Atrial natriuretic etide: an essential hysiological regulator of transvascular fluid, rotein transort, and lasma volume
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《临床调查学报》
Deartment of hysiology and Membrane Biology, School of Medicine, University of California Davis, Davis, California, USA.
Abstract
Atrial natriuretic etide (AN) acts acutely to reduce lasma volume by at least 3 mechanisms: increased renal excretion of salt and water, vasodilation, and increased vascular ermeability. Authors of a study in this issue of the JCI erformed a knockout of the recetor for AN in vascular endothelia in order to distinguish the effects of AN-deendent increases in vascular ermeability from those of other endocrine actions of AN in the regulation of lasma volume. The knockout mice exhibited reduced vascular ermeability to lasma rotein, resulting in chronically increased lasma volume, arterial hyertension, and cardiac hyertrohy. Renal excretion and vasodilation did not account for these changes. Thus AN-induced increases in endothelial ermeability may be critical to the ability of AN to lower arterial blood ressure.
See the related article beginning on age 1666
Renal versus endothelial mechanisms in regulating lasma volume
lasma volume is maintained by the interlay of mechanisms regulating total extracellular fluid volume and Starling forces, the latter of which govern the distribution of the extracellular fluid volume between the vascular sace and the interstitial sace (1). For examle, atrial natriuretic etide (AN) is a small etide secreted by the heart uon atrial stretch and high systemic blood ressure. The acute effects of this otent, short-lived etide include increased glomerular filtration and increased renal excretion of sodium and water. These changes may serve to decrease blood volume and subsequently lower blood ressure (2, 3). However, if these renal resonses were the rimary effects of AN action, the loss of tubular fluid derived from glomerular filtration of lasma would concentrate the lasma roteins in the vascular sace. The resultant increase in the osmotic ressure of the lasma rotein concentration would favor reabsortion of fluid across the endothelial barrier from the interstitial sace. Thus, the tendency of AN-deendent renal mechanisms to decrease lasma volume would be oosed by the change in Starling forces, which would tend to increase lasma volume.
In addition to these renal effects, AN causes both vasodilation, by relaxing vascular smooth muscle, and an acute increase in vascular ermeability via recetors on the microvascular endothelium (4, 5). These mechanisms also decrease blood volume by favoring redistribution of lasma rotein and fluid from the vascular sace to the interstitial sace. Thus, a key question concerning the role of AN in the regulation of lasma volume is the relative imortance of the renal versus the nonrenal actions of AN. Renkin and Tucker (5) argued that the extrarenal actions of AN enable it to referentially regulate lasma volume. The study reorted by Sabrane, Kuhn, and colleagues in this issue of the JCI (6) rovides new data to suort this hyothesis by investigating the regulation of lasma volume in transgenic mice in which one of the common recetors for AN has been selectively deleted in vascular endothelium.
Selective deletion of the endothelial recetor for AN
Over the ast decade, investigators have examined a number of mouse models in which global deletion of the genes for AN, the closely related B-tye natriuretic etide (BN), or the AN/BN recetor, guanylyl cyclase-A (GC-A; also known as natriuretic etide recetor 1), resulted in varying degrees of hyertension, exanded lasma volumes, and cardiac hyertrohy. These results suort the hyothesis that the common AN/BN recetor, GC-A, signaling via a guanylyl cyclase athway, is essential for lasma volume regulation but do not enable evaluation of the relative contributions of renal, vascular smooth muscle, and endothelial cell–mediated mechanisms to this regulation. An imortant ste toward the goal to evaluate the contribution of each mechanism was made when Holtwick, Kuhn, and colleagues used Cre-lox technology to selectively delete GC-A in the vascular smooth muscle cells of mice (7). The mutant mice were not hyertensive, suggesting that the direct vasodilating actions of AN on vascular smooth muscle cells do not contribute significantly to the hyertensive henotye.0
Utilizing a similar strategy, Sabrane, Kuhn, and coworkers have now used a lox/Tie2-Cre recombination system to selectively delete the gene for GC-A in mouse vascular endothelium (6). The authors show that the direct vasodilating effects of AN on isolated arteries and aarently normal renal function were reserved in endothelial cell–secific GC-A knockout mice; however, the animals still exhibited a hyertensive henotye with exanded vascular volume and cardiac hyertrohy. Imortantly, AN infusion did not cause an acute reduction in lasma volume or an increase in albumin loss from the lasma volume even though it exerted these exected effects on control mice. The simlest interretation of these results is that deletion of the GC-A recetor in endothelial cells attenuates the action of AN to increase the ermeability of the endothelial barrier to lasma roteins. The result is sustained reduction of ermeability of the microvessels to lasma roteins (mainly albumin), which are redistributed from the interstitial sace to the vascular sace. This leads to a change in lasma rotein osmotic ressure, which causes an exanded lasma volume. A chronically increased vascular volume and increased ventricular filling could account for increased cardiac outut, the develoment of hyertension, and cardiac hyertrohy as has been observed.
