Sildenafil Is a Pulmonary Vasodilator in Awake Lambs with Acute Pulmonary Hypertension

Background Phosphodiesterase type 5 (PDE5) hydrolyzes cyclic guanosine monophosphate in the lung, thereby modulating nitric oxide (NO)/cyclic guanosine monophosphate-mediated pulmonary vasodilation. Inhibitors of PDE5 have been proposed for the treatment of pulmonary hypertension. In this study, we examined the pulmonary and systemic vasodilator properties of sildenafil, a novel selective PDE5 inhibitor, which has been approved for the treatment of erectile dysfunction. Methods In an awake lamb model of acute pulmonary hypertension induced by an intravenous infusion of the thromboxane analog U46619, we measured the effects of 12.5, 25, and 50 mg sildenafil administered via a nasogastric tube on pulmonary and systemic hemodynamics (n = 5). We also compared the effects of sildenafil (n = 7) and zaprinast (n = 5), a second PDE5 inhibitor, on the pulmonary vasodilator effects of 2.5, 10, and 40 parts per million inhaled NO. Finally, we examined the effect of infusing intravenous l-NAME (an inhibitor of endogenous NO production) on pulmonary vasodilation induced by 50 mg sildenafil (n = 6). Results Cumulative doses of sildenafil (12.5, 25, and 50 mg) decreased the pulmonary artery pressure 21%, 28%, and 42%, respectively, and the pulmonary vascular resistance 19%, 23%, and 45%, respectively. Systemic arterial pressure decreased 12% only after the maximum cumulative sildenafil dose. Neither sildenafil nor zaprinast augmented the ability of inhaled NO to dilate the pulmonary vasculature. Zaprinast, but not sildenafil, markedly prolonged the duration of pulmonary vasodilation after NO inhalation was discontinued. Infusion of l-NAME abolished sildenafil-induced pulmonary vasodilation. Conclusions Sildenafil is a selective pulmonary vasodilator in an ovine model of acute pulmonary hypertension. Sildenafil induces pulmonary vasodilation via a NO-dependent mechanism. In contrast to zaprinast, sildenafil did not prolong the pulmonary vasodilator action of inhaled NO.

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Pulmonary vasodilation by nitric oxide gas and prodrug aerosols in acute pulmonary hypertension

Journal of Applied Physiology ◽

10.1152/jappl.1998.84.2.435 ◽

1998 ◽

Vol 84 (2) ◽

pp. 435-441 ◽

Cited By ~ 30

Author(s):

Christophe Adrie ◽

Fumito Ichinose ◽

Alexandra Holzmann ◽

Larry Keefer ◽

William E. Hurford ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Vascular Resistance ◽

Pulmonary Circulation ◽

Half Life ◽

Hemodynamic Effects ◽

Pulmonary Vasodilation ◽

Short Half Life ◽

Acute Pulmonary Hypertension ◽

Inhaled No

Adrie, Christophe, Fumito Ichinose, Alexandra Holzmann, Larry Keefer, William E. Hurford, and Warren M. Zapol. Pulmonary vasodilation by nitric oxide gas and prodrug aerosols in acute pulmonary hypertension. J. Appl. Physiol. 84(2): 435–441, 1998.—Sodium 1-( N, N-diethylamino)diazen-1-ium-1,2-diolate {DEA/NO; Et2N[N(O)NO]Na} is a compound that spontaneously generates nitric oxide (NO). Because of its short half-life (2.1 min), we hypothesized that inhaling DEA/NO aerosol would selectively dilate the pulmonary circulation without decreasing systemic arterial pressure. We compared the pulmonary selectivity of this new NO donor with two other reference drugs: inhaled NO and inhaled sodium nitroprusside (SNP). In seven awake sheep with pulmonary hypertension induced by the infusion of U-46619, we compared the hemodynamic effects of DEA/NO with those of incremental doses of inhaled NO gas. In seven additional awake sheep, we examined the hemodynamic effects of incremental doses of inhaled nitroprusside (i.e., SNP). Inhaled NO gas selectively dilated the pulmonary vasculature. Inhaled DEA/NO produced nonselective vasodilation; both systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) were reduced. Inhaled SNP selectively dilated the pulmonary circulation at low concentrations (≤10−2 M), inducing a decrease of PVR of up to 42% without any significant decrease of SVR (−5%), but nonselectively dilated the systemic circulation at larger doses (>10−2 M). In conclusion, despite its short half-life, DEA/NO is not a selective pulmonary vasodilator compared with inhaled NO. Inhaled SNP appears to be selective to the pulmonary circulation at low doses but not at higher levels.

