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Cardiovascular Research 2001 51(3):450-462; doi:10.1016/S0008-6363(01)00331-5
© 2001 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

The renal urodilatin system: clinical implications

Wolf-Georg Forssmann*, Markus Meyer and Kristin Forssmann1

IPF PharmaCeuticals GmbH, An-Institute of Hannover Medical School, Feodor Lynen-Strasse 31, D–30 625 Hannover, Germany

* Corresponding author wgforssmann{at}gmx.de

Received 4 April 2001; accepted 12 April 2001


   Abstract
Top
 Abstract
1 Introduction and general...
 2 Urodilatin, a renal...
 3 Pharmacology of Urodilatin
 4 Galenics of Urodilatin
 5 Clinical implications of...
 6 Further potential clinical...
 7 Summary of the...
 References
 
A renal natriuretic peptide and the ‘renal urodilatin system’ were identified after the observation that immunoassayable ANP in urine may not be identical to the circulating cardiac hormone ANP, which is a peptide of 28 amino acids. Urodilatin (INN: Ularitide) is a natriuretic peptide isolated from human urine and belongs to the family of A-type natriuretic peptides. Urodilatin is differentially processed to a peptide of 32 amino acids from the same precursor as ANP. It is synthesized in kidney tubular cells and secreted luminally. After secretion from epithelial cells of the distal and/or connecting tubules, Urodilatin interacts downstream at distal segments of the nephron with luminally located receptors whereby it regulates Na+ and water reabsorption. Thus, the physiological function of the renal Urodilatin system can be described as a paracrine intrarenal regulator for Na+ and water homeostasis, considering Urodilatin as a real diuretic-natriuretic regulatory peptide. However, the regulation upon which the Urodilatin secretion depends is still not clear. Since Urodilatin has been discovered, a great number of pharmacological and clinical investigations have been carried out using Urodilatin as a drug for several indications. So far, clinical phase I and II studies for acute renal failure, congestive heart failure, and bronchial asthma have been performed.

KEYWORDS Antihypertensive/diuretic agents; Blood pressure; Heart failure; Hormones; Natriuretic peptide; Renal function; Vasoconstrition/dilation


   1 Introduction and general considerations
Top
 Abstract
 1 Introduction and general...
2 Urodilatin, a renal...
 3 Pharmacology of Urodilatin
 4 Galenics of Urodilatin
 5 Clinical implications of...
 6 Further potential clinical...
 7 Summary of the...
 References
 
1.1 Discovery of natriuretic peptides
Peptide hormones of the natriuretic peptide family have been biochemically characterized since 1983 (see reviews [1–4]). They were identified as regulatory diuretic–natriuretic substances responsible for salt and water homeostasis [5,6] and as hormones lowering blood pressure [7–11]. Later, a number of homologous peptides with manifold functional implications were described [12–14]. The natriuretic hormone cardiodilatin/atrial natriuretic peptide (CDD/ANP) or A-type natriuretic peptide is synthesized in the heart atrial myoendocrine cells as a precursor molecule of 126 amino acid residues (Fig. 1), ANP-1-126 (CDD/ANP-1-126), and stored in specific granules of atrial myoendocrine cells [4,11,15]. The prohormone is processed into ANP-99-126 [16] while released into the circulation via exocytosis [15,17,18]. The other members of the natriuretic peptide family were identified from the brain as brain natriuretic peptide (BNP or B-type natriuretic peptide) [13], and CNP (C-type natriuretic peptide) [14] (Fig. 2). The natriuretic peptides share common features and exhibit a specific tissue distribution of gene expression as well as functional and pharmacological characteristics.


Figure 1
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  		Fig. 1 Primary structures of the precursor peptides of human natriuretic peptides: (a) upper line, ANP with the processed ANP-99-126 in the gray frame and the Urodilatin extension hatched. (b) and (c) show BNP and CNP, the gray frame indicates the putative processed peptides. The cysteine residues constituting the important cysteine disulfide bindings are additionally labeled. Note that the high homology is seen particularly in the segment containing the domain of biological activity in the C-terminus of the natriuretic peptides.

