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(Chest. 2006;129:417-425.)
© 2006 American College of Chest Physicians

Pulmonary Hemodynamic Responses to Brain Natriuretic Peptide and Sildenafil in Patients With Pulmonary Arterial Hypertension*

James R. Klinger, MD; Sejal Thaker, MD; Jeanne Houtchens, RN; Ioana R. Preston, MD; Nicholas S. Hill, MD and Harrison W. Farber, MD

* From the Division of Pulmonary, Sleep and Critical Care Medicine (Drs. Klinger and Thaker, and Ms. Houtchens), Rhode Island Hospital and Brown Medical School, Providence, RI; Division of Pulmonary and Critical Care Medicine (Drs. Preston and Hill), Tufts New England Medical Center and Tufts University School of Medicine, Boston, MA; and Pulmonary Center (Dr. Farber), Boston University School of Medicine, Boston, MA.

Correspondence to: James R. Klinger, MD, Division of Pulmonary, Sleep and Critical Care Medicine, Rhode Island Hospital, 593 Eddy St, Providence, RI 02903; e-mail: james_klinger{at}brown.edu

Abstract

Study objectives: Brain natriuretic peptide (BNP) blunts hypoxic pulmonary hypertension in animal models, but its acute hemodynamic effects in patients with pulmonary arterial hypertension (PAH) are not known. The aim of this study was to determine if human B-type natriuretic peptide is a safe and efficacious pulmonary vasodilator in patients with PAH and if the pulmonary hemodynamic effects are potentiated by phosphodiesterase inhibition.

Design: Open-label study.

Setting: Medical ICUs of three tertiary care hospitals in New England.

Patients: Thirteen consecutive adult patients undergoing right-heart catheterization and a pulmonary vasodilator trial for the initial evaluation of PAH.

Interventions: Patients were administered inhaled nitric oxide (iNO), IV epoprostenol, and a 3-h infusion of BNP alone and 1 h after an oral dose of the phosphodiesterase-5 inhibitor sildenafil.

Results: iNO and sildenafil alone decreased mean pulmonary artery pressure (mPAP) without a significant fall in pulmonary vascular resistance (PVR). Epoprostenol decreased both mPAP and PVR. BNP alone had no significant effect on pulmonary hemodynamics, but the combination of sildenafil plus BNP decreased mPAP and PVR for up to 6 h after stopping BNP. The decrease in mPAP with sildenafil plus BNP (± SE) was greater than after 1 h of sildenafil alone (44.6 ± 3.8 to 40.6 ± 3.9 mm Hg, p = 0.027). An acute vasodilator response, defined as a decrease in mPAP > 10 mm Hg and end mPAP < 40 mm Hg, was seen in 0 of 8 patients with iNO, 1 of 13 patients with epoprostenol, 0 of 13 patients with BNP, and 4 of 12 patients with sildenafil plus BNP. BNP decreased mean systemic arterial pressure (5.6 ± 2.8 mm Hg) but had no effect on cardiac output or systemic vascular resistance.

Conclusions: A 3-h BNP infusion does not significantly improve pulmonary hemodynamics in most patients with PAH but is well tolerated and augments the acute pulmonary vasodilator effect of sildenafil.

Key Words: cyclic guanosine monophosphate • hypertension, pulmonary • natriuretic peptides • nitric oxide • sildenafil • phosphodiesterase inhibitors • prostaglandin

Originally discovered in the porcine brain, brain natriuretic peptide (BNP) is a member of the natriuretic peptide family of proteins that share a similar 17 amino acid ring structure necessary for its biological activity.1 Like atrial natriuretic peptide (ANP), BNP is highly expressed in the heart.2 Both peptides activate the particulate guanylyl cyclase-linked receptor, natriuretic peptide receptor-A (NPR-A) to raise intracellular cyclic guanosine monophosphate (cGMP) levels that mediate their potent diuretic and vasorelaxant effects.3 In addition to their hemodynamic effects, natriuretic peptides have been shown to inhibit vascular smooth-muscle proliferation and cardiac hypertrophy.456 Furthermore, ANP and BNP can counteract the renin angiotensin system and inhibit the synthesis of growth factors such as endothelin that are implicated in the development of pulmonary hypertensive disease.78

