Published online before print October 6, 2008, doi: 10.1161/CIRCULATIONAHA.107.759241
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(Circulation. 2008;118:1729-1736.)
© 2008 American Heart Association, Inc.
Hypertension |
Chronic Actions of a Novel Oral B-Type Natriuretic Peptide Conjugate in Normal Dogs and Acute Actions in Angiotensin II–Mediated Hypertension
From the Cardiorenal Research Laboratory, Division of Cardiovascular Diseases and Internal Medicine (A.C., H.H.C., J.A.S., F.L.M., G.B., L.C.C.-B., K.D.J., K.P., M.A.M., N.B.M., K.R.B., J.C.B.), and Section of Biostatistics (K.R.B.), Mayo Clinic, Rochester Minn.
Correspondence to Alessandro Cataliotti, MD, PhD, Cardiorenal Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905. E-mail cataliotti.alessandro{at}mayo.edu
Received July 24, 2007; accepted August 18, 2008.
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Abstract |
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Background— We previously reported the feasibility of an acute, orally delivered, newly developed, conjugated form of human B-type natriuretic peptide (hBNP) in normal animals. The objective of the present study was to extend our findings and to define the chronic actions of an advanced oral conjugated hBNP (hBNP-054) administered for 6 days on sodium excretion and blood pressure. We also sought to establish the ability of this new conjugate to acutely activate cGMP and to reduce blood pressure in an experimental model of angiotensin II (ANG II) –mediated hypertension.
Methods and Results— First, we developed additional novel conjugated forms of oral hBNP that were superior to our previously reported hBNP-021 in reducing blood pressure in 6 normal dogs. We then tested the new conjugate, hBNP-054, chronically in 2 normal dogs to assess its biological actions as a blood pressure–lowering agent and as a natriuretic factor. Second, we investigated the effects of acute oral hBNP-054 or vehicle in 6 dogs that received continuous infusion of ANG II to induce hypertension. After baseline determination of mean blood pressure (MAP) and blood collection for plasma hBNP and cGMP, all dogs received continuous ANG II infusion (20 ng · kg–1 · min–1, 1 mL/min) for 4 hours. After 30 minutes of ANG II, dogs received oral hBNP-054 (400 µg/kg) or vehicle in a random crossover fashion with a 1-week interval between dosing. Blood sampling and MAP measurements were repeated 30 minutes after ANG II administration and 10, 30, 60, 120, 180, and 240 minutes after oral administration of hBNP-054 or vehicle. In the chronic study in normal dogs, oral hBNP-054 effectively reduced MAP for 6 days and induced a significant increase in 24-hour sodium excretion. hBNP was not present in the plasma at baseline in any dogs, and it was not detected at any time in the vehicle group. However, hBNP was detected throughout the duration of the study after oral hBNP-054, with a peak concentration at 30 minutes of 1060±818 pg/mL. In the acute study, after ANG II administration, plasma cGMP was not activated after vehicle, whereas it was significantly increased after oral hBNP-054 (P=0.01 between the 2 groups). Importantly, MAP was significantly increased after ANG II throughout the acute study protocol. However, although no changes occurred in MAP after vehicle administration, oral hBNP-054 reduced MAP for >2 hours (from 138±1 mm Hg after ANG II to 124±2 mm Hg at 30 minutes, 124±2 mm Hg at 1 hour, and 130±5 mm Hg at 2 hours after oral hBNP-054; P<0.001).
Conclusions— This study reports for the first time that a novel conjugated oral hBNP possesses blood pressure–lowering and natriuretic actions over a 6-day period in normal dogs. Furthermore, hBNP-054 activates cGMP and reduces MAP in a model of acute hypertension. These findings advance the concept that orally administered chronic BNP is a potential therapeutic strategy for cardiovascular diseases such as hypertension.
