Chapter 19

Nitric oxide donors & inhibitors

• NO is a potent vasodilator produced from arginine in the body.

• Certain drugs also release NO as their active metabolite.
• It is also available as a drug itself. (NO gas)
• It interacts with Fe in hemoglobin & it can be inhibited by hemoglobin.

Endogenous NO

• NO is synthesized by a family of enzymes called Nitic oxide synthase (NOS).

• These enzymes are activated by influx of Ca or by cytokines.
Arginine →Citrulline + NO
• There are 3 isoforms of NOS identified ;
- Isoform 1 found in epithelial & neural cells
- Isoform 2 found in macrophages & smooth muscle cells
- Isoform 3 found in endothelial cells
• NO is formed only when needed. Then it diffuses the region of action.
• Some drugs that stimulate release of NO are ;
*Muscarinic agents
*Histamine
*Other vasodilators like bradykinin
Exogenous NO donors

• NO is released from several drugs like ; nitroprusside, nitrates & nitrites.

• Release from nitroprusside occurs in blood by the presence of O2.
• Relase from nitrates & nitrites require mitochondrial enzyme Aldehyde dehydrogenase 2.

Effects of NO

1. On smooth muscles
- Vasodilator in vascular beds & smooth muscle relaxant.
- Mechanisms → activation of guanylyl cyclase & synthesis of cGMP.
cGMP facilitates dephosphorylation of myosin light chains.
- NO is a contributor in hypotension in septic shock.
2. Cell adhesion
- NO reduces platelet aggregation & neutrophil adhesion to vascular endothelium.
- This maybe due to reduced expression of adhesion molecules (integrins).
3. Inflammation
- Tissue injury facilitates release of NO that involves in inflammation.
- This happens via prostaglandin synthesis by cyclooxygenase 2.
4. Other effects
- NO may act as a neurotransmitter.
- NO involves in apoptosis & host reactions to parasites.
- Excessive NO causes ; hemoglobin → methemoglobin
Thus can cause hypoxia.

Clinical application of donors & inhibitors

• Inhibitors are not in clinical use till now.
• Donors like nitroprusside, nitrates & nitrites are clinically applied.
• NO gas was prepared to use in neonates with hypoxia & adults with pulmonary hypertension.