V tomto anglickom článku o úlohe obličiek (renes) v regulácii krvného tlaku sú popísané kľúčové mechanizmy, ktorými obličky disponujú v regulácii objemu telesných tekutin ako základnej determinanty určujúcej hodnotu krvného tlaku.
L. Gabriel Navar, PhD
The devastating long-term consequences of high blood pressure include stroke, heart disease, atherosclerosis, renal disease, and other end-organ damage. From a physiologic perspective, it is not apparent why the propensity for hypertension is so widespread in the general population. Clearly, an adequate arterial pressure is essential for perfusion of the tissues to provide adequate oxygenation and nutrition to the brain and other critical organs. Although the various microcirculatory beds have the capability to adjust vascular resistance to autoregulate blood flow, systemic arterial pressure is usually maintained at levels greater than required for requisite tissue perfusion. The myriad of neurohumoral mechanisms designed to protect against decreases in systemic arterial pressure provide a reserve capacity for increased perfusion when there are increased tissue demands. The unfortunate consequence of having these powerful physiologic control mechanisms is that they may be inappropriately activated in certain circumstances or by genetically determined traits, leading to hypertension and cardiovascular injury. Evidence continues to accumulate indicating that the kidney not only is victim to hypertension-related injury, but also contributes as a villain to the hypertensinogenic process.
(J Clin Hypertens. 2005;7:542–549) © Le Jacq.
The major importance of the kidneys in the development of hypertension is dramatically supported by results from transplantation studies. In experimental animals, normotensive recipients of a renal graft from genetically hypertensive donor rats develop post-transplantation hypertension. These responses have been observed in at least four different animal models of hypertension. In addition, genetically hypertensive rats that have had bilateral nephrectomy and receive a kidney from normotensive rats exhibit a reduction in arterial pressure (AP). Clinical studies also indicate that recipients of a renal graft from a donor with a genetic predisposition to hypertension develop higher blood pressures and require more antihypertensive treatment than recipients of a kidney from a normotensive donor without a family history of hypertension. These transplantation studies support the concept that many forms of essential hypertension involve a primary renal disorder that may be responsible for initiating the process. In addition, several monogenic diseases of hypertension have been shown to be characterized by critical functional derangements that compromise the kidney’s ability to respond appropriately to increased salt intake.
Powerful neural, hormonal, and hemodynamic mechanisms interact to achieve efficient regulation of AP by responding to different extrinsic disturbances capable of influencing cardiovascular function. The two major determinants of AP, cardiac output and total peripheral resistance, are continuously regulated by a combination of short- and long-term mechanisms. Some mechanisms respond within seconds to minutes, while other systems reach maximum activity only after several hours to several days. Rapidly adjusting mechanisms primarily adjust peripheral vascular resistance, cardiovascular capacitance, and cardiac performance. In contrast, mechanisms that regulate AP over the long term are intimately linked to the regulation of effective blood volume, sodium balance, and extracellular fluid volume (ECFV).
Net balance of sodium and water reflects the difference between intake and output, with intake being a function of diet and environment and output primarily determined by renal sodium excretion. Sodium and its accompanying extracellular anions, chloride and bicarbonate, constitute the major osmotically active solutes in extracellular fluid. Importantly, vasopressin and the thirst mechanisms regulate plasma osmolality and plasma sodium concentration within narrow limits such that changes in the net balance of ECFV sodium obligate accompanying fluid to maintain ECFV osmolality. Thus, when the vasopressin mechanism is intact, net sodium balance determines the level of ECFV. It is possible to control sodium balance by regulating intake; however, this does not usually occur in modern society where there is an abundance of salt in the food we eat. Consequently, the burden of regulation is on the kidneys, which normally have the capability to adjust the sodium excretion rate over a wide range in response to large variations in intake. In addition to the effects of increases in sodium intake on ECFV, the actual increases in plasma sodium concentration during increases in salt intake, although small, may contribute to the hypertensive process by influencing vascular reactivity.
