Hepatic BMAL1 and HIF1α regulate a time-dependent hypoxic response and prevent hepatopulmonary-like syndrome.

The transcriptional response to hypoxia is temporally regulated, yet the molecular underpinnings and physiological implications are unknown. We examined the roles of hepatic Bmal1 and Hif1α in the circadian response to hypoxia in mice. We found that the majority of the transcriptional response to hypoxia is dependent on either Bmal1 or Hif1α, through shared and distinct roles that are daytime determined. We further show that hypoxia-inducible factor (HIF)1α accumulation upon hypoxia is temporally regulated and Bmal1 dependent. Unexpectedly, mice lacking both hepatic Bmal1 and Hif1α are hypoxemic and exhibit increased mortality upon hypoxic exposure in a daytime-dependent manner. These mice display mild liver dysfunction with pulmonary vasodilation likely due to extracellular signaling regulated kinase (ERK) activation, endothelial nitric oxide synthase, and nitric oxide accumulation in lungs, suggestive of hepatopulmonary syndrome. Our findings indicate that hepatic BMAL1 and HIF1α are key time-dependent regulators of the hypoxic response and can provide molecular insights into the pathophysiology of hepatopulmonary syndrome.

Pulmonary vasodilation during cardiopulmonary resuscitation - A randomized, controlled porcine study.

BACKGROUND: During resuscitation pulmonary artery pressure (PAP) increases. This reduces left ventricular filling, leading to decreased blood flow. Inhaled nitric oxide (iNO) produces selective pulmonary vasodilation. We hypothesized that iNO would lower PAP during resuscitation resulting in increased survival. METHODS: 30 pigs (40 kg) were subjected to cardiac arrest for 9.5 min after myocardial ischemia induced by coronary artery occlusion of the left anterior descending artery and ventricular fibrillation. During resuscitation, the pigs were randomized to 40 ppm iNO or placebo. The primary outcome was return of spontaneous circulation (ROSC). Pigs achieving ROSC underwent 4-hours intensive care. RESULTS: The ROSC rate was 9/14 (64%) in the control group and 11/16 (69%) in the iNO group (OR 1.2 95%CI [0.3;5.6], p > 0.99). There was no difference in diastolic aorta pressure/PAP ratio (mean difference -0.99 [95% CI: -2.33-0.36], p = 0.14). Mean pulmonary artery pressure was lower in the iNO group 60 and 120 min after ROSC (mean difference: -12.18 mmHg [95%CI: -16.94; -7.43] p < 0.01 and -5.43 [95%CI: -10.39; -0.46] p = 0.03). Troponin I levels in the iNO group were significantly higher 60 and 120 min after ROSC (mean difference: 266105 ng/l [95%CI: 6356; 525855] p = 0.045 and 420049 ng/l [95%CI: 136779; 703320], p = 0.004). The area at risk of the heart was 33% (SD 1) in controls and 34% (SD 1) in the iNO group. The infarct size divided by the area at risk was 55% (SD 3) in controls and 86% (SD 1) in the iNO group, p = 0.01. CONCLUSION: Application of iNO did not improve the rate of ROSC or hemodynamic function but increased myocardial injury.

A Comparative Investigation of the Pulmonary Vasodilating Effects of Inhaled NO Gas Therapy and Inhalation of a New Drug Formulation Containing a NO Donor Metabolite (SIN-1A).

