According to the renal-body fluid feedback mechanism for long-term control of arterial pressure, extracellular fluid volume is determined by the balance between intake and excretion of salt and water by the kidneys (Fig. 39.1). A temporary higher intake than output would lead to an increase in extracellular volume and arterial pressure. If the excretory ability of the kidney is not impaired, the increase in arterial pressure raises sodium excretion and extracellular fluid volume would then decrease, thereby reducing venous return and cardiac output until blood pressure returns to normal and fluid intake and output are reestablished. Conversely, when sodium output exceeds intake and extracellular fluid volume and blood pressure fall below normal, the kidneys retain sodium and water until arterial pressure is restored to the normal set-point. Thus, according to the renal-body fluid feedback mechanism concept, the set-point for long-term blood pressure control is the arterial pressure at which sodium and water intake and output are at equilibrium.⁴,⁵,⁶,⁷

A key component of this mechanism for regulating salt and water balance is pressure natriuresis/diuresis, which is the effect of increased arterial pressure to raise sodium and water excretion. An important feature of pressure natriuresis is that various hormonal and neural control systems can amplify or blunt the pressure natriuresis mechanism.⁵,⁷,⁹,¹⁰,¹¹ For example, in most individuals, chronic increases in sodium intake are associated with only small changes in arterial pressure. The lack of significant increases in arterial pressure in response to elevations in sodium intake results in decreased formation of antinatriuretic hormones and/or increased formation of natriuretic factors, which enhance the effectiveness of pressure natriuresis and allow sodium balance to be maintained with little or no increase in arterial pressure. On the other hand, excessive activation of antinatriuretic systems or abnormalities in natriuretic systems can reduce the effectiveness of pressure natriuresis, thereby necessitating greater increases in arterial pressure to maintain sodium and water balance. Thus, excessive activation of antinatriuretic systems or abnormalities in natriuretic systems impairs the excretory ability of the kidney and shifts the relation between sodium excretion and arterial pressure toward higher levels and resets the set-point for long-term blood pressure control (Fig. 39.2).

Although total peripheral resistance and cardiac output are determinants of arterial pressure, one prediction of the renal-body fluid feedback mechanism is that if the pressure natriuresis mechanism is not impaired, a primary increase in total peripheral resistance or increases in cardiac pumping ability would not result in long-term alterations in arterial pressure.²,³,⁴,⁵,⁶ For instance, an increase in total peripheral resistance would result in an immediate elevation in arterial
pressure. The increase in arterial pressure would increase sodium and water excretion, via pressure natriuresis. As long as fluid excretion exceeds fluid intake, extracellular fluid volume will continue to decrease, reducing venous return and cardiac output, until blood pressure (BP) returns to normal and fluid balance is reestablished. Thus, according to the renal-body fluid volume control system concept, primary increases in total peripheral resistance or increases in cardiac pumping do not result in long-term alterations in arterial pressure and hypertension can develop only when something impairs the excretory ability of the kidney and shifts the relation between sodium excretion and arterial pressure toward higher levels.²,³,⁴,⁵,⁶

Although hypertension is a result of a reduction in the kidney’s ability to excrete sodium and water (reduced pressure natriuresis), the hypertension may not necessarily be associated with increases in extracellular fluid volume. Indeed, many forms of hypertension are associated with increased total peripheral resistance and reduced rather than increased extracellular fluid volume. This occurs when a vasoconstrictor, such as norepinephrine, has a potent extrarenal vasoconstrictor effect to increase total peripheral resistance but a relatively weak antinatriuretic action. The antinatriuretic effect of norepinephrine shifts pressure natriuresis and the set-point for arterial pressure to a higher level. However, because norepinephrine has a more powerful extrarenal vasoconstrictor effect, arterial pressure initially increases above the renal set-point for sodium balance and causes transient natriuresis and decrease in extracellular fluid volume. Eventually arterial pressure stabilizes at a point where sodium intake and output are balanced. Thus, sodium retaining actions of norepinephrine are masked by peripheral vasoconstriction which raises BP above the renal set-point at which sodium balance is maintained causing increased renal excretion and decreased extracellular fluid volume. It is important to reiterate that the maintenance of high blood pressure chronically depends on norepinephrine’s renal actions because norepinephrine’s extrarenal effects to increase total peripheral resistance would in itself, as pointed out previously, only result in a transient increase in blood pressure.

Another important prediction of the renal-body fluid feedback control system concept is that an increase in BP in hypertensive states is an essential compensatory mechanism that allows sodium balance to be maintained in the face of an underlying sodium retaining defect.⁵,⁶,⁷ The importance of the pressure-natriuresis mechanism in the regulation of sodium excretion can best be illustrated under conditions in which a sodium-retaining abnormality exists within the kidney and an increase in arterial pressure occurs to compensate for this abnormality. Such a condition is illustrated in the hypertension caused by aldosterone excess. To determine the importance of the pressure-natriuresis mechanism in achieving sodium balance during aldosterone-induced hypertension, Hall and colleagues¹² examined the long-term effects of aldosterone on sodium excretion and arterial pressure in normal dogs and in dogs in which renal artery pressure was prevented from increasing with an electronically servocontrolled aortic occluder. In dogs in which renal artery pressure was permitted to increase during chronic aldosterone infusion, sodium excretion decreased markedly on the first day and then returned to control levels on days 2 to 3 of aldosterone infusion as arterial pressure increased (Fig. 39.3). In contrast, in dogs in which renal artery pressure was prevented from increasing, sodium excretion decreased on the first day and remained below sodium intake for the 7 days of aldosterone infusion. The sustained sodium retention resulted in dramatic increases in cumulative sodium balance and systemic arterial pressure. The results from this study clearly demonstrated that an increase in renal arterial pressure is essential in allowing the kidneys to escape from the chronic sodium-retaining actions
of aldosterone and to achieve normal sodium balance. Similar findings were reported from the same group during chronic administration of other sodium-retaining hormones, such as angiotensin II and norepinephrine.¹³,¹⁴ Thus, it appears that during pathophysiologic conditions associated with excess levels of sodium-retaining hormones, such as aldosterone or angiotensin II, the pressure-natriuresis mechanism is important for the maintenance of sodium balance.¹⁵,¹⁶

