Dopamine

Regulation of Sodium Excretion

June 25, 2016 Cardiology, Critical Care, Nephrology, Physiology and Pathophysiology No comments , , , , , , , , , , , , , , , , , , , , , , , , ,

Percentage of Sodium Reabsorbed

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The Goals of Regulation

The overriding goals of regulating sodium and water excretion are to support the requirements of the cardiovascular system. This is manifested in 3 ways: 1.the kidneys maintain a sufficient ECF volume to fill the vascular space (mean circulatory filling pressure); 2.keep the osmolality of the ECF at a level consistent with cellular health; and 3.limit the changes in renal blood flow (RBF) and GFR that might otherwise reach deleterious levels. The kidneys and the CV system work cooperatively to ensure that peripheral tissue is sufficiently perfused. An adequate circulating volume is one of the essential requirements for tissue perfusion and it is the kidneys that control this volume. Osmolality is the ratio of solute content to water content. Sodium and chloride together account for 80% of the normal extracellular solute; thus the excretion of sodium and water by the kidneys regulates osmolality in the tight range that is needed for the health of tissue cells. There is a separate goal of regulation that differs from those stated above. Variations in RBF and GFR are major means of regulating sodium excretion. However, the kidney cannot change blood flow and filtration to such extreme values that they compromise the metabolic health of the kidneys or interfere with the excretion of substances other than sodium, particularly organic waste.

Formulas for ECF Volume

There are some formulas showing the relationship between ECF solute content, ECF osmolality, and ECF volume. Since almost all of the ECF solute is accounted for by sodium and an equivalent number of anions (mostly chloride and bicarbonate), the amount of ECF solute is approximately twice the sodium content.

ECF osmolality = ECF solute content / ECF volume (Equation 7-1)

ECF volume = ECF solute content / ECF osmolality (Equation 7-2)

ECF volume ≈ 2 x Na content / ECF osmolality (Equation 7-3)

Therefore, in the face of tightly controlled ECF osmolality, ECF volume varies directly with sodium content. But how do the kidneys know how much sodium there is in the ECF? The detection of sodium content is indirect, based on a combination of assessing sodium concentration and vascular pressures. Glial cells in regions of the brain called the circumventricular organs have sensory Na+ channels that respond to and act as detectors of extracellular sodium concentration. The glial cells modulate the activity of nearby neurons involved  in the control of body sodium. There are also neurons in the hypothalamus contain the sensory Na+ channels that respond to the sodium concentration in the cerebrospinal fluid. Thus cells in or near the hypothalamus monitor extracellular sodium concentration.

The volume affects pressure in different regions of the vasculature. It is the presssure baroreceptors in these regions of the vasculature detect the vascular pressures.

Major Controllers of Sodium Excretion

Sympathetic Stimulation 

Vascular pressures are so important in regard to sodium excretion and because volume affect pressure in different regions of the vasculature, so the changes in ECF affects pressures (arterial and/or venous) and changes in pressure affect sodium excretion (Thread "Regulation of Arterial Pressure" at http://www.tomhsiung.com/wordpress/2016/06/physiology-regulation-of-arterial-pressure/ and thread "Mean Circulatory Filling Pressure and CVP" at http://www.tomhsiung.com/wordpress/2016/06/mean-circulatory-filling-pressure-and-cvp/).

The vasculature and tubules of the kidney are innervated by postganglionic sympathetic neurons that release norepinephrine. In most regions of the kidney, norepinephrine is recognized by alpha-adrenergic receptors. In the renal vasculature activation of alpha1-adrenergic recpetors causes vasoconstriction of afferent and efferent arterioles. This reduces RBF and GFR.

GFR is a crucial determinant of sodium excretion. However, except in body emergencies such as hypovolemic shock, GFR is kept within rather narrow limits due to autoregulatory processes (detail for vascular autoregulatory regulation http://www.tomhsiung.com/wordpress/2015/07/arteriolar-tone-and-its-regulation-local-mechanisms/). Thus although neural control does affect GFR, this component of sympathetic control is probably less important in normal circumstances than its effect on sodium reabsorption. Neural control of the renal vasculature is exerted primarily on blood flow in the cortex, allowing preservation of medullary perfusion even when cortical blood flow is reduced.

The proximal tubule epithelial cells are innervated by alpha1- and alpha2-adrenergic receptors. Stimulation of these receptors in the proximal tubule by norepinephrine activates both components of the main transcellular sodium reabsorptive pathway, that is, the sodium-hydrogen antiporter NHE3 in the apical membrane and the Na-K-ATPase in the basolateral membrane. The effects of sympathetic stimulation on cells in the distal nephron are less straightforward. However, the overall outcome of sympathetic stimulation of the kidney is clearly reduced sodium excretion.

