ISSN 1916-6958

2010; Volume 1 (Number 2): Pages 54-61

REVIEW ARTICLE

A critical overview of clinical and experimental
studies on pulmonary vasodilators in newborns

Miguel GONZÁLEZ-LOZANOa,
Alejandro A. NAVA-OCAMPOb,c, María Elena
TRUJILLO-ORTEGAe, María ALONSO-SPILSBURYd, Daniel
MOTA-ROJASd,*

aPostgraduate
Division of Animal Science and Health, Faculty of Veterinary and Animal
Production, Universidad Nacional Autónoma de México, Ciudad
Universitaria, Mexico, bPharmaReasons,    Toronto, Canada, cDepartment
of Pharmacology & Toxicology, Faculty of Medicine, University of Toronto,
Toronto, Canada, dDepartment of Animal Production & Agriculture,
Cuerpo Académico Etología, Producción Porcina y Fauna
Silvestre. Área de Investigación: Ecodesarrollo de la Producción
Animal, Universidad Autónoma Metropolitana-Xochimilco, Mexico and eAnimal
Production: Swine, FMVZ, Universidad Nacional Autónoma de México,
Ciudad Universitaria. Mexico.

*Corresponding author: [email-masked]

Abstract

Pulmonary vasodilators represent a viable
alternative in the reduction of neonatal mortality and improvement of postnatal
performance. The high rate of babies born with respiratory problems facilitates
a prompt evaluation of pharmacological alternatives. This review describes the
assessment of pulmonary vasodilators in animal models as well as in some
clinical trials. The studies reviewed suggest that the use of experimental
animal models is critical for examining, in depth, current alternatives of
pulmonary vasodilators intended to be used in human neonates as well as for
developing new therapeutic options. However, interspecies differences should be
considered when evaluating the mechanisms involved in perinatal asphyxia, its
consequences, and treatment. Regarding drug therapy, the administration of
tocolytic agents for increasing gestational age has not shown to improve
neonatal conditions. Instead, time needs to be optimized by prenatally
administering corticosteroids and transferring the mother to a tertiary-care
centre with proper neonatal facilities. Currently, the pulmonary vasodilator of
choice in neonates with pulmonary hypertension is inhaled nitric oxide (iNO).
However, sildenafil has shown to be a good alternative both as a single drug or
associated with iNO.

Key words

Animal Experimentation; Persistent pulmonary
hypertension of newborn; Vasodilator agents

RÉSUMÉ

Les
vasodilatateurs pulmonaires sont une alternative valable pour réduire la
mortalité néonatale et améliorer les performances
postnatales. Le taux élevé de bébés naissant avec
des problèmes respiratoires permet une évaluation rapide
d’alternatives pharmacologiques. Cette revue décrit
l’évaluation des vasodilatateurs pulmonaires dans des
modèles animaux et dans quelques essais cliniques. Les études
suggèrent que l’utilisation des modèles animaux est
critique pour l’examen en profondeur des alternatives destinées
à être utilisées chez le nouveau-né et le
développement de nouvelles options thérapeutiques. Les
différences inter-espèces doivent toutefois être
considérées lors de l’évaluation des
mécanismes impliqués dans l’asphyxié
périnatale, ses conséquences et son traitement.
L’administration de tocolytiques pour augmenter l’âge
gestationnel n’améliore pas les conditions néonatales. Sa
durée doit par contre être optimalisée pour assurer une
corticothérapie prénatale et transférer la mère
vers un centre disposant d’un équipement néonatal
approprié. Actuellement le vasodilatateur pulmonaire de choix chez les
nouveau-nés souffrant d’hypertension pulmonaire est d’oxyde
nitreux en inhalation (iNO). Le sildénafil seul ou associé
à l’iNO constitue une bonne alternative.