Because of the close association between blood volume and ECFV, changes in ECFV are reflected within the vascular compartment as long as the plasma protein concentration is regulated appropriately and the microvasculature maintains its integrity. Various cardiovascular receptors can detect such changes and send appropriate signals to the kidneys by alterations in renal nerve sympathetic activity or through various hormones such as atrial natriuretic peptide. An increase in blood volume distends the capacitance vessels and increases mean circulatory pressure, which provides the driving pressure for blood flow back to the heart in the form of venous return. The mean circulatory pressure is the overall integrated filling pressure in the cardiovascular system and reflects the effective blood volume. Through its direct effects on venous return and cardiac output, the mean circulatory pressure influences AP. In turn, AP exerts direct effects to alter renal sodium and water excretion.
An excellent example of the effects of changes in blood volume on blood pressure is the patient on chronic dialysis who has undergone nephrectomy. Between dialysis periods, these patients must regulate their sodium balance by regulating salt intake. If they accumulate large excesses of salt and water, usually reflected as weight gain, they also have increased AP. Similarly, patients with chronic renal insufficiency who have severely limited filtered loads may not be able to sufficiently suppress tubular reabsorptive mechanisms to allow for adequate sodium excretion. Numerous neural and hormonal mechanisms interact to influence cardiovascular and renal function. Their large number and complex interactions account for the complexities of AP regulations. Some of these mechanisms are activated to protect against stimuli that lower AP, while others serve to protect against conditions of excess salt intake. In this review, only a few of the mechanisms most relevant to the role of the kidney in hypertension will be discussed in detail.
For any given steady state condition, there is a direct relationship between renal perfusion pressure and sodium excretion. Acute elevations in renal perfusion pressure produce natriuresis and diuresis. In addition, several major neurohumoral mechanisms influence the setting of the pressure natriuresis mechanism to provide a much more sensitive and complex long-term interaction between AP and sodium excretion. Under normal physiologic conditions, increased salt intake elicits an orchestrated set of physiologic responses that markedly enhance the steepness of the pressure natriuresis relationship. In contrast, during sodium depletion or reduced blood volume, the slope of the pressure natriuresis relationship is greatly reduced. The normal control of AP critically depends on the dynamic responsiveness of the pressure natriuresis mechanism to reflect the status of sodium balance and ECFV, and thus allow rapid alterations in sodium excretion to occur with minimal changes in AP.
The normal operation of the pressure natriuresis mechanism depends collectively on the integrity of all the intrarenal mechanisms that can influence sodium excretion and on the appropriate function of all the extrarenal sensing mechanisms that detect alterations in sodium balance, blood volume, or AP and communicate signals to the kidneys. Consequently, derangements in one or more of the mechanisms that regulate sodium excretion can suppress the slope of the pressure natriuresis relationship, leading to a resetting of AP up to the level required to reestablish sodium balance. The magnitude of the increase in AP depends on the quantitative relationship between AP and sodium excretion existing for that particular setting. This relationship is determined by the responsiveness of the mediating mechanism and the coexisting influences of modulating factors.