 

Figure 2
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  		Fig. 2 Sketch of natriuretic peptides showing the A-type natriuretic peptide, the C-terminus of which includes Urodilatin as well as the circulating form ANP-99-126. The homology with the B-type and C-type natriuretic peptide is shown by the hatched residues within the ring structure. Adapted from [4], with permission from Forssmann et al., Histochem Cell Biol 1998;110:335–357. Copyright 1998 Springer-Verlag, Berlin.

 
1.2 Localization und biochemistry of a-type natriuretic peptides
The different natriuretic peptides ANP, BNP, and CNP have been detected in many organs showing expression by different techniques such as immunocytochemistry, detection of specific transcripts (mRNA determination or in situ hybridization), and by immunoassays of tissue extracts (for review, see [15]). Many endocrine organs, the brain, and other systems show the widespread distribution of this peptide family. ANP (or A-type natriuretic peptide) [6–8], BNP [13], and CNP [14] exhibit a similar, homologous primary structure of their processed functional form (Fig. 2). Less homology is seen between the precursors (Fig. 1). In this review, special reference has to be made to the renal localization of natriuretic peptides (see below), which was shown in a series of immunocytochemical publications [15–23]. In summary, all natriuretic peptides share common but also specific features, exhibiting tissue-specific distribution of gene expression which results in a diversity of functional and pharmacological characteristics.

1.3 Receptors for and metabolism of natriuretic peptides
Natriuretic peptides mediate their activity by intracellular generation of cyclic guanosine 3', 5'-monophosphate (cGMP) [24,25]. Type I membrane proteins have been identified as receptors of natriuretic peptides which are characterized by an intracellular domain of functional guanylyl cyclase [26–30]. cDNA cloning resulted in the discovery of three types of natriuretic peptide receptors (NPR): NPR-A, B and C (see reviews, [28–30]). Only NPR-A and NPR-B exhibit the intracellular guanylyl cyclase catalytic domain, whereas the third cloned receptor, NPR-C, contains no guanylyl cyclase domain. The interaction with the NPR-A and G-protein-coupled receptors is depicted in Fig. 3.


Figure 3
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  		Fig. 3 Cellular mechanism of natriuretic peptides and Urodilatin in concert with G-protein-coupled receptors (such as β2-adrenergic receptor in bronchial smooth muscle), the signaling of natriuretic peptide receptor finally results in a lowered intracellular calcium concentration which reduces the smooth muscular tonus to relaxation.

 
The inactivation of natriuretic peptides probably occurs via two pathways, namely the binding to receptors and enzymatic degradation [31–37] resulting in a half-life in the range of less than a few minutes. In this respect, the physiological role of NPR-C has been described as a clearance receptor. Besides binding of circulating natriuretic peptides to NPR-C, enzymatic degradation takes place in lung, liver, and kidney [31–33]. The main enzyme responsible for this degradation is the metalloendoprotease E.C.3.4.24.11 [34,36]. The localization of this protease in the brush border of the kidney proximal tubule and in the lung shows the importance of these organs in the metabolism of natriuretic peptides. E.C.3.4.24.11 opens the loop of CDD/ANP-99-126 between positions Cys-105 and Phe-106, inhibiting the receptor affinity and inactivating the regulatory function of the peptide.


   2 Urodilatin, a renal natriuretic peptide
Top
 Abstract
 1 Introduction and general...
 2 Urodilatin, a renal...
3 Pharmacology of Urodilatin
 4 Galenics of Urodilatin
 5 Clinical implications of...
 6 Further potential clinical...
 7 Summary of the...
 References
 
2.1 Biochemistry and molecular biology of Urodilatin
Urodilatin is a non-glycosylated peptide of 32 amino acid residues [12] considered as a naturally occurring human paracrine mediator [4,15,37,38]. In 1988, Urodilatin was isolated from human urine [12]. The peptide being synthesized in kidney tubules (Fig. 4a) belongs to the family of A-type natriuretic peptides, representing a differentially processed molecular form [4] (Fig. 6). Urodilatin is N-terminally extended by 4 amino acids, comparable to the circulating atrial natriuretic peptide, ANP-99-126 [16]. Therefore, Urodilatin and ANP-99-126 are derived from the same gene and a common precursor peptide, ANP-1-126 (Fig. 6).