The Renin-Angiotensin System

AII's function

  • Reduces the RBF and GFR
  • Stimulation of sodium tubular reabsorption
  • Stimulation of the CNS: salt appetite, thirst, and sympathetic drive
  • Stimulation of aldosterone secretion

The major determinant of circulating AII is the amount of renin available to form angiotensin I.

PS: "Control of the Circulating RAAS" is ready at http://www.tomhsiung.com/wordpress/2016/06/control-of-the-circulating-raas/

AII is a potent vasoconstrictor, acting on the vasculature of many peripheral tissues, the effect of which is to raise arterial pressure. It also vasoconstricts both cortical and medullary vessels in the kidney. This reduces total RBF and reduces GFR, thus decreasing the filtered load of sodium.

AII stimulates sodium reabsorption in both the proximal tubule and distal nephron. In the proximal tubule it stimulates the same transcellular transport pathway as does norepinephrine, namely NHE3 sodium/hydrogen antiporter in the apical membrane and the Na-K-ATPase in the basolateral membrane. In the distal tubule and connecting tubule, it stimulates the activity of sodium/chloride symporters and sodium channels (ENaC) that reabsorb sodium.

AII stimulates behavioral actions in response to fluid loss that increase salt appetite and thirst. AII acts on the circumventricular organs in the brain. These function as detectors of many substances in the blood and convey information to various areas of the brain. In situations of volume depletion and low blood pressure, when circulating levels of AII are high, a key effect, in addition to vascular and tubular actions is increased thirst and salt appetite. These pathways also increase sympathetic drive.

Aldosterone is a major stimulator of sodium reabsorption in the distal nephron, that is, regions of the tubule beyond the proximal tubule and loop of Henle. We focus here on the role of aldosterone in sodium reabsorption, but aldosterone has many other important actions, including stimulation of potassium excretion and acid excretion. The most important physiological factor controlling secretion of aldosterone is the circulating level of AII, which stimulates the adrenal cortex to produce aldosterone. But keep in mind that elevated plasma potassium concentration, atrial natriuretic factors are other stimulators of aldosterone secretion. The aldosterone has enough lipid character to freely cross principal cell membrane in the collecting ducts, after which it combines with mineralocorticoid receptors (aldosterone receptors) in the cytoplasm. After being transported to the nucleus, the receptor acts as a transcription factor that promotes gene expression of specific proteins. The effect of these proteins is to increase the activity or number of luminal membrane sodium channels (ENaCs) and basolateral membrane Na-K-ATPase pumps.

Dopamine

Dopaimine inhibits sodium reabsorption in the kidney. The dopamine that acts in the kidney is not released from neurons; rather it is synthesized in proximal tubule cells from the precursor l-DOPA. l-DOPA is taken up from the renal circulation and glomerular filtrate and converted to dopamine in the proximal tubule epithelium, and then released to act in a paracrine manner on nearby cells. Although the signaling path is not clear, it is known that increases in sodium intake lead to increased production of intrarenal dopamine. Dopamine has 2 actions, both of which reduce sodium reabsorption. First, it causes retraction of NHE antiporters and Na-K-ATPase pumps into intracellular vesicles, thereby reducing transcellular sodium reabsorption. Second, it reduces the expression of AII receptors, thereby decreasing the ability of AII to stimulate sodium reabsorption.

Other Controllers of Sodium Excretion

ADH

When ADH binds to V2 reecptors in tubular cells, it increases the production of c-AMP. This results in increased activity of the NKCC multiporter in the thick ascending limb and increased sodium channel (ENaC) presence in principal cells of the distal nephron, thereby increasing the uptake of sodium that, in both regions, is actively transported into the interstitium by the Na-K-ATPase. Interestingly, in the distal nephron the mechanism proceeds, not by moving ENaCs into the membrane, but rather by decreasing their removal and degradation.

Glomerulotubular Balance

Glomerulotubular balance (not to be confused with TG feedback described previously) refers to the phenomenon whereby sodium reabsorption in the proximal tubule varies in parallel with the filtered load, such that approximately two thirds of the filtered sodium is reabsorbed even when GFR varies. The mechanism by which reabsorption varies with filtered load appears to be via mechanotransduction by the microvilli on the apical surface of the proximal tubule cells, similar in principle to mechanotransduction by primary cilia in the macula densa. As flow changes, the amount of bending of the microvilli changes, and this is converted by cellular mechanisms into changes in transport.