Previous studies by our group29 and by others10 have shown that ANP and BNP inhibit pulmonary vasoconstriction in pulmonary arterial rings and isolated rat lungs and that chronic infusion of these peptides can blunt the development of hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and muscularization of pulmonary vessels. Conversely, targeted disruption of the gene that encodes for ANP or NPR-A results in elevated pulmonary arterial pressure (PAP) under normoxic conditions and exaggerated pulmonary hypertensive and cardiac hypertrophic responses to hypoxia.111213

The human B-type natriuretic peptide nesiritide has been approved for the treatment of decompensated left ventricular failure, but limited data are available regarding its pulmonary hemodynamic effects in patients with pulmonary hypertension. Previous studies have shown that BNP infusion inhibits hypoxic pulmonary vasoconstriction in healthy human volunteers14 and that circulating BNP levels correlate strongly with pulmonary vascular resistance (PVR), cardiac output, and functional status in patients with pulmonary arterial hypertension (PAH).15 Natriuretic peptides have been shown to lower PAP in patients with chronic hypoxic lung disease and in pulmonary venous hypertension associated with ischemic cardiomyopathy or rheumatic heart disease.161718192021 In patients with decompensated left-heart failure, nesiritide causes a dose-dependent decrease in right atrial pressure, PAP, and pulmonary capillary wedge pressure (PCWP) with a moderate increase in cardiac output.22 These studies demonstrate that BNP is capable of lowering PAP in a variety of pulmonary hypertensive diseases and raise the possibility that BNP infusion may be effective at improving pulmonary hemodynamics in patients with PAH.

In the present study, we hypothesized that BNP would have acute pulmonary hemodynamic effects similar to those of inhaled nitric oxide (iNO) and IV epoprostenol in adult patients with PAH. We also hypothesized that the phosphodiesterase-5 (PDE-5) inhibitor sildenafil would augment the pulmonary vasodilator effects of BNP by virtue of its inhibitory effect on cGMP metabolism.

Materials and Methods

Subjects
The research protocol was approved by the human subjects protection committees at Rhode Island Hospital, Tufts-New England Medical Center, and Boston University Medical Center, and informed consent was obtained from each patient prior to study entry. All patients referred for pulmonary artery catheterization and a pulmonary vasodilator trial to evaluate newly diagnosed PAH between September 1, 2002, and June 30, 2003, were screened for enrollment. Patients were invited to participate if their mean PAP (mPAP) was > 25 mm Hg at rest during right-heart catheterization and if their pulmonary hypertension could not be explained on the basis of pulmonary venous hypertension, chronic lung disease, or venothromboembolic disease. Patients were excluded if they were receiving therapy with prostacyclin analogues, endothelin receptor antagonists, or phosphodiesterase inhibitors, or if they had any of the following conditions: (1) total lung capacity < 60% of predicted, (2) systolic systemic arterial BP < 100 mm Hg, (3) cardiac index < 2.0 L/min/m2, (4) serum sodium < 130 (mEq/dl Na+), or (5) serum creatinine > 2.0 (mg/dl creatinine).

Research Protocol
All patients were studied in an ICU immediately following placement of a balloon-tipped pulmonary artery catheter. The pulmonary artery catheter was placed via an internal jugular or subclavian vein using standard techniques. Hemodynamic measurements were made with the patient at rest in the supine position using the midaxillary line as the 0 mm Hg reference point. Heart rate, PAP, and pulse oximetry were measured continuously. Systemic arterial pressure was measured by automatic cuff inflation every 15 min. Cardiac output was measured by thermodilution using the mean of at least three measurements per observation. The PVR was calculated by dividing the difference between mPAP and PCWP by cardiac output, and systemic vascular resistance was calculated by dividing the difference between mean systemic arterial pressure and central venous pressure by cardiac output.

