Nitric oxide

  • It is one of the oxides of nitrogen with molecular formula NO indicating that it is a free radical with an unpaired electron.
  • smallest endogenous signal molecule and the only one which is a gas at normal temperature.
  • Furchgott and Zwadzki ( 1980) demonstrated that ACh caused vascular smooth muscle relaxation only when the endothelial lining was intact, but not when it was denuded by rubbing.
  • They proposed that on activation by ACh, the endothelial cells released a soluble ‘endothelium derived relaxing factor’ (EDRF) which diffused to the underlying smooth muscle cell causing relaxation.
  • A little earlier Farid Murad ( 1977) had already shown that GTN caused vasodilatation by releasing N0.
  • lgnarro in 1987 confirmed that EDRF infact was NO. All three, Furchgott, Murad and lgnarro received Nobel Prize in 1998 for these discoveries.

Generation and fate of NO:

  • Nitric oxide is produced in the cells from the amino acid L-arginine by the enzyme nitric oxide synthase (NOS) using molecular oxygen and NADPH, FAD, haeme act as coenzyme to NOS.
  • Three isoforms of NOS, viz.
  • neuronal NOS (nNOS or NOS- I ),
  • inducible NOS (iNOS or NOS-2) and (found in macrophages, monocytes, neutrophils, hepatocytes, etc. is induced by bacterial endotoxins, cytokines and TNFa)
  • endothelial NOS (eNOS or NOS-3).
  • Activation of eNOS and nNOS is Ca2+-calmodulin dependent.
  • Agents and mediators activate eNOS/nNOS by raising cytosolic Ca2+.
  • In contrast, iNOS is active as such, and not Ca2+ dependent.

Actions and roles of NO

Vascular system:

  • Potent vasodilator and serves to regulate vascular tone.
  • Produced in the endothelium
  • freely diffuses to the nearby smooth muscle cell and
  • activates a soluble guanylyl cyclase (sGC) raising cytosolic cGMP concentration
  • This in turn activates a cGMP-dependent protein kinase (PKG) which dephosphorylates the myosin light chain kinase (MLCK) à reduced availability of phosphorylated (active) MLCK
  • actin-myosin interaction is interfered
  • resulting in muscle relaxation.
  • Bronchial, gastrointestinal and other visceral smooth muscles are also relaxed by NO, but the effect is less marked than in blood vessels

Platelets:

  • Just as in smooth muscle, NO activates the cGMP pathway in platelets to inhibit aggregation and thrombus formation.
  • Defective endothelial and platelet NOS-NO function increases the risk of thrombosis.
  • NO also has antiatherogenic property.
  • Adhesion of leucocytes to the endothelium and cellular proIiferation/migration are suppressed by NO, conferring it a protective effect on plaque formation.

Infection, inflammation and immune function:

  • Normally the iNOS activity in macrophages, etc. is very low.
  • Bacterial endotoxins, TNFa, interferon and interleukins induce iNOS in macrophages and other inflammatory cells à generate large quantities of NO.
  • Activated macrophages also produce superoxides that combine with NO à decomposes to release free radicals à broad antimicrobiaI action on bacteria, viruses, fungi and protozoa.
  • Thus, N0 helps in combating infection.
  • N0 has many proinflammatory actions, viz. vasodilatation, increased vascular permeability and enhanced PG production.
  • excess and prolonged NO production à detrimental consequences à tissue injury.
  • Excessive production of NO has been implicated in causing severe hypotension attending septic shock

Nervous system:

  • NO serves as neurotransmitter/ neuromodulator in central as well as in peripheral nervous system.
  • Activation of NMDA glutamate receptors causes long-lasting Ca2+ influx triggering NO release
  • Function à nociception, increased cerebral blood flow, learning and memory.
  • NO is believed to mediate ‘synaptic plasticity ‘ a process by which junctional transmission is strengthened in a use dependent manner.
  • Excessive production of NO has been implicated in promoting ‘excitotoxicity’ due to over- stimulation of glutamate neurones.
  • Aberrant NO generation à causative role in degenerative neurological diseases like Huntington ‘s disease, Parkinson’s disease, amyotrophic lateral sclerosis, etc.
  • pelvic nerve stimulation causes penile erection by releasing NO from neurones in the corpora cavernosa.
  • NO relaxes cavernosal smooth muscle, filling the sinusoids with blood and causing penile tumescence
  • Accordingly, sildenafil and other PDE-5 inhibitors are effective in the treatment of erectile dysfunction, because they inhibit degradation of cGMP which mediates NO action.
  • Defective NO signaling is believed to be involved in pyloric stenosis and gastric dilatation.

Lungs:

  • NO appears to play a prominent role in the regulation of pulmonary vascular resistance and the development of pulmonary arterial hypertension (PAH)
  • Sildenafil à indirectly potentiates the vasodilator action of NO by preventing inactivation of cGMP

Nitric oxide donors

These are compounds which contain a NO or similar moiety in their structure, that is released in the body, mostly enzymatically, to elicit smooth muscle relaxation.

  • Organic nitrates, nitrites and sodium nitroprusside are the clinically useful NO donors. They are also called     ‘nitro-dilators’.

Glyceryl trinitrate (GTN):

  • rapidly acting à antianginal drug à mainly dilates veins and coronary arteries.
  • Mitochondrial aldehyde dehydrogenase is the most important enzyme which releases NO from GTN.
  • This enzyme is abundantly expressed in veins, offering an explanation for the preferential venodilator action of GTN.

Isosorbide dinitrate and lsosorbide mononitrate

  • slower acting, but the pattern of action is similar to GTN .
  • When administered continuouslyà developing tolerance (within few hours), which also weans off rapidly.

à reactive oxygen species generated during metabolism of organic nitrates inhibit mitochondrial aldehyde  dehydrogenase and other enzymes which produce the NO species, limiting further action.

Sodium nitroprusside:

  • Administered by i.v. infusion, nitroprusside equally dilates arterioles and veins by releasing NO as well as by directly activating guanylyl cyclase.
  • Rapidly lowers BP and the action is titratable.

Nitic oxide as a therapeutic agent:

  • Apart from being an important signal molecule. exogenously administered N0 gas has limited therapeutic application as well.
  • Inhaled NO à indicated in severe respiratory distress in neonates with elevated pulmonary arterial pressure.
  • It dilates pulmonary vessels, particularly in areas of the lung that are better ventilated, reducing the ventilation-perfusion mismatch and improving gaseous exchange.
  • The elevated pulmonary artery pressure is lowered and cardiopulmonary function is improved.
  • Inhaled NO improves cardiopulmonary function in adult patients as well with severe PAH, but this can only be a short-term measure.

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