Numerous research projects focused on the management of acute pulmonary hypertension as Coronavirus Disease 2019 (COVID-19) might lead to hypoxia-induced pulmonary vasoconstriction related to acute respiratory distress syndrome. For that reason, inhalative therapeutic options have been the subject of several clinical trials. In this experimental study, we aimed to examine the hemodynamic impact of the inhalation of the SIN-1A formulation (N-nitroso-N-morpholino-amino-acetonitrile, the unstable active metabolite of molsidomine, stabilized by a cyclodextrin derivative) in a porcine model of acute pulmonary hypertension. Landrace pigs were divided into the following experimental groups: iNO (inhaled nitric oxide, n = 3), SIN-1A-5 (5 mg, n = 3), and SIN-1A-10 (10 mg, n = 3). Parallel insertion of a PiCCO system and a pulmonary artery catheter (Swan-Ganz) was performed for continuous hemodynamic monitoring. The impact of iNO (15 min) and SIN-1A inhalation (30 min) was investigated under physiologic conditions and U46619-induced acute pulmonary hypertension. Mean pulmonary arterial pressure (PAP) was reduced transiently by both substances. SIN-1A-10 had a comparable impact compared to iNO after U46619-induced pulmonary hypertension. PAP and PVR decreased significantly (changes in PAP: -30.1% iNO, -22.1% SIN-1A-5, -31.2% SIN-1A-10). While iNO therapy did not alter the mean arterial pressure (MAP) and systemic vascular resistance (SVR), SIN-1A administration resulted in decreased MAP and SVR values. Consequently, the PVR/SVR ratio was markedly reduced in the iNO group, while SIN-1A did not alter this parameter. The pulmonary vasodilatory impact of inhaled SIN-1A was shown to be dose-dependent. A larger dose of SIN-1A (10 mg) resulted in decreased PAP and PVR in a similar manner to the gold standard iNO therapy. Inhalation of the nebulized solution of the new SIN-1A formulation (stabilized by a cyclodextrin derivative) might be a valuable, effective option where iNO therapy is not available due to dosing difficulties or availability.

Cardiac index is associated with oxygenation in COVID-19 acute respiratory distress syndrome.

Eleven participants with COVID-19 acute respiratory distress syndrome requiring mechanical ventilation underwent pulmonary artery catheterization for clinical indications. Clinical interventions or events concurrent with hemodynamic were recorded. Increased cardiac index was associated with worse hypoxemia. Modulation of cardiac index may improve hypoxemia in patients with COVID-19 acute respiratory distress syndrome.

Pulmonary vasodilation by sildenafil in acute intermediate-high risk pulmonary embolism: a randomized explorative trial.

BACKGROUND: To investigate if acute pulmonary vasodilation by sildenafil improves right ventricular function in patients with acute intermediate-high risk pulmonary embolism (PE). METHODS: Single center, explorative trial. Patients with PE were randomized to a single oral dose of sildenafil 50 mg (n = 10) or placebo (n = 10) as add-on to conventional therapy. The time from hospital admission to study inclusion was 2.3 ± 0.7 days. Right ventricular function was evaluated immediately before and shortly after (0.5-1.5 h) randomization by right heart catheterization (RHC), trans-thoracic echocardiography (TTE), and cardiac magnetic resonance (CMR). The primary efficacy endpoint was cardiac index measured by CMR. RESULTS: Patients had acute intermediate-high risk PE verified by computed tomography pulmonary angiography, systolic blood pressure of 135 ± 18 (mean ± SD) mmHg, increased right ventricular/left ventricular ratio 1.1 ± 0.09 and increased troponin T 167 ± 144 ng/L. Sildenafil treatment did not improve cardiac index compared to baseline (0.02 ± 0.36 l/min/m2, p = 0.89) and neither did placebo (0.00 ± 0.34 l/min/m2, p = 0.97). Sildenafil lowered mean arterial blood pressure (- 19 ± 10 mmHg, p < 0.001) which was not observed in the placebo group (0 ± 9 mmHg, p = 0.97). CONCLUSION: A single oral dose of sildenafil 50 mg did not improve cardiac index but lowered systemic blood pressure in patients with acute intermediate-high risk PE. The time from PE to intervention, a small patient sample size and low pulmonary vascular resistance are limitations of this study that should be considered when interpreting the results. TRIAL REGISTRATION: The trial was retrospectively registered at www.clinicaltrials.gov (NCT04283240) February 2nd 2020, https://clinicaltrials.gov/ct2/show/NCT04283240?term=NCT04283240&draw=2&rank=1 .

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.

Dynamic exercise changes in venous pressure and liver stiffness in Fontan patients: effects of Treprostinil.

