Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension

Ichinose, Fumito; Erana-Garcia, Juan; Hromi, Jonathan; Raveh, Yehuda; Jones, Rosemary; Krim, Lori; Clark, Martin; Winkler, Jeffrey D.; Bloch, Kenneth D.; Zapol, Warren M.

doi:10.1097/00003246-200105000-00024

Cited by 160 publications

(85 citation statements)

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“…While still effective in post op patients, the overall effect of inhaled NO and sildenafil was not significantly different. In contrast to previous animal studies 18,19 we found no significant effects on intrapulmonary shunting in our cath laboratory patients, but this was clearly an important issue in postoperative mechanically ventilated patients. In the presence of alveolar hyperoxia, the fall in arterial pO 2 was statistically significant, but was not associated with clinically relevant hypoxemia.…”

Section: Intravenous Sildenafil Compared With Inhaled No As a Specificontrasting

confidence: 99%

Intravenous Sildenafil Is a Potent Pulmonary Vasodilator in Children With Congenital Heart Disease

et al. 2003

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Background-Increased pulmonary vascular resistance (PVR) because of congenital heart disease (CHD) may be caused by a dysfunction in endogenous pulmonary endothelial nitric oxide (NO) production. In other forms of pulmonary vascular disease with increased PVR, an elevated activity of a phosphodiesterase type 5 (PDE-5), responsible for the degradation of cyclic guanidine monophosphate (cGMP), the second messenger of endothelially produced NO, has been demonstrated. This study compares the effects of inhaled NO before and after the specific inhibition of the PDE-5 by intravenous sildenafil (Viagra™) in pre-and postoperative children with increased PVR because of CHD. Methods and Results-12 children with congenital heart disease (age 0.2 to 15.7 years, median 2.4 years) and increased mean pulmonary arterial pressure, and 12 postoperative children (age 0.11 to 0.65 years, median 0.32 years) with increased PVR (8.3Ϯ1.0 Wood Units*m 2 ) were studied during cardiac catheterization ("cath laboratory"), or within 2 hours after return from cardiac surgery ("post op"), respectively. All were sedated, tracheally intubated and paralyzed. During alveolar hyperoxygenation (F i O 2 ϭ0.65), the effects of inhaled NO (20 ppm) were compared before and after the stepwise infusion of sildenafil ("cath laboratory", 1 mg/kg; post op, 0.25 mg/kg). Intravenous sildenafil more effectively reduced PVR than NO (11.5% versus 4.3% in the "cath laboratory" patient group, PϽ0.05, and 25.8% versus 14.6% in the post op patient group, Pϭ0.09. The increase in cGMP in response to NO was potentiated (2-to 2.4-fold) by PDE-5 inhibition. While the vasodilating effects of sildenafil showed pulmonary selectivity, its infusion was associated with increased intrapulmonary shunting in the postoperative patients (Q s / Q t ϭ16.5Ϯ4.7% to 25.5Ϯ18.2% Pϭ0.04). Conclusions-Intravenous sildenafil is as effective as inhaled NO as a pulmonary vasodilator in children with congenital heart disease. Although clinically insignificant in this study, increased intrapulmonary shunting with sildenafil may be disadvantageous in some patients after CHD surgery.

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Section: Intravenous Sildenafil Compared With Inhaled No As a Specificontrasting

confidence: 99%

Intravenous Sildenafil Is a Potent Pulmonary Vasodilator in Children With Congenital Heart Disease

et al. 2003

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“…In a lamb model of acute pulmonary hypertension, inhalation of nebulized sildenafil reduced pulmonary artery pressures significantly and had a synergistic effect with inhalation of nitric oxide, whereas pulmonary right-to-left shunt volume did not increase after sildenafil. 49 However, a recent study performed in normal pigs described an increase in right-to-left shunt volume and subsequently a decrease of systemic arterial oxygen tension after sildenafil, along with reduced pulmonary arterial pressure after sildenafil. 50 These experimental data suggest that at least in certain conditions with increased pulmonary arterial pressure, PDE 5 inhibition might be of benefit, and the possibility of additional inhalative application of other agents used to lower pulmonary artery pressure might provide a unique approach to achieve site-specific, additive, or even overadditive effects.…”

Section: Effects Of Pde 5 Inhibition On Pulmonary Vasculaturementioning

confidence: 96%

Therapeutic Potential of Phosphodiesterase 5 Inhibition for Cardiovascular Disease