Mots clés

Expérimentation
animale; Hypertension pulmonaire persistante du nouveau-né; Agents
vasodilatateurs

RESUMEN

Los
vasodilatadores pulmonares representan una alternative viable en la
reducción de la mortalidad neonatal y en un mejor desarrollo neonatal.
La elevada frecuencia de bebés nacidos con problemas respiratorios
facilita una pronta evaluación de alternativas terapéuticas. Sin embargo, los modelos experimentales contíuan siendo una
fuente valosa de información. En este trabajo, nosotros revisamos la
evaluación de vasodilatadores pulmonares tanto en modelos animales como
en algunos estudios clínicos. Los estudios revisados sugieren que el uso
de modelos experimentales es un aspecto crítico para examinar a
profundidad las actuales alternativas de vasodilatadores pulmonares que se
pretenden usar en neonatos humanos así como también para el desarrollo
de nuevas alternativas terapéuticas. Sin embargo, algunas diferencias
entre especies deberán ser considerads cuando se evalúan los
mecanismos de asfixia perinatal, sus consecuencias y su tratamiento. Respecto
al manejo farmacológico, la administración de tocolíticos
para incrementar la edad gestacional no ha demonstrado mejorar las condiciones
neonatales. En cambio, el tiempo necesita ser optimizada para adminsitrar
corticosteroides prenatales y transferir a la madre a un centro de tercer nivel
que cuente con la infraestructura adecuada para atender neonatos. El
vasodilatador pulmonar de elección en neonatos con hipertensión
pulmonar es, actualmente, el óxido nítrico inhalado. Sin embargo,
el sildenafil ha probado ser una buena alternativa tanto como tratamiento
único como asociado al óxido nítrico inhalado.

Palabras clave

Experimentación en animales;
Hipertensión pulmonar persistente del recién nacido;
Vasodilatadores

Introduction

Although the most common etiology of neonatal
respiratory distress is transient tachypnea that usually resolves
spontaneously, other etiologies may lead to persistent or severe respiratory distress.
Pulmonary circulation in the newborn depends on fast hemodynamic changes and
vasoactive responses at birth [1]. Persistent pulmonary hypertension of the neonate
(PPHN) significantly contributes to an increase of neonatal morbidity and
mortality, including asphyxia during delivery, meconium aspiration, and
respiratory distress syndrome (RDS) [2]. A better knowledge of the physiology of transitory
neonatal circulation and pulmonary blood flow are the basis for the treatment
of PPHN.

The high rate of babies born with respiratory
problems facilitates a prompt evaluation of pharmacological alternatives. In
this regard, experimental animal models are a valuable source of information.
Some interspecies differences, however, should be considered. In this
manuscript, we reviewed clinical and experimental studies on pulmonary
vasodilators in neonates, emphasizing the contribution of experimental models
to the field. Some well-known, basic concepts were omitted for the sake of
simplicity.

REGULATION OF VASCULAR TONE

Vasodilator and vasoconstrictor endogenous
compounds are produced by some arterial beds; however, the influence of those dilatators
produced by endothelium dominates over the constrictors produced in the smooth
muscle [3]. Endothelin is a potent vasoconstrictor working on
some vascular beds and promoting muscular proliferation. An increase in
circulating endothelin has been associated with pulmonary vascular disorders.
The effects of endothelin are excerted via activation of its receptors ETA
and ETB (ETB1 and ETB2) located in the smooth
muscular cells; ETA predominates in damaged vessels. During hypoxia,
the muscular response to endothelin blockers is lost, predisposing to
contractile responses. Bosental, an endothelin receptor blocker, has
non-selective vasodilatation effects and reduces pulmonary pressure in patients
with pulmonary hypertension [4].

Altered production of both vasodilator and
vasoconstrictor arachidonic acid metabolites has been implicated in the
pathogenesis of pulmonary hypertension in both newborns and adults [5] [6]. In newborn piglets, thromboxane, a vasoconstrictor
COX metabolite, was found to be involved in the pulmonary hypertension
resultant from short hypoxia [3]. Besides its vasoconstrictor effect, thromboxane is a
cellular mitogen of the smooth muscle [7]. Intervening with thromboxane at an early time point
may not only diminish the early elevation in pulmonary arterial pressure, but
may also inhibit progressive smooth muscle hypertrophy and thereby ameliorate
the progression of hypoxia-induced pulmonary hypertension [3].

COX inhibition reduced arachidonic
acid-induced dilation in endothelium-intact pulmonary arteries from control
piglets but did not have an effect on arachidonic acid responses in
endothelium-intact arteries from hypoxic piglets [8]. A differential regulation of COX-1 and COX-2 by
physiological stimuli has been previously described [9]. In addition, the effect on COX metabolite production
has been shown to vary with both the degree and duration of hypoxic exposure [10]. However, COX inhibition does not completely abolish
arachidonic acid-induced responses in either control or hypoxic arteries [8]. It is probable that other arachidonic acid pathways,
such as hydroxyeicosatetraenoic acids [11], could contribute to regulate the pulmonary vascular
tone in the newborn.

