Pulmonary Vasodilator In Patients Research Articles

Pulmonary vasodilators in patients with advanced chronic kidney disease and pre‐capillary pulmonary hypertension—A case series

AbstractPulmonary hypertension (PH) is a prevalent complication among patients with chronic kidney disease (CKD). In these patients, pulmonary vasodilators may be useful but are underused. We describe a group of patients with precapillary PH and advanced CKD treated with pulmonary vasodilators. This was a case series of patients with CKD stage 4 and 5 and precapillary PH (isolated or combined) based on right heart catheterization (RHC) treated with pulmonary vasodilators from 2018 to 2023. Of 263 patients with isolated precapillary or combined PH and advanced CKD, only 17 (6%) were treated with pulmonary vasodilators; 53% (n = 9) with precapillary PH and 47% (n = 8) with combined PH. Most patients (94%, n = 16) received phosphodiesterase‐5 antagonists, while 12% (n = 2) received endothelin receptor antagonists. Adverse clinical outcomes were seen in 35% of patients within a year. The use of pulmonary vasodilator did not prevent adverse outcomes in patients with precapillary PH and advanced CKD.

Selective Use of Pulmonary Vasodilators in Patients with Fontan Physiology.

Fontan-associated liver disease is a well-known sequela following the Fontan procedure for patients living with single-ventricle heart disease. Pulmonary vasodilators, such as phosphodiesterase type 5 inhibitors, have emerged as a potential therapeutic option for lowering central venous pressures by reducing pulmonary vascular resistance. We performed a single-center retrospective review of Fontan patients who were placed on pulmonary vasodilator therapy with prehemodynamic and posthemodynamic, MR elastography, and histologic assessments. A total of 125 patients with Fontan circulation underwent surveillance with cardiac catheterization during the review period. Fifty-three (42%) patients who did not have increased end-diastolic pressures at the time of cardiac catheterization were started on phosphodiesterase type 5 inhibitor therapy. Nine patients (17%) underwent posttherapy follow-up catheterization. The mean Fontan pressure decreased from 15.4 ± 3.3 mmHg to 13.3 ± 2.5 mmHg (p=0.026), after initiation of pulmonary vasodilatory therapy. There was no change in end-diastolic pressure, transpulmonary gradient, wedge pressure, pulmonary vascular resistance, cardiac index, or saturation. Eleven patients (21%) underwent pretherapy MR elastography testing with posttherapy follow-up MR elastography. We found no improvement in liver stiffness score following the application of pulmonary vasodilators. Three patients underwent pretherapy and posttherapy liver biopsies, with variable histological changes observed within the hepatic parenchyma. These data demonstrate indeterminate results for the selective use of pulmonary vasodilators but highlight the need for large prospective randomized control trials of pulmonary vasodilator therapies to fully assess the benefit of such therapies in Fontan-associated liver disease.

Predicting the response to pulmonary vasodilator therapy in systemic sclerosis with pulmonary hypertension by using quantitative chest CT.

Systemic sclerosis (SSc) is associated with pulmonary vascular disease and interstitial lung disease, making it difficult to differentiate pulmonary arterial hypertension and pulmonary hypertension (PH) due to lung diseases and/or hypoxia and to decide treatments. We aimed to predict the response to pulmonary vasodilators in patients with SSc and PH. Eighty-four SSc patients were included with 47 having PH. Chest computed tomography was evaluated using software to calculate the abnormal lung volume (ALV). To define the response to vasodilators, Δ mean pulmonary artery pressure (mPAP)/basal mPAP was used (cut-off value: 10%). The predictive value was evaluated by using the receiver operating characteristic curve. The mean (±standard deviation) value of ALV was 26.8 (±32.2) %. A weak correlation was observed between ALV and forced vital capacity (FVC) (R = -0.46). The predictive value of ALV [area under curve (AUC) = 0.74] was superior to that of FVC (AUC = 0.62) for the response to vasodilators. No hemodynamic parameters differed between patients with high and low ALV, whereas survival was worse in high ALV. Quantitative chest computed tomography well predicted the response to vasodilators in patients with SSc and PH. Our results suggest its utility in differentiating the dominance of pulmonary vascular disease or interstitial lung disease.

