone?
Nitric oxide (NO)
in which of the clinical conditions is diminished NO production observed?
- hypertension
- hyperlipidemia
- chronic kidney disease
- T2D
what are the three NOS isoforms?
- eNOS - endothelial NOS
- nNOS - neuronal NOS, NO is used as a signalling molecule in the nervous system
- iNOS - inducible NOS, in response to infection and inflammation your WBC regulate NO, very damaging free radical as they release ROS during phagocytosis
what does the oxidation of nitric oxide generates?
generates nitrate from oxidation of NO from L-arginine NOS pathway
how much nitrate is produced per day from the NOS pathway?
1mmol nitrate/day
how much nitrate per day is obtained from typical western diet?
1-2mmol/day
what are the primary source of storage of NO?
nitrate and nitrite
where is nitrite (NO3-), nitrate (NO2-) and nitric oxide (NO) obtained from?
nitrite and nitrate (NO2- and NO3-) - diet nitric oxide (NO) - NOS
outline the steps of circulation of dietary nitrate (NO3-)
- 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 - rapid and complete absorption of nitrate (NO3-) in upper gastrointestinal tract
- some of the nitrite (NO2-) undergoes acidic reduction to NO in stomach with remaining getting absorbed in blood
- 60% of ingested nitrate (NO3-) is lost/secreted in urine within 48h
what are the ways for nitrite (NO2-) reduction to nitric oxide (NO)
- acid catalysation
- xanthine oxidoreductase
- deoxyheamoglobin and other haem proteins
- nitric oxide synthase
- vitamin D
how does vitamin D mediate the NO2- conversion to NO?
in sunlight nitrite and other nitrogen species in skin and the UV radiation can liberate NO from the stores
what are the mechanisms of impaired bioavailability?
- oxdiative stress - increased ROS
- substrate/cofactor availability - arginine is nitrogen donor molecule for NO but enough oxygen required as well
- retention by altered haemoglobin - glycated hb (Diabetes)
- increased expression of intracellular inhibitor of eNOS - Caveolin-1
- increased concentration of NOS inhibitors - ADMA
what are the characterstics of organic nitrates (NO donors) when used as treatments and it used for which treatments?
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
what are the limitations of organic nitrate (NO donors) usage?
- development of tolerance - due p45 down regulation and ROS generation
- endothelial dysfunction
- extensive first pass metabolism
- high variability for bioavailability when taken orally
what are the advantages of nitrate supplementation?
- reduces systolic blood pressure and increases plasma nitrite concentration
- protection against IR (ischemic reperfusion) injury - by inhibiting superoxide dioxide in mitochondria
- improved exercise efficiency - reduces the amount of oxygen required for maximal exercise
- protection against metabolic syndrome like diabetes and heart diseases
what are the harmful effects of supplementary nitrate?
- association with cancer
2. blue baby syndrome
how do we know that supplementary nitrate provide protection against metabolic syndrome?
- MS like diabetes and heart disease – obesity, high lipid, hypertension - took some
- eNOS knock out mice – they end up heavier than their WT
- they have dysregulated glucose homeostasis
what is blue baby syndrome?
- 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
how does NO effect Ca2+ causing vasodilation?
Activate sGC (soluble guanylyl cyclase), generation cGMP, inhibition of Ca2+ influx into cells. Ca2+ influx causes smooth muscle contraction in vasculature thereby, inhibiting vasoconstriction