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Selective Pulmonary Vasodilation by Intravenous Infusion of an Ultrashort Half-life Nucleophile/Nitric Oxide Adduct

Anesthesiology ◽

10.1097/00000542-199801000-00027 ◽

1998 ◽

Vol 88 (1) ◽

pp. 190-195 ◽

Cited By ~ 10

Author(s):

Christophe Adrie ◽

Mona W. Hirani ◽

Alexandra Holzmann ◽

Larry Keefer ◽

Warren M. Zapol ◽

...

Keyword(s):

Pulmonary Vascular Resistance ◽

Vascular Resistance ◽

Pulmonary Circulation ◽

Half Life ◽

Pulmonary Vasculature ◽

Prostaglandin F2alpha ◽

Pulmonary Vasodilation ◽

Pulmonary Vasodilator ◽

Healthy Sheep ◽

Inhaled No

Background PROLI/NO (C5H7N3O4Na2 x CH3OH) is an ultrashort-acting nucleophile/NO adduct that generates NO (half-life 2 s at 37 degrees C and pH 7.4). Because of its short half-life, the authors hypothesized that intravenous administration of this compound would selectively dilate the pulmonary vasculature but cause little or no systemic hypotension. Methods In eight awake healthy sheep with pulmonary hypertension induced by 9,11-dideoxy-9alpha,11alpha-methanoepoxy prostaglandin F2alpha, the authors compared PROLI/NO with two reference drugs-inhaled NO, a well-studied selective pulmonary vasodilator, and intravenous sodium nitroprusside (SNP), a nonselective vasodilator. Sheep inhaled 10, 20, 40, and 80 parts per million NO or received intravenous infusions of 0.25, 0.5, 1, 2, and 4 microg x kg-1 x min-1 of SNP or 0.75, 1.5, 3, 6, and 12 microg x kg-1 x min-1 of PROLI/NO. The order of administration of the vasoactive drugs (NO, SNP, PROLI/NO) and their doses were randomized. Results Inhaled NO selectively dilated the pulmonary vasculature. Intravenous SNP induced nonselective vasodilation of the systemic and pulmonary circulation. Intravenous PROLI/NO selectively vasodilated the pulmonary circulation at doses up to 6 microg x kg-1 x min-1, which decreased pulmonary vascular resistance by 63% (P < 0.01) from pulmonary hypertensive baseline values without changing systemic vascular resistance. At 12 microg x kg-1 x min-1, PROLI/NO decreased systemic and pulmonary vascular resistance and pressure. Exhaled NO concentrations were higher during PROLI/NO infusion than during SNP infusion (P < 0.01 with all data pooled). Conclusions The results suggest that PROLI/NO could be a useful intravenous drug to vasodilate the pulmonary circulation selectively.

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Selective Pulmonary Vasodilation Induced by Aerosolized Zaprinast

Anesthesiology ◽

10.1097/00000542-199802000-00020 ◽

1998 ◽

Vol 88 (2) ◽

pp. 410-416 ◽

Cited By ~ 62

Author(s):

Fumito Ichinose ◽

Christophe Adrie ◽

William E. Hurford ◽

Kenneth D. Bloch ◽

Warren M. Zapol

Keyword(s):