BACKGROUND: Systemic venous hypertension and low cardiac output are believed to be important mediators of liver injury after the Fontan procedure. Pulmonary vasodilators have the potential to improve such haemodynamics. The aim of this study was to assess the acute effects of exercise on liver stiffness and venous pressures and to assess the impact of inhaled Treprostinil on this response. METHODS: In this prospective, double-blind, placebo-controlled, crossover trial, 14 patients with a Fontan circulation were randomised to inhalation of placebo and Treprostinil. Incremental and constant work rate exercise tests were performed to assess the effect of Treprostinil on exercise tolerance. Venous pressures were measured throughout and liver stiffness at rest and immediately after peak exercise. RESULTS: Mean age was 27.8 ± 7.9 years and 66% were females. Exercise acutely increased liver stiffness by 30% (mean shear wave speed: 2.38 ± 0.71 versus 2.89 ± 0.51 ms, p = 0.02). Peripheral venous pressures increased acutely during both incremental (12.1 ± 2.4 versus 22.6 ± 8.0 mmHg, p < 0.001) and constant work rate exercise (12.5 ± 2.5 versus 23.4 ± 5.2 mmHg, p < 0.001). Overall, Treprostinil failed to attenuate exercise-induced increases in liver stiffness. Compared with placebo, Treprostinil did not significantly impact venous pressure responses, VO2peak, nor exercise endurance times. CONCLUSIONS: Peripheral venous pressure increased acutely during exercise by an average of 88% above baseline and was not altered by administration of inhaled Treprostinil. Liver stiffness measured immediately post-exercise increased acutely by an average of 30%, with no attenuation following Treprostinil inhalation.

Why Pulmonary Vasodilation May Be Part of a Key Strategy to Improve Survival in COVID-19.

Oxygenation is a function of both ventilation and perfusion. While approaches to the treatment of COVID-19 have focused largely on ventilation strategies and antiviral therapies, attention towards the improvement of vascular perfusion defects has been neglected. This article examines clinical findings that indicate perfusion defects are a critical component of COVID-19 pathophysiology. They also support the notion that medications that promote perfusion with pulmonary vasodilatation can yield significantly improved outcomes that include overall survival. Calcium channel blocker usage has been associated with improved survival and outcomes in several retrospective reviews of patient populations with COVID-19 from across the world. This includes studies conducted in Paris, France; Wuhan, China; Daegu, South Korea; Brooklyn, New York; Brussels, Belgium; and a national sample from across the United States. These medications are generally prescribed to treat hypertension. Yet, they are also utilized in various pulmonary conditions to effectuate pulmonary vasodilatation. Thus, a concomitant benefit appears to have been revealed as patients that were taking these medications had significantly improved overall survival. Sildenafil is another medication that induces pulmonary vasodilatation. It was found to decrease the need for mechanical ventilation and reduce hospital length of stay in COVID-19 in a triple-blinded randomized control trial. The importance of pulmonary vasodilation in COVID-19 has been evaluated further. In a study of over 100 high-resolution CT scans, patients with COVID-19 showed a significant reduction in pulmonary blood volume contained in small blood vessels of <5 mm2 compared to healthy volunteers. Moreover, this was found to clinically correlate with a need for more oxygen supplementation. In radiologic perfusion studies, hypoperfusion was observed to occur in the healthy lung while hyperperfusion was present in non-healthy COVID-inflicted lung. It appears that perfusion of oxygen-carrying capacity, in the form of hemoglobin-carrying red blood cells, is being misappropriated towards unhealthy lung tissue. This was observed concurrently while the healthy lung had a paucity of perfusion. This can be a key aspect of hypoxic development in COVID-19. Mathematical modeling of perfusion abnormalities in COVID-19 has also implicated extensive perfusion defects, with ventilation-perfusion mismatching in the non-injured lung and hyperperfusion of up to threefold increases to afflicted regions. Vasodilation in the form of systemic intravascular medications may help improve outcomes by resetting this imbalance and by promoting perfusion of the alveolar-capillary unit where gas exchange and oxygenation occurs particularly in the non-injured lung. Furthermore, endothelialitis and microthrombosis have been observed on pathology specimens as many patients develop micro-thrombi following prolonged perfusion deficits. Vasodilatory agents can curb vasoconstriction and drive more perfusion towards healthy tissue. The temporal matching of consistent systemic intravascular vasodilation therapy throughout the gradual and progressive course of the illness may be integral to achieving improved outcomes. Improving perfusion to healthy tissue can help improve oxygenation and overall outcomes in COVID-19. These findings support further utilization and investigation of vasodilatory agents in the treatment of COVID-19.

Treprostinil palmitil, an inhaled long-acting pulmonary vasodilator, does not show tachyphylaxis with daily dosing in rats.

