Monday, 17 April 2017 BODY FLUID HOMEOSTASIS

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1 Monday, 17 April 2017 BODY FLUID HOMEOSTASIS Phenomenon: shipwrecked sailor on raft in ocean ("water, water everywhere but not a drop to drink") Why are the sailors thirsty? (What stimulated thirst?) Why don't they drink the sea water? Body Fluids -body water = ~2/3 of lean body weight -fluid is compartmentalized (2/3 in cells, 1/3 extracellular) -1/4 extracellular fluid is in blood, 3/4 is extravascular -fluid has osmolytes dissolved in it, mostly ions: Na+, Cl- (in ECF), and K+ (in ICF) -three dimensions to body fluids -- osmolality, blood volume, and blood pressure -- with separate homeostatic control system for each -note: isotonic fluid is a relatively dilute solution equal to the osmolality of mammalian body fluids (~300 mosm/l = 0.15 M NaCl = 0.9% NaCl = 9 g/1000 ml); thus, hypertonic >300 mosm/l, hypotonic <300 mosm/l Osmoregulation -plasma osmolality (posm) refers to the concentration of plasma (osmolytes/volume), which can be raised either by adding osmolytes to body fluids or by subtracting volume -two responses to dehydration: secretion of vasopressin (VP; which conserves urinary water) and thirst (which leads to increased water intake that repairs the water deficit) Vasopressin Secretion -VP is synthesized in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus, and is secreted from the posterior pituitary in response to 1-2% increase in systemic posm -VP acts on VP receptors in the kidneys to promote reabsorption of water from urine, thereby making the urine more concentrated and conserving body water -note: due to dilution of hormones in blood once they are secreted, they must be synthesized and released in relatively large quantities to be effective on their target tissues and this is reflected in the relatively large size of the hypothalamic VP (and OT) neurons -kidneys are very sensitive to VP (maximal antidiuresis at blood levels of 6-8 pg/ml, which is little more than basal blood levels of 2-3 pg/ml) -note: much higher blood levels of VP (>50 pg/ml) are required to act on the VP-1 receptors on blood vessels to cause vasoconstriction than are required to act on the VP-2 receptors in the kidneys to cause antidiuresis -conversely, consumption of water in excess amounts producing a 2% decrease in systemic posm inhibits VP secretion, which permits rapid excretion of the excess water in dilute urine (which raises posm back to normal levels) -diabetes insipidus (DI) occurs either when VP is absent (hypothalamic damage or disease) or when renal VP receptors are absent or ineffective (kidney disease) -note: hypothalamic DI can be treated with VP replacement whereas renal DI cannot -human DI patients excrete liters/day of dilute urine, and comparable amounts of fluid must be consumed to maintain water balance -note: alcohol inhibits VP secretion, causing uncontrolled water loss in dilute urine (i.e., transient DI-like condition)