Shift in production of arachidonic acid
metabolites, away from dilators toward constrictors, occurs during exposure to
short hypoxia [8]. In addition, differences amongst species must be
considered when evaluating mechanisms underlying pulmonary hypertension. For
example, porcine pulmonary arteries may be more prone to production of
constrictor prostaglandins than other species [12]. Dilatation provoked by Ach (acetylcholine), is weak
in the lungs of newborn piglets exposed to hypoxia [13] [14].

EFFECTS OF tocolytic DRUGS

The tocolytics used in clinical practice can
be grouped into five classes: betamimetics, calcium channel blockers, magnesium
sulfate, non-steroidal anti-inflammatory agents, and oxytocin receptor
antagonists (atosiban). Ideally, the use of tocolytics should significantly
decrease the rates of perinatal death, RDS, intraventricular hemorrhage, and
necrotizing enterocolitis in the offspring [15]. Betamimetic drugs, however, are associated with an
increased risk of pulmonary edema, cardiac arrhythmias, and hypokalemia in
newborns.

Babies born prematurely show a high incidence
and severity of intracranial hemorrhage [11]; those born with respiratory complications have an
independent relation with a high risk of intracranial hemorrhage [16] [17]. Beta-sympatho-mimetic tocolytic agents augment
aortic blood flow and fetal cardiac output, which could be restricted to the
left ventricle, favoring flow redistribution to the upper part of the body.
Additionally, the systolic blood pressure may rise, increasing cerebral blood
flow in the fetus and favoring the incidence of intracranial hemorrhages in
immature fetus encephalon [18]. However, this increased risk of cerebral hemorrhages
was not confirmed by another study [16].

Calcium-channel antagonists have been used as
tocolytic agents. These agents inhibit calcium ion influx across the cell
membrane, thereby decreasing the tone in the smooth muscle vasculature. The
tocolytic efficacy of nifedipine is associated with a decrease in the neonatal
morbidity, RDS, intracranial hemorrhage and neonatal jaundice [19]. Its safety was also confirmed in experimental animal
models [20]. Papatsonis et al., [21] showed that the total incidence of intracranial
hemorrhages and bleeding was significantly reduced in the fetus born to women
treated with nifedipine for premature labor.

In human adults, calcium channel blockers
improved five-year survival rates in patients with primary pulmonary
hypertension [22]. This led to the theory that neonatal RDS may also be
reduced by a direct effect of nifedipine on improving neonatal pulmonary perfusion
[19] [21]. Although nifedipine has been shown to have a more
favorable neonatal outcome and better prolongation of gestation, there are
still some concerns about a theoretical risk to fetal and placental
circulations with its use [23]. In addition, there is no consensus about the dosage,
route, and formulation that should be used in a tocolytic regimen of nifedipine
[15].

Verapamil has a vasodilatory effect in
fetuses, favoring oxygen distribution to the brain when administered to the dam
[24] [25]. Administration of verapamil in pregnant females
during four weeks caused a decrease in lactate levels, which was possibly
related to an increase in blood flow through the brain due to the vasodilatory
action of this calcium antagonist [26]. This effect may minimize the blood flow
redistribution to the heart, liver, adrenals and other organs observed during
perinatal asphyxia. The return to a normal blood flow may increase oxygen
concentration in the brain and return to an aerobic cascade of glucose
oxidation minimizing lactate production in the fetus encephalum.

Magnesium sulfate can decrease uterine
activity, probably by competing with calcium influx in the myometrial cells
through voltage-gated channels. Magnesium sulfate is a potent vasodilator and
therefore has the potential to reduce the high pulmonary arterial pressures
associated with PPHN. However, a recent systematic review found no eligible
trials comparing magnesium sulfate versus placebo to support its use in the treatment
of PPHN [27].