Figure 4
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  		Fig. 4 Urodilatin and NPR-A localization in kidney tubules constituting the intrarenal paracrine system. (a) Immunocytochemistry reveals Urodilatin (also ANP-like immunoreactivity) staining in distal tubules (porcine kidney) as shown by immunoperoxidase staining. (b) The localization of downstream located receptors (rat) by immunofluorescence and antibodies against NPR-A is seen in the collecting ducts (modified from [4] with permission from Forssman et al., Histochem Cell Biol 1998;110:335–357. Copyright 1998 Springer-Verlag, Berlin).

 

Figure 6
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  		Fig. 6 Illustration of the differential processing of circulating A-type natriuretic peptide and Urodilatin. From the gene located in chromosome 1, 3 exons are transcribed forming the ANP-mRNA. The translation of prepro CDD/ANP results from this mRNA. After cleavage of the signal peptide, which is different in heart and kidney from the prepropeptide, the mature regular peptide of hormonal or paracrine function is processed. The biological action and route of elimination is also depicted (from [4] reproduced with permission from Forssman et al., Histochem Cell Biol 1998;110:335–357. Copyright 1998 Springer-Verlag, Berlin).

 
Urodilatin applied by intravenous injection, like other natriuretic peptides, is inactivated by binding to the natriuretic peptide clearance receptor (NPR-C) and by enzymatic degradation through the neutral endopeptidase NEP, E.C.3.4.24.11 [39]. In comparison to ANP-99-126, Urodilatin is characterized by a higher stability against this enzymatic degradation by neutral endoproteases [34], which explains why the renal effects are more effective when exogenous infusions of Urodilatin and ANP-99-126 are compared [40,41].

2.2 Receptors of Urodilatin
As mentioned above, Urodilatin exerts its function by stimulation of intracellular guanylyl cyclase at the intracellular domain of the natriuretic peptide receptor A (NPR-A), the enzyme that catalyzes the conversion of guanosine triphosphate (GTP) to 3',5'-cyclic guanosine monophosphate (cGMP) [42,43] (Fig. 3). This receptor (NPR-A) is located in kidney tubules (Fig. 4b) and also in the vascular smooth muscle of the kidney [4,44–50] as shown by different techniques of molecular biology, immunocytochemistry, and autoradiography. In the signaling, cGMP-dependent protein kinase is activated which in turn inhibits Na+ reabsorption via an amiloride-sensitive channel. Furthermore, in kidney arterial smooth muscle, a relaxation occurs via a change of intracellular Ca2+ concentration [42,43,45] (see also Figs. 3 and 5Go).


Figure 5
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  		Fig. 5 Renal effect of ANP extract infusion as seen by in vivo preparations showing the vasorelaxation induced by natriuretic peptides in a small renal cortical artery. (a) Control. (b) Infusion of the prefurified ANP, extracted from porcine heart atria, shows strong vasorelaxant activity (modified from [4] with permission from Forssman et al., Histochem Cell Biol 1998;110:335–357. Copyright 1998 Springer-Verlag, Berlin).

 
Recently it was shown that natriuretic peptides may also regulate renal electrogenic transport processes via cGMP-dependent and cGMP-independent pathways based on the presence of CNP-activated NPR-B which exists in at least two splice variants [51]. The significance of this ‘CNP natriuretic system’ of the proximal tubular epithelium may be explained by regulation of the Na+ transport by influencing the potassium conductance [51].

