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Control of Proximal Reabsorption of Sodium in the Kidney
CONTROL OF PROXIMAL REABSORPTION OF SODIUM IN THE KIDNEY William D. Blake Professor Department of Physiology University of Maryland School of Medicine Baltimore, Maryland Major physiological assumptions are that:
support of the above assumptions. One type of renal response is evoked by direct electrical stimulation of the perifornical area of the hypothalamus in rabbits (1) or above-threshold stimulation of the renal nerves in dogs (2). There is marked reduction in renal blood flow (RBF) and glomerular filtration rate (GFR) , the latter more than the former so that filtration fraction (FF) decreases, indicating predominantly afferent arteriolar constriction. Urine flow and Na excretion decrease nearly in proportion to the fall in GFR so that decrease in absolute reabsorption is associated with some increase in fractional Na reabsorption. The response is predominantly neurally mediated since a paired, denervated kidney fails to show these changes. This type of response may be seen during induced apnea of diffusion respiration in anesthetized dogs (3) or in man during severe stress , e.g. some patients circulatory stress, in shock (4), during exercise in patients with valvular heart disease (5) or during exercise in normal individuals undergoing heat stress and dehydration (6). Neural mediation of the decreased GFR was not proven fo r the studies in men.
a) cardiovascular homeostatic systems evoke neurally-mediated Na conservation by the kidney by two seemingly different mechanisms, b) afferent and efferent arterioles in outer cortical and juxtamedullary regions do not necessarily respond to altered renal nerve activity or blood-borne vasov asoactive substances with similar changes in resistance, c) although directional change in filtration fraction (FF) cannot be used to define afferent and efferent arteriolar resistance changes, especially when blood pressure changes, an increasing FF suggests greater efferent arteriolar involvement and a decreasing FF greater afferent arteriolar involvement whenever total renal resistance has increased. The extent of afferent vasoconstriction is modified by the change in arterial blood pressure via "autoregulatory" behavior, d) absolute sodium (Na) reabsorption by tubular segements proximal to the macula densa may be considered a functional entity, hereafter called "proximal" Na reabsorption, even though fractional reabsorption in proximal segment and loop of Henle may not behave similarly under all circumstances, e) "proximal" Na reabsoprtion depends on glomerular filtration rate, peritubular capillary osmotic (both "kinetic" and static) and hydrostatic pressures, hereafter called net "Starling" forces, and activity of the Na pump, and f) there are baroreceptors in pre- and postglomerular vessels and glomeruli and Na-sensitive receptors in the macula densa and perhaps elsewhere.
A second type of response is evoked by indirect activation of renal efferent nerves by pentobarbital anesthesia (7,8) or cardiovascular reflexes (9)or by direct electrical stimulation of the abdominal splanchnic nerves at threshold (10) RBF, usually, and GFR frequently, frequently , but not invariably, decrease, decrease , the latter usually less than the former with no change or increase in FF, suggesting mixed or predominantly efferent arteriolar constriction. Urine flow and Na excretion decrease out of proportion to the decrease in filtration rate and any decrease in absolute reabsorption (with decreased GFR) is associated
The following evidence is presented in
"Superior numbers refer to similarly-numbered references at the end of this paper."
424
afferent nerves are unknown.
with increased fractional Na reabsorption. Part of the response, in particular any significant increase in FF, may be mediated by catecholamines or angiotensin formed by release of renin from the kidney. This type of response is blocked by prior renal denervation or adrenergic blockade(7,8,lO) blockade(7,8,10) or by electrical stimulation in the sympathoinhibitory area of the septum(l).
Systematic assumptions are that the demonstrated and assumed neural elements, including the pressure and Na-sensitive receptors, function as two interlocking control systems. System I is directed toward (the principal output) acute blood pressure homeostasis with a secondary output of maximizing Na and water reabsorption by the kidney. System 11 is directed toward subacute blood volume homeostasis, in this instance "proximal" Na and water reabsorption, with feedback elements also pertaining to the nonelectrolyte excretory function of the kidney which is dependent on GFR. Nonlinearity is assumed and the evidence is barely adequate to suggest the functional interrelationships among the system elements described below.