BACKGROUND: Treprostinil palmitil (TP) is an inhaled long-acting pulmonary vasodilator prodrug of treprostinil (TRE) that has been formulated for delivery as a suspension (treprostinil palmitil inhalation suspension; TPIS) and as a dry powder (treprostinil palmitil inhalation powder; TPIP). In humans, tachyphylaxis is frequently observed with continuous intravenous (IV) or subcutaneous (SC) infusion of TRE and requires dosage escalation to maintain activity. The aim of the present study was to determine whether tachyphylaxis occurs with repeat daily administration of inhaled TPIS. METHODS: Experiments were performed in male Sprague-Dawley rats prepared with a telemetry probe implanted into the right ventricle to measure the change in right ventricular pulse pressure (ΔRVPP) induced by exposure to a 10% oxygen gas mixture. TPIS (6 mL) at concentrations of 0.25, 0.5, and 1 mM was given by nose-only inhalation using an Aeroneb Pro nebulizer, either as a single administration or daily for 16 or 32 consecutive days. In studies involving consecutive daily administrations of TPIS, the delivered TP dosage was 140.3 µg/kg at 1 mM and ranged from 40.2 to 72.2 µg/kg at 0.5 mM. A separate cohort of telemetered rats received continuous IV infusion of TRE via an Alzet mini-pump at a dosage rate of 250 ng/kg/min for 16 days. Blood and lung tissue samples were obtained, and the concentration of TRE in the plasma and TRE and TP in the lungs were measured approximately 1 h after TPIS administration. RESULTS: Dose-response studies with TPIS administered as a single administration inhibited the hypoxia-induced increase in RVPP in both a concentration-dependent (0.25, 0.5, and 1 mM) and time-dependent (1-24 h) manner. TPIS, given QD or BID at inhaled doses ranging from 40.2 to 140.3 µg/kg for 16 or 32 consecutive days, produced statistically significant (P < .05) inhibition of the increase of RVPP due to hypoxia over the full duration of the dosing periods. By contrast, the inhibition of the hypoxia-induced increase in RVPP observed with IV TRE infusion (250 ng/kg/min) disappeared after 16 days of infusion. The plasma concentrations of TRE were significantly higher after IV TRE (range, 2.85-13.35 ng/mL) compared to inhaled TPIS (range, 0.22-0.73 ng/mL) CONCLUSIONS: There was no evidence of tachyphylaxis with repeat daily dosing of TPIS for a period of up to 32 days. The absence of tachyphylaxis with TPIS is likely related to its local vasodilatory effects within the lungs, combined with an absence of sustained high plasma concentrations of TRE.

Advances in Diagnostic Imaging of Hepatopulmonary Syndrome.

Hepatopulmonary syndrome (HPS) is a serious pulmonary complication of progressive liver disease that leads to a poor clinical prognosis. Patients with HPS may develop acute respiratory failure, which requires intensive care and therapy. At present, the only effective treatment is liver transplantation; therefore, early diagnosis and timely treatment are of considerable significance. The three main features of HPS are liver disease, oxygenation disorder, and intrapulmonary vascular dilatation (IPVD). Diagnosing HPS is challenging due to the difficulty in detecting the presence or absence of IPVD. As such, imaging examination is very important for detecting IPVD. This paper reviews the imaging methods for diagnosing HPS such as ultrasound, dynamic pulmonary perfusion imaging, pulmonary angiography, and computed tomography.

Heterogeneous Perfusion in COVID-19 and High Altitude Pulmonary Edema: A Review of Two Cases Followed by Implications for Hypoxic Pulmonary Vasoconstriction, Thrombosis Development, Ventilation Perfusion Mismatch and Emergence of Treatment Approaches.