After baseline measurements were obtained, patients were tested for the presence of an acute vasodilator response using iNO and/or IV epoprostenol. All patients received epoprostenol infusion. iNO was not available to five patients studied at one of the three enrollment centers. iNO (n = 8) was delivered by closed facemask starting at 5 ppm. The dose of iNO was doubled every 15 min to a maximum dose of 20 ppm. The concentrations of NO and nitrogen dioxide delivered to the facemask were monitored continuously. Vital signs and hemodynamic measurements were made after breathing iNO for 15 min at each dose. Approximately 30 min after stopping iNO, a new set of baseline measurements were obtained and an IV infusion of epoprostenol was begun. Epoprostenol infusion was started at a dose of 1 to 2 ng/kg/min and increased by 1 to 2 ng/kg/min every 15 min until side effects such as headache, hypotension, jaw pain, bone pain, or nausea developed. Vital signs and hemodynamic measurements were made after at least 15 min of each dose of epoprostenol. Approximately 1 h after stopping epoprostenol, baseline measurements were repeated and patients were administered two trials of BNP infusion. For both trials, the human B-type natriuretic peptide nesiritide was administered as a 0.2-µg bolus IV infusion over 20 min followed by 0.01 µg/kg/min IV infusion for a total of 3 h. In the first trial, BNP was administered alone. In the second trial, BNP was administered 1 h after a single oral dose of sildenafil. In an earlier study23 of PAH patients receiving sildenafil, we found no further decrease in mPAP after the first hour of treatment. Patients were administered 100 mg of sildenafil unless they were > 65 years old, in which case they received 50 mg of sildenafil. Vital signs and hemodynamic measurements were made at baseline, 1 h after sildenafil, 15 min, 60 min and 3 h after starting BNP, and 1 h, 3 h, and 6 h after completing the BNP infusions. BNP infusion trials were run concurrently separated by an overnight stay in the ICU. Venous blood was obtained for plasma BNP levels at baseline, at the end of BNP infusion, and 6 h after completing BNP infusion. Plasma was assayed for the active circulating form of human BNP (BNP77–108) using an automated immunodiagnostic system (Advia Centaur; Bayer Diagnostics; Tarrytown, NY) with antibodies that recognize the 17 amino acid loop and C-terminal portions of human BNP. This assay does not cross-react with {alpha}-human ANP or the N-terminal portion of pro-BNP. This assay has been shown to detect increases in plasma BNP levels following administration of nesiritide with return to endogenous plasma BNP levels approximately 2 h after infusion.

Statistical Analysis
Data shown are mean ± SEM. Differences in mean values from baseline for each treatment were assessed by one-way analysis of variance repeated measures using Dunett post hoc analysis. Differences in mean values between treatment groups were assessed by paired t test. Differences were considered significant at p < 0.05.

Results

Patient Demographics
The mean age of the 3 men and 10 women was 59.4 ± 4.7 years. Pulmonary hypertension was idiopathic or associated with connective tissue disease or HIV infection (Table 1 ). Two patients had a remote history of pulmonary sarcoidosis but had no evidence of obstructive or restrictive defects on pulmonary function testing and were not being treated for pulmonary sarcoidosis. The mean mPAP was 48.6 ± 3.7 mm Hg, and mean PVR was 698 ± 105 dyne·cm/s2. None of the patients had been treated for pulmonary hypertension prior to the study. Patient 11 had been receiving weekly BNP infusions for 6 weeks prior to the study for an initial diagnosis of congestive heart failure. Pulmonary hypertension was diagnosed during left-heart catheterization, and weekly BNP infusions were stopped 2 weeks prior to the study. All patients received BNP alone. One patient was not administered sildenafil plus BNP because she had transient hypotension that developed during the initial infusion of BNP.


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  		Table 1.. Age, Sex, New York Heart Association Class, and WHO Category of Pulmonary Hypertension*

 
Hemodynamic Responses
Both iNO and epoprostenol infusion lowered mPAP (Table 2 ). Epoprostenol infusion increased cardiac index and decreased PVR and mean systemic arterial pressure, whereas iNO had no effect on these parameters (Table 2). BNP infusion alone had no effect on mPAP or PVR, nor was there any change in mPAP or PVR for up to 6 h after stopping BNP infusion (Fig 1 ). One hour after sildenafil, mPAP and PVR were significantly lower than baseline (Fig 2 ). Infusion of BNP in patients pretreated with sildenafil resulted in a further decrease in mPAP compared to values obtained 1 h after sildenafil (Fig 2). Both mPAP and PVR in the sildenafil-plus-BNP treatment patients remained significantly lower than baseline for up to 6 h after stopping BNP infusion or 10 h after receiving sildenafil.


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  		Table 2.. Effect of iNO and IV Epoprostenol on Pulmonary and Systemic Hemodynamics*

 

Figure 1
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  		Figure 1.. mPAP and PVR after 15 min, 60 min, and 3 h of BNP infusion and 1 h, 3 h, and 6 h after infusion was stopped (4 h, 6 h, and 9 h after start of BNP infusion, respectively). Values shown are mean ± SE; n = 13.

