Atrial Natriuretic Peptide and Related Peptides

The original peptide (see Fig. 4) was discovered by purification of atrial extracts which exhibited striking diuretic and natriuretic properties [6, 58]. Atrial natriuretic peptide is stored in secretory granules of the atrial myocyte as a 126-amino-acid propeptide (pro-ANP) which is cleaved during or soon after secre-

FIGURE 4. Structure of human atrial natriuretic peptide (human ANP) and urodilatin (Human URO). Darkened amino acid residues on human URO represent an amino terminal extension when compared with human ANP.

tion into several fragments including ANP99_126 and ANP31_67, both of which have natriuretic and diuretic properties [6, 24, 58]. Urodilatin (URO) arises from the same gene product but is synthesized in the renal cortex, where it undergoes different processing from ANP, resulting in a 4 amino acid extension, and is secreted into the luminal fluid in the connecting segment [47, 58]. Whether URO is also secreted into the renal circulation is unclear.

Three ANP99_126 or natriuretic peptide receptor (NPR) subtypes have been identified. Two, NPR-A and NPR-B, contain cytoplasmic guanylyl cyclase domains which become active, converting GTP to cGMP, when ligand is bound to the extracellular domain. A third subtype, NPR-C, lacks the cytoplasmic guanylyl cyclase domain, and may participate mostly in clearance of bound ANP [1]. Although a lack of specific antisera has hampered localization studies, differential binding and detection of specific mRNAs have localized NPR-A to the renal cortex, including glomeruli, and medulla, while both NPR-A and NPR-B are found in peripheral vasculature and the adrenal gland. NPR-C is present in glomeruli and large renal vessels and absent in the medulla [55, 58].

ANP exhibits significant hypotensive, natriuretic, and diuretic effects (see Table 1). It lowers blood pressure by reducing cardiac output and peripheral vascular resistance [58], ANP diminishes cardiac output by reducing preload and by blunting the hypotension-induced reflex rise in sympathetic efferent nerve activity and heart rate. ANP decreases preload by reducing intravascular volume, both by stimulating salt and water excretion and by stimulating redistribution of intravascular volume into the interstitial space. ANP either lowers peripheral vascular resistance or prevents a reflex rise in intravascular resistance (which would occur due to its hypotensive effect) by reducing renin secretion, thereby diminishing the circulating levels of the vasoconstrictor, angiotensin II. ANP can also effect relaxation of preconstricted vascular smooth muscle in vitro, but the importance of this effect in vivo has been difficult to establish. The importance of ANP in long-term blood pressure regulation was recently emphasized in studies of transgenic mice with a disruption of the pro-ANP gene and an inability to synthesize ANP (and urodilatin and ANP31_67) [27]. Homozygotes for disrupted pro-ANP gene exhibited no atrial granules and were hypertensive on standard and high salt chow. Heterozygotes showed an intermediate number of atrial granules, and were hypertensive only on high salt chow [27].

ANP enhances salt and water excretion via several synergistic mechanisms involving both direct renal effects and several extrarenal effector mechanisms. ANP attenuates sympathetic activity and lowers the levels of circulating cate-choleamines [58], This effect plus a direct effect on the macula densa inhibits release of renin, lowering circulating and renal levels of angiotensin II. Diminished sympathetic nerve activity and circulating angiotensin II levels, combined

TABLE 1 Effects of ANP on Blood Pressure and Renal Salt and Water Excretion

I. Actions of ANP to reduce blood pressure

A. Reduced cardiac output

1. Reduced preload a. Reduced total body volume by natriuresis/diuresis b. Redistribution of volume from vascular to extravascular space c. Reduced tone of capacitance veins, reducing venous return i. Reduced sympathetic nerve activity ii. Possible direct relaxation of venous vascular smooth muscle