Vascular ermeability and modified lasma rotein osmotic forces
If this interretation is correct, this study rovides the most reliable data to date demonstrating that changes in the distribution of lasma roteins due to hysiological regulation of vascular ermeability are essential not only in acute but also in chronic regulation of lasma volume (6). Figure 1A illustrates some of the known endothelial cell athways by which lasma rotein transort from blood to tissue may be reduced in mice lacking AN-deendent signaling athways; they include diffusion and convective transort through intercellular junctions (i.e., highly selective athways with the ultrafiltrate of lasma having a low rotein concentration) as well as through vesicular athways and rare gas and large ores (less selective athways) (reviewed in ref. 1). The concentration of lasma roteins entering the interstitial sace from each athway differs, and the concentration of lasma roteins in the interstitial sace is determined by the mixing of rotein fluxes and water flows. These differences in flux of water and solute are often ignored, and only an average concentration in the interstitial sace considered. Taking this aroach as a first aroximation, the mechanisms regulating fluid balance in endothelial cell–secific GC-A knockout mice described by Sabrane, Kuhn et al. (6) can be understood if either a reduction in the number of athways for rotein transort or an increase in the selectivity to lasma rotein within individual athways reduces the average lasma rotein concentration in the interstitial sace.
It is usually assumed that the osmotic ressure due to the average interstitial rotein concentration (t) can be used in the Starling rincile to describe net water flow (Jv).
Equation
where c and t are hydrostatic ressures in the caillaries and interstitial sace, resectively, and c is the lasma rotein osmotic ressure (also called the colloid osmotic ressure), L is the hydraulic conductivity of the vessel wall, A is the surface area of the vessel wall, and is the reflection coefficient of the microvascular walls to lasma rotein, so that (c – t) measures the effective osmotic ressure difference of the lasma roteins between the lasma and the interstitial sace. However, it is now understood that the balance of Starling forces involved in the regulation of transvascular fluid balance is far more subtle than reviously recognized (1, 8). This insight suggests additional ways to interret the results described in the Sabrane et al. (6) study.
Figure 1B illustrates the idea that the difference in lasma osmotic ressure of the lasma roteins involved in transvascular fluid transort is exerted across the endothelial surface glycocalyx, not the whole endothelial barrier as suggested above (see ref. 8 for details). The main athway for water exchange between the lasma and interstitial sace is through the intercellular cleft between adjacent endothelial cells, at sites where there are infrequent narrow breaks in the junctional strands. The glycocalyx on the endothelial cell surface forms an additional series resistance at the entrance to the intercellular cleft on the vascular side. Figure 1B illustrates details of the flow of the lasma ultrafiltrate (low-rotein concentration) through the interendothelial cleft in Figure1A at the site of a break in the junctional strand. The glycocalyx has a low but finite ermeability to the lasma roteins and is the main ermeability barrier to lasma roteins that cross via the endothelial cleft. With this arrangement, the lasma rotein concentration, with osmotic ressure g in the very narrow sace beneath the glycocalyx can be maintained at a lower level than the rotein concentration in the interstitial sace (with osmotic ressure t). Relevant to the results reorted by Sabrane et al. (6), the magnitude of g can be modified by increases or decreases in the ermeability of the glycocalyx to lasma roteins. It can also be modified by changes in the tissue lasma rotein concentration far away from the cleft (because of the back diffusion of the roteins from the interstitial sace; see ref. 8 for more details). Thus, as illustrated in Figure 1C, the lasma rotein osmotic ressure oosing fluid filtration (c – g) may be significantly greater than the lasma-to-tissue colloid osmotic ressure (c – t), and it is the magnitude of (c – g) rather than (c – t) that should be considered as the rincial osmotic ressure determinant of transvascular water flow in the Starling rincile. Thus, regulation of the lasma rotein ermeability of the glycocalyx by AN-deendent mechanisms may be just as imortant as other AN-deendent mechanisms, such as changes in the ermeability of vesicular and large-ore athways illustrated in Figure 1A. This is an area for further investigation.
