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Case study- Significance of Nitric oxide
An obese, middle-aged man was brought to the emergency room after an automobile accident. The patient stated that he had been short of breath and dizzy just before the accident. There was chest discomfort also.
The patient was admitted for observation and blood samples for enzyme assays were collected periodically. A chest X- ray was taken. And a12-lead ECG was recorded.
On general examination, his blood pressure was 150/90 mm Hg, pulse was 60/min. and he was sweating profusely. There was no evidence of cardiac failure. His initial ECG showed changes in certain leads, indicative of myocardial ischemia. Enzyme profile was normal. The patient was diagnosed to be having Angina. He was immediately shifted to the cardiac care unit. Treatment with nitroglycerine was started to dilate his coronaries.
What is the rationale behind this treatment with nitroglycerine?
Nitroglycerin, amyl nitrite, (isobutyl nitrite or similar) and other nitrite derivatives are used in the treatment of heart disease: The compounds are converted to nitric oxide, which in turn dilates the coronary artery, thereby increasing its blood supply. These drugs, however, are predominantly vasodilators; dilating peripheral veins and hence reducing venous return and preload to the heart. This reduces the oxygen requirement of the myocardium and subsequently lessens the anginal pain felt with myocardial ischemia.
Nitric oxide- Nitric oxide is a highly reactive gas. It participates in many chemical reactions. Endothelium-derived relaxing factor was originally the name given to several proposed factors causing vasodilatation. The major endothelial derived relaxing factor was later discovered to be nitric oxide (NO).
Nitric oxide synthesis
Nitric oxide is synthesized by nitric oxide synthase (NOS). There are three isoforms of the NOS enzyme:
1) Endothelial (eNOS),
2) Neuronal (nNOS), and
3) Inducible (iNOS) – each with separate functions.
The neuronal enzyme (NOS-1) and the endothelial isoform (NOS-3) are calcium-dependent and produce low levels of gas as a cell signaling molecule. The inducible isoform (NOS-2) is calcium independent and produces large amounts of gas which can be cytotoxic.
NOS oxidizes the guanidine group of L-arginine in a process that consumes five electrons and results in the formation of NO with stoichiometric formation of L-Citrulline. The process involves the oxidation of NADPH and the reduction of molecular oxygen (figure-1).The transformation occurs at a catalytic site adjacent to a specific binding site of L-arginine.
Figure-1- showing the formation of Nitric oxide from Arginine, the enzyme is Nitric oxide synthase
Functions of NO
NO is an important regulator and mediator of numerous processes in the nervous, immune and cardiovascular systems, including smooth muscle relaxation. The various functions are as follows-
1) Vasodilatation- Nitric Oxide (NO) is of critical importance as a mediator of vasodilatation in blood vessels. It is induced by several factors, and once synthesized by eNOS it results in activation of guanylate cyclase to form cGMP, which in turn causes phosphorylation of several proteins through activation of c GMP dependent protein kinases that cause smooth muscle relaxation by decreasing the intracellular Ca++ concentration (Figure-2).The vasodilator action of nitric oxide plays a key role in renal control of extra cellular fluid homeostasis and is essential for the regulation of blood flow and blood pressure.
NO also inhibits the aggregation of platelets and thus keeps inappropriate clotting from interfering with blood flow.
Nitric oxide also acts on cardiac muscle to decrease contractility and heart rate. NO contributes to the regulation of cardiac contractility. Emerging evidence suggests that coronary artery disease (CAD) is related to defects in generation or action of NO. Adequate availability of NO prevents the coronary artery disease.
Figure-2- showing the mechanism of vasodilatation by NO
The vasodilatatory effect of NO, in turn, also plays a role in development and maintenance of erection. Vasodilatation of blood vessels supplying the corpus cavernosum results in more blood flowing in and hence erection. This is the biological basis of sildenafil (Viagra), which works to inhibit the enzyme phosphodiesterase PDE5 that lowers the cGMP concentration by converting it back to GMP.
3) Other Actions on Smooth Muscles –
The peristaltic movements are aided by the relaxing effect of NO on the smooth muscle in its walls.
NO also inhibits the contractility of the smooth muscle wall of the uterus. Near term the production of NO decreases.
Release of NO around the glomeruli of the kidneys increases blood flow through them thus increasing the rate of filtration and urine formation.
4) Immune system- Macrophages, certain cells of the immune system, produce nitric oxide in order to kill invading bacteria. In this case, the nitric oxide Synthase is inducible NOS.
Under certain conditions, there is excess production of nitric oxide by macrophages (e.g. during fulminant infections), leading to vasodilatation, probably one of the main causes of hypotension in sepsis. The inducible isoform of nitric oxide synthase is expressed and produces cytotoxic levels of nitric oxide.
5) Neurotransmitter- Nitric oxide also serves as a neurotransmitter between nerve cells. Unlike most other neurotransmitters that only transmit information from a presynaptic to a postsynaptic neuron, the small nitric oxide molecule can diffuse all over and can thereby act on several nearby neurons, even on those not connected by a synapse. It is conjectured that this process may be involved in memory through the maintenance of long-term potentiation. Nitric oxide is an important non-adrenergic, non-cholinergic (NANC) neurotransmitter in various parts of the gastrointestinal tract. It causes relaxation of the gastrointestinal smooth muscle. In the stomach it increases the capacity of the fundus to store food/fluids.
6) Deficiency of Nitric oxide- People with diabetes usually have lower levels of Nitric Oxide than patients without diabetes. Diminished supply of Nitric Oxide can lead to vascular damage, such as endothelial dysfunction and vascular inflammation. Vascular damage can lead to decreased blood flow to the extremities, causing the diabetic patient to be more likely to develop Neuropathy, non-healing ulcers, and be at a greater risk for lower limb amputation.
Thus nitric oxide, is cardio protective, maintains kidney functions, acts as a potent neurotransmitter and has an important role in immune system.
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