The ability of the kidney to alter urine flow and sodium excretion in response to acute changes in renal perfusion pressure has been of interest to investigators for many years.¹⁷,¹⁸,¹⁹ Changes in sodium excretion in response to changes in renal perfusion pressure are thought to be due to alterations in tubular reabsorption of sodium, because glomerular filtration rate (GFR) and the filtered load of sodium are usually well autoregulated.²⁰ Thus, a decrease in renal perfusion pressure results in an increase in tubular reabsorption of sodium and a decrease in sodium excretion. In contrast, increases in renal perfusion pressure lead to decreases in tubular reabsorption of sodium and increases in sodium excretion, a phenomenon commonly referred to as pressure natriuresis.

The specific intrarenal mechanism responsible for the decrease in tubular reabsorption in response to increases in renal perfusion pressure appears to be related to increases in hemodynamic factors such as medullary blood flow and renal interstitial hydrostatic pressure (Fig. 39.4).²⁰,²¹,²²,²³,²⁴,²⁵ The mechanism whereby renal interstitial hydrostatic pressure (RIHP) increases in the absence of discernible changes in whole kidney renal blood flow and peritubular capillary hydrostatic and/or oncotic pressures may be related to increases in renal medullary flow as a result of nitric oxide-induced reductions in renal medullary vascular resistance.²⁶ Preventing RIHP from increasing in response to increases in renal perfusion pressure markedly attenuates pressure natriuresis.²⁴ Furthermore, direct increases in RIHP, comparable to increases measured in response to increases in renal perfusion pressure, have been shown to significantly decrease tubular reabsorption of sodium in the proximal tubule and increase sodium excretion.²⁰,²¹,²²,²³,²⁴ The exact mechanism whereby RIHP influences tubular reabsorption is unknown but may be related to alterations in tight junction permeability to sodium in proximal tubules, redistribution of apical sodium transporters, and/or release of renal autacoids such as prostaglandin E2.²⁷,²⁸,²⁹,³⁰,³¹

Several lines of evidence support an important role for the kidneys in the development and maintenance of hypertension. Some of the strongest evidence for a key role of the kidneys in hypertension derives from renal cross-transplantation studies.⁴ Transplantation of a kidney from a hypertensive donor into a normotensive recipient has been demonstrated to produce sustained elevations in arterial pressure in numerous genetic models of hypertension (e.g., SHR, Dahl).³² Of particular relevance to human hypertension is the study of Curtis et al.³³ demonstrating that BP returns to normal levels in hypertensive patients who were recipients of kidneys from normotensive donors. Another observation that points toward abnormal kidney function as a key factor in causing hypertension is that almost all forms of experimental hypertension are caused by perturbations to the kidneys that alter renal hemodynamics or tubular reabsorption and reduce the kidney’s ability to excrete sodium and water. For example, constriction of the renal arteries (e.g., Goldblatt hypertension), compression of the kidneys (e.g., perinephritic hypertension), or administration of sodium-retaining hormones (e.g., ANG II) are all associated with either initial reductions in renal blood flow and GFR or increases in renal tubular reabsorption prior to development of hypertension.⁷,³⁴ Further evidence
supporting an important role for the kidneys in the development and maintenance of hypertension is that in all known monogenic forms of human hypertension, the common pathway to hypertension appears to be increased renal tubular reabsorption caused by mutations that directly increase renal electrolyte transport (e.g., Liddle or Gordon syndromes) or the synthesis and/or activity of antinatriuretic hormones (e.g., glucocorticoid remediable aldosteronism).⁸

Although specific abnormalities of kidney function are difficult to identify in most patients with primary hypertension, the one aspect of kidney function that is abnormal in all types of experimental and clinical hypertension is renal pressure natriuresis.⁴,⁵,⁷,¹⁵,¹⁶,³⁴ A shift in the pressure natriuresis relationship can occur as a result of intrarenal abnormalities such as enhanced formation of angiotensin II, reactive oxygen species (ROS), inflammatory cytokines, and endothelin (via ET_A receptor activation) or decreased synthesis of nitric oxide and natriuretic prostanoids or even genetic defects that enhance renal sodium transport mechanisms (Fig. 39.2). In other instances, the altered kidney function is caused by extrarenal disturbances, such as increased sympathetic nervous system (SNS) activity or excessive formation of antinatriuretic hormones such as aldosterone. The remaining portion of this chapter discusses how these intra- and extrarenal factors impair renal pressure natriuresis and lead to chronic hypertension.