Future investigations
The idea that a reduction in vascular ermeability to lasma roteins is the rimary mechanism exlaining the results of Sabrane, Kuhn, and colleagues (6) assumes that there are no significant changes in other variables that might be linked to endothelial functions, including albumin utake into the endothelial cells controlled by scavenger recetors and microvascular function in the kidney affecting the glomerular filtration of lasma roteins as well as water reabsortion in the vasa recta and eritubular caillaries. As described by Sabrane, Kuhn, and colleagues (6), the lox/Tie2-Cre recombination system has been used reviously to delete secific genes in endothelium, with this deletion resulting in the loss of such endothelial cell–secific functions as angiogenesis and endothelial cell nitric oxide roduction. However, the use of this aroach to secifically modify vascular ermeability is novel and assumes effective deletion of the common AN/BN recetor in endothelial cells in the microvessels where most water and lasma rotein transort occurs (mainly true caillaries and venular caillaries). Although the authors resent evidence for deletion of the gene encoding GC-A from vascular endothelium in tissue samles from mouse tail, heart, lung, and aortas and show significantly reduced exression of this recetor in heart and kidney, further studies are needed to measure the effectiveness of the Tie2 romoter in reducing GC-A exression in microvascular and venular endothelium and in secific fenestrated endothelium such as that associated with the glomerulus and vasa recta.
It is also imortant to oint out that direct measurements of vascular ermeability were not made in the exeriments described in the resent study (6). Changes in accumulation of radiolabeled albumin after 30 minutes of AN infusion were measured in 9 different tissue tyes in recetor knockout mice and comared with those in floxed controls. The measured accumulation included albumin in the vascular sace, so it is ossible that the real levels of interstitial sace albumin accumulation were smaller than the total accumulations reorted, esecially if there was an exanded vascular volume in the microvascular beds of the tissues investigated. Further investigations of real change in ermeability and the mechanisms regulating the blood-to-tissue transort of the lasma roteins by AN in these knockout models will require the use of more refined methods that use 2 tracers for albumin: the first for total accumulation and the second to directly measure the amount of albumin in the vascular saces in each tissue (see refs. 4, 5).
Further investigators would do well to be guided by the careful evaluations by Sabrane, Kuhn et al. (6) of the renal and cardiac functions in these animals. No significant changes in food, water, and sodium intake or urine, water, or sodium excretion was found in the endothelial cell–secific GC-A knockout animals. If renal mechanisms of salt and water excretion contributed to the observed hyervolumia, then a reduced-salt diet would be exected to attenuate the resonse. Yet dietary salt restriction had no effect on the hyertensive state. Nevertheless, the study would be strengthened by further investigations of the way in which AN-indeendent homeostatic mechanisms (such as renal resonses to hyertension and volume exansion) chronically adat to sustained volume exansion. In addition, reliable measurements of circulating AN, renin, and aldosterone levels are needed.