Efficacy and safety of pulmonary vasodilators in the patients with Eisenmenger syndrome: a meta-analysis of randomized controlled trials.

Few meta-analyses evaluated the efficacy and safety of pulmonary vasodilators in patients with Eisenmenger syndrome. Recently, some studies have reported conflicting results regarding improvements in exercise capacity. This study evaluated the efficacy and safety of pulmonary vasodilators in patients with Eisenmenger syndrome. Relevant studies were identified by searching major databases. Pooled outcomes were used to assess the efficacy and safety of pulmonary vasodilators. In total, five studies with 508 patients were included. Meta-analysis indicated that the pulmonary vasodilators reduced the mortality (odd risk (OR) = 0.35; 95% CI, 0.13 to 0.95; P = 0.04), slashed the mean pulmonary artery pressure (mean difference (MD) = −4.35 mmHg; 95% CI, −7.19 to −1.50; P = 0.003), decreased pulmonary vascular resistance index (MD = −480.08 dyn · s · cm−5 · m2; 95% CI, −753.51 to −206.64; P = 0.0006), increased the 6-min walk distance (MD = 28.38 m; 95% CI, 2.99 to 53.77; P = 0.03), and elevated the systemic oxygen saturation at rest (MD = 1.00%; 95% CI, 0.12 to 1.88; P = 0.03). Four studies reported side effects, but only two studies reported serious adverse effects which were mostly rare and curable. The present meta-analysis indicated that pulmonary vasodilators decrease mortality and improve hemodynamics and exercise capacity in patients with Eisenmenger syndrome. Overall, pulmonary vasodilators are well tolerated.

Pulmonary Vasodilator Use in Children with Heterotaxy Syndrome Undergoing Surgical Intervention for Congenital Heart Disease

Purpose Patients with heterotaxy syndrome have a high rate of congenital heart disease, often requiring surgical interventions, including palliative procedures to augment or restrict pulmonary blood flow. Pulmonary hypertension in this setting complicates surgical interventions and overall management. Pulmonary vasodilators may be used to treat pulmonary hypertension and facilitate surgical interventions. We describe the use of pulmonary vasodilators in patients with heterotaxy syndrome. Methods Single-center retrospective chart review of patients with heterotaxy syndrome who underwent at least one cardiac operation from Jan 1 2008 to Oct 31 2019. The diagnosis of heterotaxy syndrome was established from imaging studies performed prior to intervention. Surgical interventions were reviewed from operative reports. Pulmonary vasodilator use was assessed from progress notes and medication reconciliation at all inpatient and outpatient encounters. Results Thirty-four patients with heterotaxy syndrome were treated at our center during the study period, with follow up ranging from 18 to 3385 days. Palliative surgical interventions included restriction of pulmonary blood flow in 8 patients and augmentation of pulmonary blood flow in 11 patients. Pulmonary vasodilators were used in 16 patients (47%): 7 (20%) received inhaled nitric oxide while admitted, 3 (9%) received supplemental oxygen as outpatients, 12 (35%) received sildenafil as outpatients, 5 (14%) received multiple agents. Treatment was initiated in the inpatient setting in all patients. All patients on supplemental oxygen and the majority of patients on sildenafil continued on treatment at most recent follow up (10 patients, 83% of patients ever prescribed). There was no difference in pulmonary vasodilator use when stratified by surgical palliation strategy, and no differences in survival between patients with and without pulmonary vasodilator use. Conclusion Pulmonary vasodilator use is common in patients with heterotaxy syndrome undergoing surgical interventions for congenital heart disease. It is typically initiated in the inpatient setting but well-tolerated on a long-term basis, and may facilitate treatment in this challenging population.