Vetrabutin chlorhydrate (VC) is a derivative
of papaverine that acts as a vasodilator, with direct action on the smooth muscle
fibers of the uterine body and cervix [28]. It does not have neurotropic activity, and acts on
the myometrial cells, sealing off the membrane against potassium ion flux,
thereby increasing membrane potential [29]. A study in farrowing sows showed that animals
treated with VC had a shorter interval expulsion between piglets and a shorter
parturition compared with the control group [30]. In addition, they found that uterine contractions
and frequencies were lower, and piglets had a higher incidence of ruptured and
hemorrhagic umbilical cords with the use of VC in the parturient sow [31].

Beta-agonists such as atosiban and calcium
channel blockers are more popular tocolytic agents. A tocolytic agent that
improves neonatal outcome without maternal or neonatal side effects has not yet
surfaced [15].

Non-selective pulmonary vasodilators

A non-selective vasodilator may cause
pulmonary and systemic vasodilatation. Commonly used non-selective vasodilators
include tolazoline, nitroprusside, PGI2 (epoprostenol, iloprost),
fentanyl, isoproterenol and chlorpromazine; these have been administered
intravenously and intratracheally
in neonates with PPHN [32]. However, these agents are frequently associated with
systemic hypotension and other undesirable vascular responses [33] [34], or are still under evaluation [35] [36].

Intravenous vasodilators with systemic
effects have limitations, as they cause systemic hypotension and induce reflex sympatic
stimulation at the lung level causing pulmonary vasoconstriction and
exacerbating the pulmonary arterial hypertension. Systemic hypotension
diminishes the right ventricular contractibility secondary to coronary
perfusion pressure [37].

Some drugs have negative inotropic effects
blocking calcium channels. Therefore, whenever selective pulmonary dilators are
available, tolazoline, hidralazin, isoproterenol and nifedipine should preferably
be avoided [38] [39].

Selective pulmonary
vasodilators

In 1991, Frostell et al. reported that
inhaling low concentrations of nitric oxide (NO) decreased pulmonary artery
pressure in lambs with experimental pulmonary hypertension [40]. Since then, inhaled nitric oxide (iNO) has
revolutionized the treatment of acute pulmonary hypertension [41] [42] [43] [44] [45] [46] [47]. However, close monitoring of NO toxic metabolites is
advisable [48].

Sildenafil is an unspecific inhibitor of
type-5 phosphodiesterases (5-PDE) that enhances the vasodilatory effects of
nitric oxide by decreasing the biodegradation of a second-messenger GMPc [49] [50] [51]. Sildenafil is an effective pulmonary vasodilator in
patients suffering arterial pulmonary hypertension, thromboembolic pulmonary
hypertension and severe pulmonary hypertension due to a decrement on RVP [52] [53]. Its administration counteracts the deleterious
effects of induced hypoxia in animal models of chronic pulmonary hypertension [41].

Recently, we showed that sildenafil 500
µg kg-1 administered from day 35 to the end of gestation in
guinea pigs resulted in enhanced fetal growth and better tolerability to
induced intra-partum asphyxia than sildenafil 50 µg kg-1 [54]; both treatments resulted in better fetal outcomes,
compared with controls, and there was no evidence of gross malformations in the
piglets born to treated mothers. Sildenafil is gaining popularity for treating
adults and babies with pulmonary hypertension [52] [53] [55] [56] [57] [58].

A recently proposed alternative is the combination
of oral sildenafil and iNO, as they have shown to act synergistically in
patients with pulmonary hypertension and thromboembolic pulmonary hypertension [52]. In patients with pulmonary hypertension, the oral
administration of 12.5 mg or 50 mg of sildenafil lowered arterial pulmonary
pressure showing a dependent doses-effect [51].

Sildenafil produced important systemic
side-effects in humans and animals when administered in combination with
nitrates. In patients who previously received iNO, administration of sildenafil
was associated with hypotension [59]. On the other hand, an experiment with animals
previously treated with iNO and 1 mg kg-1 of sildenafil, showed a
decrease in the systemic vascular resistances resulting in arterial hypotension
[41].

Evaluation of physiological and metabolic
responses in experimental animal models may help to further characterize the
role of sildenafil in neonate tolerance to asphyxia [60]. Due to the lack of large clinical trials supporting
the safety and effectiveness of sildenafil for pulmonary hypertension in
neonates, its use is recommended to be restricted to randomized clinical trials
[61].