2. Reduced contractility and heart rate a. Reduced sympathetic nerve activity b. Reduced circulating catecholeamines

B. Reduced peripheral vascular resistance

1. Direct relaxation of smooth muscle of resistance arterioles

2. Reduced sympathetic nerve activity

3. Reduced circulating catecholeamines

4. Reduced renin production, leading to reduced angiotensin II

11. Actions of ANP to increase renal salt and water excretion

A. Increased glomerular filtration rate

1. Increased glomerular capillary pressure (PGC)

a. Afferent arteriolar vasodilatation b. Efferent arteriolar vasoconstriction

2. Increased glomerular surface area for filtration by actions on mesangial cells

B. Inhibition of tubular reabsorption of salt and water

1. Inhibition of proximal tubule Na+ reabsorption a. Direct inhibition of tubule response to angiotensin b. Reduced sympathetic nerve activity c. Reduced circulating catecholeamines d. Reduced renin production, leading to reduced angiotensin II

2. Inhibition of cortical and inner medullary collecting duct Na+ reabsorption a. Direct inhibition of amiloride-sensitive cation/Na+ channels b. Reduced circulating levels of aldosterone i. Direct inhibition of aldosterone production ii. Reduced renin production, leading to reduced angiotensin II

iii. Reduced circulating catecholeamines iv. Reduced sympathetic nerve activity

3. Antagonism of ADH-stimulated water reabsorption a. Direct inhibition of ADH-stimulated water reabsorption in collecting duct.

b. Reduction of ADH release in response to osmotic or volume stimuli

Note. Reported effects of ANP relevant to blood pressure and salt and water excretion are listed. Actions are detailed in the text and reviewed in [6, 58]. The importance of these effects in determining the physiological response to ANP will depend on factors such as the circulating concentration of ANP and the underlying state of the subject.

with a direct inhibitory effect on the adrenal glomerulosa cells reduce aldosterone release and circulating levels. The decreases in both renal sympathetic nerve activity and in angiotensin II levels lower proximal tubular reabsorption of salt and water. Reductions in aldosterone levels diminish renal salt reabsorption, principally in the distal convoluted tubule and collecting duct. Direct and coordinated effects of ANP along the nephron act synergistically with the reductions in salt-retaining stimuli to stimulate markedly salt and water excretion. Thus ANP directly enhances glomerular filtration rate (GFR), attenuates proximal tubular sodium reabsorption in response to catecholamines and angiotensin II, and blocks collecting duct Na+ and water reabsorption.

ANP increases GFR by increasing both the glomerular capillary pressure and the ultrafiltration coefficient [58]. Glomerular capillary pressure rises as a result of dilatation of the arcuate, interlobular, and afferent arterioles in a setting where efferent arteriolar tone is unaltered or even increased. ANP may raise the ultrafiltration coefficient by enhancing the relaxation of mesangial cells, thereby expanding the surface area available for ultrafiltration. There is some controversy as to whether the glomerular actions of ANP occur at levels of the peptide which circulate physiologically, or whether they represent a pharmacologic effect. The vasorelaxant effects of ANP are mediated by stimulation of NPR-A, resulting in increased cGMP within vascular smooth muscle and mesangial cells.

ANP reduces tubular Na+ reabsorption in the proximal tubule and collecting duct [58]. In the proximal tubule, studies involving micropuncture in intact animals and microperfusion of isolated proximal tubule segments demonstrated that ANP did not alter basal Na+ reabsorption, but did inhibit catechol-amine- and angiotensin II-stimulated Na+ reabsorption, an effect which was duplicated by exogenous cGMP. It is of interest that proximal tubule cells do not appear to have high levels of NPR-A relative to other tubule segments, but it appears likely that ANP binding to NPR-A mediates these responses.

In cortical and inner medullary collecting duct, ANP binding to NRP-A leads to striking increases in intracellular cGMP. cGMP, in turn, inhibits Na+ reabsorption [25, 62, 63], In the inner medullary collecting duct, the apical cation channel (which conducts Na+) appears to be amiloride-sensitive and resembles that of the regina; cGMP itself can reduce the open probability of the channel. An additional portion of the response to cGMP appears to be mediated by a cGMP-dependent protein kinase [29, 30]. In the cortical collecting duct, where the Na+ channel is made up of the highly Na+ selective ENaC subunits (for epithelial Na+ channels), the specific mechanism of action of cGMP remains unclear [12,37,39],

ANP also inhibits ADH-stimulated water reabsorption in both cortical and medullary collecting duct [18, 38]. In the rabbit cortical collecting duct, ANP appears to act by inhibiting cAMP generation in response to ADH, because forskolin, which stimulates cAMP accumulation independent of the ADH re ceptor, and exogenous cAMP gave equivalent increases in water flow in the absence and presence of ANP [18]. By contrast, ANP inhibited ADH and cAMP-stimulated water flow in rat cortical and medullary collecting duct, indicating that its effect of blocking water flow occurs at a site beyond the generation of cAMP [38]. In the rat, this action likely involves inhibition of trafficking of water channel containing vesicles to the apical membrane [60].