2003

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“…No animal had an intracardiac shunt, which could potentially influence (or limit) any acute effect of an intravenous pulmonary vasodilator upon oxygenation. However, a number of previous investigations of pulmonary vasodilators in models of acute pulmonary hypertension (27,29,41) and, specifically, therapies for meconium aspiration syndrome (42,43) have been explored in more mature animals. Indeed, having demonstrated an acute rise in ET-1 levels coincident with an increase in PVR after meconium aspiration, it would seem appropriate to investigate the subsequent actions of an ET-A receptor antagonist in our model.…”

Section: Discussionmentioning

confidence: 99%

Endothelin-A Receptor Blockade and Inhaled Nitric Oxide in a Porcine Model of Meconium Aspiration Syndrome

et al. 2004

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Acute neonatal pulmonary hypertension is associated with increased activation of the endogenous endothelin pathway. We investigated the role of selective endothelin-A receptor blockade using i.v. BQ-123 in a piglet model of meconium aspiration syndrome. Meconium aspiration was induced in 18 anesthetized piglets. Six controls received no further intervention. Six piglets received 1 mg/kg BQ-123 at 120 min, with the addition of 20 ppm inhaled nitric oxide at 240 min. Six commenced nitric oxide therapy at 120 min, and were given i.v. BQ-123 at 240 min. The total study duration was 360 min. Meconium aspiration resulted in acute pulmonary hypertension and elevated endothelin-1 levels in all animals. There were no changes in pulmonary hemodynamics or endothelin-1 levels beyond 120 min in controls. In the group receiving BQ-123 first, this agent alone reduced the pulmonary artery pressure and pulmonary vascular resistance, and the subsequent addition of inhaled nitric oxide further reduced pulmonary artery pressure. In the group first receiving nitric oxide alone, this reduced the pulmonary artery pressure, and the addition of BQ-123 resulted in a fall in pulmonary vascular resistance. Endothelin-1 levels increased with both agents. BQ-123 was found to be a highly effective pulmonary vasodilator and augmented the effects of nitric oxide in this model of acute pulmonary hypertension. Abbreviations PPHN, persistent pulmonary hypertension of the newborn PVR, pulmonary vascular resistance ET, endothelin iNO, inhaled nitric oxide PPHN occurs when there is a failure of the normal rapid fall in PVR and increase in pulmonary blood flow with the onset of respiration at birth (1). Meconium aspiration syndrome is the single most common cause of PPHN, and can result in significant morbidity and mortality in term and near-term infants (2).The normal transition from the high-resistance fetal circulation to the low-resistance postnatal pulmonary circulation is associated with activation of the endogenous vasodilator nitric oxide-cyclic guanosine 5'-monophosphate pathway, and reduced release of the potent pulmonary vasoconstrictor, ET (3). The ET-1 isopeptide is a 21-amino acid polypeptide (4) that is produced within the pulmonary endothelium by the cleavage of its precursor, pro-ET (big ET), by ET converting enzyme. ET-1 is released by the vascular endothelium, and produces its effects through its interaction with at least two receptor subtypes-the A and B receptors, located on the vascular smooth muscle and endothelium. The pulmonary vasoconstrictor effects of ET-1 result mainly from activation of the G-proteincoupled smooth muscle A receptor, whereas stimulation of the endothelial ET-B receptor has been shown to result in vasodilatation (5). ET-1 is present in high levels at birth, with a gradual fall during the early neonatal period in healthy individuals (6). Elevated ET-1 levels have been demonstrated in animal models of meconium aspiration (7), in neonates with PPHN (3,8,9), and in older children (10) and adults (11) with pulmo...

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Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension

Abstract: Nebulized sildenafil is a selective pulmonary vasodilator that can potentiate the pulmonary vasodilating effects of inhaled NO.

Cited by 160 publications

References 15 publications

Intravenous Sildenafil Is a Potent Pulmonary Vasodilator in Children With Congenital Heart Disease

Intravenous Sildenafil Is a Potent Pulmonary Vasodilator in Children With Congenital Heart Disease

Therapeutic Potential of Phosphodiesterase 5 Inhibition for Cardiovascular Disease

Endothelin-A Receptor Blockade and Inhaled Nitric Oxide in a Porcine Model of Meconium Aspiration Syndrome

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