 

Figure 2
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  		Figure 2.. mPAP and PVR after 1 h of sildenafil, and after 15 min, 60 min, and 3 h of BNP infusion, and 1 h, 3 h, and 6 h after infusion was stopped (4 h, 6 h, and 9 h after start of BNP infusion, respectively). Values shown are mean ± SE; n = 12, *p < 0.05 vs baseline; +p < 0.05 vs 0 time point.

 
The change in mPAP and PVR with each treatment is shown in Figure 3 . The greatest decrease in mPAP was seen with the combination of sildenafil plus BNP. The combination of sildenafil-plus-BNP infusion resulted in a greater decrease in mPAP than that observed 1 h after sildenafil alone (p = 0.027).


Figure 3
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  		Figure 3.. Change in mPAP and PVR at the end of each treatment. Values shown are mean ± SE; n = 13 for iNO, epoprostenol (PGI2), and BNP; n = 12 for sildenafil and sildenafil plus BNP. *p < 0.05 vs baseline; +p < 0.05 vs sildenafil.

 
Few patients had a positive pulmonary vasodilator response to any of the treatments given. Using the criteria adopted by the World Health Organization (WHO) for a positive vasodilator response (> 10 mm Hg drop in mPAP and mPAP < 40 mm Hg), no patients had a positive vasodilator response to iNO or BNP alone and only one patient had a vasodilator response to epoprostenol or sildenafil alone (Table 3 ). In contrast, 4 of 12 patients had a positive vasodilator response with the combination of sildenafil plus BNP.


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  		Table 3.. Ratio of Patients With Pulmonary Vasodilator Responses in Each Treatment Group

 
BNP infusion was well tolerated. As a group, no statistically significant change in cardiac index or systemic vascular resistance was seen during BNP infusion, although mean systemic arterial pressure fell slightly 1 h after BNP infusion (Table 4 ). Mean systemic arterial pressure, systemic vascular resistance, and central venous pressure fell 1 h after sildenafil (Table 5 ). The addition of BNP infusion in patients pretreated with sildenafil did not result in a further reduction in any of these variables (Table 5).


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  		Table 4.. Effect of BNP on Hemodynamic Measurements, Respiratory Rate, and Pulse Oximetry*

 

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  		Table 5.. Effect of Sildenafil Plus BNP on Systemic Hemodynamic Measurements, Respiratory Rate, and Pulse Oximetry*

 
Adverse Events
One patient experienced transient hypotension, defined as systolic BP < 90 mm Hg, during bolus infusion of BNP alone. She was asymptomatic, and her BP returned to normal shortly after stopping the infusion. She did not receive sildenafil plus BNP in accordance with the research protocol. The only other adverse event was an attack of gout in one patient the day after completing both BNP infusions. The relation of this event to the infusions was not clear.

Plasma BNP Levels
Mean plasma BNP levels at baseline were above the upper limits for normal laboratory values (Fig 4 ). BNP infusion was associated with a sixfold increase in plasma BNP that returned to baseline levels within 6 h of completing the infusion (Fig 4).


Figure 4
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  		Figure 4.. Change in plasma BNP levels 3 h after infusion and 6 h after stopping infusion compared to baseline levels. Values shown are mean ± SE; n = 7; *p < 0.05 vs baseline.

 
Discussion

Data on the safety and efficacy of BNP as a pulmonary vasodilator in patients with pulmonary hypertension are limited. Several studies16171819 have shown that the natriuretic peptides lower PAP in patients with chronic hypoxic lung disease, although in some cases this occurs at the expense of increased hypoxemia.18 In two anecdotal reports, BNP infusion improved pulmonary hemodynamics in patients with pulmonary venous hypertension associated with ischemic cardiomyopathy20 and rheumatic heart disease.21 In a preliminary report published in abstract form,24 BNP infusion decreased PAP in seven patients with postcapillary pulmonary hypertension defined as PCWP > 15 mm Hg but had no effect on PAP in five patients with precapillary pulmonary hypertension. However, in that study,24 pulmonary hemodynamic measurements were made after only 30 min of BNP infusion.