Because of its combined effect of counteracting antinatriuretic influences and inhibiting renal salt and water reabsorption, ANP is a potent natriuretic and diuretic. Efforts to apply these properties clinically have centered on infusions of ANP in edematous states. In cirrhosis with attendant ascites, basal ANP levels tend to remain normal. However, following head out water immersion or placement of a La Veen peritoneovenous shunt, there is a rise in circulating ANP levels, an increase in urinary cGMP excretion (denoting ANP action in the kidney) , and an increase in salt and water excretion [ 11, 20 ]. These results suggest that an increase in preload in cirrhosis leads to an increase in ANP levels which can augment salt and water excretion. However, infusion of ANP without measures to increase preload has led to severe hypotension which has precluded significant natriuretic responses. In congestive heart failure, ANP levels are high, likely in response to the chronic enlargement of the atria [14]. Despite the high levels of ANP, patients retain excessive salt, indicating that antinatriuretic influences such as increases in sympathetic outflow and angiotensin II and aldosterone levels override the natriuretic effect of ANP. Indeed, the high levels of ANP may dampen the salt retention, because infusion of anti-ANP antibodies into rats with congestive heart failure leads to increased salt and water retention [5]. As occurred in cirrhosis with ascites, infusion of ANP into patients with congestive heart failure led to intolerable hypotension, which prevented effective diuresis [ 14].

Because a major proportion of ANP degradation occurs via neutral endopep-tidase, which is located in the proximal tubule brush border, several studies have examined the effects of increasing endogenous ANP levels by inhibiting ANP degradation. In normal man and rat, administration of inhibitors of neutral endopeptidase such as candoxatrilat can increase circulating ANP levels, increase urinary cGMP excretion, and stimulate natriuresis and diuresis [40, 48]. These effects are more pronounced in volume-loaded men and hypertensive rats. In humans, dogs, and rats with congestive heart failure, inhibition of neutral endopeptidase also gave an increase in salt and water excretion. The natriuretic and diuretic response was more pronounced in the setting of less severe heart failure, and symptomatic hypotension was also less severe [35]. Since inhibition of neutral endopeptidase also increases local levels of kinins, this dual action of the inhibitors may account for the salutary response. It is possible that these agents will find a role in the symptomatic treatment of congestive heart failure in the future.

Urodilatin is known to be secreted into the tubule fluid and does not appear systemically [43]. Since most actions of hormones including those of ANP are thought to be mediated via basolateral receptors, the urinary secretion of urodilatin was thought to be ineffective in mediating a natriuresis. however, micro-catheterization studies have shown that luminal ANP can inhibit inner medullary collecting duct Na+ reabsorption; similarly, ADH can also act via luminal receptors [50]. It is therefore possible that luminal urodilatin acts as a renal mediator of salt excretion. At present, the mechanisms governing urodilatin release into the urine are unclear. However, if the secretion of this peptide could be stimulated in vivo, the natriuretic effect might be observed. Such a response may be particularly beneficial in salt-retaining states, because urodilatin is confined to the urinary tract and therefore cannot alter systemic hemodynamics.

ANP31_67 is also released when pro-ANP is cleaved [54, 58]. Studies in rats and humans have demonstrated that this peptide circulates at levels close to those of ANP [54]. Infusions of this peptide to achieve levels close to those obtaining in vivo have led to diuresis and natruresis without a change in GFR [33]. Moreover, this peptide inhibits Na+ transport in inner medullary collecting duct cells by a prostaglandin-mediated mechanism [24], The role of this peptide in regulating Na+ excretion in vivo remains unclear, and there have been no trials of the peptide as a potential natriuretic and diuretic agent.

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