Thornton, Simon N. PhD
The thesis developed in this article is that despite the well-known physiological mechanisms of body fluid regulation, many human health problems, such as obesity, diabetes, cancer, Alzheimer’s disease, and of course cardiovascular disease, involve treatments that block the renin-angiotensin-aldosterone system. This would suggest that mild but chronic hypovolemia (or hypohydration that stimulates the production of angiotensin) could be the major common pathway in the initiation, development, and/or maintenance of these serious diseases.
The drinking of water is a fundamental behavior to ensure continued life on earth for all animals including humans. The ingested water participates in the composition of all cells and of the blood, to the regulation of the cardiovascular system, helps distribution of nutrients via the cardiovascular system to all cells of the body, helps to regulate body temperature, provides the basis for all chemical reactions, lubricates joints, and moistens tissues exposed to the atmosphere such as the mouth, nose, and eyes. Water in the body is distributed into 2 major fluid-filled compartments, that inside the cells, or intracellular, for roughly two-thirds and that outside the cells, or extracellular, for the rest. This latter compartment is made up essentially of the interstitial fluid and the blood, or rather the plasma (blood without the red cells). For humans, postpartum life starts as babies composed of roughly 75% water, and there is a tendency for a decrease in this percentage, indicating continued chronic mild dehydration, throughout adolescence, adulthood, and into old age.1
Sodium is the principal cation in the extracellular fluid, whereas potassium holds this position in the intracellular compartment. It is the concentration gradient set up by the content of ions and other molecules in both compartments that encourages water to move between them from a region of low concentration to that of higher concentration, that is, via a process called osmosis, in order to maintain roughly the same concentration throughout the body. The osmolality of the plasma, or the physiological solute concentration of blood, is set between 285 and 295 mOsm/kg water. This is roughly equivalent to a solution of 9 g of sodium in a liter of water. Furthermore, measurement of extracellular sodium concentration can thus give a reasonably accurate picture of what is happening inside the body as far as gradients are concerned.
Along with drinking another important behavior implicated in the regulation of body fluids is urinating. It is something all animals do in order to eliminate excess fluid and substances in the blood not needed by the organism. For most animals, this does not pose a problem as they tend to urinate where they stand. For humans, on the other hand, this can be particularly difficult as they tend to prefer to use toilets for this purpose, and their availability is not always guaranteed. This could have an influence on human drinking behavior as toilet unavailability could incite people to drink less so as to avoid the need to have to urinate.
Drinking, however, is not the only way we can obtain water. It can come from the food we eat, especially if there are lots of fruit and vegetables present, as well as a small amount from the metabolism of all this food. On the other hand, obligatory losses of water occur also through breathing, transpiration through the skin, and a little with the feces. The losses through breathing can be important, for example, with increased physical activity, oral breathing at night (eg, sleep apnea), as well as when breathing at altitude where the partial pressure of water is low, and thus water is lost faster through the lungs.
With such an important need of fluid, it is not surprising to find that input and output are controlled by well-regulated physiological mechanisms. In his Physiological Society Monograph of 1979, James Fitzsimons2 described these mechanisms and divided the physiological regulation of “thirst” into that of intracellular (or osmotic) and extracellular (or volemic) origins.
INTRACELLULAR OR OSMOTIC THIRST
An increase in the concentration of sodium in the extracellular fluid compartment (eg hypohydration or increased salt intake) induces water to leave cells down the concentration gradient. Osmoreceptors, specialized cells in the hypothalamus of the brain, are stimulated by this decrease in their cell water, and their activation initiates the thirst mechanism, that is, drinking of water and the release into the blood of antidiuretic hormone (ADH or vasopressin) from the pituitary gland. The threshold for release of ADH and the stimulation of thirst is a 2% increase in plasma osmolality. Antidiuretic hormone acts on 2 types of specialized 7 transmembrane domain receptors; in the kidney, activation of the V2 receptor stimulates the insertion of aquaporin 2, specialized water channels, in the wall of the collecting duct to reduce the loss of water in the urine (water molecules move into the medulla of the kidney down a concentration gradient, thus producing an antidiuresis). Any water drunk at this time would be absorbed rapidly into the blood supply, which would tend to reduce the concentration gradient and thus work toward reestablishing the normal concentrations and volumes in both compartments. A decrease in osmolality would reduce activation of the osmoreceptors, which would reduce levels of ADH and allow the cells of the body to function normally and the kidney to produce urine again. However, if drinking does not occur rapidly, or not enough is consumed, then plasma osmolality would continue to increase, and more and more ADH would be released, producing less and less urine with an increasing concentration. This usually can be sensed by going to the toilet less often with urine darker in color than normal.3 Furthermore, ADH in the blood can stimulate also the V1 receptor located in the vasculature, which produces mild vasoconstriction (hence the name vasopressin), with the objective of tightening the vascular walls around the remaining blood.