In the present study, we found that a 3-h BNP infusion was well tolerated in adult patients with PAH. Although as a group, BNP alone had no effect on mPAP or PVR, the combination of sildenafil followed by BNP infusion caused a statistically significant reduction in both parameters that persisted for up to 6 h after stopping the BNP infusion. The reduction in mPAP with sildenafil plus BNP was at least as great as that seen with any of the other pulmonary vasodilators used in this trial and greater than that observed 1 h after sildenafil alone. These findings suggest that the combination of a PDE-5 inhibitor plus BNP may have potential as a new therapeutic approach to PAH.

Our inability to demonstrate a decrease in mPAP or PVR with BNP alone in the present study may have been due to an insufficient dose or duration of BNP infusion. Unlike iNO, which was administered over a dose range that was previously found to be effective, or epoprostenol infusion, which was increased to a maximal tolerable dose, we used a single dose of BNP and a limited duration of infusion. We chose this dose because it has been shown to be safe and effective in patients with congestive heart failure22 and because higher doses have been associated with a greater incidence of symptomatic hypotension.25 The duration of BNP infusion (3 h) was selected to allow time for elevation of circulating BNP levels (given the circulating half-life of BNP of approximately 18 min) and allow an adequate washout time (6 h) before the sildenafil-plus-BNP combination, while limiting the total duration of the trial to < 36 h for patient comfort. The sixfold elevation of plasma BNP levels over baseline achieved in this study is similar to that reported for the dose of BNP used.38 We acknowledge that higher infusion rates or a longer duration of infusion may be needed to lower PAP or PVR in patients with established pulmonary hypertension. Another possible explanation for the lack of significant change in pulmonary hemodynamics with BNP infusion alone, that natriuretic peptide receptors are saturated in the face of endogenously elevated circulating BNP levels, seems unlikely considering that BNP infusion decreases PCWP and left ventricular afterload in patients with decompensated left-sided failure despite endogenous plasma BNP levels that are even higher than those measured in the current study.22

The present study aimed to determine if the combination of sildenafil plus BNP was more effective than either agent alone. The drop in mPAP (approximately 10%) that occurred an hour after the BNP infusion was started in patients receiving sildenafil strongly suggests that such an amplification occurred. We did not monitor the hemodynamic response to sildenafil alone for more than an hour, but it is unlikely that the further reduction in mPAP after starting BNP was due to sildenafil alone. Plasma levels of sildenafil peak within an hour of an oral dose, and its elimination half-life is approximately 3 h.26 For this reason, most studies2728 examining the effects of sildenafil have measured pulmonary hemodynamics within the first hour after administration. In one study,29 the maximum reduction in mPAP and PVR occurred within 15 min and 30 min of receiving sildenafil, respectively, and no further reduction in mPAP or PVR was seen over the next 60 min. In another study30 that examined the acute pulmonary hemodynamic effects of three different PDE-5 inhibitors in patients with PAH, the greatest reduction in mPAP caused by sildenafil occurred 60 min after dosing (95% confidence interval, 52 to 67.5 min). Similarly, we found no difference in mPAP between 1 h and 2 h after sildenafil in three PAH patients who had a > 20% decrease in mPAP.23

Several lines of evidence support the concept that the combination of sildenafil, an inhibitor of cGMP degradation, and BNP, a stimulator of cGMP production, should work synergistically to lower PAP in pulmonary hypertensive patients. Animal studies have found that ANP is the primary source of increased cGMP production in pulmonary hypertensive lungs31 and that PDE-5 expression is increased in some forms of experimental pulmonary hypertension.32 Thus, increasing natriuretic peptide levels while inhibiting the increase in cGMP metabolism should have a pronounced effect on raising cGMP levels. Indeed, we have shown33 that sildenafil plus ANP increases plasma cGMP levels in rats during acute hypoxia more than either agent alone. Because ANP and BNP utilize the same guanylyl cyclase-linked receptor, NPR-A, to raise intracellular cGMP, similar results would be expected from the combination of sildenafil and BNP. In a study27 in humans, sildenafil has been shown to enhance the pulmonary vasodilator effect of iNO, another stimulator of cGMP production, in patients with PAH. Likewise, in the present study, mPAP 1 h after adding BNP to sildenafil was lower than 1 h after sildenafil alone. Furthermore, sildenafil alone caused a positive pulmonary vasodilator response, as defined by the WHO criteria, in only 1 of 12 patients, whereas the combination of sildenafil plus BNP resulted in a vasodilator response in 4 of 12 patients.