Key Words: blood pressure • natriuretic peptides • cyclic GMP
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Introduction |
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B-type natriuretic peptide (BNP) is an endogenous peptide produced under physiological and pathological conditions by the heart as a nonactive 108–amino acid prohormone.1–3 BNP is cleaved and activated into its 32–amino acid mature form by the transmembrane enzymes corin and furin4–6 and possesses natriuretic, diuretic, vasorelaxant, lusitropic, antialdosterone properties, and direct and indirect antifibrotic actions7,8 that could mediate cardiorenal protection in cardiovascular diseases.9,10 Although approved as an intravenous agent for heart failure, hypertension may be an equally logical therapeutic target because its phenotype is elevated blood pressure, often vasoconstriction, diastolic dysfunction, and cardiac fibrosis, together with impaired pressure natriuresis in the kidney. Moreover, both experimental and human studies demonstrate a lack of activation of BNP in the early stages of hypertension that could be viewed as a relative BNP deficiency.11 Indeed, the phenotype of mice lacking the receptor to which BNP binds is characterized by hypertension, left ventricular hypertrophy, cardiac fibrosis, and sudden death.12–14
Clinical Perspective p 1736
Despite the specificity and efficacy of peptides that make them desirable as drugs, oral administration of peptides has been a longstanding therapeutic challenge that has limited the development of chronic protein therapy and largely relegated them to parenteral delivery. Recently, however, new technologies have been developed that make this aim achievable. Indeed, we previously reported the acute actions of subcutaneous and orally administered conjugated human BNP (hBNP) in normal conscious dogs.9 In those studies, conjugated hBNP (hBNP-021) was absorbed and present in the plasma after subcutaneous and oral administration. More important, acute subcutaneous and oral conjugated BNP activated cGMP, the second messenger of BNP, which implied a maintained structure of the conjugate that retained the intrinsic ability to bind and activate the natriuretic peptide receptor type-A, resulting in a significant reduction in mean arterial pressure (MAP). This previous study was the first demonstration of an oral BNP molecule or derivative that was absorbed intact and promoted biological actions. These encouraging data support the importance of pursuing further studies with oral administration of conjugated forms of hBNP for the treatment of cardiovascular diseases, especially hypertension.
Continued work has led to the discovery of 2 new conjugates (hBNP-050 and hBNP-054) that show greater oral efficacy than the original hBNP-021. As with the original molecule, these derivatives were intended to improve the pharmacokinetic and pharmacodynamic profiles of the peptide to enable oral administration. In vitro activity studies have demonstrated the importance of conjugating at lysine 3 of hBNP,15 so these 2 conjugates incorporate this key feature.
The first aim was to extend our previous report and to characterize for the first time in normal canines the action of 6 days of oral hBNP on MAP and sodium excretion after identifying the most optimal conjugated hBNP chemical entity. Our second aim was to demonstrate that acute oral administration of conjugated hBNP-054 would result in an increase in plasma levels of hBNP and cGMP, together with a reduction in MAP, in a model of acute angiotensin II (ANG II) – induced hypertension.
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Methods |
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The present study was performed in accordance with the Animal Welfare Act and was approved by the Mayo Institutional Animal Care and Use Committee.
Synthesis of Conjugated hBNP
Two new hBNP monoconjugates, hBNP-050 and hBNP-054, were prepared by regioselective attachment of branched, amphiphilic PEG oligomers to the lysine 3 of hBNP. The syntheses of the monodispersed oligomers and the conditions for conjugation have been described previously.15,16 The resultant conjugates were purified by reversed-phase high-performance liquid chromatography (Phenomenex, Torrance, CA; C18; 1.0-cm ID by 25-cm length) using a gradient system (A, H2O with 0.1% TFA; B, acetonitrile with 0.1% TFA; %B, 25 to 75 over 120 minutes).
