OBJECTIVE 3: TO UNDERSTAND THE VARIOUS EFFECTOR
MECHANISMS THAT ALTER ECF VOLUME BY CHANGING THE RATE OF SALT AND WATER
EXCRETION.
The various effector mechanisms that are controlled by the volume receptors are those indicated in Figs. 8-2, and 8-3: ADH, atrial natriuretic factor, GFR, the renin-angiotensin-aldosterone axis and peritubular capillary pressures. They are discussed below. The direct sympathetic innervation of the tubules, as will be described below is another effector mechanism.
A. ADH also plays a role in volume regulation. Secretion is stimulated by a fall in blood volume (atrial volume receptors, Fig 8-2) and in blood pressure (arterial baroreceptors). ADH secretion is much more sensitive to changes in plasma osmolality. A rise in osmolality of 1% is sufficient to stimulate an increase in plasma ADH concentration whereas a fall in blood volume or pressure approaching 10% is required to stimulate ADH secretion. Nevertheless, inhibition of the atrial volume receptors and the arterial baroreceptors can induce a much higher level of ADH in plasma than stimulation of the osmoreceptors (Fig. 8-4). The concentration required to maximally stimulate tubular water reabsorption is less than 5 pg/mL. At higher concentrations ADH has additional effects. Acting through V1 receptors it causes vasoconstriction of arterioles in several peripheral circulatory beds (the V2 receptor is the tubular cell receptor). Inhibition of the atrial volume receptors and the arterial baroreceptors by a fall in blood volume/pressure will move the inflection point in Fig. 7-2 to lower osmolalities and increase the slope of the line relating ADH concentration to osmolality. Stimulation of the receptors by a rise in blood volume/pressure has the opposite effect.
Fig. 8-4. The relative effects of osmolality, blood volume and arterial pressure on plasma ADH concentration.
B. Atrial Natriuretic Factor (ANF) increases the excretion of salt and water (Fig 8-5). This peptide hormone has a number of names including atrial natriuretic peptin or peptide, auriculin, atriopeptin and cardionatrin.
1. ANF is formed and released by atrial muscle cells. It is stored as a pre-propeptide in dense cytoplasmic granules. The circulating active form consists of about 28 amino acids although there seem to be multiple active forms in the circulation. The primary stimulus for ANF secretion is distension of the atrium, usually caused by blood volume expansion (Fig.8-2).
Fig. 8-5. Role of ANF in response to changes in blood volume.
2. ANF increases salt and water excretion by increasing GFR, decreasing renin and aldosterone secretion and inhibiting salt reabsorption by the collecting tubule. It increases GFR by vasodilitation of the afferent arteriole and vasoconstriction of the efferent arteriole. It inhibits renin secretion which in turn reduces aldosterone secretion. ANF also acts directly on the adrenal cortex to inhibit aldosterone secretion. In addition it acts on the collecting duct through its second-messenger, cGMP, to inhibit the ENaC sodium channel.
C. Obviously changes in GFR can alter the rate of excretion of salt and water. The extent to which a change in GFR alters the rate of excretion of salt and water depends upon the initial GFR and the extent to which other factors, such as aldosterone, are affecting tubular reabsorption (fig. 8-6). If the GFR is moderate or low initially, an increase or a decrease in GFR will cause only small changes in the rate of excretion. If the initial GFR is large, changes in GFR have a larger effect. If factors that affect tubular reabsorption have depressed reabsorption (diuresis in Fig. 8-6b), the effect of a change in GFR on excretion will be larger.
Fig. 8-6. The effect of changes in GFR on reabsorption and excretion of salt and water. FR = fractional reabsorption. FE = fractional excretion
1. In the absence of other changes, the tubule tends to reabsorb a constant fraction of the filtered salt and water (glomerulotubular balance). Thus, if GFR increases, the rate of reabsorption increases (Fig. 8-6a) and fractional reabsorption changes only slightly (Fig. 8-6b). Excretion also increases (Fig. 8-6a) but again fractional excretion changes very little (Fig 8-6b). The mechanisms that maintain this balance are not completely understood. However the changes that occur in hydrostatic and colloid osmotic pressures in the peritubular capillaries when GFR is altered probably play a major role (See below). In addition an increase in delivery of salt and water to the distal sections of the nephron also results in increased reabsorption by those structures.
2. Changes in the factors affecting tubular reabsorption will exert a larger effect on fractional excretion when GFR is high than when GFR is low (Fig. 8-6b), the difference between the lines for antidiuresis and diuresis). For instance, an increase in circulating aldosterone levels will cause a greater reduction in fractional excretion of salt and water when GFR is high than when GFR is low. This is simply because GFR affects the degree of salt and water delivery to the collecting duct where aldosterone has its effect. If delivery is low, the extent to which aldosterone can cause additional reabsorption is also low.
D. Pressures in the peritubular capillary exert an
important influence on the rate of salt and water reabsorption (Fig
8-7). In those capillaries, the colloid osmotic pressure (
b)
normally exceeds the hydrostatic pressure (Pc), facilitating
reabsorption of fluid from the proximal tubule. Both pressures may be
altered in a given situation.
Fig. 8-7. The effect of blood volume expansion on pressures in the peritubular capillaries.