The renal autoregulatory mechanism efficiently maintains renal blood flow (RBF), glomerular filtration rate (GFR), and filtered sodium load during changes in renal AP over a wide range. Thus, the increases in sodium excretion in response to increases in AP are due to progressive reductions in fractional sodium reabsorption. The specific mechanisms and tubule segments responsible for the AP-dependent changes in sodium excretion have not been firmly established. Some investigators have suggested that the changes in tubule reabsorption rate are mediated by associated changes in renal interstitial fluid pressure, peritubular physical forces, or changes in medullary blood flow that occur even in the presence of RBF and GFR autoregulation. Other studies have implicated a local hormonal mechanism that responds to alterations in AP and elicits a change in proximal tubule reabsorption rate by altering the rate or abundance of the transport proteins. Alternatively, changes in tubular reabsorption may occur primarily at distal nephron and collecting duct segments as a consequence of changes in the activity of the sodium channels and the sodium-chloride cotransporters. Several studies have provided evidence that endothelial-derived nitric oxide (NO) may be a principal mediator of pressure natriuresis. Increases in arteriolar shear stress caused by increases in AP stimulate intrarenal production of NO, which has dual effects to inhibit tubule sodium reabsorptive mechanisms and exert vasodilatory actions. The attractive aspect of this hypothesis is that it provides a mechanistic link between the changes in AP and the release of a mediator agent that is able to directly alter net sodium reabsorption. This hypothesis is supported by studies showing that a deficiency of intrarenal NO levels contributes to impaired sodium excretory function in some forms of salt-sensitive hypertension. In addition to its vascular effects, NO increases intracellular cyclic guanosine monophosphate in tubular cells, which leads to a reduced reabsorption rate through cyclic guanosine monophosphate-sensitive sodium entry pathways. Thus, NO may play a pivotal role in the regulation of AP by influencing vascular tone throughout the cardiovascular system as well as by serving as the direct link between AP and sodium excretion. Consequently, disease conditions involving endothelial dysfunction lead to hypertension, not only because of the altered vascular responsiveness, but also because of the critical role of NO in the pressure natriuresis relationship.
As mentioned, the pressure natriuresis mechanism is dynamic, with its slope subject to continuous adjustment by a large number of modulating factors including angiotensin II (Ang II), various arachidonic acid metabolites, atrial natriuretic peptides, renal sympathetic activity, and physical mechanisms such as renal interstitial fluid pressure, renal hemodynamic status, and peritubular capillary colloid osmotic pressure. Furthermore, the impact of a natriuretic stimulus is greatly influenced by the prevailing status of the pressure natriuresis relationship as well as the AP. The higher the AP, or the greater the slope of the pressure natriuresis relationship, the greater the response to natriuretic stimulus. Thus, stimuli such as increased renal sympathetic tone, increased activity of the RAS, and increased circulating catecholamines that can exert a sustained reduction in the slope of the pressure natriuresis relationship may exert hypertensinogenic effects.
The magnitude of the pressure natriuresis relationship is influenced by the prevailing level of RBF and GFR. Studies of renal function have shown varying degrees of reduced RBF and GFR in hypertensive subjects. Increases in renal vascular resistance can lead to diminished sodium excretion by either decreasing the GFR or enhancing peritubular reabsorption. Many individuals predisposed to hypertension manifest reduced RBF and elevated filtration fraction even before the development of hypertension. The attenuated response may be due to an inability to exhibit an appropriate renal vasodilatory response to increases in sodium intake. Borderline hypertensive patients have also been shown to have greater renal vasoconstrictor responses to various stimuli such as postural changes or adrenergic stimulation. Thus, although not always observed, a substantial subset of hypertensive patients may initially exhibit increased renal vascular resistance and reduced renal hemodynamics. In addition, patients with compromised renal function due to chronic kidney disease have a greater prevalence of hypertension. Chronic renal failure patients with marked reductions in GFR are able to suppress fractional reabsorption rate, but the absolute sodium excretion may still remain less than is needed to maintain sodium balance unless intake is reduced.
At the level of the postglomerular circulation, the net balance of hydrostatic and oncotic forces allows the elevated colloid osmotic pressure to serve as the predominant force responsible for return of tubular reabsorbate into the vasculature. Renal vasoconstriction reduces hydrostatic pressure and increases filtration fraction, leading to an enhanced peritubular reabsorptive force and subsequent increases in tubular reabsorption. The associated reductions in renal interstitial fluid pressure and/or changes in local paracrine factors enhance the tubular reabsorption rate. Changes in medullary blood flow are also associated with alterations in net reabsorption by the loops of Henle and collecting ducts. Decreases in medullary blood flow enhance the accumulation of solutes in the interstitium and are associated with reductions in urinary flow and sodium excretion. The antinatriuresis may be due to greater volume abstraction from the descending loop of Henle as a result of increased medullary tonicity, resulting in decreased tubule fluid flow that reaches the ascending limb of the loop of Henle. Therefore, changes in medullary blood flow constitute a parallel hemodynamic mechanism by which various neurohumoral systems regulate sodium excretion.