Specifically, >50 conjugates were prepared by rational design and synthesis and were subjected to various screens. One of the more promising conjugates of BNP, hBNP-050, was tested in a crossover comparison against hBNP-021, which we previously demonstrated to be efficacious in reducing MAP in normal dogs.9 The comparison showed that hBNP-050 was superior to hBNP-021 in reducing MAP in 6 conscious normal dogs. Another of the more promising candidates, hBNP-054, resulted in blood pressure properties similar to those of hBNP-050. The conjugate hBNP-054 was selected for the oral in vivo study in normal and hypertensive dogs because of its comparatively facile synthesis.
Study Protocol
Normal adult male mongrel dogs (15 to 20 kg) were used in these studies. Before experiments, an arterial port was placed in the femoral artery as previously reported.17 Dogs were fed a fixed sodium diet of 100 mEq/d for 5 days before initiation of studies with ad libitum access to water; they were acclimated to standing calm in a sling. On the day of the experiment, the dogs were fasted and placed in a sling in a quiet room for 30 minutes before the beginning of the experiment.
First, we designed a randomized study in which hBNP-054 (n=5; 350 µg/kg), native hBNP (n=6; 350 µg/kg), or vehicle (n=6) was administered orally in normal dogs (hBNP-054 was administered to only 5 dogs because of the limited supply of conjugated hBNP). Baseline measurements of MAP and blood sampling for hBNP and cGMP were made. MAP and blood samplings were repeated at 10, 30, 60, 120, 180, and 240 minutes after oral administration. In a proof-of-concept study, we continued in 2 normal dogs daily oral administration of 350 µg/kg hBNP-054 once a day for 6 days. On day 7, vehicle instead of the active hBNP-054 was administered to the 2 dogs. Blood pressure was measured daily before (baseline) and at 10, 30, 60, 120, 180, and 240 minutes after oral administration of BNP-054 on each day for the 6 consecutive days. Blood pressure also was measured 7 days before and after oral administration of vehicle. A 24-hour urine collection was performed for 8 days starting the day before oral hBNP-054 administration, continued for the 6 days of oral hBNP-054 administration, and concluded on day 7 when vehicle was administered instead of active drug.
Finally, we investigated in a randomized crossover-designed study the effects of oral hBNP-054 or vehicle in 6 dogs that received concomitant continuous intravenous infusion of ANG II to induce acute hypertension. After baseline determination of MAP and blood collection for plasma hBNP and cGMP, all 6 dogs received continuous ANG II infusion (20 ng · kg–1 · min–1, 1 mL/min) for >4 hours. After 30 minutes of ANG II administration, all dogs received oral hBNP-054 (400 µg/kg) or vehicle in a random crossover fashion (with a 1-week interval). Blood sampling and MAP measurements were repeated 30 minutes after ANG II administration and 10, 30, 60, 120, 180, and 240 minutes after oral administration of hBNP-054 or vehicle.
Hormone Analysis
Plasma hBNP and cGMP were assessed by radioimmunoassay as previously described.18,19
Statistical Analysis
Descriptive statistics are reported as mean±SEM. For the acute studies, data were assessed by 1-way ANOVA for comparisons within groups, followed by posthoc Bonferroni’s test. Two-way ANOVA repeated measurements was used for comparisons between groups, followed by Bonferroni’s posttest. Student’s unpaired t test was performed for single comparisons between groups (GraphPad Prism software 4.0). Statistical significance was accepted at values of P<0.05. Specifically, for the crossover comparative study, the within-treatment analyses of effect over time were done with 1-way ANOVA for repeated measures to test the global time effects, with the time contrasts (each postbaseline time versus baseline) as the effects of interest tested by a posthoc Bonferroni test when the global test was significant. For the treatment comparison (active versus vehicle), a 2-way ANOVA for repeated measures was performed, with the main treatment effect tested as the numerator mean square and the treatment-by-dog interaction mean square as the denominator mean square. This is equivalent to a paired t test on the average values of each parameter between the 2 treatment periods, with the dog as the observation. Treatment contrasts at specific time points were then tested with the Bonferroni correction.