2.3 Systemic function of the intrarenal paracrine system
The integration of the intrarenal paracrine system using Urodilatin as a diuretic regulator is considered to be of great importance in systemic regulation, namely the control of renal Na+ and water excretion (Fig. 7). Thus, basically the homeostasis of body fluid and electrolytes depends on this paracrine Urodilatin system [52–56]. The relation of renal Urodilatin excretion and different experiments in electrolyte homeostasis and imbalance have been investigated in animal studies and preclinical trials. Long-term Na+ diets in healthy volunteers revealed a significant correlation between natriuresis and Urodilatin excretion: increased Na+ load was found by our group [52] to induce an elevated Urodilatin excretion and an enhanced Na+ excretion, as also shown by others [57]. Similarly, acute volume load by saline infusion [54], balloon dilatation of the left atrium [53], and water immersion [58] result in stimulated Urodilatin secretion and increased Na+ excretion. Furthermore, circadian rhythm of urinary Na+ excretion is correlated with Urodilatin excretion [59]. In some of these experiments in which a natriuretic response is observed, circulating ANP-99-126 plasma levels are not changed at all [60–62]. Thus Urodilatin, the renal natriuretic peptide, is, by means of its paracrine interaction, an essential physiological factor responsible for Na+ and water regulation.


Figure 7
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  		Fig. 7 Intrarenal actions of infused Urodilatin compared to ANP-99-126. For details, see text. Reprinted with permission from Meyer (1997) [39]. Copyright 1997 Holzapfel Verlag, München.

 

   3 Pharmacology of Urodilatin
Top
 Abstract
 1 Introduction and general...
 2 Urodilatin, a renal...
 3 Pharmacology of Urodilatin
4 Galenics of Urodilatin
 5 Clinical implications of...
 6 Further potential clinical...
 7 Summary of the...
 References
 
3.1 General pharmacological actions of Urodilatin
Systemic administration of the peptide in normal rats [63], dogs with cardiomyopathy [64], and healthy volunteers [65] shows the pharmacological effects on renal, cardiovascular, or pulmonary parameters of Urodilatin. Enhanced diuresis, natriuresis, and a variable drop in blood pressure have been observed. These effects are related to the predominant vasodilation in renal, pulmonary, and coronary arterial vessels and to electrolyte transport in renal tubules (Fig. 8). The lack of response or little sensitivity of vasorelaxation of other arterial vessels such as mesenteric or peripheral arteries by Urodilatin results in a redistribution of the blood stream in the body.


Figure 8
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  		Fig. 8 The various functions exerted by natriuretic peptides in the different organs and/or organ systems resulting in the physiological and pharmacological actions. For details, see text.

 
Bolus injections of Urodilatin in healthy volunteers are followed by a natriuresis and diuresis which are double that of exogenously applied ANP-99-126 in the same dose ranges. In contrast, the hypotensive effect of Urodilatin is apparent only at higher doses than with ANP-99-126 [63–68].

Pulmonary parameters are distinctly influenced by Urodilatin, i.e. a bronchodilation (see below), as well as a decrease of pulmonary arterial pressure and of pulmonary wedge pressure are found after bolus injection of the peptide [69]. Urodilatin applied as a bolus in patients suffering from congestive heart failure produces a moderate hypotension and a subsequent reflex tachycardia. In spite of these changes, Urodilatin is of benefit to the patients as it significantly ameliorates cardiac index and stroke volume [70].

3.2 Toxicology of Urodilatin
Toxicology and pharmacological effects in animal models have so far shown no incompatibility reactions during or after local and systemic application of Urodilatin. When doses used in preclinical acute and long-term infusions were applied in amounts 10–100-fold higher than those administered in clinical trials, these were tolerated and led to no clinical toxic effects. Urodilatin-related histopathological alterations in different species were not observed (unpublished data). Daily intravenous administration of Urodilatin to pregnant rats showed no influence on organogenesis and no adverse effects on maternal performance or survival, growth, and embryonic development. No hints of mutagenic activity or chromosomal aberrations were detected in any in vitro experiments (unpublished, see investigator's brochure of CardioPep Pharma GmbH [105]).