These two types of response are differentiated by decreased FF ( afferent arteriolar constriction) and little decrease in V/GFR in the first and increased FF (mixed or predominantly efferent arteriolar constriction) and markedly decreased V/ GFR in the second. V/GFR These two responses might represent different intensities of of neural activation, since threshold electrical stimulation of the nerves to the kidney does not necessarily decrease whereas more intense stimulation usually FF Whereas does (10,2), or they might reflect different populations of nerve fibers being activated, the populations differing with respect to anatomical distribution (11) and/ or type of neurotransmitter released. and/or
The systems are presented as a block diagram. In System I arterial pressure receptors are located in carotid sinus, aortic arch, and renal artery and "volume" receptors in the cardiac atria. These send inhibitory input to the central nervous system (CNS) "center" which activat e s efferent e fferent fibers to renal r e nal cortical activates afferent arterioles, juxtaglomerular secreting) , juxtagranular cells (renin secreting), medullary pre- and postglomerular resistance vessels, and the adrenal medulla. (Other cardiovascular elements will not be considered). In essence, a fall in v olume evokes blood pressure or atrial volume increased afferent (opposed by an intrinsic autoregulatory device) and efferent arteriolar resistances, and secretion of renin (kidney) and catecholamines (in kidney and adrenal). If the circulatory stress is severe, afferent arteriolar constriction is maximal (autoregulation is overriden), glomerular filtration pressure falls, and GFR decreases more than REF leading to decreased FF. Decreased GFR decreases "proximal" Na reabsorption, an effect abetted by decreased net "Starling" forces (decreased "kinetic" and static osmotic forces from decreased concentration) , plasma flow and protein concentration), but possibly opposed by catecholamines and (not included in system) failure of glomerulo-tubular balance (at low GFR), and / or redistribution of filtration to and/or nephrons of greater reabsorptive capacity (consequence of nerve distribution, see above) •
Proximal tubular Na reabsorption varies with GFR but the relationship may be influenced by factors which alter the net "Starling" forces across the peritubular capillary membrane and possibly by catecholamines. Forces enhancing absorption of fluid from interstitial space to intravascular compartment enhance Na reabsorption and vice versa (12). Catecholamines may stimulate Na transport (Other possible hormones con(13,14). trolling Na transport are not relevant to this discussion). These factors influencing proximal Na reabsorption may have similar effects on loop of Henle and therefore, "proximal" Na reabsorption. In afferent renal nerves, spontaneous or induced firing rate may be altered by arterial , venous, venous , or changes in renal arterial, ureteral pressure (15,16). Infusion of hypertonic NaCl into the renal artery or the above stimuli may alter spontaneous firing rate of single cells in the hypothalamus (Jurf and Blake, unpublished data). There are baroreceptors in preexis~s glomerular vessels but no proof exis~s for the presence of baroreceptors in the glomerulus to measure "filtration" pressure or in postglomerular vessels. The locations of Na-sensitive receptors involved in renin release, perhaps in the macula densa(17) or for activation of renal
In System 11, filtration pressure receptors
425
References
are assumed to exist in the glomeruli and macula densa Na receptors may be likened to filtration "volume" or rate receptors. These receptors provide negative feedback to "centers" controlling efferent arteriolar resistance and possibly positive feeback to "centers" controlling afferent arteriolar resistance. (Again, however, afferent resistance control may be almost exclusively autoregulatory except during intense neural activation).