Finally, the 2-dog chronic administration study was too small to make inferences to the population of dogs. Instead, to test whether the drug had a reproducible effect in the 2 dogs in the study, analysis was conducted as follows. For the analysis of drug effect on MAP, the null hypothesis of no blood pressure reduction associated with oral BNP was tested by calculating the average MAP after drug administration within the first 2 hours (10, 30, 60, and 120 minutes) on each day for each dog. For each dog, the 6 daily postdrug averages were compared with the predrug baseline by use of a paired t test with 5 df. The resulting 1-sided probability values were combined across the 2 dogs by the Fisher method of combining independent probability values.20 For the analysis of drug effect on 24-hour sodium excretion, the 6 values for the days on drug were compared with the 2 values for days off drug by a 2-sample t test for each dog, and the resulting 1-sided probability values were similarly combined.20
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Comparisons Between Previous and New Forms of Conjugated hBNP in Normal Dogs
The novel conjugate hBNP-050 resulted in more potent blood pressure–lowering effect compared with the previously reported conjugated hBNP-021 when administered orally in normal dogs (Figure 1). A structurally similar compound (hBNP-054; Figure 2) possessed similar blood pressure–lowering actions in normal dogs (the Table). Because of advantages in synthesis, hBNP-054 was used in the remainder of the studies.
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) and hBNP-021 (
) in 6 normal conscious dogs. Columns represent mean±SEM. *P<0.05 vs baseline, 1-way ANOVA with Bonferroni’s multiple-comparison test. P=0.0065 between hBNP-050 and hBNP-021 groups, 2-way ANOVA.
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Acute Studies With hBNP-054 in Conscious Normal Dogs
Conjugated hBNP-054 was administered orally in normal dogs and compared with native hBNP and vehicle. Figure 3A, 3B, and 3C illustrates the humoral and blood pressure responses to orally administered hBNP-054, native hBNP, and vehicle in normal conscious dogs.
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), and vehicle (
P<0.05 vs vehicle, 
P<0.05 vs native hBNP, 2-way ANOVA with Bonferroni’s posttest. B, Plasma cGMP. *P<0.05 vs baseline, 1-way ANOVA with Bonferroni’s multiple-comparison test. P<0.0001 between hBNP-054 and native hBNP, 2-way ANOVA. Plasma hBNP was not detectable in the dogs at baseline or after vehicle. After oral administration of hBNP-054 and native hBNP, plasma hBNP was detected throughout the time course of the study. Specifically, plasma hBNP was significantly higher after 10 minutes of hBNP-054 (6489±3956 pg/mL) compared with baseline (P<0.05), native hBNP (P<0.05), and vehicle (P<0.05). During the study, plasma hBNP was significantly higher after hBNP-054 compared with native hBNP administration (P=0.0116 between groups; Figure 3A).
Plasma cGMP significantly increased for 60 minutes after dosing of hBNP-054 (from 12.4±1 pmol/mL at baseline to 46.3±8 pmol/mL after 10 minutes, 55.6±10 pmol/mL after 30 minutes, and 45.5±9 pmol/mL after 60 minutes; P<0.05), whereas it was significantly reduced after vehicle (from 13.9±2 pmol/mL at baseline to 7.7±1 pmol/mL after 60 minutes, 7.9±2 pmol/mL after 120 minutes, 7.6±1 pmol/mL after 180 minutes, and 7.7±2 pmol/mL after 240 minutes; P<0.05). By comparison, cGMP levels were not statistically different from baseline levels after native hBNP administration, and overall cGMP levels were greater after hBNP-054 compared with native hBNP and vehicle (P<0.0001 between hBNP-054 and the other groups; Figure 3B).
MAP decreased at 30 minutes and remained decreased through 240 minutes after hBNP-054 administration (from 120±1 at baseline to 115±4 mm Hg after 10 minutes, 96± 8 mm Hg after 30 minutes, 95±7 mm Hg after 60 minutes, 91.2±7 mm Hg after 120 minutes, 92.4±10 mm Hg after 180 minutes, and 93.8±10 mm Hg after 240 minutes). In contrast, MAP did not change after native hBNP or vehicle administration throughout the study (P=0.0006 between groups; Figure 3C).