Because even relatively small changes in the pressures and flows can cause substantial alterations in filtered load and postglomerular dynamics, the renal circulation exhibits highly efficient autoregulation of RBF and GFR in response to changes in AP. During autoregulation, the intrarenal pressures in the glomerular and peritubular capillaries and in the proximal tubules also exhibit autoregulatory behavior, indicating that the major site for autoregulatory resistance adjustments is preglomerular. Several studies have demonstrated that there is a progressive impairment of autoregulatory capability and pressure responsiveness of the preglomerular vasculature in several experimental models of hypertension.
Two mechanisms interact to provide highly efficient renal autoregulation: the macula densa feedback mechanism and the myogenic mechanism. The macula densa mechanism, also known as tubuloglomerular feedback (TGF), responds to perturbations that cause changes in distal tubular fluid flow past the macula densa and associated changes in the tubule fluid solute concentration. In turn, a paracrine signal is generated by the macula densa cells and sent to afferent arterioles such that increases in flow past the macula densa elicit vasoconstriction, whereas decreases in flow cause afferent vasodilation. Blocking flow to the distal tubule or interrupting the feedback loop attenuates the autoregulatory efficiency of RBF, GFR, and glomerular pressure, indicating that an intact TGF mechanism is required for the highly efficient autoregulation characteristic of the kidney. Thus, the TGF mechanism is an important intrinsic mechanism that helps to balance the hemodynamically dependent filtered sodium load with the reabsorbtive capabilities of the nephron and helps regulate the load to the distal nephron segments. Various hypertensive conditions are associated with enhanced activity of the TGF mechanism.
The myogenic mechanism responds to changes in arteriolar wall tension occurring in response to alterations in AP, and activates a vascular sensor element that regulates vascular smooth muscle tone. Interlobular and arcuate arteries and afferent arterioles, but not efferent arterioles, exhibit myogenic responses to changes in wall tension. The residual autoregulatory capacity that exists during blockade of the TGF mechanism indicates that the myogenic mechanism contributes to autoregulatory responses of the renal vasculature. Collectively, these processes allow the autoregulatory mechanism to stabilize the microcirculatory environment throughout the kidney as well as the filtered load to the nephron. Tubular Transport
Derangements in tubular transport mechanisms can cause hypertension even in the absence of overt reductions in renal hemodynamics. Under normal conditions, less than 1% of the filtered sodium load is excreted, and small percentile changes in the fractional sodium reabsorption can translate into large changes in daily sodium excretion. Therefore, any factor that changes the delicate balance existing between the hemodynamically determined filtered load and the tubular reabsorption rate can lead to inappropriate retention of salt and water. An example is excess aldosterone secretion attributable to adenoma or hyperplasia of the adrenal cortex. Aldosterone stimulates reabsorption of sodium by distal tubule and collecting duct segments. Aldosterone binds to specific intracellular receptors and the hormone-receptor complex is translocated to the nucleus where it promotes transcription of messenger RNA, leading to increased NaVK+ adenosine triphosphatase activity at the basolateral membranes and increased sodium channels on the luminal membrane. There is also evidence for nongenomic actions of aldosterone that can occur more rapidly and enhance net sodium reabsorption. Excessive formation of aldosterone reduces sodium excretion for any given level of AP and GFR.
Several interesting genetically linked forms of hypertension are similar to that seen with hyperaldosteronism in that they are due primarily to an enhanced sodium reabsorptive rate in distal tubule and collecting duct segments. Several of these genetically linked forms of hypertension involve a single gene mutation, which has allowed their analysis by molecular genetic approaches. Glucocorticoid-remediable aldosteronism involves a gene defect in which aldosterone secretion becomes primarily regulated by adrenocorticotropic hormone. Defects in the enzymes 11β-hydroxylase or 17α-hydroxylase lead to the inability to synthesize cortisol, which leads to overproduction of mineralocorticoids. Other defects cause a deficiency in kidney cells of 11β-hydroxysteriod dehydrogenase, which normally metabolizes cortisol to cortisone. Since cortisol can activate the mineralocorticoid receptor, the accumulated intracellular cortisol then causes the same syndrome as hyperaldosteronism. The hypertension caused by overingestion of licorice is due to licorice-induced inhibition of 11β-hydroxysteroid dehydrogenase. In these and similar situations, there is an enhanced activation of mineralocorticoid-induced sodium reabsorptive mechanisms, which leads to sodium retention.