Coronavirus disease 2019 (COVID-19) has been compared to high altitude pulmonary edema (HAPE). Multiple similarities between the two conditions were drawn in the past. This article seeks to further clarify potential underlying mechanisms related to hypoxia and pulmonary vascular responses. It does so by looking at perfusion imaging of patients with COVID-19 and comparing them with patterns observed in HAPE and hypoxic exposure. Two separate clinical cases are reviewed. The salient aspect of each case that is emphasized is the perfusion scintigraphy results that revealed heterogeneous perfusion patterns in both patients. Heterogeneous or non-homogeneous perfusion is also observed in HAPE. A detailed clinical course of each patient is described. Medications utilized to treat the conditions are outlined as well as laboratory parameters and clinical findings. Interestingly, both of these patients were treated with calcium channel blockers and this class of medications is utilized to prevent HAPE as well. Discussion following the case presentations attempts to contextualize possible implications of this and other studies on the broader pathophysiology of COVID-19 disease. Findings related to pathophysiologic patterns and treatment strategies are also described. Micro-thrombi formation has been reported in both COVID-19 and HAPE as well and may be an accessory complication of perfusion compromise. In a separate study, vasodilatation with calcium channel blocker (CCB) therapy has been associated with improved mortality in COVID-19 and potential pathophysiologic mechanisms were previously presented. This case report provides further clinical findings that support the notion that perfusion deficits are an integral component of hypoxia in COVID-19. It also advances the basis for use of vasodilator therapy as part of treatment regimens in COVID-19. Vasodilators may improve micro-perfusion. In this way, oxygenation may be promoted by decreasing impedance and improving flow via the alveolar-capillary unit.

Nifedipine and Amlodipine Are Associated With Improved Mortality and Decreased Risk for Intubation and Mechanical Ventilation in Elderly Patients Hospitalized for COVID-19.

Dihydropyridine calcium channel blockers (CCB) are typically used agents in the clinical management of hypertension. Yet, they have also been utilized in the treatment of various pulmonary disorders with vasoconstriction. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been implicated in the development of vasoconstrictive, proinflammatory, and pro-oxidative effects. A retrospective review was conducted on CCB use in hospitalized patients in search of any difference in outcomes related to specific endpoints: survival to discharge and progression of disease leading to intubation and mechanical ventilation. The electronic medical records for all patients that tested positive for SARS-CoV-2 that were at or above the age of 65 and that expired or survived to discharge from a community hospital in Brooklyn, NY, between the start of the public health crisis due to the viral disease up until April 13, 2020, were included. Of the 77 patients that were identified, 18 survived until discharge and 59 expired. Seven patients from the expired group were excluded since they died within one day of presentation to the hospital. Five patients were excluded from the expired group since their age was above that of the eldest patient in the survival group (89 years old). With 65 patients left, 24 were found to have been administered either amlodipine or nifedipine (CCB group) and 41 were not (No-CCB group). Patients treated with a CCB were significantly more likely to survive than those not treated with a CCB: 12 (50%) survived and 12 expired in the CCB group vs. six (14.6%) that survived and 35 (85.4%) that expired in the No-CCB treatment group (P<.01; p=0.0036). CCB patients were also significantly less likely to undergo intubation and mechanical ventilation. Only one patient (4.2%) was intubated in the CCB group whereas 16 (39.0%) were intubated in the No-CCB treatment group (P<.01; p=0.0026). Nifedipine and amlodipine were found to be associated with significantly improved mortality and a decreased risk for intubation and mechanical ventilation in elderly patients hospitalized with COVID-19. Further clinical studies are warranted. Including either nifedipine or amlodipine in medication regimens for elderly patients with hypertension hospitalized for COVID-19 may be considered.

Sodium Nitroprusside-Enhanced Cardiopulmonary Resuscitation Improves Blood Flow by Pulmonary Vasodilation Leading to Higher Oxygen Requirements.

Sodium nitroprusside-enhanced cardiopulmonary resuscitation has shown superior resuscitation rates and neurologic outcomes in large animal models supporting the need for a randomized human clinical trial. This study is the first to show nonselective pulmonary vasodilation as a potential mechanism for the hemodynamic benefits. The pulmonary shunting that is created requires increased oxygen treatment, but the overall improvement in blood flow increases minute oxygen delivery to tissues. In this context, hypoxemia is an important safety endpoint and a 100% oxygen ventilation strategy may be necessary for the first human clinical trial.

An overview of the biology of a long-acting inhaled treprostinil prodrug.