Pulmonary Hypertension ◽

Muscle Relaxation ◽

Recovery Period ◽

Phosphodiesterase Inhibitor ◽

Smooth Muscle Relaxation ◽

Pulmonary Vasculature ◽

Pulmonary Vasodilation ◽

Chronic Pulmonary Hypertension ◽

Selective Pulmonary Vasodilation ◽

Inhaled No

Background Zaprinast, an inhibitor of guanosine-3',5'-cyclic monophosphate (cGMP)-selective phosphodiesterase, augments smooth muscle relaxation induced by endothelium-dependent vasodilators (including inhaled nitric oxide [NO]). The present study was designed to examine the effects of inhaled nebulized zaprinast, alone, and combined with inhaled NO. Methods Eight awake lambs with U46619-induced pulmonary hypertension sequentially breathed two concentrations of NO (5 and 20 ppm), followed by inhalation of aerosols generated from solutions containing four concentrations of zaprinast (10, 20, 30, and 50 mg/ml). The delivered doses of nebulized zaprinast at each concentration (mean +/- SD) were 0.23 +/- 0.06, 0.49 +/- 0.14, 0.71 +/- 0.24, and 1.20 +/- 0.98 mg x kg(-1) x min(-1), respectively. Each lamb also breathed NO (5 and 20 ppm) and zaprinast (0.23 +/- 0.06 mg x kg[-1] x min[-1]) in combination after a 2-h recovery period. Results Inhaled NO selectively dilated the pulmonary vasculature. Inhaled zaprinast selectively dilated the pulmonary circulation and potentiated and prolonged the pulmonary vasodilating effects of inhaled NO. The net transpulmonary release of cGMP was increased by inhalation of NO, zaprinast, or both. The duration of the vasodilation induced by zaprinast inhalation was greater than that induced by NO inhalation. Conclusions Aerosolization of a cGMP-selective phosphodiesterase inhibitor alone or combined with NO may be a useful noninvasive therapeutic method to treat acute or chronic pulmonary hypertension.

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Abstract 14: Pulmonary Hemodynamics in Neonatal Lambs with Pulmonary Hypertension - Effect of Resuscitation with 21% versus 100% Oxygen

Circulation ◽

10.1161/circ.116.suppl_16.ii_925-d ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Satyan Lakshminrusimha ◽

Daniel D Swartz ◽

Sylvia F Gugino ◽

Karen A Wynn ◽

Rita M Ryan ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Neonatal Resuscitation ◽

Optimal Level ◽

Published Data ◽

Pulmonary Hemodynamics ◽

Pulmonary Vasodilation ◽

Subsequent Decrease ◽

Pulmonary Vasodilator ◽

Neonatal Lambs ◽

Inhaled No

The optimal level of O 2 supplementation during neonatal resuscitation is controversial. We recently published data that resuscitation with 21% or 100% O 2 for 30 min results in similar decreases in pulmonary vascular resistance (PVR) in normal newborn lambs ( Pediatr Res in press) . However, the effect of resuscitation with 21% or 100% O 2 on pulmonary hemodynamics in lambs with in-utero pulmonary hypertension (PH) is not known. Methods: PH was induced in fetal lambs by antenatal ductal ligation at 126 d of gestation (term ~ 145 d). Lambs were delivered 9 d later by C-section and ventilated with 21% O 2 or 100% O 2 for 30 min. Control lambs without PH were ventilated similarly for comparison (n=4 −7 in each group). The lambs were instrumented to measure PVR prior to delivery. After 30 min, lambs with PH were ventilated with 50% O 2 and pulmonary vasodilator responses to inhaled NO 20 ppm were evaluated. Results: PVR was significantly higher in lambs with PH compared to control. The decrease in PVR was similar by 30 min in 21% and 100% O 2 resuscitated control lambs. In contrast, 100% O 2 resuscitation resulted in a significantly greater decrease in PVR in lambs with PH (fig A ). However, 100% O 2 resuscitation impaired subsequent decrease in PVR in response to inhaled NO in both control and PH lambs (fig B ). Conclusions: 100% O 2 resuscitation results in a greater decrease in PVR but impairs subsequent pulmonary vasodilation to NO in lambs with PH. Speculation: Ventilation of PH lambs with 100% O 2 significantly increases lung isoprostane levels ( AJRCCM 2006 174 12:1370 ). We speculate that a similar increase in reactive oxygen species following 100% O 2 resuscitation interferes with the vasodilator response to NO.

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Pulmonary vasoconstrictor influence of endothelin in exercising swine depends critically on phosphodiesterase 5 activity

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00057.2013 ◽

2014 ◽

Vol 306 (5) ◽

pp. L442-L452 ◽

Cited By ~ 11

Author(s):

Zhichao Zhou ◽

Vincent J. de Beer ◽

Daphne de Wijs-Meijler ◽

Shawn B. Bender ◽

Maaike Hoekstra ◽

...

