Combined Therapy with Inhaled Nitric Oxide and Intravenous Vasodilators During Acute and Chronic Experimental Pulmonary Hypertension

Aranda, Margaret; Bradford, Katherine Kilroy; Pearl, Ronald G.

doi:10.1097/00000539-199907000-00027

Cited by 7 publications

(8 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…But although we applied U46619 doses up to 6000 ng/100 g/min, which was sixfold higher than described previously [45], we were not able to induce a robust right ventricular hypertension. Instead of that, we observed a massive bronchial obstruction and so we stopped this study section.…”

Section: Discussioncontrasting

confidence: 55%

Inhalation of the BKCa-Opener NS1619 Attenuates Right Ventricular Pressure and Improves Oxygenation in the Rat Monocrotaline Model of Pulmonary Hypertension

et al. 2014

View full text Add to dashboard Cite

BackgroundRight heart failure is a fatal consequence of chronic pulmonary hypertension (PH). The development of PH is characterized by increased proliferation of vascular cells, in particular pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery endothelial cells. In the course of PH, an escalated right ventricular (RV) afterload occurs, which leads to increased perioperative morbidity and mortality. BKCa channels are ubiquitously expressed in vascular smooth muscle cells and their opening induces cell membrane hyperpolarization followed by vasodilation. Moreover, BK activation induces anti-proliferative effects in a multitude of cell types. On this basis, we hypothesized that treatment with the nebulized BK channel opener NS1619 might be a therapy option for pulmonary hypertension and tested this in rats.Methods(1) Rats received monocrotaline injection for PH induction. Twenty-four days later, rats were anesthetized and NS1619 or the solvent was administered by inhalation. Systemic hemodynamic parameters, RV hemodynamic parameters, and blood gas analyses were measured before as well as 30 and 120 minutes after inhalation. (2) Rat PASMCs were stimulated with PDGF-BB in the presence and absence of NS1619. AKT, ERK1 and ERK2 activation were investigated by western blot analyses, and relative cell number was determined 48 hours after stimulation.ResultsInhalation of a 12 µM and 100 µM NS1619 solution significantly reduced RV pressure without affecting systemic arterial pressure. Blood gas analyses demonstrated significantly reduced carbon dioxide and improved oxygenation in NS1619-treated animals pointing towards a considerable pulmonary shunt-reducing effect. In PASMC’s, NS1619 (100 µM) significantly attenuated PASMC proliferation by a pathway independent of AKT and ERK1/2 activation.ConclusionNS1619 inhalation reduces RV pressure and improves oxygen supply and its application inhibits PASMC proliferation in vitro. Hence, BK opening might be a novel option for the treatment of pulmonary hypertension.

show abstract

Section: Discussioncontrasting

confidence: 55%

Inhalation of the BKCa-Opener NS1619 Attenuates Right Ventricular Pressure and Improves Oxygenation in the Rat Monocrotaline Model of Pulmonary Hypertension

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Some studies suggest that U46619 reveals greater effects on pulmonary than on systemic circulation. 20,22,35,36 In our investigation, the infusion of the thromboxane analogue increased both RVSP and systemic arterial pressure. It might be possible that the applied dosage of U46619 per body weight contributed to the differences.…”

Section: Discussionsupporting

confidence: 45%

“…For the latter two animals the dosage of U46619 might have been too small, since other investigators have used either a higher steady infusion rate such as 374–506 ng/min of U46619 or priming doses followed by continuous infusion of 150–250 ng/min of U46619. 20,35,36 The above-quoted studies adjusted the infusion rate of U46619 to achieve a mean pulmonary arterial pressure of approximately 30 mmHg. 20,35,36 Retrospectively, it might have been better to have had set a target value for the RVSP even though the range of vascular preconstriction might differ among the animals.…”

Section: Discussionmentioning

confidence: 99%

“…20,35,36 The above-quoted studies adjusted the infusion rate of U46619 to achieve a mean pulmonary arterial pressure of approximately 30 mmHg. 20,35,36 Retrospectively, it might have been better to have had set a target value for the RVSP even though the range of vascular preconstriction might differ among the animals. Within a predefined range of pulmonary artery pressure Aranda and colleagues have successfully investigated the effects of 100 ppm inhaled NO and other vasodilators on the pulmonary and systemic circulation in thromboxane-challenged rats.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Search for an animal model to investigate selective pulmonary vasodilation