Liddle’s syndrome presents another interesting form of hypertension caused by a single gene mutation that is similar to that of mineralocortical excess but without elevated aldosterone levels. Patients with this condition have a mutation in one of the genes encoding for one of the subunits of the amiloride-sensitive sodium channel that is present on the luminal side of the collecting tubule cells. The mutation prevents the removal or inactivation of these sodium channels, which augment overall sodium reabsorption.
Other genetic defects lead to the overexpression and/or overactivity of specific proteins involved in the tubular reabsorption of sodium. For example, the Milan hypertensive strain of rat has been found to have enhanced activity of Na+ /K+ adenosine triphosphatase, which has a major role in regulating sodium reabsorption throughout the tubule. Likewise, genetic mutations that prevent the normal regulation of the proximal reabsorption rate by dopamine or other paracrine agents such as prostaglandins may also contribute to excess sodium reabsorption during conditions of high salt intake. Thus, genetic factors that cause overactivity of various sodium regulatory mechanisms may lead to an inappropriate elevation in sodium reabsorption which, if not corrected by other counteracting mechanisms, leads to hypertension.
These forms of hypertension can be thought of as being primarily volume-dependent in that the initial causal event reduces the ability of the kidneys to excrete sufficient sodium necessary to prevent accumulation and increased ECFV. Because these are conditions of actual or relative volume expansion, the volume expansion may actually reduce overall sympathetic tone and inhibit major vasoconstrictor systems responsible for sodium conservation such as the renin-angiotensin system (RAS). Thus, such patients may not exhibit substantive responses to angiotensin-converting enzyme (ACE) inhibitors or Ang II receptor antagonists.
Although volume-dependent hypertension is conceptually easier to understand, most hypertensive patients have a more complex form that involves excessive production of vasoconstrictor substances that elicit effects on the kidney to reduce RBF and GFR and enhance fractional tubular sodium reabsorption. Of these systems, the most significant with regard to clinical relevance and physiologic impact is the RAS. Furthermore, because renin—the main physiologic determinant of Ang II levels—is formed primarily by juxtaglomerular cells in the kidneys, hypertension caused by an inappropriately activated RAS is hypertension of renal origin.
Normally, the RAS serves vital homeostatic functions to protect against life-threatening loss of salt and ECFV under conditions of a salt-deficient environment. The efficiency and power of the RAS also make it a prime contributor to hypertension if it is inappropriately activated under conditions of relative salt abundance or in various types of renal injury. Renin, released primarily from the juxtaglomerular cells of afferent arterioles, generates Ang I from angiotensinogen, which is formed primarily by the liver but also in the kidney. The decapeptide is subsequently cleaved to the octapeptide, Ang II, by ACE. ACE is abundant in the lungs but is also found to bind to endothelial cells in many other organs, including the kidney. In addition to endothelial localization, ACE is present on the proximal tubules bound to the brush border. While several other angiotensin peptides exert biologic effects, Ang II remains the most potent and clinically relevant of the angiotensin peptides. Two major types of Ang II receptors have been identified (ATX and AT2 ). The AT1 receptor exerts the most profound role as the receptor responsible for activating the many powerful hypertensinogenic influences of the RAS.
Ang II exerts multiple intrarenal effects, including direct renal vasoconstriction, augmentation of TGF sensitivity, and stimulation of proximal and distal tubular reabsorption rate. Ang II stimulates the activity of the luminal Na+ /H+ exchanger and the basolateral NaHCO3 cotransporter in the proximal tubule cell. Ang II also regulates distal nephron sodium reabsorptive mechanisms including the Na+ /H+ exchanger and the amiloride-sensitive sodium channel.