1. Expansion of the circulating blood volume, acting through the atrial volume receptors will reduce sympathetic neural impulses to the kidney (Fig. 8-2). The fall in renal resistance, probably in both afferent and efferent arterioles, will increase RPF to a greater extent than GFR and the filtration fraction (GFR/RPF) will fall. That will reduce
2. A rise in angiotensin II levels preferentially constricts the efferent arteriole. This results in a larger fall in RPF than in GFR. The filtration fraction increases and this results in a rise in the protein concentration in the plasma flowing into the peritubular capillary bed, that is,
E. Changes in angiotensin and aldosterone levels that occur following expansion or contraction of blood volume are triggered by changes in renin secretion.
1. Three major pathways exist for controlling renin secretion (Fig. 8-8):
Fig. 8-8. The three factors that act upon the j.g. apparatus to increase the secretion of renin.
Intrarenal Baroreceptor. A fall in pressure within the afferent arteriole will directly stimulate renin release by the granular cells.
Sympathetic Input. Sympathetic neural and humoral input
to the j.g. apparatus stimulates renin secretion. Stimulation of 
receptors on the granular cells causes the release of renin. The
sympathetic input is thought to be regulated primarily by the atrial
volume receptors. The carotid and aortic baroreceptors have a smaller
effect on renin secretion.
Macula Densa Feedback. A reduction in the delivery of salt via the tubular fluid to the macula densa cells stimulates renin release. This may occur as the result of a rise in filtration fraction (increasing proximal tubular reabsorption) or a fall in GFR. Either or both may occur as a result of the fall in arterial pressure and increase in sympathetic activity. Recall that the macula densa is also involved in control of GFR. In that mechanism a rise in solute delivery to the macula densa causes a fall in GFR. It is uncertain whether and angiotensin are not involved in that autoregulation mechanism. Until the evidence is more complete it is best to consider these two functions of the macula densa as two separate, unrelated, mechanisms.
2. Renin increases the production of angiotensin II, a potent vasoconstrictor. Its effect on peripheral resistance throughout the body may significantly affect arterial pressure. AII also stimulates the zona glomerulosa of the adrenal cortex to increase the secretion of aldosterone. This leads to increased reabsorption of salt and water by the collecting tubule.
In addition to its effect on RBF, GFR and aldosterone secretion, angiotensin II also has a direct effect on proximal tubular transport mechanisms. It stimulates Na-H exchange across the apical membrane and Na-HCO3 cotransport across the basolateral membrane. It does this by activating an inhibitory G protein (Gi) that decreases adenylate cyclase activity. This reduces the cellular level of the cyclic AMP. This 2nd messenger inhibits these transport mechanisms so the effect of angiotensin II reduces this inhibition. Angiotensin II also stimulates Na-glucose transport across the apical membrane. Thus it stimulates NaHCO3 reabsorption and glucose reabsorption and thereby increases water reabsorption.
3. Aldosterone secretion by the zona glomerulosa of the adrenal cortex is stimulated by AII. Other major factors can also alter the rate of secretion of aldosterone. A rise in plasma potassium concentration directly stimulates secretion. Atrial natriuretic factor inhibits secretion. ACTH and a fall in plasma sodium concentration also stimulate secretion.
This mineralocorticoid hormone stimulates sodium reabsorption and potassium secretion by principal cells in the cortical collecting tubule and in the late sections of the distal tubule. It also stimulates proton secretion by intercalated cells in the outer medullary sections of the collecting tubule. Aldosterone enters target cells by diffusion, binds to a cytoplasmic receptor and is translocated into the nucleus. There it induces formation of mRNA which in turn induces synthesis of specific proteins. The aldosterone induced proteins (AIP) have multiple effects on Na transport. The initial effect of the AIPs is an increased conductance of the apical membrane to Na (see fig. 6-8). This is due both to an increased population of Na channels (the ENaC channel) and to activation of channels already present. The AIPs also stimulate the supply of energy to Na transport by increasing the activity of citrate synthetase. Na-K-ATPase activity in the basolateral membrane is also increased. Whether this is a primary effect of AIPs or a secondary effect due to the enhanced apical conductance to Na is not resolved. In the chronic situation insertion of this enzyme into basolateral membrane increases the surface area of that membrane in principal cells.The changes that aldosterone induces in ion transport do not occur rapidly. The rise in Na transport that is induced by an increase in aldosterone secretion is not apparent for 60-90 min and a much longer period of time is required to achieve the full effect. This means that changes in aldosterone secretion do not play a role in rapid alterations in salt and water excretion. However, the role of aldosterone in daily and long term regulation of salt and water balance is quite important.
QUESTIONS:
7. What limits the increase in salt
and water excretion when GFR rises?
8. What limits the magnitude of the effect of
aldosterone on salt reabsorption in the collecting tubule?
9. Compare and contrast
the effect on ADH release of an increase in the osmotic concentration of
plasma and a fall in blood volume.
10. What is the effect of a fall in the filtration
fraction on reabsorption of water and salt by the proximal tubule? What is
the effect of a rise in resistance to blood flow in the kidney on salt and
water reabsorption in the proximal tubule?
11. What are the three stimuli that act on the
juxtaglomerular apparatus to cause changes in renin secretion? How can
renin affect the circulating blood volume?
12. What factors other than angiotensin stimulate
aldosterone release?
13. How does aldosterone affect salt reabsorption
by principal cells in the collecting duct?
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