CONCLUSIONS

Experimental animal models are critical for
examining, in depth, current pharmacological alternatives for treating human
babies as well as for developing new therapeutic options. However, interspecies
differences should be considered when evaluating the mechanisms involved in
perinatal asphyxia, its consequences and treatment.

Regarding drug therapy, the evidence reviewed
herein points to two major conclusions. First, the administration of tocolytic
agents for increasing gestational age has not shown to improve neonatal
conditions. Instead, time needs to be optimized by prenatally administering
corticosteroids and transferring the mother to a tertiary-care centre with
proper neonatal facilities. Second, the pulmonary vasodilator of choice in
neonates with pulmonary hypertension is currently iNO. However, sildenafil has
shown to be a good alternative both as a single drug or associated with iNO.

Authors’
Participation

M G-L and D M-R
conceived the idea; all the authors participated
drafting the manuscript and discussing the findings.

Acknowledgments

M G-L acknowledges the financial support from
the Consejo Mexicano de Ciencia y Tecnología, Mexico, as a graduate student. ME
T, M A-S and D M-R are being supported, as members, by the Sistema Nacional de
Investigadores, Mexico.

Conflict of
Interests/Disclaimers

AA N-O, M A-S, and D M-R are members of the
Editorial Board.

References

[1]      Aschner JL, Kovacs N, Perciaccante JV, Figueroa JP,
Thrikawala N, Robins GS, et al. Endothelial nitric oxide synthase gene transfer
enhances dilation of newborn piglet pulmonary arteries. Am J Physiol 1999; 277:
H371-H379.

[2]      Larrue B, Jaillard S, Lorthioir M, Roubliova X, Butrous
G, Rakza T, et al. Pulmonary vascular effects of sildenafil on the development
of chronic pulmonary hypertension in the ovine fetuses. Am J Physiol Lung Cell
Mol Physiol 2005; 288: L1193-L1200.

[3]
Fike
CD, Pfister SL, Kaplowitz MR, Madden JA. Cyclooxygenase
contracting factors and altered pulmonary vascular responses in chronically
hypoxic newborn pigs. J Appl Physiol 2002; 92: 67-74.

[4]
Channick
RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, et al. Effects of
the dual endothelin-receptor antagonist bosentan in patients with pulmonary
hypertension: a randomised placebo-controlled study. Lancet 2001; 358:
1119-1123.

[5]
Shaul
PW, Kinane B, Farrar MA, Bruja LM, Madness RR. Prostacyclin
production and mediation of adenylate cyclase activity in the pulmonary artery:
alterations after prolonged hypoxia in the rat. J Clin Invest 1991; 88:
447-455.

[6]
Tuder
RM, Cool CD, Geraci MW, Wang J, Abman SH, Wright L et al. Prostacyclin synthase
expression is decreased in lungs from patients with severe pulmonary
hypertension. Am J Respir Crit Care Med 1999; 159: 1925-1932.

[7]
Sachinidis
A, Flesch M, Ko Y, Schrör K, Böhm M, Düsing R et al. Thromboxane
A2 and vascular smooth muscle cell proliferation. Hypertension 1995; 26:
771-780.

[8]
Fike
CD, Kaplowitz MR, Pfister SL. Arachidonic acid metabolites and an early stage of
pulmonary hypertension in chronically hypoxic newborn pigs. Am J Physiol Lung
Cell Mol Physiol 2003; 284: L316-L323.

[9]
McCormick
SM, Whitson PA, Wu KK, McIntire LV. Shear stress differentially regulates
PGHS-1 and PGHS-2 protein levels in human endothelial cells. Ann Biomed Eng
2000; 28: 824-833.

[10]
Farber
HW, Barnett HF. Differences in prostaglandin metabolism in cultured aortic and
pulmonary arterial endothelial cells exposed to acute and chronic hypoxia. Circ
Res 1991; 68: 1446-1457.

[11]  Zhu D, Birks EK, Dawson CA, Patel M, Falck JR, Presberg
K, et al. Hypoxic pulmonary vasoconstriction is modified by
P-450 metabolites. Am J Physiol Heart Circ Physiol 2000; 279: H1526-H1533.

[12]  Lawrence RN, Clelland C, Beggs D, Salama FD, Dunn WR,
Wilson VG. Differential role of vasoactive prostanoids in porcine and human
isolated pulmonary arteries in response to endothelium-dependent relaxants. Br
J Pharmacol 1998; 125: 1128-1137.

