Stress and Hypertension, Oxidative Stress & Nitric Oxide

​I have exposed the link between stress and altered digestive functions leading to a reduced assimilation of nutrients. I have also touch upon inflammation, especially in part 1. But inflammation is such a broad word that many people might only relate to pain, red skin, or to the obvious symptoms; however, inflammation can occur anywhere in the body, and is sometimes called “silent” for it has no obvious symptoms, or creates very little disturbances, only when the accumulation of little adaptations (which can include DNA mutation) generates the occurrence of a disease. 
   Inflammation occurring in the gut, in addition to chronic stress, in a self-feeding circle, can lead to hypertension. Remember, the body needs to flood the muscle and the brain with nutrients and energy, as to run away from danger, and redirecting water into blood vessels. This results in the heart pushing with overexerted force to keep the blood circulating. This condition can lead to actual physical remodelling of the heart, and of arteries.
   “The predominant response during the general adaptation syndrome is a defensive (prophylactic) vasoconstriction and hypertension,” wrote Hams Selye, in the British Medical Journal, as far back as in 1950, adding: "There is much to suggest that at least certain types of stress (e.g. emotional stimuli) can increase the production of antidiuretic hormone.” So that the body can retain water and blood pressure high.   

​   Changes can happen elsewhere. Arteries may not cope with the pressure of the extra blood knocking on their wall, day and night (lack of sleep, another evidence of stress, prevents natural healing and repair, and gives little chance for the heart to slow down), and this can lead to atherosclerosis. The phenomena could not be anymore simple. 
   The extra pressure can lead to damage to the Arterial wall(s), and the body self-mechanism of self-preservation is to call upon all the help it can get: this includes immune cells and Cholesterol. Why Cholesterol? Cholesterol comes to patch the area and prevents further damage to the wall, and it is when it becomes oxidized (from the extra oxygen present in the blood) that it might have negative effects. Further damage can occur from breaking of the plaque (also called Clot or Thrombus) that has formed over the lesion, and the part that has broken off to become an embolism.   

   An embolism can lodge itself anywhere in the body, anywhere where there is a narrowing of arteries, that can be in the lower legs (and other extremities), lungs, heart and brain, a leading cause of stroke and infarction. The reduced flow of blood can also lead to heart tissue death (ischemia), or of parts of the brain. 

​   How did this started? What is (are) the process(es) involved in the development of such life-altering and threatening conditions?
   Nitric Oxide (NO) is the answer. 

  "Nitric oxide (NO) is produced by many cells in the body; however, its production by vascular endothelium is particularly important in the regulation of blood flow. Because of its importance in vascular function, abnormal production of NO, as occurs in different disease states, can adversely affect blood flow and other vascular functions.” writes Richard E. Klabunde, in Cardiovascular Physiology Concepts (2012, 2nd ed.), which explains further how NO is produced (from L-Arginine, an Amino Acid) and the action of an enzyme Nitric Oxide Synthase (NOS, or eNOS). eNOS is Calcium dependant. Shearing forces acting on the vascular endothelium (arterial wall) generated by blood flow causes a release of calcium, stimulating NO production. 
   "The reaction of NO with superoxide (O2•−) to form the much more powerful oxidant peroxynitrite (ONOO−),” explain Pacher Pál and his colleague in the Physiological Reviews (2007), adding: "Neither superoxide nor NO is particularly toxic in vivo because there are efficient means to minimize their accumulation. Superoxide is rapidly removed by high concentrations of scavenging enzymes called superoxide dismutases (SOD). NO is rapidly removed by its rapid diffusion through tissues into red blood cells, where it is rapidly converted to nitrate by reaction with oxyhemoglobin. This limits the biological half-life of NO in vivo to less than a second.”
 
Vascular Effects of NO:
Vascular actions of NO include the following:

• Direct vasodilation (flow dependent and receptor mediated)
• Indirect vasodilation by inhibiting vasoconstrictor influences 
• Anti-thrombotic effect - inhibits platelet adhesion to the vascular endothelium
• Anti-inflammatory effect - inhibits leukocyte adhesion to vascular endothelium; scavenges superoxide
• Anti-proliferative effect - inhibits smooth muscle hyperplasia

Because of the above actions of NO, when its production is impaired or its bioavailability is reduced, the following can result:

• Vasoconstriction (e.g., coronary vasospasm, elevated systemic vascular resistance, hypertension)
• Thrombosis due to platelet aggregation and adhesion to vascular endothelium
• Inflammation due to upregulation of leukocyte and endothelial adhesion molecules
• Vascular hypertrophy and stenosis

 
Free Radicals:
   Reactive Oxygen Species (ROS), also known as Free Radicals, can cause considerable damage to our body, and our body must be able to produce adequate amount of Antioxidants to disable the harmful molecules by giving the missing electron that makes those molecules so dangerous, without become Free Radicals themselves.
   The issue with Free Radicals is that they will steal the missing atom from a body cell in order to be stable (anything in nature wants and needs to be stable), subsequently, the body cell, now with a missing atom, wanting to be stable again, will steal an atom of a neighbouring cell, starting a damaging chain reaction. The final cell loosing away an atom, which can also be attacked by other Free Radicals, may be loosing more than an atom, and as a result can die. 
​
   Superoxide Dismutase (SOD), naturally produced by the body, is the answer to fight Free Radicals, especially in the blood vessel walls. 
   When Superoxide reacts with Nitric Oxide (see illustration above), it forms one of the most damaging Free Radicals: Peroxynitrite. 
   "Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis [cell death]. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders."
   Superoxide reduces NO availability as a vasodilator, keeping the arteries constricted and forcing the blood pressure to remain high. 

   When Superoxide reacts with Nitric Oxide (see illustration above), it forms one of the most damaging Free Radicals: Peroxynitrite. 
   "Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis [cell death]. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders."
   Superoxide reduces NO availability as a vasodilator, keeping the arteries constricted and forcing the blood pressure to remain high. ​

HYPERTENSION AND THE DEVELOPMENT OF ATHEROSCLEROSIS

ATHEROSCLEROSIS IN DETAILS

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References
Indo, HP. et al. (2015). A mitochondrial superoxide theory for oxidative stress diseases and aging. Journal of Clinical Biochemistry and Nutrition. 56(1), pp 1–7 
Pacher, P. Beckman, JS. Liaudet, L. (2007). Nitric Oxide and Peroxynitrite in Health and Disease. Physiological Reviews. 87 (1), pp. 315–424.
Kim, TW. et al. (2015). Comparison of the effects of acute exercise after overnight fasting and breakfast on energy substrate and hormone levels in obese men. Journal of Physical Therapy Science. 27 (6), pp. 1929–1932.
Klabunde, R (2012). Cardiovascular Physiology Concepts. 2nd ed. Baltimore: Lippincott Williams and Wilkins.