3.3 Impact of specific pharmacological actions of Urodilatin
The Urodilatin system plays an important role in smooth muscle dilatation, electrolyte-body fluid homeostasis, and immune defense. To further understand the multi-functional role of Urodilatin, in particular as a drug candidate for potential clinical indications, the pharmacological effects of Urodilatin and other natriuretic peptides are summarized in this following section (see Fig. 8).

Smooth muscle relaxation by Urodilatin results from a stimulation of intracellular guanylyl cyclase via the intracellular domain of the NPR-A (Fig. 3). Further downstream, the generation of cGMP then leads to the activation of cGMP-dependent protein kinase and subsequently to a decrease of intracellular Ca2+ concentration thereby relaxing smooth muscle. This effect is in concert with several GPCRs (G protein-coupled receptors) such as β2-receptors (see Fig. 3). The resulting vasorelaxant activity of Urodilatin and synthetic human ANP-99-126 in physiological and pharmacological concentrations was determined on precontracted vascular strips and demonstrated an equipotent dose-dependent relaxation [36].

The airway-relaxing effects of Urodilatin were shown in vitro [71], using tracheal muscle strips and in in vivo experiments in rodents [72]. Catecholamine inhibition is detected in studies demonstrating that ANP-99-126 decreases sympathetic nervous activity by stimulation of vagal afferences [73], and thereby contributing to the diminution of the smooth muscular tonus of the vascular system.

Na+ homeostasis is triggered by several mechanisms such as the antagonism of renin and the inhibition of angiotensin. ANP-99-126 and BNP decrease renin secretion from the macula densa, directly inhibit aldosterone secretion from the zona glomerulosa, and attenuate the stimulatory effect of angiotensin II on aldosterone release [73,74]. The interaction with aldosterone was seen in studies with healthy volunteers. These demonstrated that aldosterone levels decrease significantly in a dose-dependent manner following Urodilatin infusion [75,76].

The diuretic effect of Urodilatin is certainly the primary physiological role of this regulatory peptide. As shown in trials with healthy volunteers, Urodilatin induces a strong diuresis and natriuresis under different Na+ diets [65]. Furthermore, Urodilatin administered in bolus injections in healthy volunteers results in a natriuresis and diuresis which are stronger than those induced by ANP-99-126 [69].

The impact of natriuretic peptides modulating the immune defense is derived from the observation that ANP-99-126 inhibits macrophage activity. This action is suggested to be mediated by the NPR-A expressed in macrophages and the subsequent increase of intracellular cGMP levels which in turn reduces e.g. the activation of NF-{kappa}B [77].


   4 Galenics of Urodilatin
Top
 Abstract
 1 Introduction and general...
 2 Urodilatin, a renal...
 3 Pharmacology of Urodilatin
 4 Galenics of Urodilatin
5 Clinical implications of...
 6 Further potential clinical...
 7 Summary of the...
 References
 
Urodilatin-acetate as a basic peptide comprising 32 amino acids, including its two L-cysteines with an intrapeptide disulfide bridge, is manufactured synthetically in two fragments by the Merrifield solid phase method and then condensed and highly purified. The acetate serves as the neutralizing and stabilizing counter ion and is introduced at the final purification stage. By definition of our formulation, acetate is part of the Urodilatin-acetate molecule and is contained in the active ingredient preparation. The finished product Urodilatin-acetate is supplied as sterile lyophilisate in vials for injection purposes containing Urodilatin-acetate corresponding to 1.0 mg of pure Urodilatin. The formula which is used in clinical trials contains mannitol as the only other excipient. Urodilatin is administered by intravenous infusion after being dissolved in physiological Na+ chloride solution.