Pressure Natriuresis and Diuresis

Because the kidneys are responsive to arterial pressure, there are situations in which elevated blood pressure can lead directly to increased excretion of sodium. This phenomenon is called pressure natriuresis, and because natriuresis is usually accompanied by water, it is often called pressure diuresis. This is an intrarenal phenomenon, not requiring external signaling. However, external signals normally override pressure natriuresis.

Natriuretic Peptides

Several tissues in the body synthesize members of a hormone family called natriuretic peptides. Key among these are atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). The main source of both natriuretic peptides is the heart. The natriuretic peptides have both vascular and tubular actions. The relax the afferent arteriole, thereby promoting increased filtration, and act at several sites in the tubule. They inhibit release of renin, inhibit the actions of AII that normally promote reabsorption of sodium, and act in the medullary collecting duct to inhibit sodium absorption. The major stimulus for increased secretion of the natriuretic peptides is distention of the atria, which occurs during plasma volume expansion. This is probably the stimulus for the increased natriuretic peptides that occurs in persons on a high salt diet.

Residents Series – Inflammatory Shock Syndromes

November 14, 2015 Cardiology, Critical Care, Infectious Diseases No comments , , , , , , , , , , ,

Grim-ReaperDefinitions and Impactions

SIRS/Systemic inflammatory response syndrome is a condition that is characterized by signs of systemic inflammation (e.g., fever, leukocytosis). The diagnosis of SIRS requires at least 2 of the following:

1.Temperature >38 C or <36 C

2.Heart rate >90 beats/min

3.Respiratory rate >20 breaths/min, or arterial PCO2 <32 mm Hg

4.WBC count >12,000/mm3 or <4000/mm3, or >10% immature neutrophils (band forms)

Sepsis is a kind of SIRS caused by an infection.

Severe sepsis is a sepsis condition accompanied by dysfunction in one or more vital organs, or an elevated blood lactate level (>4 mM/L).

Septic shock is a severe sepsis accompanied by hypotension that is refractory to volume infusion.

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Inflammatory injury involving more than one vital organ is called multiorgan dysfunction syndrome (MODS), and the subsequent failure of more than one organ system is called multiorgan failure (MOF).

The organs most often damaged by systemic inflammation are the lungs, kidneys, cardiovascular system, and central nervous system. The most common manifestation of inflammatory organ injury is the acute respiratory distress syndrome (ARDS), which has been reported in 40% of patients with severe sepsis, and is one of the leading causes of acute respiratory failure in critical ill patients.

The number of organs that are damaged by inflammatory injury has important prognostic implications. There is a direct relationship between the mortality rate and the number of organ failures related to inflammation. This demonstrates the lethal potential of uncontrolled systemic inflammation.


The Physiologic Characteristics of Septic Shock

Severe sepsis and septic shock have been implicated in one of every four deaths worldwide, and the incidence of these conditions is steadily rising. The mortality rate averages about 30-50%, and varies with age and the number of associated organ failures. The mortality rate is not related to the site of infection or the causative organism, including multidrug-resistant organisms. This observation is evidence that inflammation, not infection, is the principal determinant of outcome in severe sepsis and septic shock.

Hemodynamic Alterations

  • The principal hemodynamic problem is systemic vasodilatation (involving both arteries and veins), which reduces ventricular preload and ventricular afterload. The vascular changes are attributed to the enhanced production of nitric oxide (a free radical) in vascular endothelial cells.
  • Oxidant injury in the vascular endothelium (from neutrophil attachment and degranulation) leads to fluid extravasation and hypovolemia, which adds to the decreased ventricular filling from venodilation.
  • Proinflammatory cytokines promote cardiac dysfunction (both systolic and diastolic dysfunction); however, the cardiac output is usually increased as a result of tachycardia and volume resuscitation.
  • Despite the increased cardiac output, splanchnic blood flow is typically reduced in septic shock. This can lead to disruption of the intestinal mucosa, thereby creating a risk for translocation of enteric pathogens and endotoxin across the bowel mucosa and into the systemic circulation. This, of course, will only aggravate the inciting condition.

The typical hemodynamic pattern in septic shock includes low cardiac filling pressure (CVP or wedge pressure), a high cardiac output, and a low systemic vascular resistance (SVR). Because of the high cardiac output and peripheral vasodilatation, septic shock is also known as hyperdynamic shock or warm shock. In the advanced stages of septic shock, cardiac dysfunction is more prominent and the cardiac output is reduced, resulting in a hemodynamic pattern that resembles cardiogenic shock (i.e., high CVP, low CO, high SVR). A declining cardiac output in septic shock usually indicates a poor prognosis.