2 -osmoreceptor cells, located in anterior hypothalamus (OVLT: vascular organ of the lamina terminalis), stimulate VP secretion (and thirst) when the cells lose water by osmosis -OVLT lacks a blood-brain barrier (BBB), which enables osmoreceptor cells to detect 1-2% changes in systemic posm -osmoreceptors are not special detectors but have special neural connections to PVN and SON in hypothalamus -when destroy OVLT, animals cannot detect increases in systemic posm and cannot initiate VP secretion (or thirst) in response to such changes -VP also is secreted in response to decrease in blood volume (hypovolemia), decrease in arterial blood pressure (hypotension), and increase in blood angiotensin II (AngII) -hypovolemia is detected by cardiac baroreceptors, hypotension by arterial baroreceptors, and AngII by AngII receptors in subfornical organ (SFO, which also lacks a BBB) -note that VP is secreted in response to hypovolemia/hypotension because it is a vasconstrictor in addition to being an antidiuretic hormone -note: increased systemic posm also increases secretion of oxytocin (OT) from the posterior lobe of the pituitary gland in rats -OT stimulates the secretion of atrial natriuretic peptide (ANP) from the heart, which acts in the kidneys to increase the excretion of Na+ in urine and thereby lower posm -however, OT is not be secreted in response to elevated systemic posm in humans; instead, VP is secreted which acts directly in the kidneys to increase Na+ loss in urine while also decreasing urinary water loss -note: maximum urine osmolality from salts in humans is ~600 mosm/l; since sea water is more concentrated (~1000 mosm/l), shipwrecked sailors would aggravate dehydration if they drank that hypertonic fluid (aside from the additional problems caused by consuming a fluid with a high magnesium concentration) THIRST -defined as strong motivation to seek, obtain, and consume water -not caused by dry mouth (i.e., decreased salivary flow) -in fact, multiple stimuli control thirst (3 excitatory, 4 inhibitory) Phenomenon-1: Animals (including human subjects) become thirsty when they eat salty food. Excitatory Stimulus #1: osmotic dehydration (central osmoreceptors) -DATA: (a) 1-2% increase in posm is threshold for thirst, as it is for VP secretion -(b) destruction of OVLT eliminates thirst and VP secretion in response to elevated posm -thus, osmoregulatory thirst (and VP secretion) is signaled by OVLT osmoreceptors, which detect the increase in posm in the circulatory system ("systemic posm") that arises in response to water deprivation or a salt load -(c) destruction of the median preoptic nucleus (MnPO; also on the lamina terminalis) also eliminates thirst (but not VP secretion) in response to elevated posm -thus, signals from OVLT stimulate the MnPO, which somehow mediates thirst -note: the signal is due to osmotic loss of water from the cells, not the increase in posm itself, because infusion of urea or glucose (to which brain cell membranes are permeable)

3 raises posm but does not cause osmosis or stimulate thirst or VP secretion -note: VP is not a stimulus of thirst -note: rats fed high-salt diet drink water (and secrete VP) before systemic posm increases -thus, a presystemic signal mediated by visceral osmoreceptors is thought to provide excitatory stimulation of thirst Phenomenon-2: dehydrated dogs (humans, etc.) drink water only for a few minutes, and stop (as does VP secretion) before changes in systemic posm are observed -thus, some early preabsorptive signal provides a rapid inhibition of thirst and VP secretion -note: a simple single-loop negative feedback system cannot account for the control of osmoregulatory water intake Inhibitory Stimulus #1: swallowing (oropharyngeal receptors) DATA: (a) while dehydrated dogs (and humans) drank water, thirst and VP secretion were reduced within a few minutes despite absence of an early decrease in systemic posm -note: this inhibition of thirst and VP secretion lasted for minutes, by which time the water was absorbed and systemic posm had decreased to normal levels -(b) this rapid reduction in thirst and VP secretion occurred even when dehydrated dogs had an open gastric fistula that drained the stomach, so ingested water never reached the small intestine -(c) water intubated directly into the stomach (bypassing the throat and the act of swallowing) had no effect on VP secretion or thirst until it reached the circulation and diluted posm -(d) dehydrated dogs (and humans) reduced thirst and VP secretion rapidly even when they drank isotonic NaCl solution -thus, in dogs (and humans), an early oropharyngeal signal associated with the rapid swallowing characteristic of drinking inhibits thirst and VP secretion despite the continued presence of elevated posm (which normally is an excitatory signal of thirst) -note: gastric distension also inhibits water intake (but not VP secretion) in dogs and humans Regulation of Blood Volume and Pressure Phenomenon-3: hemorrhage stimulates VP secretion and thirst despite absence of change in posm -complementary physiological and behavioral responses contribute to volume regulation Excitatory Stimulus #2: plasma volume deficit (cardiac baroreceptors) -i.e., thirst associated with reduction in plasma volume in absence of change in posm DATA: (a) water intake is proportional to hypovolemia (5-7% decrease in plasma volume is threshold for thirst, as it is for VP secretion) -(b) hypovolemia and increased posm have additive effects on water intake and VP secretion -note: neural signal from cardiac baroreceptors to NTS and then to MnPO stimulates thirst, and from NTS to SON and PVN provides stimulation of VP secretion Inhibitory Stimulus #2: osmotic dilution (central osmoreceptors) -DATA: 2-4% decrease in posm (presumably detected by OVLT osmoreceptors) inhibits thirst stimulated by hypovolemia