The renal vasoconstrictive effects of Ang II result in decreases in RBF and, to a lesser extent, in GFR; thus there is usually an increase in filtration fraction. Although it is often stated that Ang II primarily constricts the efferent arterioles, Ang II constricts both preglomerular and postglomerular arteriolar segments, which accounts for its ability to increase filtration fraction. The preglomerular effects of Ang II are due to direct vasoconstrictive actions as well as to effects caused by increased sensitivity of the TGF mechanism. Ang II also reduces the glomerular filtration coefficient. In addition, medullary hemodynamics may be responsive to Ang II at concentrations lower than those required to elicit cortical vasoconstriction.
In renal vascular smooth muscle cells, Ang II increases cytosolic Ca2+ levels by enhancing Ca2+ entry as well as by mobilization of Ca2+ release from intracellular storage sites. Ang II-induced depolarization of preglomerular vascular smooth muscle cells leads to activation of L-type voltage-gated calcium channels and subsequent vasoconstriction. Accordingly, the preglomerular vasoconstrictor responses to Ang II are blocked by L-type calcium channel blockers. In contrast, the effects of Ang II on efferent arterioles are not blocked by L-type calcium channel blockers but are blocked by T-type calcium channel blockers, indicating interesting differences in vasoconstrictor mechanisms in afferent and efferent arterioles.
The overall influence of intrarenal Ang II on renal function is amplified by the powerful synergistic interactions that exist between the renal vascular and tubular actions of Ang II. The effects of Ang II to enhance the rate of proximal tubular reabsorption will lead to decreases in fluid and solute delivery to the macula densa segment. Because of the TGF mechanism, which senses flow-dependent changes in tubular fluid solute concentration at the level of the macula densa and adjusts afferent arteriolar resistance, these decreases in distal fluid delivery would elicit afferent arteriolar vasodilation, thus counteracting Ang II-mediated increases in the rate of proximal reabsorption. Importantly, Ang II increases TGF responsiveness, which allows GFR to be maintained at a lower rate of distal nephron volume delivery. This synergistic interaction between the effects of Ang II on the TGF mechanism and the proximal tubular effects of Ang II provides a powerful sodium-conserving mechanism, whereby increases in intrarenal Ang II levels can cause sustained decreases in distal nephron volume delivery and sodium excretion. The direct effects of Ang II on distal tubule transport mechanisms as well as those exerted by the Ang II-mediated enhancement of aldosterone secretion contribute further to a cascading action of Ang II. Collectively, the Ang II-mediated effects lead to a marked suppression of the pressure-natriuresis relationship, as has been observed in several models of Ang Independent hypertension.
The impact of the RAS within the kidney is enhanced further because of the progressive augmentation of intrarenal Ang II that occurs in response to relatively modest increases in circulating Ang II. Even in nonhypertensive conditions, the intrarenal Ang II levels are much greater than can be explained on the basis of equilibration with plasma Ang II concentrations, regardless of variations in salt intake. In hypertension, the intrarenal Ang II levels increase further and are mediated by several mechanisms. Because of all the components needed for formation of Ang II, there is a robust increase in intrarenal Ang II whenever renin synthesis and release are stimulated by various conditions such as low dietary salt intake, enhanced sympathetic tone, and various stress-related stimuli. In addition to intrarenal formation of Ang II, the kidney sequesters Ang II from the circulation via AT1 receptor-mediated mechanisms. Sustained increases in circulating Ang II cause progressive uptake of Ang II by the kidney, and this mechanism can continue even under conditions where there is marked suppression of renin formation. Increased intrarenal Ang II levels have been shown in several models of hypertension, such as during chronic Ang II infusions and two-kidney-one-clip Goldblatt hypertension. The accumulation of Ang II in intracellular endosomes and intermicrovillar clefts reflects receptor-mediated endocytosis and the existence of an intracellular pool of Ang II. Thus, there are elevations of both interstitial and intracellular levels of Ang II and the maintenance of high levels of intratubular Ang II in hypertensive conditions.