Keyword(s):

Pde5 Inhibitor ◽

Systemic Circulation ◽

Guanosine Monophosphate ◽

Receptor Blockade ◽

Vasodilator Effect ◽

Pulmonary Vasodilation ◽

Pde5 Inhibition ◽

Pulmonary Vasodilator ◽

Phosphodiesterase 5

Both phosphodiesterase 5 (PDE5) inhibition and endothelin (ET) receptor blockade have been shown to induce pulmonary vasodilation. However, little is known about the effect of combined blockade of these two vasoconstrictor pathways. Since nitric oxide (NO) exerts its pulmonary vasodilator influence via production of cyclic guanosine monophosphate (cGMP) as well as through inhibition of ET, we hypothesized that interaction between the respective signaling pathways precludes an additive vasodilator effect. We tested this hypothesis in chronically instrumented swine exercising on a treadmill by comparing the vasodilator effect of the PDE5 inhibitor EMD360527, the ETA/ETB antagonist tezosentan, and combined EMD360527 and tezosentan. In the systemic circulation, vasodilation by tezosentan and EMD360527 was additive, both at rest and during exercise, resulting in a 17 ± 2% drop in blood pressure. In the pulmonary circulation, both EMD360527 and tezosentan produced vasodilation. However, tezosentan produced no additional pulmonary vasodilation in the presence of EMD360527, either at rest or during exercise. Moreover, in isolated preconstricted porcine pulmonary small arteries (∼300 μm) EMD360527 (1 nM–10 μM) induced dose-dependent vasodilation, whereas tezosentan (1 nM–10 μM) failed to elicit vasodilation irrespective of the presence of EMD360527. However, both PDE5 inhibition and 8Br-cGMP, but not 8Br-cAMP, blunted pulmonary small artery contraction to ET and its precursor Big ET in vitro. In conclusion, in healthy swine, either at rest or during exercise, PDE5 inhibition and the associated increase in cGMP produce pulmonary vasodilation that is mediated in part through inhibition of the ET pathway, thereby precluding an additional vasodilator effect of ETA/ETB receptor blockade in the presence of PDE5 inhibition.

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Inhibition of phosphodiesterase 1 augments the pulmonary vasodilator response to inhaled nitric oxide in awake lambs with acute pulmonary hypertension

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00485.2004 ◽

2006 ◽

Vol 290 (4) ◽

pp. L723-L729 ◽

Cited By ~ 23

Author(s):

Oleg V. Evgenov ◽

Cornelius J. Busch ◽

Natalia V. Evgenov ◽

Rong Liu ◽

Bodil Petersen ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Arterial Pressure ◽

Pulmonary Arterial Pressure ◽

Selective Inhibition ◽

Pulmonary Vasodilation ◽

Mean Pulmonary Arterial Pressure ◽

Pulmonary Vasodilator ◽

Pulmonary Arterial ◽

Inhaled No

Phosphodiesterase 1 (PDE1) modulates vascular tone and the development of tolerance to nitric oxide (NO)-releasing drugs in the systemic circulation. Any role of PDE1 in the pulmonary circulation remains largely uncertain. We measured the expression of genes encoding PDE1 isozymes in the pulmonary vasculature and examined whether or not selective inhibition of PDE1 by vinpocetine attenuates pulmonary hypertension and augments the pulmonary vasodilator response to inhaled NO in lambs. Using RT-PCR, we detected PDE1A, PDE1B, and PDE1C mRNAs in pulmonary arteries and veins isolated from healthy lambs. In 13 lambs, the thromboxane A2 analog U-46619 was infused intravenously to increase mean pulmonary arterial pressure to 35 mmHg. Four animals received an intravenous infusion of vinpocetine at incremental doses of 0.3, 1, and 3 mg·kg−1·h−1. In nine lambs, inhaled NO was administered in a random order at 2, 5, 10, and 20 ppm before and after an intravenous infusion of 1 mg·kg−1·h−1 vinpocetine. Administration of vinpocetine did not alter pulmonary and systemic hemodynamics or transpulmonary cGMP or cAMP release. Inhaled NO selectively reduced mean pulmonary arterial pressure, pulmonary capillary pressure, and pulmonary vascular resistance index, while increasing transpulmonary cGMP release. The addition of vinpocetine enhanced pulmonary vasodilation and transpulmonary cGMP release induced by NO breathing without causing systemic vasodilation but did not prolong the duration of pulmonary vasodilation after NO inhalation was discontinued. Our findings demonstrate that selective inhibition of PDE1 augments the therapeutic efficacy of inhaled NO in an ovine model of acute chemically induced pulmonary hypertension.