Chronic Studies With hBNP-054 in Conscious Normal Dogs
We furthered our observation in normal dogs in which hBNP-054 was administered chronically for 6 days, followed by vehicle on the seventh day. Blood pressure was measured before and after oral administration of hBNP-054 or vehicle for 4 hours. Each time hBNP-054 was administered, we observed a significant reduction in MAP. Figure 4A illustrates the average MAP for all 6 days of orally administered hBNP-054. Of note, on the seventh day, MAP was not reduced after administration of vehicle (Figure 4B). When the 4 postinfusion MAP values were averaged and compared with the baseline MAP value for each of 6 days, the resulting paired t tests produced 1-sided values of P=0.01125 and P=0.0188, which, when combined using the Fisher method, gave a 1-sided value of P=0.002 or a 2-sided value of P=0.004, indicating evidence that MAP was significantly lowered in these 2 dogs.
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Of note, 24-hour sodium excretion increased every day during chronic oral hBNP-054 compared with the day before hBNP-054 was initiated, being significantly elevated on days 5 and 6 with oral hBNP-054 administration compared with the day before conjugate therapy was begun (P<0.05). Importantly, 24-hour sodium excretion markedly decreased the day of vehicle administration (day 7), returning to baseline levels (Figure 5). When the 6 days with drug were compared with the 2 days (baseline and day 7) off drug by use of a 2-sample t test for each dog, the resulting 1-sided values were P=0.0909 and P=0.0272, respectively; combining by use of the Fisher procedure gave a 1-sided value of P=0.018 or a 2-sided value of P=0.036, providing significant evidence that urinary sodium excretion was increased in these 2 dogs by administration of the drug.
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Acute Studies With hBNP-054 in Conscious Hypertensive Dogs
In a second phase of the present study, we tested the hypothesis that oral hBNP-054 is efficacious in reducing MAP in a model of acute hypertension induced by ANG II. Here, we administered oral hBNP-054 or vehicle in dogs that received concomitant continuous intravenous infusion of ANG II to induce acute hypertension.
As expected, hBNP was not present in the plasma at baseline in any dogs, and it was not detected in the vehicle group. However, hBNP was detected throughout the duration of the study after oral hBNP-054 with peak concentrations at 10, 30, and 60 minutes (841±300, 1122±303, and 1060± 818 pg/mL, respectively) compared with baseline (P<0.05) and vehicle (P<0.05). During the time course of the study, plasma hBNP was overall significantly higher after hBNP-054 compared with vehicle (P=0.008; Figure 6A).
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During ANG II infusion, plasma cGMP was not activated after vehicle. In contrast, cGMP levels significantly increased after oral hBNP-054 (P=0.01 between the 2 groups; Figure 6B). This plasma increase in cGMP after hBNP-054 lasted for 2 hours (P<0.05 versus baseline), and it was significantly greater than vehicle at 10, 30, and 60 minutes (P<0.01; Figure 6B).
MAP was significantly increased during infusion of ANG II throughout the study in both the hBNP-054 and vehicle groups. However, although no changes occurred in MAP after vehicle administration, oral hBNP-054 was followed by a significant reduction in MAP for >2 hours (from 138± 2 mm Hg after ANG II to 124±2 mm Hg at 30 minutes, 124±2 mm Hg at 1 hour, and 130±2 mm Hg at 2 hours after oral hBNP-054 respectively; P=0.004; Figure 6C).