et al. 2016

View full text Add to dashboard Cite

Pulmonary arterial hypertension is a life-threatening disease with a poor prognosis. Oral treatment with vasodilators is often limited by systemic hypotension. Inhalation of vasodilators offers the opportunity for selective pulmonary vasodilation. Testing selective pulmonary vasodilation by inhaled nitric oxide or alternative substances in animal models requires an increased pulmonary vascular tone. The aim of this study was to identify animal models that are suitable for investigating selective pulmonary vasodilation. To do so, a haemodynamic stable pulmonary hypertension was initiated, with a 30 min duration deemed to be a sufficient time interval before and after a possible intervention. In anaesthetized and mechanically-ventilated Sprague-Dawley rats pulmonary hypertension was induced either by acute hypoxia due to reduction of the inspired oxygen fraction from 0.21 to 0.1 ( n = 6), a fixed infusion rate of the thromboxane analogue U46619 (240 ng/min; n = 6) or a monocrotaline injection (MCT; 60 mg/kg applied 23 days before the investigation; n = 7). The animals were instrumented to measure right ventricular and systemic arterial pressures. Acute hypoxia caused a short, and only transient, increase of pulmonary artery pressure as well as profound systemic hypotension which suggested haemodynamic instability. U46619 infusion induced variable changes in the pulmonary and systemic vascular tone without sufficient stabilization within 30 min. MCT provoked sustained pulmonary hypertension with normal systemic pressure values and inhalation of nitric oxide caused selective pulmonary vasodilation. In conclusion, out of the three examined rat animal models only MCT-induced pulmonary hypertension is a solid and reliable model for investigating selective pulmonary vasodilation.

show abstract

“…Adenosine increases intracellular cAMP via A 2 receptor agonism [207], and when administered intravenously, acts as a potent selective pulmonary vasodilator because of its rapid endothelial metabolism [208]. It has been used as a therapy for adult PH in some settings, including after cardiac surgery [209], but may elevate LV end-diastolic pressure [210] and cause bradycardia and bronchospasm [211].…”

Section: Resultsmentioning

confidence: 99%

Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review

et al. 2010

View full text Add to dashboard Cite

IntroductionPulmonary vascular dysfunction, pulmonary hypertension (PH), and resulting right ventricular (RV) failure occur in many critical illnesses and may be associated with a worse prognosis. PH and RV failure may be difficult to manage: principles include maintenance of appropriate RV preload, augmentation of RV function, and reduction of RV afterload by lowering pulmonary vascular resistance (PVR). We therefore provide a detailed update on the management of PH and RV failure in adult critical care.MethodsA systematic review was performed, based on a search of the literature from 1980 to 2010, by using prespecified search terms. Relevant studies were subjected to analysis based on the GRADE method.ResultsClinical studies of intensive care management of pulmonary vascular dysfunction were identified, describing volume therapy, vasopressors, sympathetic inotropes, inodilators, levosimendan, pulmonary vasodilators, and mechanical devices. The following GRADE recommendations (evidence level) are made in patients with pulmonary vascular dysfunction: 1) A weak recommendation (very-low-quality evidence) is made that close monitoring of the RV is advised as volume loading may worsen RV performance; 2) A weak recommendation (low-quality evidence) is made that low-dose norepinephrine is an effective pressor in these patients; and that 3) low-dose vasopressin may be useful to manage patients with resistant vasodilatory shock. 4) A weak recommendation (low-moderate quality evidence) is made that low-dose dobutamine improves RV function in pulmonary vascular dysfunction. 5) A strong recommendation (moderate-quality evidence) is made that phosphodiesterase type III inhibitors reduce PVR and improve RV function, although hypotension is frequent. 6) A weak recommendation (low-quality evidence) is made that levosimendan may be useful for short-term improvements in RV performance. 7) A strong recommendation (moderate-quality evidence) is made that pulmonary vasodilators reduce PVR and improve RV function, notably in pulmonary vascular dysfunction after cardiac surgery, and that the side-effect profile is reduced by using inhaled rather than systemic agents. 8) A weak recommendation (very-low-quality evidence) is made that mechanical therapies may be useful rescue therapies in some settings of pulmonary vascular dysfunction awaiting definitive therapy.ConclusionsThis systematic review highlights that although some recommendations can be made to guide the critical care management of pulmonary vascular and right ventricular dysfunction, within the limitations of this review and the GRADE methodology, the quality of the evidence base is generally low, and further high-quality research is needed.

show abstract

Combined Therapy with Inhaled Nitric Oxide and Intravenous Vasodilators During Acute and Chronic Experimental Pulmonary Hypertension

Abstract: In therapy of pulmonary hypertension, inhaled nitric oxide should produce additional selective pulmonary vasodilation when combined with a vasodilator whose mechanism of action is not dependent on cyclic guanosine 3',5'-monophosphate.

Cited by 7 publications

References 25 publications

Inhalation of the BKCa-Opener NS1619 Attenuates Right Ventricular Pressure and Improves Oxygenation in the Rat Monocrotaline Model of Pulmonary Hypertension

Inhalation of the BKCa-Opener NS1619 Attenuates Right Ventricular Pressure and Improves Oxygenation in the Rat Monocrotaline Model of Pulmonary Hypertension

Search for an animal model to investigate selective pulmonary vasodilation

Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review

Contact Info

Product

Resources

About