   5 Clinical implications of Urodilatin
Top
 Abstract
 1 Introduction and general...
 2 Urodilatin, a renal...
 3 Pharmacology of Urodilatin
 4 Galenics of Urodilatin
 5 Clinical implications of...
6 Further potential clinical...
 7 Summary of the...
 References
 
5.1 Heart failure
Cardiovascular effects important in the treatment of heart failure, have been shown for Urodilatin. In this respect, the increase of cardiac index and heart rate produced by the peptide is of great importance [69]. As Urodilatin also decreases mean pulmonary arterial pressure, pulmonary capillary wedge pressure (PCWP), and systemic vascular resistance in healthy human volunteers, the peptide was proposed as an effective drug candidate [69].

In patients with congestive heart failure NYHA III–IV, intravenously administered Urodilatin increased cardiac index and decreased pulmonary artery pressure, pulmonary capillary wedge pressure, pulmonary and systemic vascular resistance [70,78,79]. In a randomized, double-blind, placebo-controlled study, infusion of Urodilatin (15 ng/kg/min) for 10 hrs significantly decreased systolic blood pressure and central venous pressure. Furthermore, urine flow as well as urinary Na+ excretion were significantly increased. These effects are accompanied by an increase in plasma and urinary cGMP levels. No neurohumoral activation or adverse side effects were observed [78].

The beneficial effects of Urodilatin in patients suffering from cardiac failure have been confirmed by other natriuretic peptides. Infusion of ANP-99-126 or brain natriuretic peptide (BNP) in patients with congestive heart failure improved left ventricular function by vasodilation and noticeable natriuretic action [79].

5.2 Urodilatin in renal insufficiency
Acute renal failure (ARF) is a frequent post-operative complication after major surgical interventions due to hemodynamic, ischemic or vasoconstrictive mechanisms [80–82]. The vasoconstrictive effect of cyclosporine A on arterial circulation [81] was suggested to be a particular reason for ARF in the post-operative phase after organ transplantation. Therefore, the predominant vasorelaxant effect of natriuretic peptides on vascular smooth muscle in the kidney was postulated to intervene with incipient renal failure in major surgery. Experimental studies showed that natriuretic peptides such as Urodilatin may exert a beneficial effect in ARF [83,84].

In the past, Urodilatin was used for prevention and therapy of acute renal failure following e.g. organ [85,86] and bone marrow transplantation [87] in pilot studies. Overall, Urodilatin significantly improved the deteriorated renal function as demonstrated by the decrease in serum creatine and blood urea nitrogen and the reduction of hemodialysis/hemofiltration.

A pivotal phase II trial assessing the effects of Urodilatin in patients with oliguric ARF following cardiac surgery, heart or liver transplantation [86] did not reveal a significant difference in patient outcome (avoidance of hemodialysis) in the Urodilatin-treated groups versus placebo. These results are in contrast not only with our previous results but also with a study which was performed by Allgren and coworkers [88]. In this trial, ANP administration revealed a significant improvement of dialysis-free survival in a subgroup analysis in patients with oliguric acute tubular necrosis. The reason for the differences observed in these trials, is probably the difference in criteria for inclusion of patients. In the studies without successful treatment, the patient collective contained mostly multimorbid cases and patients with serious clinical conditions. These results with the different trials indicate that an earlier intervention at the onset of oliguria/anuria would have been more adequate to demonstrate the beneficial effect of Urodilatin. As the time interval of incipient oliguria/anuria was too long, the renal deterioration possibly due to peri- or post-operative renal hypoperfusion could already have entered into an irreversible tubular necrosis. These considerations favor an approach by prophylactic treatment with Urodilatin in risk patients for ARF.

5.3 Urodilatin in bronchoconstriction and acute asthma
Urodilatin was shown to exhibit airway-relaxing effects in vitro using tracheal muscle strips [89]. In vivo experiments in rodents confirmed these results [90] and later in patients with mild asthma [91]. The bronchodilatory activity by Urodilatin is based on its stimulation of intracellular cyclic guanosine monophosphate (cGMP) as an alternative pathway to β2-agonists such as albuterol, the current first-line bronchodilator, which interacts with smooth bronchial muscle by an increase of intracellular concentration of cyclic adenosine monophosphate (cAMP) inducing a bronchodilation.