BNP infusion had no significant effect on cardiac output or systemic vascular resistance and only modestly reduced mean systemic arterial pressure. This reduction in systemic arterial pressure induced by BNP was similar to that observed after 1 h of sildenafil alone. Unlike mPAP, however, the combination of sildenafil plus BNP did not lower systemic arterial pressure more than sildenafil alone, suggesting a preferential effect of sildenafil plus BNP on the pulmonary circulation. A preferential effect on the pulmonary circulation was also suggested by the PVR/SVR ratio. In this study, BNP or sildenafil alone had no effect on PVR/SVR, whereas sildenafil plus BNP decreased PVR/SVR by 7.5 ± 4.0%; in 4 of 12 patients who had a positive vasodilator response, PVR/SVR fell by 13.3 ± 8.4%.

No serious adverse events were noted with BNP infusion either alone or after pretreatment with sildenafil. Asymptomatic and transient systemic arterial hypotension developed in one patient during the bolus infusion of BNP alone. Another patient with a distant history of gout had an acute attack the day after completing the study. To our knowledge, gout has not previously been reported in other trials of BNP infusion.

The close correlation between circulating BNP levels and PVR in patients with PAH15 supports the idea that endogenous BNP synthesis is increased to counter the rise in right ventricular afterload. Raising plasma BNP levels further with long-term infusion of exogenous BNP could improve cardiopulmonary performance by a variety of mechanisms. In addition to its pulmonary vasodilatory effect, BNP has been shown to limit the degree of pathologic left ventricular hypertrophy that occurs during chronic left ventricular overload.6 Mice with disrupted NPR-A signaling develop massive left ventricular hypertrophy and myocardial fibrosis that results in early cardiac death.34 This inhibitory effect of NPR-A activity on pathologic cardiac hypertrophy may be due to the inhibitory effect of BNP on transforming growth factor-ß–induced proliferation of cultured cardiac myofibroblasts and increased production of collagen 1 and fibronectin.35 Increasing circulating BNP levels in pulmonary hypertensive patients may help to slow progression of cardiac remodeling in the right ventricle and preserve systolic function. BNP has also been found to inhibit proliferation of pulmonary vascular smooth muscle in vitro,36 and long-term administration could impede pulmonary vascular remodeling as has been shown in animals studies.910 Natriuretic peptides also inhibit endothelin synthesis8 and could potentiate the favorable effects of endothelin receptor blockade. Finally, natriuretic peptides antagonize many effects of the renin-angiotensin system and have been shown to decrease aldosterone levels in patients with cor pulmonale.18 The inhibitory effect of BNP on salt and fluid retention may be particularly helpful in mitigating the degree of right ventricular failure that occurs as pulmonary hypertension progresses.

The need for a prolonged period of IV infusion presently makes long-term administration of BNP cumbersome and expansive even if given intermittently. However, new methods of BNP delivery are being developed that could greatly facilitate chronic BNP use in the outpatient setting. For example, subcutaneous administration of nesiritide every 12 h has been found to be effective at raising plasma BNP and cGMP levels and at improving cardiopulmonary hemodynamics in patients with congestive heart failure.37 Transdermal and oral preparations of BNP are also presently under development and if successful could be used for extended outpatient treatment. These new approaches to BNP delivery have the potential to make combination therapy with a phosphodiesterase inhibitor a viable approach to treating PAH.

Conclusions

BNP infusion is well tolerated in patients with PAH but has no pulmonary hemodynamic effects in most patients at the doses used in this study. BNP infusion appears to enhance the pulmonary vasodilator effect of sildenafil. Further studies are needed to determine if higher doses of BNP or a longer duration of infusion can improve pulmonary hemodynamics. As better methods for chronic BNP administration become available, augmentation of circulating BNP levels, at least in combination with PDE-5 inhibition, may offer a new approach to treating PAH.

Footnotes

Abbreviations: ANP = atrial natriuretic peptide; BNP = brain natriuretic peptide; cGMP = cyclic guanosine monophosphate; iNO = inhaled nitric oxide; mPAP = mean pulmonary arterial pressure; NPR-A = natriuretic peptide receptor-A; PAH = pulmonary arterial hypertension; PAP = pulmonary arterial pressure; PCWP = pulmonary capillary wedge pressure; PDE-5 = phosphodiesterase-5; PVR = pulmonary vascular resistance; WHO = World Health Organization

This study was supported by a grant from Scios, Inc. and American Heart Association Grant EIG 0240190N (Dr. Klinger).