[13]  Fike CD, Kaplowitz MR. Chronic hypoxia alters nitric
oxide-dependent pulmonary vascular responses in lungs of newborn pigs. J Appl
Physiol 1996; 81: 2078-2087.

[14]  Le Cras TD, McMurtry IF. Nitric oxide production in the
hypoxic lung. Am J Physiol Lung Cell Mol Physiol 2001; 280: L575-L582.

[15]  Tan
TC, Devendra K, Tan LK, Tan HK. Tocolytic treatment for the management of preterm
labour: a systematic review. Singapore Med J 2006; 47: 361-366.

[16]  Levene MI, Fawer CL, Lamont RF. Risk
factors in the development of intraventricular haemorrhage in the preterm
neonate. Arch Dis Child 1982; 57: 410-417.

[17]  Low JA, Galbraith RS, Sauerbrei EE, Muir DW, Killen
HL, Pater EA, et al. Maternal, fetal and newborn complications associated with
newborn intracranial hemorrhage. Am J Obstet Gynecol 1986; 154: 345-351.

[18]  Groome LJ, Goldenberg RL, Cliver SP, Davis RO, Copper
RL. Neonatal periventricular-intraventricular hemorrhage after maternal
beta-sympathomimetic tocolysis. The March of Dimes Multicenter Study Group. Am
J Obstet Gynecol 1992; 167: 873-879.

[19]
Papatsonis
DN, Van Geijn HP, Adèr HJ, Lange FM, Bleker OP, Dekker GA. Nifedipine
and ritodrine in the management of preterm labor: A randomized multicenter
trial. Obstet Gynecol 1997; 90: 230-234.

[20]
Harake
B, Gilbert RD, Ashwal S, Power GG. Nifedipine: effects on fetal and maternal
hemodynamics in pregnant sheep. Am J Obstet Gynecol 1987; 157: 1003-1008.

[21]
Papatsonis
DN, Kok JH, Van Geijn HP, Bleker OP, Adèr HJ, Dekker GA. Neonatal
effects of nifedipine and ritodrine for preterm labor. Obstet Gynecol 2000; 95:
447-481.

[22]
Rich
S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on
survival in primary pulmonary hypertension. N Engl J Med 1992; 327: 76-81.

[23]
Blea
CW, Barnard JM, Magness RR, Phernetton TM, Hendricks SK. Effect of nifedipine on fetal and maternal hemodynamics
and blood gases in the pregnant ewe. Am J Obstet Gynecol
1997; 176: 922-930.

[24]
Ortega R, Clarembaux J,
Hernandez C, Gil E. El verapamil en las resistencias fetales altas. Rev. Mex.
Pueril. Ped. 1995; 3: 38-44.

[25]
Ortega R, Clarembaux J,
Salazar E, Guevara F, Urbina D, Hernández A. Efectos de aspirina y
verapamil sobre resistencias materno fetales en primigestas con riesgo de
preeclampsia. Rev Obstet Ginecol Venez 1993; 53: 17-22.

[26]
Dubiel
M, Gunnarsson G, Gudmundsson S. Blood redistribution in the fetal brain during
chronic hypoxia. Ultrasound Obstet Gynecol 2002; 20: 117-121.

[27]  Ho JJ, Rasa G. Magnesium sulfate for persistent
pulmonary hypertension of the newborn. Cochrane Database Syst Rev 2007: 18:
CD005588.

[28]
Phillipp
H, Justus C. Clinical investigation using monzal in sows during the farrowing
period. Boehringer Ingelheim Vetmedica 1992; Gmb-H. Federal Republic of
Germany.

[29]
EAEMP.
The European Agency for the Evaluation of Medical Products: Veterinary
Medicines Evaluation Unit. Committee for Veterinary Medicinal Products.  1999.

[30]
Mota-Rojas
D, Rosales AM, Trujillo ME, Orozco H, Ramírez R, Alonso-Spilsbury M. The
effects of vetrabutin chlorhydrate and oxytocin on stillbirth rate and asphyxia
in swine. Theriogenology 2005; 64: 1889-1897.