Treprostinil (TRE) is a prostanoid analog pulmonary vasodilator drug marketed with subcutaneous, intravenous (i.v.), oral, and inhaled routes of administration for the treatment of pulmonary arterial hypertension (PAH). Due to its short half-life, TRE requires either continuous infusion or multiple dosing, which exacerbates its side effects. Therefore, a long-acting prostanoid analog that maintains the positive attributes of TRE but has fewer TRE-related side effects could be of clinical benefit. In this report, we describe the discovery, preclinical development, and biology of the TRE ester prodrug, treprostinil palmitil (TP), which is formulated in a lipid nanoparticle (LNP) for administration as a nebulized inhaled suspension (TPIS). In screening assays focused on the conversion of prodrug to TRE, TP (16 carbon alkyl chain) had the slowest rate of conversion compared with short-alkyl chain TRE prodrugs (i.e., 2-8 carbon alkyl chain). Furthermore, TP is a pure prodrug and possesses no inherent binding to G-protein coupled receptors including prostanoid receptors. Pharmacokinetic studies in rats and dogs demonstrated that TPIS maintained relatively high concentrations of TP in the lungs yet had a low maximum plasma concentrations (Cmax) of both TP and, more importantly, the active product, TRE. Efficacy studies in rats and dogs demonstrated inhibition of pulmonary vasoconstriction induced by exposure to hypoxic air or i.v.-infused U46619 (thromboxane mimetic) over 24 h with TPIS. Cough was not observed with TPIS at an equivalent dose at which TRE caused cough in guinea pigs and dogs, and there was no evidence of desensitization to the inhibition of pulmonary vasoconstriction in rats with repeat inhaled dosing. TPIS was also more efficacious than i.v.-infused TRE in a sugen/hypoxia rat model of PAH to inhibit pulmonary vascular remodeling, an effect likely driven by local activities of TRE within the lungs. TPIS also demonstrated antifibrotic and anti-inflammatory activity in the lungs in rodent models of pulmonary fibrosis and asthma. In a phase 1 study in healthy human participants, TPIS (referred to as INS1009) had a lower plasma TRE Cmax and fewer respiratory-related side effects at equimolar doses compared with inhaled TRE. We have now formulated TP as an aerosol powder for delivery by a dry powder inhaler (referred to as treprostinil palmitil inhalation powder-TPIP), and as an aerosol solution in a fluorohydrocarbon solvent for delivery by a metered dose inhaler. These options may reduce drug administration time and involve less device maintenance compared with delivery by nebulization.

Effects of Interatrial Shunt on Pulmonary Vascular Function in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Implantation of an interatrial shunt device (IASD) in patients with heart failure (HF) reduces left atrial hypertension by shunting oxygenated blood to the right heart and lungs. The attendant increases in pulmonary blood flow (Qp) and oxygen content may alter pulmonary vascular function, while left-to-right shunting might compromise systemic perfusion. OBJECTIVES: The authors hypothesized that IASD would improve indexes of pulmonary artery (PA) function at rest and during exercise in HF patients without reducing systemic blood flow (Qs). METHODS: This is a pooled analysis from 2 trials assessing the effects of the IASD on resting and exercise hemodynamics in HF patients (n = 79) with EF ≥40% with baseline and repeated hemodynamic evaluation between 1 and 6 months. Patients with pulmonary vascular resistance (PVR) >4 WU or right ventricular dysfunction were excluded. RESULTS: Qp and PA oxygen content increased by 27% and 7% following IASD. These changes were associated with salutary effects on pulmonary vascular function (17% reduction in PVR, 12% reduction in PA elastance [pulmonary Ea], and 24% increase in PA compliance). Qp increased during exercise to a greater extent following IASD compared with baseline, which was associated with reductions in exercise PVR and pulmonary Ea. Patients with increases in PA compliance following IASD experienced greater improvements in supine exercise duration. There was no reduction in Qs following IASD at rest or during exercise. CONCLUSIONS: Implantation of an IASD improves pulmonary vascular function at rest and during exercise in selected patients with HF and EF ≥40%, without compromising systemic perfusion. Further study is warranted to identify underlying mechanisms and long-term pulmonary hemodynamic effects of IASD. (REDUCE LAP-HF Trial [REDUCE LAP-HF]; NCT01913613; and REDUCE LAP-HF Randomized Trial I [REDUCE LAP-HF I]; NCT02600234).

Chronic Intermittent Hypobaric Hypoxia (4600 M) Attenuates Pulmonary Vasodilation Induced by Acetylcholine or Sodium Nitroprusside.