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Discussion |
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BNP is an endogenous peptide produced by the heart under physiological and pathological conditions. It possesses natriuretic, diuretic, vasorelaxant, lusitropic, antialdosterone, and antifibrotic actions that could mediate cardiorenal protection in cardiovascular diseases.7,21 Its plasma concentration increases progressively in patients with congestive heart failure (CHF) and has been reported to be increased in hypertensive heart disease when accompanied by left ventricular hypertrophy.22,23 In advanced CHF, increased immunoreactive BNP may not reflect the biologically active BNP1-32 but may represent unprocessed pro-BNP1-108, which lacks biological activities.24,25 In hypertension, there are various findings on BNP levels. Although studies have reported an increase in BNP levels in patients with hypertension with left ventricular hypertrophy,23,26,27 more in-depth analyses have shown that early stages of hypertension are characterized by a lack of activation of BNP that begins to rise only in later stages of the disease process.11 Nevertheless, despite this increase in circulating BNP in cardiovascular disease states, exogenous administration in experimental and human hypertension and CHF may have favorable actions.28,29
Use of recombinant hBNP has been approved for the treatment of acute CHF since 2001. Colucci et al30 reported the beneficial actions on cardiovascular hemodynamics of acute intravenous BNP (nesiritide) in patients with decompensated CHF. New data from the Nesiritide Administered Peri-Anesthesia trial support the prolonged use of BNP in patients with left ventricular dysfunction undergoing cardiac surgery, providing renal protection.31 In agreement with such observations, we previously reported that repeated chronic subcutaneous administration of native BNP for 10 days during the evolution of left ventricular dysfunction in a model of mild CHF resulted in an improvement in cardiac hemodynamics.32 More recently, Chen et al33 extended these data in human CHF patients, once again demonstrating the potential beneficial effects of chronic BNP therapy. Furthermore, in experimental hypertension, long-acting subcutaneous BNP fused to albumin induced a sustained blood pressure reduction in spontaneously hypertensive rats.34
The therapeutic use of peptides continues to increase because they are generally characterized by high potency and few adverse events, yet their administration has been relegated almost exclusively to either intravenous infusion or subcutaneous injection. Although oral administration would be preferred in many cases, potential denaturation in the stomach, proteolysis in the stomach and small intestine, and insufficient transport across the intestinal mucosa and epithelium have proved to be formidable barriers. Although many efforts are underway to deliver native peptides orally via novel formulation technologies,35 the approach used for oral BNP has been based on derivatization of the therapeutic peptide with small, amphiphilic oligomers that are monodispersed and are made up of both a hydrophobic (alkyl) moiety and a hydrophilic polyethylene glycol (PEG) moiety.
Although hBNP-021 was the first orally active conjugate discovered, continued research led to the superior conjugates hBNP-050 and hBNP-054, as studied in vivo in the present studies. Both of these derivatives are monoconjugates in which the respective oligomers are attached to the lysine 3 position. Because binding to the natriuretic peptide receptor type A was believed to occur mostly in the loop region, it had been hypothesized that activity could be compromised on conjugation to lysine 14 and perhaps lysine 27. Indeed, it was later shown that conjugation at either of these 2 sites resulted in a loss of both potency and activity. In contrast, conjugation at lysine 3 resulted in virtually complete retention of activity.15
In the present study, we chose the conjugated form of hBNP (hBNP-054) that in normal dogs possessed the most favorable profile in terms of blood pressure lowering and synthesis. This novel conjugated form of BNP (Figure 2) induced a significant increase in plasma hBNP 10 minutes after its oral administration and remained detectable in the circulation for 4 hours. Although a formal pharmacokinetic study was not part of the present investigation, the detection of hBNP in canine plasma up to 4 hours after oral administration of hBNP-054 in all treated dogs may underscore an extended half-life of this new conjugated BNP compared with native BNP, which has a half-life of 
20 minutes. Alternatively, the presence of hBNP in the circulation up to 4 hours after administration of hBNP-054 may reflect a different absorption rate. Therefore, more formal pharmacokinetic studies with intravenous injection of a bolus of hBNP-054 are necessary. Only oral hBNP-054, not native BNP, significantly activated cGMP. Furthermore, the increased levels of hBNP and cGMP after oral hBNP-054 administration induced a significant and sustained reduction in MAP for the duration of the entire study. Of note, we observed different levels of plasma hBNP after oral conjugated hBNP among dogs, underscoring the need for continued improvement in this technology to optimize bioavailability and reproducibility in both animals and humans.