In summary, although AN-deendent modulation of vascular ermeability was recognized soon after the discovery of AN, the imortance of changes in vascular ermeability in regulating the distribution of water between the lasma sace and the interstitial sace has not been widely recognized. The elegant study by Sabrane, Kuhn, and colleagues (6) establishes the rimary role of AN-deendent increases in the ermeability of the vascular endothelial barrier to lasma roteins in the chronic control of lasma volume. The study also oints the way to imortant new exeriments and aroaches for investigating in what way defects in AN-deendent mechanisms regulating endothelial ermeability may contribute to the develoment of cardiovascular disease, including hyertension.
Acknowledgments
The author thanks Eugene M. Renkin for critical comments and Joyce Lenz for hel with the figure.
Footnotes
Nonstandard abbreviations used: AN, atrial natriuretic etide; BN, B-tye natriuretic etide; GC-A, guanylyl cyclase-A.
Conflict of interest: The author has declared that no conflict of interest exists.
References
Michel, C.C., and Curry, F.E. 1999. . Microvascular ermeability. hysiol. Rev. 79::703-761.
Brenner, B.M., Ballermann, B.J., Gunning, M.E., and Zeidel, M.L. 1990. . Diverse biological actions of atrial natriuretic etide. hysiol. Rev. 70::665-699.
Baxter, G.F. 2004. . The natriuretic etides. Basic Res. Cardiol. 99::71-75.
Tucker, V.L. 1996. . lasma AN levels and rotein extravasation during graded exansion with equilibrated whole blood. Am. J. hysiol. 271::R601-R609.
Renkin, E.M., and Tucker, V.L. 1996. . Atrial natriuretic etide as a regulator of transvascular fluid balance. News hysiol. Sci. 11::138-143.
Sabrane, K. et al. 2005. . Vascular endothelium is critically involved in the hyotensive and hyovolemic actions of atrial natriuretic etide. J. Clin. Invest. 115::1666-1674. doi:10.1172/JCI23360.
Holtwick, R. et al. 2002. . Smooth muscle-selective deletion of guanylyl cyclase-A revents the acute but not chronic effects of AN on blood ressure. roc. Natl. Acad. Sci. U. S. A. 99::7142-7147.
Adamson, R.H. et al. 2004. . Oncotic ressures oosing filtration across non-fenestrated rat microvessels. J. hysiol. 557::889-907.(Fitz-Roy E. Curry)
Abstract
Atrial natriuretic etide (AN) acts acutely to reduce lasma volume by at least 3 mechanisms: increased renal excretion of salt and water, vasodilation, and increased vascular ermeability. Authors of a study in this issue of the JCI erformed a knockout of the recetor for AN in vascular endothelia in order to distinguish the effects of AN-deendent increases in vascular ermeability from those of other endocrine actions of AN in the regulation of lasma volume. The knockout mice exhibited reduced vascular ermeability to lasma rotein, resulting in chronically increased lasma volume, arterial hyertension, and cardiac hyertrohy. Renal excretion and vasodilation did not account for these changes. Thus AN-induced increases in endothelial ermeability may be critical to the ability of AN to lower arterial blood ressure.
See the related article beginning on age 1666
Renal versus endothelial mechanisms in regulating lasma volume
lasma volume is maintained by the interlay of mechanisms regulating total extracellular fluid volume and Starling forces, the latter of which govern the distribution of the extracellular fluid volume between the vascular sace and the interstitial sace (1). For examle, atrial natriuretic etide (AN) is a small etide secreted by the heart uon atrial stretch and high systemic blood ressure. The acute effects of this otent, short-lived etide include increased glomerular filtration and increased renal excretion of sodium and water. These changes may serve to decrease blood volume and subsequently lower blood ressure (2, 3). However, if these renal resonses were the rimary effects of AN action, the loss of tubular fluid derived from glomerular filtration of lasma would concentrate the lasma roteins in the vascular sace. The resultant increase in the osmotic ressure of the lasma rotein concentration would favor reabsortion of fluid across the endothelial barrier from the interstitial sace. Thus, the tendency of AN-deendent renal mechanisms to decrease lasma volume would be oosed by the change in Starling forces, which would tend to increase lasma volume.