Moraga, Fernando A., Giselle Miranda, Vasthi López, Carmen Vallejos, and Daniel Silva. Chronic intermittent hypobaric hypoxia (4600 M) attenuates pulmonary vasodilation induced by acetylcholine or sodium nitroprusside. High Alt Med Biol. 19:149-155, 2018. BACKGROUND: Previous studies performed in rats exposed to chronic intermittent hypobaric hypoxia (CIHH), at a simulated altitude of 4600 m, showed reduced nitric oxide (NO) production, increased arginase activity, and increased oxidative stress. However, studies on vascular function are scarce. Our aim was to measure plasma nitrate and nitrite (NOx) concentration and study pulmonary vascular function in rats exposed to CIHH in the presence of potassium chloride (KCl), acetylcholine (Ach), and sodium nitroprusside (SNP). METHODS: Thirty male Wistar rats were divided into two groups: A control group (normoxia (N), n = 10) and a CIHH group (2N × 2H × 30 days, n = 20). CIHH exposure was performed in a hypobaric chamber at 428 Torr (4600 m). Noninvasive systolic blood pressure (SBP), heart rate, and body weight (BW) were measured. Blood samples were obtained to measure NOx levels and hematocrit (Hct). CIHH animals that gained BW and presented a Hct <20% and maintained SBP were classified as tolerant, and animals that lost >30% of their BW, increased Hct and SBP >20% were classified as intolerant. Animals were sacrificed and small pulmonary arteries (SPA) were obtained to perform concentration-response curves to KCl, Ach, and SNP. RESULTS AND CONCLUSIONS: Intolerant rats (30%) had decreased NOx levels. SPA had a larger vasocontraction response to KCl and a lower dilation response to SNP in the SPA compared to tolerant and control animals. In addition, SPA had a lower dilatation response to Ach compared with the control. Together, these results show that CIHH alters endothelium-dependent vasodilation.

Inhaled hexadecyl-treprostinil provides pulmonary vasodilator activity at significantly lower plasma concentrations than infused treprostinil.

INS1009 is a long acting pulmonary vasodilator prodrug of treprostinil (TRE) that is formulated in a lipid nanoparticle for inhaled delivery by nebulization. This study examined the ability of INS1009 to inhibit vasoconstriction in the pulmonary vasculature of rats and dogs and the extent to which local activity within the lung contributes to its activity. Rats received a single dose of INS1009 by nose-only inhalation or were given a continuous intravenous (i.v.) infusion of TRE, followed by an i.v. challenge of the thromboxane mimetic pulmonary vasoconstrictor U46619 and the increase in pulmonary arterial pressure (PAP) was measured. In beagle dogs, INS1009 was given by inhalation via face mask and TRE was given by continuous i.v. infusion; vasoconstriction was then induced by inhaled hypoxia with reduction of FIO2 to 0.10. Changes in the dog's right ventricular pulse pressure (RVPP) were measured using implanted telemetry probes. Blood samples were collected in rats and dogs immediately after the challenge to measure the plasma TRE concentration. Exposure of rats to inhaled INS1009 (0.5, 3.0 and 20.9 µg/kg) inhibited the U46619-induced increase in PAP at all doses up to 6 h with statistically significant inhibition up to 24 h with the pooled dose-response data. The concentration of TRE in the plasma at which PAP was reduced by 50% was approximately 60-fold lower for INS1009 (EC50 = 0.08 ng/mL) as compared to i.v. TRE (EC50 = 4.9 ng/mL). In dogs, INS1009 (2.7-80.9 µg/kg) inhibited the hypoxia-induced increase in RVPP at all doses up to 6 h with activity once again observed with the pooled dose-response of 10 µg/kg and higher at 24 h. The concentration of TRE in the plasma at which RVPP was reduced by 50% was approximately 550-fold lower for INS1009 (EC50 = 0.0075 ng/mL) as compared to i.v. TRE (EC50 = 4.1 ng/mL). These studies, in two species and by two different pulmonary vasoconstrictor challenges, demonstrate that inhaled INS1009 not only has long-acting vasodilatory effects but also that the local activity within the lung contributes to this response. Therefore, INS1009 may offer the opportunity to effect pulmonary vasodilation for long periods but with substantially lower systemic exposure than infused TRE.