A randomized, double-blind, placebo-controlled clinical phase II study with cross-over design, using intravenous infusions of Urodilatin at various doses (Fig. 9) showed beneficial effects in patients suffering from bronchial asthma [92]. Urodilatin increases forced expiratory volume in 1 s (FEV 1.0), maximal vital capacity (VCmax), peak expiratory flow (PEF), maximal expiratory flow at 75% (MEF75), at 50% (MEF50) and at 25% (MEF25) of forced vital capacity (FVC) at infusion doses of 10, 30 or 60 ng/kg/min. Optimal effects were observed at Urodilatin doses of 30 and 60 ng/kg/min. A further objective of this study was to show whether the bronchodilatory effects of intravenously administered Urodilatin compared with inhaled albuterol or whether a combination of the two drugs can improve the efficacy of the treatment. Urodilatin monotherapy shows a bronchodilation which is comparable to that induced by a standard dose of albuterol. Urodilatin infusion combined with albuterol inhalation results in a significantly stronger bronchodilatory effect compared to that obtained by monotherapy of either drug [91] (Fig. 9). The pharmacological effects of Urodilatin, such as diuresis, drop in central venous pressure, and pulmonary resistance, are considered to be of additional benefit for patients suffering from cor pulmonale. We conclude from this study [92] that the use of Urodilatin combined with a β2-agonist in the treatment of acute asthma exacerbation will result in a significant improvement in the outcome of these patients [92,93].


Figure 9
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  		Fig. 9 Summary of the results of a clinical phase II study using Urodilatin for the treatment of mild asthma exacerbation: This study showed the advantage of combined Urodilatin and albuterol treatment (see upper trace). The FEV1 values in combined albuterol (200 µg single inhalation) and Urodilatin (infusion 30 ng/kg/min infused for 60 min) is compared to treatment with albuterol alone, Urodilatin alone, and control. The combined application shows the highest efficacy comparable to maximum bronchodilation by 1250 mg albuterol. The placebo treatment of control shows no changes in the FEV1 values (modified from [92,93] with permission from Fluge et al., Eur J Med Res 4:411–415. Copyright 1999 Holapfer Verlag, München and Forssmann et al., Prog Respir Res, Vol. 31, Basel: Karger, 2001, pp. 81–84. Copyright 2001 S. Karger AG, Basel).

 
Urodilatin infusion may also result in an improvement of pulmonary function in patients with bronchial asthma and other obstructive pulmonary diseases when given periodically. Urodilatin treatment can be of advantage for patients with cardiovascular risk and in patients when the intervention via the cAMP-mediated mechanism of bronchodilation is not effective, due to receptor desensitization and downregulation. Then, the alternative cGMP-mediated bronchodilatory mechanism induced by Urodilatin can be used for more beneficial treatment [93].


   6 Further potential clinical applications of natriuretic peptides
Top
 Abstract
 1 Introduction and general...
 2 Urodilatin, a renal...
 3 Pharmacology of Urodilatin
 4 Galenics of Urodilatin
 5 Clinical implications of...
 6 Further potential clinical...
7 Summary of the...
 References
 
6.1 Hepatorenal syndrome
The clinical course of patients with decompensated Laennec's cirrhosis is frequently complicated by progressive impairment of renal Na+ handling, leading to formation of ascites and peripheral edema [94–96]. Since the natriuretic peptides are shown to participate in the regulation of volume homeostasis [97,98], there are theoretical considerations suggesting a potential role for ANP-99-126 in the pathogenesis of the impaired Na+ homeostasis in cirrhosis. Infusions of ANP-99-126 to overcome the Na+-retaining status in these patients, however, led to various results, and in particular blunted natriuretic effects combined with hypotensive episodes were observed [99]. As shown earlier, Urodilatin is known to exhibit stronger natriuretic effects and less hypotensive side effects compared with ANP-99-126 [65,100]. Therefore, the therapeutic effect of Urodilatin administered in patients suffering from hepatorenal syndrome combined with ascites was assessed and Urodilatin was found to be effective in increasing Na+ and urine output in these patients [101].