Oxygen and pulmonary arterial hypertension: effects, mechanisms, and therapeutic benefits.

Oxygen is a pulmonary vasodilator. Although treatment of pulmonary arterial hypertension (PAH) is focused on pulmonary vasodilation, treatment guidelines do not recommend O2 therapy for patients unless they develop hypoxaemia. These guidelines point to a lack of evidence of benefit of O2 therapy from randomized controlled trials (RCTs) and to evidence of lack of benefit in a single RCT involving patients with Eisenmenger syndrome. These guidelines did not identify major limitations with the Eisenmenger study or consider other evidence of therapeutic benefit. Recent advances in mechanistic understanding of O2 effects on pulmonary vascular tone, along with substantial evidence of acute effects of O2 in PAH patients, challenge the view that benefits of O2 arise only through correction of hypoxaemia. Evidence presented in this review shows that O2 acts as a pulmonary vasodilator in patients who are normoxaemic; that this probably involves an alveolar mechanism in addition to a blood-borne (oxyhaemoglobin) mechanism; and that therapeutic benefit of O2 does not depend on arterial O2 levels. This suggests that O2 has potential therapeutic benefit for all patients with PAH. Clinical guidelines and practice related to O2 therapy need to be reassessed, and further research is needed.

Oxygen therapy for pulmonary arterial hypertension: We need to rethink and investigate.

Oxygen therapy for pulmonary arterial hypertension: We need to rethink and investigate.

Pulmonary vasodilator therapy after the Fontan procedure: a meta-analysis.

We aimed to assess the efficacy and safety of pulmonary vasodilators in patients after the Fontan procedure. The PubMed, EMBASE, and Cochrane Library databases were searched through November 2019 for studies comparing pulmonary vasodilators and controls in Fontan patients. The variables assessed included change in pulmonary resistance, heart function, exercise capacity, quality of life, mortality, and adverse events after drug administration. A random/fixed effects model was used to assess the mean difference (MD)/risk ratio (RR) with 95% confidence intervals (CIs). Subgroup analysis was stratified by drug category. In total, 449 Fontan patients from 13 studies were included. Pooled estimates of the change in pulmonary arterial pressure (MD, - 1.07; 95% CI, - 2.75 to 0.60; p = 0.21), New York Heart Association class (MD, - 0.57; 95% CI, - 1.41 to 0.28; p = 0.19), peak oxygen consumption (MD, 1.46; 95% CI, 0.01 to 2.90; p = 0.05), Short Form 36 (MD, 1.39; 95% CI, - 0.62 to 3.39; p = 0.17), mortality (RR, 0.37; 95% CI, 0.08 to 1.65; p = 0.19), and any adverse event (RR, 0.94; 95% CI, 0.71 to 1.24; p = 0.64) were not significantly different between the drug and control groups. Likewise, most results of the subgroup analysis revealed no significant between-group differences. Pulmonary vasodilator therapy appears to be safe, but not beneficial, in the categories of pulmonary resistance, heart function, or quality of life in patients who have undergone a Fontan procedure. No significant evidence was found to confirm that most pulmonary vasodilators could improve exercise capacity in Fontan patients.

The efficacy and safety of pulmonary vasodilators in patients with Fontan circulation: a meta-analysis of randomized controlled trials.