Received for publication April 18, 2005. Accepted for publication June 27, 2005.

References

  1. Sudoh, T, Kangawa, K, Minamino, N, et al (1988) A new natriuretic peptide in porcine brain. Nature 332,78-81[CrossRef][Medline]
  2. Hill, NS, Klinger, JR, Warburton, RR, et al Brain natriuretic peptide: possible role in the modulation of hypoxic pulmonary hypertension. Am J Physiol 1994;266,L308-L315
  3. Levin, ER, Gardner, DG, Samson, WK Natriuretic peptides. N Engl J Med 1998;339,321-328[Free Full Text]
  4. Itoh, H, Pratt, RE, Dzau, VJ Atrial natriuretic polypeptide inhibits hypertrophy of vascular smooth muscle cells. J Clin Invest 1990;86,1690-1697
  5. Hutchinson, HG, Trindade, PT, Cunanan, DB, et al Mechanisms of natriuretic-peptide-induced growth inhibition of vascular smooth muscle cells. Cardiovasc Res 1997;35,158-167[Abstract/Free Full Text]
  6. Knowles, JW, Esposito, G, Mao, L, et al Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice. J Clin Invest 2001;107,975-984[ISI][Medline]
  7. Wijeyaratne, CN, Moult, PJA The effect of {alpha}-human atrial natriuretic peptide on plasma volume and vascular permeability in normotensive subjects. J Clin Endocrinol Metab 1993;76,343-346[Abstract]
  8. Hu, RM, Levin, ER, Pedram, A, et al Atrial natriuretic peptide inhibits the production and secretion of endothelin from cultured endothelial cells: mediation through the C receptor. J Biol Chem 1992;267,17384-17389[Abstract/Free Full Text]
  9. Klinger, JR, Warburton, RR, Pietras, L, et al Brain natriuretic peptide attenuates the development of pulmonary hypertension in hypoxia-adapted rats. J Appl Physiol 1998;84,1646-1652[Abstract/Free Full Text]
  10. Jin, H, Yang, RH, Chen, YF, et al Atrial natriuretic peptide attenuates the development of pulmonary hypertension in rats adapted to chronic hypoxia. J Clin Invest 1990;85,115-120
  11. Klinger, JR, Warburton, R, Pietras, L, et al Genetic disruption of atrial natriuretic peptide causes pulmonary hypertension in normoxic and hypoxic mice. Am J Physiol 1999;276,L868-L874
  12. Zhao, L, Long, L, Morrell, NW, et al NPR-A-pulmonary deficient mice show increased susceptibility to hypoxia-induced hypertension. Circulation 1999;99,605-607[Abstract/Free Full Text]
  13. Klinger, JR, Warburton, R, Pietras, L, et al Targeted disruption of the gene for natriuretic peptide receptor-A worsens hypoxia-induced cardiac hypertrophy Am J Physiol 2002;282,H58-H65
  14. Cargill, RI, Lipworth, BJ Acute effects of ANP and BNP on hypoxic pulmonary vasoconstriction in humans. Br J Clin Pharmacol 1995;40,585-590[ISI][Medline]
  15. Leuchte, HH, Holzapfel, M, Baumgartner, RA, et al Clinical significance of brain natriuretic peptide in primary pulmonary hypertension. J Am Coll Cardiol 2004;43,764-770[Abstract/Free Full Text]
  16. Adnot, S, Andrivet, P, Chabrier, PE, et al Atrial natriuretic factor in chronic obstructive lung disease with pulmonary hypertension: physiological correlates and response to peptide infusion. J Clin Invest 1989;83,986-993
  17. Rogers, TK, Sheedy, W, Waterhouse, J, et al Haemodynamic effects of atrial natriuretic peptide in hypoxic chronic obstructive pulmonary disease. Thorax 1994;49,233-239[Abstract/Free Full Text]
  18. Andrivet, P, Chabrier, PE, Defouilloy, C, et al Intravenously administered atrial natriuretic factor in patients with COPD: effects on ventilation-perfusion relationships and pulmonary hemodynamics. Chest 1994;106,118-124[Abstract/Free Full Text]
  19. Cargill, RI, Lipworth, BJ Atrial natriuretic peptide and brain natriuretic peptide in cor pulmonale: hemodynamic and endocrine effects. Chest 1996;110,1220-1225[Abstract/Free Full Text]