(1) Jurf,A., Blake,W. Circulation Res. 1Q: 322-333, 1972. lQ:322-333, Ship1ey,R. Am. J. Physiol. (2) Study, R., Shipley,R. 163:442-453, 1950. (3) Bohr,V., Ral1s,R., Ralls,R., Westermeyer,R. Am.J.Physiol. 194:143-148, 1958. (4) Lauson,H., Bradley, Brad1ey, S., Cournand,A. J. Clin.lnvest. 23:381-402, 1944. (5) Judson, W., Hollander,W., Hatcher, J., Ha1perin, J.C1in.lnvest.l1:1546Halperin, M. The J.Clin.lnvest.21:15461558, 1955. Activation of efferent neural elements, (6) Smith, J., Robinson, S., Pearcy, M. both centrally and peripherally, has been J. App. Physiol. ~:659-667, ~:659-667, 1952. described above. Few studies have been (7) Kaplan, S., West, C., C. , Foman, S. done on renal afferent fibers, except to Am. J. Physiol. Physi01. 175:363-374, 1953. show that they exist (see above). Attempts B1ake, W. Am. J. Physiol. (8) Blake, 191:393to show functional changes in contralateral 398, 1957. renal function by direct electrical stimu(9) B1ake, Blake, W. Am. J. Pbysiol. Physio1. 181:399lation of renal afferents have been unsuccessful (15), possibly because of 416, 1955. (10) Blake, W. Am. J. Physiol. Physio1. 173:337mixed effects. For example, in the anes344, 1953. thetized dog, denervation of one kidney (11) Mc Kenna, 0., Angelakos, E. Circulation McKenna, appears to enhance sympathetic nerve activity (decreased FF and fractional exRes. ~:345-354, ~:345-354, 1968. nner, B. ,Tadokoro, M. , (12) Falchuk, Fa1chuk, K. ,Bre ,Brenner,B. ,Tadokoro,M. cretion of Na) to the contra-lateral kidney (7,9) whereas unilateral renal rliner,R.Am.J.Physiol. 220:14 27,1971 Be Ber1iner,R.Am.J.Physi01. 220:1427,1971 Hoffman,W. ,Jr., Kagan, A. (13) Berne, R., Hoffman,W.,Jr., A.,, arterial clamping would appear to depress Levy, M. Am. J. Physiol. 171.:564-571, 171.: 564-571, sympathetic nerve activity (enhanced 1952. fractional excretion of water) to the (14) Gill, J.,Jr., J. ,Jr., Casper,A. Am. J. Physio1. Physiol. contra-lateral kidney, a response respons2 which 223:1201-1205,1972. 223:1201-1205, 1972. fails to appear if the clamped kidney has been previously denervated (18). Acta_~hYsiol. These (15) Astrom, A., Crafoord, J. Acta_~hYsio1. Scand. 74:69-78, 1968. observations, if confirmed, could indicate (16) Beacham,W., Kunze, D. J. Physiol. loss of negative or positive feedback 201:73-85, 1969. respectively from one or another ~aro baro(17) Shade, R., Davis, J. J.,, Johnson, J., receptor or from Na receptors. Witty,R.,Braverman,B. Witty,R. ,Braverman,B. Am. Soc. Neph. Abst. (5th Annual) pg. 71, 1971. (18) Blake, B1ake, W. Am. J. Physiol. Physi01. 199:503-508 1960.
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support of the above assumptions. One type of renal response is evoked by direct electrical stimulation of the perifornical area of the hypothalamus in rabbits (1) or above-threshold stimulation of the renal nerves in dogs (2). There is marked reduction in renal blood flow (RBF) and glomerular filtration rate (GFR) , the latter more than the former so that filtration fraction (FF) decreases, indicating predominantly afferent arteriolar constriction. Urine flow and Na excretion decrease nearly in proportion to the fall in GFR so that decrease in absolute reabsorption is associated with some increase in fractional Na reabsorption. The response is predominantly neurally mediated since a paired, denervated kidney fails to show these changes. This type of response may be seen during induced apnea of diffusion respiration in anesthetized dogs (3) or in man during severe stress , e.g. some patients circulatory stress, in shock (4), during exercise in patients with valvular heart disease (5) or during exercise in normal individuals undergoing heat stress and dehydration (6). Neural mediation of the decreased GFR was not proven fo r the studies in men.
a) cardiovascular homeostatic systems evoke neurally-mediated Na conservation by the kidney by two seemingly different mechanisms, b) afferent and efferent arterioles in outer cortical and juxtamedullary regions do not necessarily respond to altered renal nerve activity or blood-borne vasov asoactive substances with similar changes in resistance, c) although directional change in filtration fraction (FF) cannot be used to define afferent and efferent arteriolar resistance changes, especially when blood pressure changes, an increasing FF suggests greater efferent arteriolar involvement and a decreasing FF greater afferent arteriolar involvement whenever total renal resistance has increased. The extent of afferent vasoconstriction is modified by the change in arterial blood pressure via "autoregulatory" behavior, d) absolute sodium (Na) reabsorption by tubular segements proximal to the macula densa may be considered a functional entity, hereafter called "proximal" Na reabsorption, even though fractional reabsorption in proximal segment and loop of Henle may not behave similarly under all circumstances, e) "proximal" Na reabsoprtion depends on glomerular filtration rate, peritubular capillary osmotic (both "kinetic" and static) and hydrostatic pressures, hereafter called net "Starling" forces, and activity of the Na pump, and f) there are baroreceptors in pre- and postglomerular vessels and glomeruli and Na-sensitive receptors in the macula densa and perhaps elsewhere.