No previous meta-analysis has evaluated the efficacy and safety of pulmonary vasodilators in Fontan physiology. Recent relative trials have obtained conflicting results regarding improvements in peak oxygen consumption; the relatively small number of patients in each study may be a limiting factor. We aimed to evaluate the efficacy and safety of pulmonary vasodilators in Fontan patients. Relevant studies were identified by searching the PubMed, Embase, and Cochrane Library databases. Pooled outcomes were determined to assess the efficacy and safety of pulmonary vasodilators in Fontan patients. Nine randomized controlled studies involving 381 patients with Fontan circulation were included. Pulmonary vasodilator therapy led to significant improvement (mean difference = −0.39, 95% CI: [−0.72, −0.05]) in the New York Heart Association (NYHA) functional class. The 6-minute walking distance (6MWD) was significantly increased by 134 m (95% CI: [86.07, 181.94]), and the peak VO2 was also significantly improved (mean difference = 1.42 ml·(kg·min)-1, 95% CI: [0.21, 2.63]). Additionally, the mean pulmonary artery pressure (mPAP) was significantly reduced (mean difference = −2.25 mmHg, 95% CI: [−3.00, −1.50]). No significant change was found in mortality or in brain natriuretic peptide (BNP) or N-terminal pronatriuretic peptide (NT-proBNP). Four studies reported no side effects and good drug tolerance, and two studies reported mild adverse effects. The present meta-analysis indicated that pulmonary vasodilators (primarily the PDE-5 inhibitor and endothelin-1 receptor antagonist) significantly improved the hemodynamics of Fontan patients, reduced the NYHA functional class and increased the 6MWD. The peak oxygen consumption was also improved. No significant change was observed in mortality or in the BNP or NT-proBNP level. Overall, the pulmonary vasodilators were well tolerated. This finding needs to be confirmed in future studies.

Ventricular Performance is Associated with Need for Extracorporeal Membrane Oxygenation in Newborns with Congenital Diaphragmatic Hernia

To compare echocardiography (ECHO) findings of patients with congenital diaphragmatic hernia (CDH) who required extracorporeal membrane oxygenation (ECMO) to non-ECMO treated patients. We reviewed clinical and ECHO data of newborns with CDH born between 2009 and 2016. Exclusions included major anomalies, genetic syndromes, or no ECHO prior to ECMO. Pulmonary hypertension was assessed by ductal shunting and tricuspid regurgitant jet. Speckle tracking echocardiography (STE) assessed function by quantifying deformation. Patients with CDH (15 ECMO and 29 with no ECMO) were analyzed. Most patients had a left CDH (88.6%). Age at ECHO was similar between groups. Outborn status (P = .009) and liver position (P = .009) were associated with need for ECMO. Compared with non-ECMO patients, patients who required ECMO had significantly decreased left and right ventricular function by both conventional and STE measures, as well as decreased right and left ventricular output. The right ventricular eccentricity index was higher in ECMO vs non-ECMO patients (2.2 vs 1.8, P = .02). There was no difference in pulmonary hypertension between CDH groups. Need for ECMO was associated with decreased left and right ventricular function, as assessed by standard and STE measures. There was no difference in pulmonary hypertension between non ECMO and ECMO patients. Abnormal cardiac function may explain nonresponse to pulmonary vasodilators in patients with CDH. Management strategies to improve cardiac function may reduce the need for ECMO in newborns with CDH.

Management of advanced adult congenital heart disease

There are increasing numbers of adults with congenital heart disease. These patients remain at lifelong risk of complications including heart failure, arrhythmias and premature death. This review examines the management of those patients with advanced disease, with particular reference to patients with either a systemic right ventricle or a univentricular circulation. Drugs used to treat left ventricular dysfunction in acquired heart disease have been shown to have little benefi t in this setting. There are, however, promising results from small trials looking at selective pulmonary vasodilators in patients with a previous Fontan operation. Whilst there is evidence of a benefi t with implantable cardiac defi brillators and cardiac resynchronisation, there remains a lack of clear guidelines as to which patients will benefi t from these invasive therapies. Cardiac transplantation in these patients is associated with an increased early mortality but the long term outcome is similar to those with acquired heart failure. Transplantation however, is limited by both the patient’s suitability and the availability of a matched organ. End of life care should be discussed with all patients with advanced disease and ideally this should be done early on and in parallel to other therapies.

Outcome of oral sildenafil in neonatal persistent pulmonary hypertension of non-cardiac causes.