Tissue Oxygenation

The impaired energy metabolism in septic shock is not the result of inadequate tissue oxygenation, but is caused by a defect in oxygen utilization in mitochondria. This condiditon is known as cytopathic hypoxia, and the culprit is oxidant-induced inhibition of cytochrome oxidase and other proteins in the electron transport chain. A decrease in oxygen utilization would explain the observation that the PO2 in skeletal muscle is increased in patients with severe sepsis.

The proposed decrease in oxygen utilization in sepsis is not consistent with the increase in whole-body O2 consumption that is often observed in sepsis. This discrepancy can be resolved by proposing that the increased O2 consumption in sepsis is not a reflection of aerobic metabolism, but is a manifestation of the increased O2 consumption that occurs during neutrophil activation (i.e., the respiratory burst).

The discovery that tissue oxygenation is (more than) adequate in severe sepsis and septic shock has important implications because it means that efforts to improve tissue oxygenation in these conditions (e.g., with blood transfusions) are not justified.

Serum Lactate Levels

The increase in serum lactate levels in severe sepsis and septic shock is not the result of inadequate tissue oxygenation, but instead appears to be the result of enhanced production of pyruvate and inhibition of pyruvate dehydrogenase, the enzyme that converts pyruvate to acetyl coenzyme A in mitochondria. Endotoxin and other bacterial cell wall components have been implicated in the inhibition of this enzyme. This mechanism of lactate accumulation is consistent with the notion that tissue oxygenation is not impaired in severe sepsis and septic shock.


Management

The management of septic shock is outlined in Table 14-3, and is organized in "bundles", which are sets of instructions that must be followed without deviation to provide a survival benefit. The acute sepsis bundle is considered the most important, and must be completed within 6 hours after the diagnosis of septic shock. Screen Shot 2015-11-14 at 8.15.07 PM

Volume Resuscitation

Volume resuscitation is often necessary in septic shock because cardiac filling pressures are reduced from venodilatation and fluid extravasation. The volume resuscitation requires the insertion of a central venous catheter to monitor the central venous pressure (CVP).

1.Infuse 500-1,000 mL of crystalloid fluid or 300-500 mL of colloid fluid over 30 minutes.

2.Repeat as needed until the CVP reaches 8 mm Hg, or 12 mm Hg in ventilator-dependent patients.

If CVP measurements are not available, a volume of at least 20 mL/kg (crystalloid fluid) can be used for the volume resuscitation.

After the initial period of volume resuscitation, the infusion rate of intravenous fluids should be reduced to avoid unnecessary fluid accumulation. A positive fluid balance is associated with increased mortality in septic shock, so attention to avoid fluid accumulation will improve the chances of a favorable outcome.

Vasopressors

If hypotension persists after the initial volume resuscitation, infusion of a vasoconstrictor drug (vasopressor) like norepinephrine or dopamine should begin. Vasoconstrictor drugs must be infused through a central venous catheter, and the goal is to achieve a mean arterial pressure (MAP) >=65 mm Hg.

Norepinephrine is favored by many because it is more likely to raise the blood pressure than dopamine, and is less likely to promote arrhythmias. However, neither agent has proven superior to the other for improving the outcome in septic shock.

When hypotension is refractory to norepinephrine and dopamine, vasopressin may be effective in raising the blood pressure (Vasopressin is used as an additional pressor rather than a replacement for norepinephrine or dopamine). Vasopressin is a pure vasoconstrictor that can promote splanchnic and digital ischemia, especially at high dose rates. Although vasopressin may help in raising the blood pressure, the accumulated experience with vasopressin shows no influence on outcomes in septic shock.

Corticosteroids

Corticosteroids have two actions that are potentially beneficial in septic shock: they have antiinflammatory activity, and they magnify the vasoconstrictor response to catecholamines. Unfortunately, after more than 50 years of investigations, there is no convincing evidence that steroids provide any benefit in the treatment of septic shock. Yet steroids therapy continues to be popular in septic shock. The following comments reflect the current recommendations regarding steroid therapy in spetic shcok.

1.Steroid therapy should be considered in cases of septic shock where the blood pressure is poorly responsive to intravenous fluids and vasopressor therapy. Evidence of adrenal insufficiency (by the rapid ACTH stimulation test) is not required.

2.Intravenous hydrocortisone is preferred to dexamethasone (because of the mineralocorticoid effects of hydrocortisone), and the dose should not exceed 300 mg daily (to limit the risk of infection).

3.Steroid therapy should be continued as long as vasopressor therapy is required.

Antimicrobial Therapy

For the pharmacotherapy of antimicrobial therapy please view the thread of Systematic Approach for Selection of Antimicrobials at http://www.tomhsiung.com/wordpress/2014/03/systematic-approach-for-selection-of-antimicrobials/