A second type of response is evoked by indirect activation of renal efferent nerves by pentobarbital anesthesia (7,8) or cardiovascular reflexes (9)or by direct electrical stimulation of the abdominal splanchnic nerves at threshold (10) RBF, usually, and GFR frequently, frequently , but not invariably, decrease, decrease , the latter usually less than the former with no change or increase in FF, suggesting mixed or predominantly efferent arteriolar constriction. Urine flow and Na excretion decrease out of proportion to the decrease in filtration rate and any decrease in absolute reabsorption (with decreased GFR) is associated
The following evidence is presented in
"Superior numbers refer to similarly-numbered references at the end of this paper."
424
afferent nerves are unknown.
with increased fractional Na reabsorption. Part of the response, in particular any significant increase in FF, may be mediated by catecholamines or angiotensin formed by release of renin from the kidney. This type of response is blocked by prior renal denervation or adrenergic blockade(7,8,lO) blockade(7,8,10) or by electrical stimulation in the sympathoinhibitory area of the septum(l).
Systematic assumptions are that the demonstrated and assumed neural elements, including the pressure and Na-sensitive receptors, function as two interlocking control systems. System I is directed toward (the principal output) acute blood pressure homeostasis with a secondary output of maximizing Na and water reabsorption by the kidney. System 11 is directed toward subacute blood volume homeostasis, in this instance "proximal" Na and water reabsorption, with feedback elements also pertaining to the nonelectrolyte excretory function of the kidney which is dependent on GFR. Nonlinearity is assumed and the evidence is barely adequate to suggest the functional interrelationships among the system elements described below.
These two types of response are differentiated by decreased FF ( afferent arteriolar constriction) and little decrease in V/GFR in the first and increased FF (mixed or predominantly efferent arteriolar constriction) and markedly decreased V/ GFR in the second. V/GFR These two responses might represent different intensities of of neural activation, since threshold electrical stimulation of the nerves to the kidney does not necessarily decrease whereas more intense stimulation usually FF Whereas does (10,2), or they might reflect different populations of nerve fibers being activated, the populations differing with respect to anatomical distribution (11) and/ or type of neurotransmitter released. and/or
The systems are presented as a block diagram. In System I arterial pressure receptors are located in carotid sinus, aortic arch, and renal artery and "volume" receptors in the cardiac atria. These send inhibitory input to the central nervous system (CNS) "center" which activat e s efferent e fferent fibers to renal r e nal cortical activates afferent arterioles, juxtaglomerular secreting) , juxtagranular cells (renin secreting), medullary pre- and postglomerular resistance vessels, and the adrenal medulla. (Other cardiovascular elements will not be considered). In essence, a fall in v olume evokes blood pressure or atrial volume increased afferent (opposed by an intrinsic autoregulatory device) and efferent arteriolar resistances, and secretion of renin (kidney) and catecholamines (in kidney and adrenal). If the circulatory stress is severe, afferent arteriolar constriction is maximal (autoregulation is overriden), glomerular filtration pressure falls, and GFR decreases more than REF leading to decreased FF. Decreased GFR decreases "proximal" Na reabsorption, an effect abetted by decreased net "Starling" forces (decreased "kinetic" and static osmotic forces from decreased concentration) , plasma flow and protein concentration), but possibly opposed by catecholamines and (not included in system) failure of glomerulo-tubular balance (at low GFR), and / or redistribution of filtration to and/or nephrons of greater reabsorptive capacity (consequence of nerve distribution, see above) •
Proximal tubular Na reabsorption varies with GFR but the relationship may be influenced by factors which alter the net "Starling" forces across the peritubular capillary membrane and possibly by catecholamines. Forces enhancing absorption of fluid from interstitial space to intravascular compartment enhance Na reabsorption and vice versa (12). Catecholamines may stimulate Na transport (Other possible hormones con(13,14). trolling Na transport are not relevant to this discussion). These factors influencing proximal Na reabsorption may have similar effects on loop of Henle and therefore, "proximal" Na reabsorption. In afferent renal nerves, spontaneous or induced firing rate may be altered by arterial , venous, venous , or changes in renal arterial, ureteral pressure (15,16). Infusion of hypertonic NaCl into the renal artery or the above stimuli may alter spontaneous firing rate of single cells in the hypothalamus (Jurf and Blake, unpublished data). There are baroreceptors in preexis~s glomerular vessels but no proof exis~s for the presence of baroreceptors in the glomerulus to measure "filtration" pressure or in postglomerular vessels. The locations of Na-sensitive receptors involved in renin release, perhaps in the macula densa(17) or for activation of renal
In System 11, filtration pressure receptors
425
References
are assumed to exist in the glomeruli and macula densa Na receptors may be likened to filtration "volume" or rate receptors. These receptors provide negative feedback to "centers" controlling efferent arteriolar resistance and possibly positive feeback to "centers" controlling afferent arteriolar resistance. (Again, however, afferent resistance control may be almost exclusively autoregulatory except during intense neural activation).