Despite recent treatment modalities, mortality from persistent pulmonary hypertension (PPHN) remains significant. In instances where infants do not respond to inhaled nitric oxide (iNO), oral sildenafil could hold promise as a selective pulmonary vasodilator. Further studies are still needed to explore its efficacy and safety in newborns with PPHN. To validate the efficacy of oral sildenafil on oxygenation and its short-term safety in newborns with persistent pulmonary hypertension. A total of 27 newborns ≥36 weeks gestational age were admitted to NICU with oxygenation index (OI) ≥15 and confirmed diagnosis of PPHN with echocardiography. Oral sildenafil given at a dose of 1-2 mg/kg every 6 hours. We monitored improvement in oxygenation, safety and short-term outcomes. Among 27 newborns, oral sildenafil was efficacious in 21 patients (78%) with reduction of OI from 34.9 ± 9.6 to 13 ± 3.2 (p < 0.001), increase of PaO2 from 42.4 ± 13.5 to 78 ± 11.5 mmHg (<0.001), and reduction of FiO2 from 1.0 ± 0 to 0.3 ± 0.06 (<0.001). OI decreased by 6.3 % from baseline after the first dose of sildenafil and continued to decrease with subsequent doses. In 6 patients (22%) sildenafil did not work; 5/6 patients (18%) transferred to another tertiary NICU and one patient (4%) died of sepsis. None of the patients had significant systemic hypotension. Oral sildenafil is a promising pulmonary vasodilator in patients with PPHN, particularly in medical facilities with no available iNO and ECMO. It is well tolerated with no significant short term complications.

Potential Role of CT Metrics in Chronic Obstructive Pulmonary Disease with Pulmonary Hypertension.

Recent imaging studies demonstrated the usefulness of quantitative computed tomographic (CT) analysis assessing pulmonary hypertension (PH) in patients with chronic obstructive lung disease (COPD-PH). The aim of this study was to investigate whether it would be also valuable for predicting and evaluating the effect of pulmonary vasodilators in patients with COPD-PH. We analyzed a correlation between the extent of cystic destruction (LAA%) and total cross-sectional areas of small pulmonary vessels less than 5mm(2) (%CSA <5) in many CT slices from each of four COPD-PH patients before and after the initiation of pulmonary vasodilator. To evaluate those generalized data from patients with COPD, we evaluated multiple slices from 42 patients whose PH was not clinically suspicious. We also selected five PH patients with idiopathic interstitial pneumonia (IIP-PH) and analyzed serial changes of pulmonary artery enlargement (PA:A ratio). In 42 COPD patients without PH, LAA% had a statistically significant negative correlation with %CSA <5. However, three of four COPD-PH patients manifested no such correlation. In two patients, clinical findings were dramatically improved after the initiation of pulmonary vasodilator. Notably, LAA% and %CSA <5 in those patients correlated significantly after its treatment. In COPD-PH, the PA:A ratio was significantly decreased after the initiation of pulmonary vasodilator therapy (1.25±0.13 vs. 1.13±0.11, p=0.019), but not in IIP-PH. Our study demonstrates that the use of quantitative CT analysis is a plausible and beneficial tool for predicting and evaluating the effect of pulmonary vasodilators in patients with COPD-PH.

Should we pursue pulmonary vasodilation in patients with COPD?

Pulmonary hypertension is a pathophysiological disorder defined as an increase in pulmonary arterial pressure, as assessed by right heart catheterisation (mean pressure ≥25 mm Hg at rest). Pulmonary hypertension can arise in various clinical disorders, which have been classified by WHO into five clinical groups, on the basis of mechanisms, with different pathogenic, prognostic, and therapeutic features.1 The first group is defined as pulmonary arterial hypertension, whereas the third group encompasses pulmonary hypertension due to lung diseases or hypoxaemia, including hypertension due to chronic obstructive pulmonary disease (COPD), interstitial lung disease, and sleep-disordered breathing.