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Repurposing of the PDE5 inhibitor sildenafil for treatment of persistent pulmonary hypertension in neonates

Current Medicinal Chemistry ◽

10.2174/0929867327666200923151924 ◽

2020 ◽

Vol 27 ◽

Author(s):

Erika L. Poitras ◽

Stephen L. Gust ◽

Paul M. Kerr ◽

Frances Plane

Keyword(s):

Pulmonary Hypertension ◽

Erectile Dysfunction ◽

Soluble Guanylate Cyclase ◽

Vascular Endothelial Cells ◽

Pde5 Inhibitor ◽

Cyclic Guanosine Monophosphate ◽

Effector Proteins ◽

Guanosine Monophosphate ◽

Persistent Pulmonary Hypertension ◽

Current Evidence

: Nitric oxide (NO), an important endogenous signalling molecule released from vascular endothelial cells and nerves, activates the enzyme soluble guanylate cyclase to catalyze production of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate. cGMP, in turn, activates protein kinase G to phosphorylate a range of effector proteins in smooth muscle cells that reduce intracellular Ca2+ levels to inhibit both contractility and proliferation. The enzyme phosphodiesterase type 5 (PDE5) curtails the actions of cGMP by hydrolyzing it into inactive 5’-GMP. Small molecule PDE5 inhibitors (PDE5is) such as sildenafil prolong the availability of cGMP and so enhance NO-mediated signalling. PDE5is are the first line treatment for erectile dysfunction but are also now approved for treatment of pulmonary arterial hypertension (PAH) in adults. Persistent pulmonary hypertension in neonates (PPHN) is currently treated with inhaled NO but this is an expensive option and around 1/3 of newborns are unresponsive resulting in the need for alternative approaches. Here we summarize the development, chemistry and pharmacology of PDE5is, the use of sildenafil for erectile dysfunction and PAH, and then critically review current evidence for the utility of further repurposing of sildenafil as a treatment for PPHN.

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Plasma Cyclic Guanosine Monophosphate Reflecting the Severity of Persistent Pulmonary Hypertension of the Newborn

Neonatology ◽

10.1159/000047128 ◽

2001 ◽

Vol 80 (2) ◽

pp. 107-112 ◽

Cited By ~ 5

Author(s):

M. Turanlahti ◽

E. Pesonen ◽

M. Pohjavuori ◽

P. Lassus ◽

F. Fyhrquist ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Persistent Pulmonary Hypertension

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Thiamine-Responsive Acute Pulmonary Hypertension of Early Infancy (TRAPHEI)—A Case Series and Clinical Review

Children ◽

10.3390/children7110199 ◽

2020 ◽

Vol 7 (11) ◽

pp. 199

Author(s):

Nalinikanta Panigrahy ◽

Dinesh Kumar Chirla ◽

Rakshay Shetty ◽

Farhan A. R. Shaikh ◽

Poddutoor Preetham Kumar ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Case Reports ◽

Case Series ◽

Early Infancy ◽

Right Atrial ◽

Voice Leading ◽

Vasodilator Therapy ◽

Polished Rice ◽

Pulmonary Vasodilator ◽

Acute Pulmonary Hypertension

Persistent pulmonary hypertension of the newborn (PPHN) is a syndrome of high pulmonary vascular resistance (PVR) commonly seen all over the world in the immediate newborn period. Several case reports from India have recently described severe pulmonary hypertension among infants in the postneonatal period. These cases typically present with respiratory distress in 1–6-month-old infants, breastfed by mothers on a polished rice-based diet. Predisposing factors include respiratory tract infection such as acute laryngotracheobronchitis with change in voice, leading to pulmonary hypertension, right atrial and ventricular dilation, pulmonary edema and hepatomegaly. Mortality is high without specific therapy. Respiratory support, pulmonary vasodilator therapy, inotropes, diuretics and thiamine infusion have improved the outcome of these infants. This review outlines four typical patients with thiamine-responsive acute pulmonary hypertension of early infancy (TRAPHEI) due to thiamine deficiency and discusses pathophysiology, clinical features, diagnostic criteria and therapeutic options.

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