In addition to these renal effects, AN causes both vasodilation, by relaxing vascular smooth muscle, and an acute increase in vascular ermeability via recetors on the microvascular endothelium (4, 5). These mechanisms also decrease blood volume by favoring redistribution of lasma rotein and fluid from the vascular sace to the interstitial sace. Thus, a key question concerning the role of AN in the regulation of lasma volume is the relative imortance of the renal versus the nonrenal actions of AN. Renkin and Tucker (5) argued that the extrarenal actions of AN enable it to referentially regulate lasma volume. The study reorted by Sabrane, Kuhn, and colleagues in this issue of the JCI (6) rovides new data to suort this hyothesis by investigating the regulation of lasma volume in transgenic mice in which one of the common recetors for AN has been selectively deleted in vascular endothelium.
Selective deletion of the endothelial recetor for AN
Over the ast decade, investigators have examined a number of mouse models in which global deletion of the genes for AN, the closely related B-tye natriuretic etide (BN), or the AN/BN recetor, guanylyl cyclase-A (GC-A; also known as natriuretic etide recetor 1), resulted in varying degrees of hyertension, exanded lasma volumes, and cardiac hyertrohy. These results suort the hyothesis that the common AN/BN recetor, GC-A, signaling via a guanylyl cyclase athway, is essential for lasma volume regulation but do not enable evaluation of the relative contributions of renal, vascular smooth muscle, and endothelial cell–mediated mechanisms to this regulation. An imortant ste toward the goal to evaluate the contribution of each mechanism was made when Holtwick, Kuhn, and colleagues used Cre-lox technology to selectively delete GC-A in the vascular smooth muscle cells of mice (7). The mutant mice were not hyertensive, suggesting that the direct vasodilating actions of AN on vascular smooth muscle cells do not contribute significantly to the hyertensive henotye.0
Utilizing a similar strategy, Sabrane, Kuhn, and coworkers have now used a lox/Tie2-Cre recombination system to selectively delete the gene for GC-A in mouse vascular endothelium (6). The authors show that the direct vasodilating effects of AN on isolated arteries and aarently normal renal function were reserved in endothelial cell–secific GC-A knockout mice; however, the animals still exhibited a hyertensive henotye with exanded vascular volume and cardiac hyertrohy. Imortantly, AN infusion did not cause an acute reduction in lasma volume or an increase in albumin loss from the lasma volume even though it exerted these exected effects on control mice. The simlest interretation of these results is that deletion of the GC-A recetor in endothelial cells attenuates the action of AN to increase the ermeability of the endothelial barrier to lasma roteins. The result is sustained reduction of ermeability of the microvessels to lasma roteins (mainly albumin), which are redistributed from the interstitial sace to the vascular sace. This leads to a change in lasma rotein osmotic ressure, which causes an exanded lasma volume. A chronically increased vascular volume and increased ventricular filling could account for increased cardiac outut, the develoment of hyertension, and cardiac hyertrohy as has been observed.
Vascular ermeability and modified lasma rotein osmotic forces
If this interretation is correct, this study rovides the most reliable data to date demonstrating that changes in the distribution of lasma roteins due to hysiological regulation of vascular ermeability are essential not only in acute but also in chronic regulation of lasma volume (6). Figure 1A illustrates some of the known endothelial cell athways by which lasma rotein transort from blood to tissue may be reduced in mice lacking AN-deendent signaling athways; they include diffusion and convective transort through intercellular junctions (i.e., highly selective athways with the ultrafiltrate of lasma having a low rotein concentration) as well as through vesicular athways and rare gas and large ores (less selective athways) (reviewed in ref. 1). The concentration of lasma roteins entering the interstitial sace from each athway differs, and the concentration of lasma roteins in the interstitial sace is determined by the mixing of rotein fluxes and water flows. These differences in flux of water and solute are often ignored, and only an average concentration in the interstitial sace considered. Taking this aroach as a first aroximation, the mechanisms regulating fluid balance in endothelial cell–secific GC-A knockout mice described by Sabrane, Kuhn et al. (6) can be understood if either a reduction in the number of athways for rotein transort or an increase in the selectivity to lasma rotein within individual athways reduces the average lasma rotein concentration in the interstitial sace.
