Inhaled therapy for the management of perioperative pulmonary hypertension

Thunberg, Christopher A.; Morozowich, Steven T.; Ramakrishna, Harish

doi:10.4103/0971-9784.159811

Cited by 24 publications

(7 citation statements)

References 81 publications

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“…Unfortunately, however in PH, systemic hypotension is quite problematic, as it decreases the coronary perfusion pressure and consequently worsens left and right ventricular function [ 66 ]. To find a way to prevent systemic side effects, we evaluated the possibility and efficacy to apply imatinib locally via the airways [ 18 ], as it is already usual in PH for NO-donors, prostanoids or PDE-inhibitors [ 67 , 68 ]. In the IPL, we could show that nebulized imatinib reduces the ET-1-induced increase of R post .…”

Section: Discussionmentioning

confidence: 99%

Imatinib relaxes the pulmonary venous bed of guinea pigs

et al. 2017

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BackgroundRecently, the IMPRES study revealed that systemic imatinib improves exercise capacity in patients with advanced pulmonary arterial hypertension. Imatinib blocks the tyrosine kinase activity of the platelet-derived growth factor (PDGF)-receptor (PDGFR), acts antiproliferative and relaxes pulmonary arteries. However so far, the relaxant effects of imatinib on pulmonary veins (PVs) and on the postcapillary resistance are unknown, although pulmonary hypertension (PH) due to left heart disease (LHD) is most common and primarily affects PVs. Next, it is unknown whether activation of PDGFR alters the pulmonary venous tone. Due to the reported adverse effects of systemic imatinib, we evaluated the effects of nebulized imatinib on the postcapillary resistance.MethodsPrecision-cut lung slices (PCLS) were prepared from guinea pigs. PVs were pre-constricted with Endothelin-1 (ET-1) and the imatinib-induced relaxation was studied by videomicroscopy; PDGF-BB-related vascular properties were evaluated as well. The effects of perfused/nebulized imatinib on the postcapillary resistance were studied in cavine isolated perfused lungs (IPL). Intracellular cAMP/cGMP was measured by ELISA in PVs.ResultsIn PCLS, imatinib (100 μM) relaxed pre-constricted PVs (126%). In PVs, imatinib increased cAMP, but not cGMP and inhibition of adenyl cyclase or protein kinase A reduced the imatinib-induced relaxation. Further, inhibition of KATP-channels, -channels or Kv-channels diminished the imatinib-induced relaxation, whereas inhibition of NO-signaling was without effect. In the IPL, perfusion or nebulization of imatinib reduced the ET-1-induced increase of the postcapillary resistance. In PCLS, PDGF-BB contracted PVs, which was blocked by imatinib and by the PDGFR-β kinase inhibitor SU6668, whereas inhibition of PDGFR-α (ponatinib) had no significant effect. Conversely, PDGFR-β kinase inhibitors (SU6668/DMPQ) relaxed PVs pre-constricted with ET-1 comparable to imatinib, whereas the PDGFR-α kinase inhibitor ponatinib did not.ConclusionsImatinib-induced relaxation depends on cAMP and on the activation of K+-channels. Perfused or nebulized imatinib significantly reduces the postcapillary resistance in the pre-constricted (ET-1) pulmonary venous bed. Hence, nebulization of imatinib is feasible and might reduce systemic side effects. Conversely, PDGF-BB contracts PVs by activation of PDGFR-β suggesting that imatinib-induced relaxation depends on PDGFR-β-antagonism. Imatinib combines short-term relaxant and long-term antiproliferative effects. Thus, imatinib might be a promising therapy for PH due to LHD.

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Section: Discussionmentioning

confidence: 99%

Imatinib relaxes the pulmonary venous bed of guinea pigs

et al. 2017

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“…They also can worsen oxygenation by blunting hypoxic pulmonary vasoconstriction and impairing ventilation-perfusion matching. Therefore, the use of inhaled rather than systemic pulmonary vasodilators is strongly recommended [ 102 ]. Pulmonary vasodilator therapy relies on three pathways: nitric oxide (NO) donors (guanylate cyclase (GC) stimulators), adenylate cyclase (AC) stimulators, and phosphodiesterase (PDE) inhibitors ( Figure 2 ).…”

Section: Treatmentmentioning

confidence: 99%

Acute Right Ventricular Dysfunction in Intensive Care Unit

Grignola

Domingo

2017

BioMed Research International

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The role of the left ventricle in ICU patients with circulatory shock has long been considered. However, acute right ventricle (RV) dysfunction causes and aggravates many common critical diseases (acute respiratory distress syndrome, pulmonary embolism, acute myocardial infarction, and postoperative cardiac surgery). Several supportive therapies, including mechanical ventilation and fluid management, can make RV dysfunction worse, potentially exacerbating shock. We briefly review the epidemiology, pathophysiology, diagnosis, and recommendations to guide management of acute RV dysfunction in ICU patients. Our aim is to clarify the complex effects of mechanical ventilation, fluid therapy, vasoactive drug infusions, and other therapies to resuscitate the critical patient optimally.

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“…These agents have demonstrated efficacy in reducing PVR in a variety of settings, but it is unclear if there are additive/synergistic effects of using both iNO and prostacyclin analogs. Of note, inhaled epoprostenol has a glycine buffering agent that has the potential to cause ventilator valve malfunction [ 21 ]. As salvage therapy for patients who have not responded adequately to iNO or prostacyclin, inhaled milrinone has been used with some effectiveness [ 22 ].…”

Section: Discussionmentioning

confidence: 99%