(1) Jurf,A., Blake,W. Circulation Res. 1Q: 322-333, 1972. lQ:322-333, Ship1ey,R. Am. J. Physiol. (2) Study, R., Shipley,R. 163:442-453, 1950. (3) Bohr,V., Ral1s,R., Ralls,R., Westermeyer,R. Am.J.Physiol. 194:143-148, 1958. (4) Lauson,H., Bradley, Brad1ey, S., Cournand,A. J. Clin.lnvest. 23:381-402, 1944. (5) Judson, W., Hollander,W., Hatcher, J., Ha1perin, J.C1in.lnvest.l1:1546Halperin, M. The J.Clin.lnvest.21:15461558, 1955. Activation of efferent neural elements, (6) Smith, J., Robinson, S., Pearcy, M. both centrally and peripherally, has been J. App. Physiol. ~:659-667, ~:659-667, 1952. described above. Few studies have been (7) Kaplan, S., West, C., C. , Foman, S. done on renal afferent fibers, except to Am. J. Physiol. Physi01. 175:363-374, 1953. show that they exist (see above). Attempts B1ake, W. Am. J. Physiol. (8) Blake, 191:393to show functional changes in contralateral 398, 1957. renal function by direct electrical stimu(9) B1ake, Blake, W. Am. J. Pbysiol. Physio1. 181:399lation of renal afferents have been unsuccessful (15), possibly because of 416, 1955. (10) Blake, W. Am. J. Physiol. Physio1. 173:337mixed effects. For example, in the anes344, 1953. thetized dog, denervation of one kidney (11) Mc Kenna, 0., Angelakos, E. Circulation McKenna, appears to enhance sympathetic nerve activity (decreased FF and fractional exRes. ~:345-354, ~:345-354, 1968. nner, B. ,Tadokoro, M. , (12) Falchuk, Fa1chuk, K. ,Bre ,Brenner,B. ,Tadokoro,M. cretion of Na) to the contra-lateral kidney (7,9) whereas unilateral renal rliner,R.Am.J.Physiol. 220:14 27,1971 Be Ber1iner,R.Am.J.Physi01. 220:1427,1971 Hoffman,W. ,Jr., Kagan, A. (13) Berne, R., Hoffman,W.,Jr., A.,, arterial clamping would appear to depress Levy, M. Am. J. Physiol. 171.:564-571, 171.: 564-571, sympathetic nerve activity (enhanced 1952. fractional excretion of water) to the (14) Gill, J.,Jr., J. ,Jr., Casper,A. Am. J. Physio1. Physiol. contra-lateral kidney, a response respons2 which 223:1201-1205,1972. 223:1201-1205, 1972. fails to appear if the clamped kidney has been previously denervated (18). Acta_~hYsiol. These (15) Astrom, A., Crafoord, J. Acta_~hYsio1. Scand. 74:69-78, 1968. observations, if confirmed, could indicate (16) Beacham,W., Kunze, D. J. Physiol. loss of negative or positive feedback 201:73-85, 1969. respectively from one or another ~aro baro(17) Shade, R., Davis, J. J.,, Johnson, J., receptor or from Na receptors. Witty,R.,Braverman,B. Witty,R. ,Braverman,B. Am. Soc. Neph. Abst. (5th Annual) pg. 71, 1971. (18) Blake, B1ake, W. Am. J. Physiol. Physi01. 199:503-508 1960.
ARTE-RIAL
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7
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426