Prognostic significance of remaining severe left ventricular diastolic dysfunction after cardiac resynchronizaion therapy

reduced the dose to 40 mgand her symptom soon disappeared; 6 MWD improved to 250 m. Right heart catheterization revealed reduction of pulmonary vascular resistance (from2057 to 1658 [dyne·s·cm]) and mean pulmonary arterial pressure (from 66 to 60 [mm Hg]) compared to those of pre-administration of sildenafil. Although it is difficult to predict the unfavorable response of pulmonary vasodilators in patients with PVOD, sildenafil would be an effective and feasible drug if you carefully determine the dosage.

World Health Organization Pulmonary Hypertension Group 2: Pulmonary hypertension due to left heart disease in the adult—a summary statement from the Pulmonary Hypertension Council of the International Society for Heart and Lung Transplantation

Pulmonary hypertension associated with left heart disease is the most common form of pulmonary hypertension encountered in clinical practice today. Although frequently a target of therapy, its pathophysiology remains poorly understood and its treatment remains undefined. Pulmonary hypertension in the context of left heart disease is a marker of worse prognosis and disease severity, but whether its primary treatment is beneficial or harmful is unknown. An important step to the future study of this important clinical problem will be to standardize definitions across disciplines to facilitate an evidence base that is interpretable and applicable to clinical practice. In this current statement, we provide an extensive review and interpretation of the current available literature to guide current practice and future investigation. At the request of the Pulmonary Hypertension (PH) Council of the International Society for Heart and Lung Transplantation (ISHLT), a writing group was assembled and tasked to put forth this document as described above. The review process was facilitated through the peer review process of the Journal of Heart and Lung Transplantation and ultimately endorsed by the leadership of the ISHLT PH Council.

Prostacyclin and milrinone by aerosolization improve pulmonary hemodynamics in newborn lambs with experimental pulmonary hypertension

Aerosolized prostacyclin (PGI2) produces selective pulmonary vasodilation in patients with pulmonary hypertension (PH). The response to PGI2 may be increased by phosphodiesterase type 3 inhibitors such as milrinone. We studied the dose response effects of aerosolized PGI2 and aerosolized milrinone both alone and in combination on pulmonary and systemic hemodynamics in newborn lambs with Nomega-nitro-L-arginine methyl ester (L-NAME)-induced PH. We hypothesized that coaerosolization of PGI2 with milrinone would additively decrease pulmonary vascular resistance (PVR), prolong the duration of action of PGI2, and selectively dilate the pulmonary vasculature. Near-term lambs were delivered by C-section and instrumented and PH was induced by L-NAME (bolus 25 mg/kg; infusion 10 mg.kg(-1).h(-1)) and indomethacin. In the first set of experiments, PGI2 was aerosolized at random doses of 2, 20, 100, 200, 500, and 1,000 ng.kg(-1).min(-1) followed by milrinone at doses of 0.1, 1, and 10 microg.kg(-1).min(-1) over 10 min. In the second set of experiments, milrinone at 1 microg.kg(-1).min(-1) was aerosolized in combination with PGI2 at doses of 20, 100, and 200 ng.kg(-1).min(-1) over 10 min. Pulmonary arterial pressures (PAP) and PVR decreased significantly with increasing doses of aerosolized PGI2 and milrinone. The combination of PGI2 and milrinone significantly reduced PAP and PVR more than either of the drugs aerosolized alone. Addition of milrinone significantly increased the duration of action of PGI2. When aerosolized independently, PGI2 and milrinone selectively dilated the pulmonary vasculature but the combination did not. Milrinone enhances the vasodilatory effects of PGI2 on the pulmonary vasculature but caution must be exercised regarding systemic hypotension.