6.2 Immune defense
Natriuretic peptides have been shown to be involved in a number of further physiological and pharmacological mechanisms which may be of future clinical interest. The implication of ANP-99-126 and macrophage functions in the sense of suppression of macrophage activation by autoregulation is under discussion [77]. Thereby, the NPR-A of macrophages inhibit by cGMP increase the activation of NF-{kappa}B and AP-1 which in turn reduces the TNF-{alpha} transcription and release of TNF-{alpha} [101].

6.3 Modulation and innate defense mechanisms
Recent results indicate that BNP exhibits an antimicrobiotic effect on specific germs [102], the significance of which is still under investigation.

6.4 Erectile dysfunction
The induction of penile erection depends on a complex system of signal transduction pathways resulting in cyclic nucleoside monophosphate changes of corpus cavernosus smooth muscle. In particular, cAMP and cGMP generated by the corresponding adenylyl and guanylyl cycles as well as the modulation of the activity of the cyclic nucleoside monophosphate degrading phosphodiesterases play a pivotal role in the modulation of the smooth muscle tonus of corpus cavernosus. Thus, the enzymes involved represent important target molecules for the development of drugs for the treatment of erectile dysfunction [103]. Guanylyl cyclase B (NPR-B), a receptor for the C-type natriuretic peptide (CNP) is expressed in human corpus cavernosus [104]. CNP induces an increase in intracellular cGMP levels as well as the relaxation of penile smooth muscle strips showing the role of CNP and its receptor in penile erection and its possible future use as a therapeutical approach in erectile dysfunction.


   7 Summary of the status quo of the clinical development of natriuretic peptides
Top
 Abstract
 1 Introduction and general...
 2 Urodilatin, a renal...
 3 Pharmacology of Urodilatin
 4 Galenics of Urodilatin
 5 Clinical implications of...
 6 Further potential clinical...
 7 Summary of the...
References
 
7.1 Urodilatin
Urodilatin (INN: Ularitide) is currently developed for the treatment of acute heart failure [105].

7.2 BNP
BNP (INN: Nesiritide) is currently developed for the treatment of acute heart failure in the USA. The peptide is planned to be administered during the first 24 h of hospitalization for AHF to normalize hemodynamic disturbances [106]. The therapeutic benefit of BNP has been substantiated in phase II and phase III trials in patients suffering from AHF [107–109]. The pharmacological concept for BNP is suggested to be an alternative to nitrates in the treatment of AHF. Food and Drug Administration approval is expected for the year 2001.

7.3 ANP
ANP (INN: Carperitide) is registered for the market in Japan for the therapy of AHF. Studies in patients with AHF revealed beneficial hemodynamic effects such as decrease in PCWP, systemic vascular resistance, and an increase in natriuresis and diuresis. Administration of ANP-99-126 in patients suffering from AHF results in a significant improvement of left ventricular function by reduction of pre- and afterload [110–113].

In conclusion, natriuretic peptides demonstrate a pharmacological profile which is desirable for the treatment of patients suffering from AHF. Clinical studies of ANP-99-126, BNP, and Urodilatin as well as approval of ANP-99-126 and the expected FDA approval for BNP support the potential of these human peptides to have a significant impact as an ‘add-on’ therapy for the treatment of patients admitted to the hospital for AHF.

Time for primary review 5 days.


   Notes
 
1 Working at CardioPep Pharma GmbH. Back


   References
Top
 Abstract
 1 Introduction and general...
 2 Urodilatin, a renal...
 3 Pharmacology of Urodilatin
 4 Galenics of Urodilatin
 5 Clinical implications of...
 6 Further potential clinical...
 7 Summary of the...
 References
 

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