EXTRACELLULAR OR VOLEMIC THIRST
Loss of water, or volume, specifically from the extracellular compartment can occur also (extreme examples are with hemorrhage or vomiting). This decrease in blood volume is sensed by specialized cells in various parts of the cardiovascular system, which signal the brain to release ADH and to stimulate the drinking of water. Specialized volume/pressure-sensitive cells in the kidney release into the blood the enzyme renin in response to hypovolemia. This starts a cascade of reactions to increase levels of another hormone called angiotensin II (AngII); renin acts on angiotensinogen, produced continuously from various organs including the liver, producing the decapeptide angiotensin I. Angiotensin-converting enzyme (ACE) in the lungs converts this to the octapeptide AngII, which has several important actions: it is vasoactive; that is, it produces a decrease in the diameter of the blood vessels; it stimulates the release of ADH and stimulates drinking behavior; and it stimulates the release of yet another hormone aldosterone from the adrenal glands. One of the main actions of aldosterone is to decrease the amount of sodium excreted in the urine, by increasing the number of sodium potassium ATP-dependent pumps, which increase reabsorption of sodium into the blood in the distal part and the top of the collecting duct of the kidney nephron. The concerted actions of the volume receptors and of AngII are to try and ensure that water and sodium are retained so that the blood volume will not decrease to a level that is dangerous to health. When water drinking is initiated, then the volume will be returned to normal values rapidly, and the hormone levels will decrease as well, allowing the cells of the body to function normally and the kidneys to produce urine normally. If, however, drinking does not occur, or not enough is drunk, then, as described above, more and more ADH, AngII, and aldosterone are released, thus reducing more and more the production of urine. Once again, this usually can be sensed as going to the toilet less often with urine darker in color than normal. In animal studies, AngII and aldosterone can act synergistically in the brain to produce an appetite for sodium.4 This would make physiological sense as the hypovolemia signal requires both water and sodium to repair volume losses. Furthermore, AngII is also vasoactive and may play an important role in the development of arterial stiffness leading to hypertension.5
DYSFUNCTION AND CONCLUSION
Under normal circumstances, thirst involves dehydration of both intracellular and extracellular fluid compartments and should cover all hydrational needs of the body by initially reducing water loss in the urine and then stimulating fluid (and sodium) intake to restore blood osmolality and volume to their normal values. Once osmolality and volume are restored, then the blood levels of the hormones implicated in this hydromineral balance, that is, ADH, AngII, and aldosterone, should return to their normal low levels as well. However, it is important to note that drugs that block the formation of AngII (ACE inhibition) and/or inhibit the AngII type 1–specific receptor make up more than 80% of treatments for cardiovascular disease along with hypertension and heart failure. This would suggest that the renin-AngII-aldosterone system is activated in this particular health problem, yet the main physiological signal for activation of this system is hypohydration, or more importantly hypovolemia. This would then suggest that hypovolemia plays an important part of the initiation, development, and/or maintenance of cardiovascular disease. This would suggest also that some humans do not respond appropriately to thirst stimuli and thus do not drink sufficient volumes of water and thus remain chronically but mildly dehydrated.
In a recent study of the French population and their fluid consumption, it was observed that on average total fluids drunk per day were between 1 and 1.3 L/d, which is slightly less than that recommended by the French Programme National Nutrition Santé of 1.5 L of fluid per day. Other studies have shown high urine osmolality, a sign of dehydration, in children in Europe and the United States arriving at school suggesting that for some reason the children are not drinking before going to school.6–8 It could be that the children do not drink during school hours either as they have limited access to the toilet during classes. The reasons for this hypohydration may be many but could include “not knowing the benefits of fluid or not remembering to drink or disliking the taste of water, lack of thirst and lack of availability, and finally the need to void frequently and related workplace disruptions.”9 It could be suggested then in humans that there appears to be a form of cognitive control on responding to the thirst signals and perhaps an ability to override the physiologically motivated signals leading in the long term to an inability to perceive correctly thirst, causing some individuals to stay hypohydrated for long periods during their lifetime. Cognitive assessment of toilet availability could play a role also in decisions about when and where to drink despite the presence of physiological thirst signals.
Although no specific health problems have been shown scientifically to be due to long-term mild dehydration or hypohydration (not drinking sufficient water every day), drugs that block the formation of AngII (ACE inhibition) and/or inhibit the angiotensin type 1–specific receptor are used to treat cardiovascular disease, as mentioned earlier, as well as to treat other modern health problems such as obesity, diabetes, cancer, and even Alzheimer’s disease (see Thornton10–12 for references). The presence of increased blood levels of AngII is thus the common denominator in these modern health problems. This suggests then that there is a strong link between long-term mild extracellular dehydration and these modern health problems as the release of renin into the blood, and thus the generation of AngII, is the physiological response to hypovolemia.13
In conclusion, it may just be possible, by increasing daily water intake in order to reduce blood levels of the hormones released in response to hypovolemia, specifically AngII, to drink ones way to better health.
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