  20. Bhat, G, Costea, A Reversibility of medically unresponsive pulmonary hypertension with nesiritide in a cardiac transplant recipient. ASAIO J 2003;49,608-610[CrossRef][Medline]
  21. Kurian, DC, Wagner, IJ, Klapholz, M Nesiritide in pulmonary hypertension. Chest 2004;126,302-305[Abstract/Free Full Text]
  22. Colucci, WS, Elkayam, U, Horton, DP, et al Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. Nesiritide Study Group. N Engl J Med 2000;343,246-253[Abstract/Free Full Text]
  23. Preston, IR, Klinger, JR, Houtchens, J, et al Acute and chronic effects of sildenafil in patients with pulmonary arterial hypertension. Respir Med 2006;99,1501-1510
  24. Michaels, AD, Chatterjee, K, Madden, J, et al Hemodynamic effects of intravenous nesiritide in patients with pulmonary hypertension [abstract]. J Am Coll Cardiol 2004;43,A192
  25. Burger, AJ, Aronson, D, Horton, DP, et al Comparison of the effects of dobutamine and nesiritide (B-type natriuretic peptide) on ventricular ectopy in acutely decompensated ischemic versus nonischemic cardiomyopathy. Am J Cardiol 2003;91,1370-1372[Medline]
  26. Jackson, G, Benjamin, N, Jackson, N, et al Effects of sildenafil citrate on human hemodynamics. Am J Cardiol 1999;83,13C-20C[ISI][Medline]
  27. Lepore, JJ, Maroo, A, Pereira, NL, et al Effect of sildenafil on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension. Am J Cardiol 2002;90,677-680[CrossRef][ISI][Medline]
  28. Michelakis, E, Tymchak, W, Lien, D, et al Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 2002;105,2398-2403[Abstract/Free Full Text]
  29. Wilkens, H, Guth, A, Konig, J, et al Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation 2001;104,1218-1222[Abstract/Free Full Text]
  30. Ghofrani, HA, Voswinckel, R, Reichenberger, F, et al Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: a randomized prospective study. J Am Coll Cardiol 2004;44,1488-1496[Abstract/Free Full Text]
  31. Muramatsu, M, Tyler, RC, Gutkowska, J, et al Atrial natriuretic peptide accounts for increased cGMP in hypoxia-induced hypertensive rat lungs. Am J Physiol 1997;272,L1126-L1132
  32. Murray, F, MacLean, MR, Pyne, NJ Increased expression of the cGMP-inhibited cAMP-specific (PDE3) and cGMP binding cGMP-specific (PDE5) phosphodiesterases in models of pulmonary hypertension. Br J Pharmacol 2002;7,1187-1194[CrossRef]
  33. Preston, IR, Hill, NS, Gambardella, LS, et al Synergistic effects of ANP and sildenafil on cGMP levels and amelioration of acute hypoxic pulmonary hypertension. Exp Biol Med 2004;229,920-925[Abstract/Free Full Text]
  34. Oliver, PM, Fox, JE, Kim, R, et al Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A. Proc Natl Acad Sci U S A 1997;94,14730-14735[Abstract/Free Full Text]
  35. Kapoun, AM, Liang, F, O’Young, G, et al B-type natriuretic peptide exerts broad functional opposition to transforming growth factor-ß in primary human cardiac fibroblasts: fibrosis, myofibroblast conversion, proliferation, and inflammation. Circ Res 2004;94,453-461[Abstract/Free Full Text]
  36. Arjona, AA, Hsu, CA, Wrenn, DS, et al Effects of natriuretic peptides on vascular smooth-muscle cells derived from different vascular beds. Gen Pharmacol 1997;28,387-392[ISI][Medline]
  37. Chen, HH, Redfield, MM, Nordstrom, LJ, et al Subcutaneous administration of the cardiac hormone BNP in symptomatic human heart failure. J Card Fail 2004;10,115-119[CrossRef][ISI][Medline]
  38. Physicians Desk Reference, 2006 Edition, Thomson Healthcare: Montclair, NJ, page 3124




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