4 -note: although increased blood volume is known to inhibit VP secretion stimulated by increased posm, there is no evidence that an increase in blood volume inhibits water intake in dehydrated dogs or humans Excitatory Stimulus #3: angiotensin II (AngII receptors in SFO) -AngII is a peptide hormone, formed in blood after renin is secreted from the kidneys during hypovolemia or arterial hypotension, which acts in brain at the subfornical organ (SFO) to stimulate thirst -the SFO is located on the dorsal end of the lamina terminalis, at the dorsal crown of the third cerebral ventricle; it lacks a blood-brain barrier and has numerous AngII receptors which enables it to detect AngII in the blood -DATA: (a) iv AngII causes dose-related increase in water intake -(b) SFO lesions eliminate the stimulatory effects of iv AngII on thirst -(c) injection into the SFO of tiny amounts of AngII (one trillionth of 1 g) elicits water intake -(d) injection of AngII receptor blocker into SFO eliminates drinking elicited by iv AngII -note: during hypovolemia, thirst occurs in nephrectomized rats and in rats with SFO lesions (presumably it is mediated by neural signals from cardiac baroreceptors), although the threshold of the drinking responses is higher as if AngII sensitized the animal to the neural input -hypovolemic thirst also occurs in rats with NTS lesions (presumably it is mediated by AngII when baroreceptor input is absent) -in other words, either cardiac baroreceptors or AngII receptors in the SFO are necessary for the stimulation of thirst during hypovolemia, but both do not have to be present (i.e., redundant systems) -arterial hypotension activates the renin-angiotensin system and stimulates thirst in rats -Hypothesis: circulating AngII stimulates thirst during arterial hypotension -DATA: water intake elicited during arterial hypotension is blocked by treatments that eliminate the renin-angiotensin system (e.g., bilateral nephrectomy, pharmacological inhibition of AngII synthesis, pharmacological blockade of AngII receptors in the SFO) -note: these findings indicate that a neural signal from arterial baroreceptors does not stimulate thirst during arterial hypotension -blood levels of AngII during arterial hypotension are much lower than those associated with thirst elicited by iv infusion of AngII -Hypothesis 1: thirst is inhibited by a signal that is elicited by iv AngII that is not present during arterial hypotension; specifically, an increase in arterial blood pressure (ABP) Inhibitory Stimulus #3: acute arterial hypertension -DATA: (a) iv AngII elicits more water intake when ABP is clamped at normal levels than when ABP is allowed to rise -(b) iv AngII elicits more water intake in rats with denervated arterial baroreceptors than in control rats -thus, the inhibitory effect of arterial hypertension is abolished when the signal is eliminated -in other words, iv AngII provides a mixed stimulus of thirst, an excitatory component that stimulates drinking and an inhibitory component that suppresses drinking -(c) increased ABP also inhibits water intake in rats made thirsty by increased posm or by hypovolemia, but it does not inhibit VP secretion under those circumstances

5 Summary: thirst and VP secretion -three dimensions to body fluid regulation: osmolality, blood volume, blood pressure -each dimension is monitored via its own receptor -each receptor provides an excitatory signal for VP secretion during dehydration -each receptor provides an inhibitory signal for VP secretion during overhydration -osmoreceptor, cardiac baroreceptor also provide signal for thirst whereas AngII mediates thirst from arterial hypotension (no BBB for osmo-, AngII-receptor) -excitatory signals are additive, inhibition can trump excitation