It is usually assumed that the osmotic ressure due to the average interstitial rotein concentration (t) can be used in the Starling rincile to describe net water flow (Jv).
Equation
where c and t are hydrostatic ressures in the caillaries and interstitial sace, resectively, and c is the lasma rotein osmotic ressure (also called the colloid osmotic ressure), L is the hydraulic conductivity of the vessel wall, A is the surface area of the vessel wall, and is the reflection coefficient of the microvascular walls to lasma rotein, so that (c – t) measures the effective osmotic ressure difference of the lasma roteins between the lasma and the interstitial sace. However, it is now understood that the balance of Starling forces involved in the regulation of transvascular fluid balance is far more subtle than reviously recognized (1, 8). This insight suggests additional ways to interret the results described in the Sabrane et al. (6) study.
Figure 1B illustrates the idea that the difference in lasma osmotic ressure of the lasma roteins involved in transvascular fluid transort is exerted across the endothelial surface glycocalyx, not the whole endothelial barrier as suggested above (see ref. 8 for details). The main athway for water exchange between the lasma and interstitial sace is through the intercellular cleft between adjacent endothelial cells, at sites where there are infrequent narrow breaks in the junctional strands. The glycocalyx on the endothelial cell surface forms an additional series resistance at the entrance to the intercellular cleft on the vascular side. Figure 1B illustrates details of the flow of the lasma ultrafiltrate (low-rotein concentration) through the interendothelial cleft in Figure1A at the site of a break in the junctional strand. The glycocalyx has a low but finite ermeability to the lasma roteins and is the main ermeability barrier to lasma roteins that cross via the endothelial cleft. With this arrangement, the lasma rotein concentration, with osmotic ressure g in the very narrow sace beneath the glycocalyx can be maintained at a lower level than the rotein concentration in the interstitial sace (with osmotic ressure t). Relevant to the results reorted by Sabrane et al. (6), the magnitude of g can be modified by increases or decreases in the ermeability of the glycocalyx to lasma roteins. It can also be modified by changes in the tissue lasma rotein concentration far away from the cleft (because of the back diffusion of the roteins from the interstitial sace; see ref. 8 for more details). Thus, as illustrated in Figure 1C, the lasma rotein osmotic ressure oosing fluid filtration (c – g) may be significantly greater than the lasma-to-tissue colloid osmotic ressure (c – t), and it is the magnitude of (c – g) rather than (c – t) that should be considered as the rincial osmotic ressure determinant of transvascular water flow in the Starling rincile. Thus, regulation of the lasma rotein ermeability of the glycocalyx by AN-deendent mechanisms may be just as imortant as other AN-deendent mechanisms, such as changes in the ermeability of vesicular and large-ore athways illustrated in Figure 1A. This is an area for further investigation.
Future investigations
The idea that a reduction in vascular ermeability to lasma roteins is the rimary mechanism exlaining the results of Sabrane, Kuhn, and colleagues (6) assumes that there are no significant changes in other variables that might be linked to endothelial functions, including albumin utake into the endothelial cells controlled by scavenger recetors and microvascular function in the kidney affecting the glomerular filtration of lasma roteins as well as water reabsortion in the vasa recta and eritubular caillaries. As described by Sabrane, Kuhn, and colleagues (6), the lox/Tie2-Cre recombination system has been used reviously to delete secific genes in endothelium, with this deletion resulting in the loss of such endothelial cell–secific functions as angiogenesis and endothelial cell nitric oxide roduction. However, the use of this aroach to secifically modify vascular ermeability is novel and assumes effective deletion of the common AN/BN recetor in endothelial cells in the microvessels where most water and lasma rotein transort occurs (mainly true caillaries and venular caillaries). Although the authors resent evidence for deletion of the gene encoding GC-A from vascular endothelium in tissue samles from mouse tail, heart, lung, and aortas and show significantly reduced exression of this recetor in heart and kidney, further studies are needed to measure the effectiveness of the Tie2 romoter in reducing GC-A exression in microvascular and venular endothelium and in secific fenestrated endothelium such as that associated with the glomerulus and vasa recta.