We also were able to demonstrate that chronic oral conjugated hBNP administration maintained its biological actions, as shown by a significant reduction in MAP after oral hBNP-054 for the 6 days of administration (Figure 4A). The sustained biological actions of hBNP-054 were further demonstrated by a continuous rise in sodium excretion, which was followed by a marked reversal of effect when oral hBNP-054 was discontinued (Figure 5). Because of limited hBNP-054, chronic studies were performed in only 2 dogs. These data taken together show that hBNP-054 did not lead to tachyphylaxis or result in signs of accumulation during the study period.
Finally, we demonstrated that this novel, orally active conjugated form of hBNP reduces blood pressure in experimental hypertension. Although numerous drugs are available for hypertension, BNP emerges as going beyond blood pressure reduction alone because it possesses a pleiotropic set of beneficial cell- and tissue-protective properties, warranting further studies and more refined technology to enhance bioavailability and improve pharmacokinetics. The use of a model of acute hypertension can be viewed as a limitation. However, this model of ANG II–mediated acute hypertension has been used extensively in the past and in key studies in the development of antihypertensive agents.36–41 Importantly, whether BNP-mediated antihypertensive properties have advantages over other antihypertensive mechanisms remains to be seen.
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Conclusions |
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We report a novel form of conjugated hBNP that is absorbed and detectable in the circulation when administered orally. Furthermore, conjugated hBNP was capable of activating cGMP and reducing MAP even when administered in a model of acute hypertension and displayed a magnitude and duration of action superior to native hBNP. These data suggest the importance of pursuing further studies with oral administration of conjugated forms of hBNP for the long-term treatment of cardiovascular diseases such as hypertension and perhaps overt CHF, thus opening a new and innovative phase of cardiovascular therapeutics.
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Acknowledgments |
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Sources of Funding
This study was supported by grants RO1 HL-36634, PO1 HL76611, and TG HL-07111 from the National Institutes of Health; by grant 0365411Z from the American Heart Association; by the Mayo Foundation; and by the Italian Ministry of Research Progetto Rientro dei Cervelli.
Disclosures
None.
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References |
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Related Article:
CLINICAL PERSPECTIVE
Although B-type natriuretic peptide (BNP) has been approved as an intravenous agent for acute heart failure, increasing research suggests that an additional prime clinical target may be human hypertension to complement its therapeutic use in heart failure in which molecular forms with reduced biological actions have been reported. Several lines of investigation support a strategy for the therapeutic use of BNP or other natriuretic peptides for hypertension. The evidence includes relative deficiency of biologically active BNP in the early stages of hypertension, the ability to chronically enhance sodium excretion and reduce blood pressure as demonstrated in the current studies, potent antifibrotic and prolusitropic actions, and the ability to suppress aldosterone synthesis and release. Importantly, in hypertension, we take advantage of the blood pressure–lowering effects that characterize the inherent properties of the natriuretic peptides, although this effect is a potential limitation for their indiscriminate use in heart failure patients. What is lacking in clinical practice, however, is the ability to chronically deliver peptides by means other than subcutaneous injections. Our report ushers in a new day in protein therapeutics in which we see the ability of advanced alkylPEGylation that modifies the hydrophilicity/hydrophobicity of BNP, permitting its chronic oral delivery. As stated in population studies from Canada, the rise in hypertension prevalence will likely far exceed the predicted prevalence for 2025, and strategies to manage hypertension and its sequelae are urgently needed. We advance here the concept for cardiovascular disease that the chronic use of natriuretic peptides like oral BNP as therapeutic agents will prove highly attractive.
Circulation 2008 118: 1689-1690.
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