Comparison of inhaled and intravenous milrinone in patients with pulmonary hypertension undergoing mitral valve surgery

Increased pulmonary vascular resistance (PVR) is detrimental to cardiac output in postoperative cardiac-surgery patients. The aim of this study was to investigate the postoperative hemodynamic effects of milrinone inhalation, and determine whether it has a selective effect of pulmonary vasodilation in patients with pulmonary hypertension undergoing mitral valve replacement surgery. In this study, 48 patients with pulmonary hypertension who underwent mitral valve replacement surgery were included. Patients were randomly divided into two groups with 24 patients in each: the inhaled group and the control group (intravenous [i.v.] milrinone). In the inhaled group, milrinone was administered with a jet nebulizer, and nebulized for 4 hours. In the control group, patients received a bolus of 50 microg/kg i.v. milrinone, then received a continuous milrinone infusion, 0.5 microg/kg/min, for 4 hours. A number of hemodynamic changes in all patients were evaluated. With milrinone administration, mean pulmonary artery pressure (MPAP) and PVR showed a comparable decrease in both groups. However, after initiation of milrinone, both mean arterial pressure and systemic vascular resistance in the inhaled group were significantly higher than in the control group. MPAP and PVR returned to baseline values 60 minutes after termination of milrinone inhalation. In addition, in the inhaled group, there was a reduction in intrapulmonary shunt fraction (Qs/Qt), with an improvement in PaO(2)/FiO(2) (arterial oxygen tension/fraction of inspired oxygen). The major advantage of inhaled milrinone is its pulmonary selectivity, thereby avoiding systemic side effects and ventilation-perfusion mismatch. Inhaled milrinone is an effective pulmonary vasodilator and appears to be an alternative promising approach in addressing the problem of right-ventricular decompensation following cardiopulmonary bypass.

Synergy between Natriuretic Peptides and Phosphodiesterase 5 Inhibitors Ameliorates Pulmonary Arterial Hypertension

Phosphodiesterase 5 (PDE5) inhibitors (e.g., sildenafil) are selective pulmonary vasodilators in patients with pulmonary arterial hypertension. The mechanism(s) underlying this specificity remains unclear, but studies in genetically modified animals suggest it might be dependent on natriuretic peptide bioactivity. We explored the interaction between PDE5 inhibitors and the natriuretic peptide system to elucidate the (patho)physiological relationship between these two cyclic GMP (cGMP)-regulating systems and potential of a combination therapy exploiting these cooperative pathways. Pharmacological evaluation of vascular reactivity was conducted in rat isolated conduit and resistance vessels from the pulmonary and systemic circulation in vitro, and in anesthetized mice in vivo. Parallel studies were undertaken in an animal model of hypoxia-induced pulmonary hypertension (PH). Sildenafil augments vasodilatation to nitric oxide (NO) in pulmonary and systemic conduit and resistance arteries, whereas identical vasorelaxant responses to atrial natriuretic peptide (ANP) are enhanced only in pulmonary vessels. This differential activity is mirrored in vivo where sildenafil increases the hypotensive actions of ANP in the pulmonary, but not systemic, vasculature. In hypoxia-induced PH, combination of sildenafil plus the neutral endopeptidase (NEP) inhibitor ecadotril (which increases endogenous natriuretic peptide levels) acts synergistically, in a cGMP-dependent manner, to reduce many indices of disease severity without significantly affecting systemic blood pressure. These data demonstrate that PDE5 is a key regulator of cGMP-mediated vasodilation by ANP in the pulmonary, but not systemic, vasculature, thereby explaining the pulmonary selectivity of PDE5 inhibitors. Exploitation of this mechanism (i.e., PDE5 and neutral endopeptidase inhibition) represents a novel, orally active combination therapy for pulmonary arterial hypertension.

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

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. Open-label study. Medical ICUs of three tertiary care hospitals in New England. Thirteen consecutive adult patients undergoing right-heart catheterization and a pulmonary vasodilator trial for the initial evaluation of PAH. Patients were administered inhaled nitric oxide (iNO), i.v. epoprostenol, and a 3-h infusion of BNP alone and 1 h after an oral dose of the phosphodiesterase-5 inhibitor sildenafil. 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. 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.