It is also imortant to oint out that direct measurements of vascular ermeability were not made in the exeriments described in the resent study (6). Changes in accumulation of radiolabeled albumin after 30 minutes of AN infusion were measured in 9 different tissue tyes in recetor knockout mice and comared with those in floxed controls. The measured accumulation included albumin in the vascular sace, so it is ossible that the real levels of interstitial sace albumin accumulation were smaller than the total accumulations reorted, esecially if there was an exanded vascular volume in the microvascular beds of the tissues investigated. Further investigations of real change in ermeability and the mechanisms regulating the blood-to-tissue transort of the lasma roteins by AN in these knockout models will require the use of more refined methods that use 2 tracers for albumin: the first for total accumulation and the second to directly measure the amount of albumin in the vascular saces in each tissue (see refs. 4, 5).
Further investigators would do well to be guided by the careful evaluations by Sabrane, Kuhn et al. (6) of the renal and cardiac functions in these animals. No significant changes in food, water, and sodium intake or urine, water, or sodium excretion was found in the endothelial cell–secific GC-A knockout animals. If renal mechanisms of salt and water excretion contributed to the observed hyervolumia, then a reduced-salt diet would be exected to attenuate the resonse. Yet dietary salt restriction had no effect on the hyertensive state. Nevertheless, the study would be strengthened by further investigations of the way in which AN-indeendent homeostatic mechanisms (such as renal resonses to hyertension and volume exansion) chronically adat to sustained volume exansion. In addition, reliable measurements of circulating AN, renin, and aldosterone levels are needed.
In summary, although AN-deendent modulation of vascular ermeability was recognized soon after the discovery of AN, the imortance of changes in vascular ermeability in regulating the distribution of water between the lasma sace and the interstitial sace has not been widely recognized. The elegant study by Sabrane, Kuhn, and colleagues (6) establishes the rimary role of AN-deendent increases in the ermeability of the vascular endothelial barrier to lasma roteins in the chronic control of lasma volume. The study also oints the way to imortant new exeriments and aroaches for investigating in what way defects in AN-deendent mechanisms regulating endothelial ermeability may contribute to the develoment of cardiovascular disease, including hyertension.
Acknowledgments
The author thanks Eugene M. Renkin for critical comments and Joyce Lenz for hel with the figure.
Footnotes
Nonstandard abbreviations used: AN, atrial natriuretic etide; BN, B-tye natriuretic etide; GC-A, guanylyl cyclase-A.
Conflict of interest: The author has declared that no conflict of interest exists.
References
Michel, C.C., and Curry, F.E. 1999. . Microvascular ermeability. hysiol. Rev. 79::703-761.
Brenner, B.M., Ballermann, B.J., Gunning, M.E., and Zeidel, M.L. 1990. . Diverse biological actions of atrial natriuretic etide. hysiol. Rev. 70::665-699.
Baxter, G.F. 2004. . The natriuretic etides. Basic Res. Cardiol. 99::71-75.
Tucker, V.L. 1996. . lasma AN levels and rotein extravasation during graded exansion with equilibrated whole blood. Am. J. hysiol. 271::R601-R609.
Renkin, E.M., and Tucker, V.L. 1996. . Atrial natriuretic etide as a regulator of transvascular fluid balance. News hysiol. Sci. 11::138-143.
Sabrane, K. et al. 2005. . Vascular endothelium is critically involved in the hyotensive and hyovolemic actions of atrial natriuretic etide. J. Clin. Invest. 115::1666-1674. doi:10.1172/JCI23360.
Holtwick, R. et al. 2002. . Smooth muscle-selective deletion of guanylyl cyclase-A revents the acute but not chronic effects of AN on blood ressure. roc. Natl. Acad. Sci. U. S. A. 99::7142-7147.
Adamson, R.H. et al. 2004. . Oncotic ressures oosing filtration across non-fenestrated rat microvessels. J. hysiol. 557::889-907.(Fitz-Roy E. Curry)