In addition to increased uptake of Ang II, there is also a positive amplification mechanism in the renal proximal tubule cells that lead to a stimulation of the expression of angiotensinogen message and enhanced synthesis and release of angiotensinogen by proximal tubule cells. Much of the angiotensinogen that is formed is secreted into the tubular lumen of proximal tubules, leading to formation of more Ang II, which can then act on luminal AT1 receptors to stimulate sodium reabsorption. This positive feedback mechanism helps make the kidney more efficient at conserving sodium under conditions of low dietary salt intake, but may contribute to inappropriately elevated intratubular and intrarenal Ang II levels in various hypertensive conditions. When stimulated, there is increased angiotensinogen secretion into the proximal tubule, which leads to spillover of angiotensinogen into distal nephron segments and is reflected as increased urinary angiotensinogen excretion rates. Because principal cells in connecting tubule and collecting duct segments have available renin and ACE, when more angiotensinogen is delivered to the distal nephron, there is increased generation of Ang I and formation of Ang II, which can then act on the distal nephron AT1 receptors to stimulate sodium entry further.
The additive effects of Ang II on distal nephron transport function coupled with the associated actions of elevated aldosterone levels markedly increase the sodium-retaining ability of the kidney. When this augmentation of intrarenal Ang II is sustained in a setting of hypertension, progressive cellular proliferation and renal injury can occur. These findings help explain why effective treatment strategies must also block the intrarenal RAS as well as reduce AP.
The widespread effectiveness of antagonists of the RAS indicates that inappropriate or pathologic increases in the activity of the RAS is a major cause of sodium retention, hypertension, and vascular injury. Thus, antihypertensive therapy is often directly targeted at the RAS. ACE inhibitors and, more recently, Ang II receptor antagonists are extensively utilized to reduce the activity of the RAS. Treatment with ACE inhibitors or Ang II receptor antagonists causes a potent net effect because of the synergistic consequences of reductions in vascular tone of the afferent and efferent arterioles, increases in medullary blood flow, attenuation of the sensitivity of the TGF mechanism, inhibition of Ang II-dependent tubular sodium reabsorption, and the diminished distal nephron sodium reabsorption caused by reduced levels of aldosterone.
The pathophysiology of hypertension remains a challenging problem because there are many interactions among the various neural, hormonal, and paracrine mechanisms regulating cardiovascular and renal function. Systemic AP is a dynamic and responsive physiologic parameter that can be influenced by many different factors. In particular, short-term changes in AP are produced by a myriad of mechanisms that affect cardiac output, total peripheral resistance, and cardiovascular capacitance. In the long run, however, most of these actions can be buffered or compensated by appropriate renal adjustments of sodium balance, ECFV, and blood volume. As long as the mechanisms regulating sodium excretion can maintain sodium balance by appropriately modulating the sensitivity of the pressure-natriuresis relationship, normal AP can be sustained. Derangements that compromise the ability of the kidneys to maintain sodium balance, however, can result in the kidney’s need for an elevated AP to reestablish net salt and water balance. The nature of the derangement may vary depending on the disease involved, from overt chronic renal insufficiency to subtle hormonal or neural settings that lead to inappropriate sodium-retaining responses by the kidney. Some hypertensive conditions are thought to be primarily volume-dependent, because there is no evidence for the inappropriate activation of vasoconstrictor systems. In the majority of cases, however, there is probably overactivity of one or more vasoconstrictor systems that also affect the kidneys’ ability to effectively regulate sodium excretion. Of these systems, the most powerful appears to be the RAS because of its synergistic actions. When stimulated, enhanced intrarenal Ang II causes a marked suppression of the pressure-natriuresis relationship, which cannot be adequately counteracted by other physiologic mechanisms leading to sustained elevations in AP.
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