[31]
Mota-Rojas D, Trujillo-Ortega
ME, Villanueva-García D, González-Lozano M, Orozco-Gregorio H,
Ramírez-Necoechea R, et al. Can uterotonics reduce fetal and newborn piglet
mortality by perinatal asphyxia and improve functional vitality? J Med Sci 2006; 6:
884-893.

[32]
Goetzman
BW, Sunshine P, Johnson JD, Wennberg RP, Hackel A, Merten DF, et al. Neonatal
hypoxia and pulmonary vasospasm: response to tolazoline. J Pediatr 1976; 89:
617-621.

[33]
Alonso-Spilsbury M, Mota-Rojas
D, Villanueva-García D, Martínez-Burnes J, Orozco H,
Ramírez-Necoechea R, et al. Perinatal asphyxia pathophysiology in pig and human: a
review. Anim Reprod Sci 2005; 90: 1-30.

[34]  Nakayama
T, Shimada H, Takatsuki S, Hoshida H, Ishikita T, Matsuura H, et al. Efficacy
and limitations of continuous intravenous epoprostenol therapy for idiopathic
pulmonary arterial hypertension in Japanese children. Circ J 2007; 71:
1785-1790.

[35]  Chotigeat U, Jaratwashirakul S. Inhaled iloprost for
severe persistent pulmonary hypertension of the newborn. J Med Assoc Thai 2007;
90: 167-170.

[36]  Eifinger F, Sreeram N, Mehler K, Huenseler C, Kribs A,
Roth B. Aerosolized iloprost in the treatment of pulmonary hypertension in
extremely preterm infants: a pilot study. Klin Padiatr 2008; 220: 66-69.

[37]
Villanueva-García D,
Mota-Rojas D. Hipertensión Arterial Pulmonar Persistente del
Recién Nacido. In: Mota-Rojas D, Nava-Ocampo A. A.,
Villanueva-García D, Alonso-Spilsbury M. (eds.), Perinatología
Animal. Enfoques Clínicos y Experimentales, Primera Edición ed.
ISBN 970-95024-0-9. México: BM Editores SA de CV; 2006: 71-84.

[38]  Abman SH. New developments in the pathogenesis and
treatment of neonatal pulmonary hypertension. Pediatr Pulmonol Suppl 1999; 18:
201-204.

[39]  Abman SH. Neonatal pulmonary hypertension: a
physiologic approach to treatment. Pediatr Pulmonol Suppl 2004; 26: 127-128.

[40]
Frostell
C, Fratacci MD, Wain JC, Jones R, Zapol WM. Inhaled nitric oxide. A selective
pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation
1991; 83: 2038-2047.

[41]  Shekerdemian LS, Ravn HV, Penny DJ. Interaction
between inhaled nitric oxide and intravenous sildenafil in a porcine model of
meconium aspiration syndrome. Pediatr Res 2004; 55: 413-418.

[42]  Berger JI, Gibson RL, Redding GJ, et al. Effect
of inhaled nitric oxide during group B streptococcal sepsis in piglets. Am Rev
Respir Dis 1993; 147: 1080-1086.

[43]  Zayek M, Wild L, Roberts JD, Morin FC 3rd. Effect of
nitric oxide on the survival rate and incidence of lung injury in newborn lambs
with persistent pulmonary hypertension. J Pediatr 1993; 123: 947-952.

[44]  McQueston JA, Kinsella JP, Ivy DD, McMurtry IF, Abman
SH. Chronic pulmonary hypertension in utero impairs
endothelium-dependent vasodilation. Am J Physiol 1995; 268: H288-H294.

[45]  Roberts JD Jr, Fineman JR, Morin FC 3rd, Shaul PW,
Rimar S, Schreiber MD, et al. Inhaled nitric oxide and persistent pulmonary
hypertension of the newborn. N England J Med 1997; 336: 605-610.

[46]  Kinsella JP, Truog WE, Walsh WF, Goldberg RN,
Bancalari E, Mayock DE et al. Randomized, multicenter trial of inhaled nitric
oxide and high frequency oscillatory ventilation in severe, persistent
pulmonary hypertension of the newborn. J Pediatr 1997; 131: 55-62.

[47]
Chotigeat
U, Khorana M, Kanjanapattanakul W. Inhaled nitric oxide in newborns with severe
hypoxic respiratory failure. J Med Assoc Thai 2007; 90: 266-271.

[48]  Villanueva
GD, Fernández MP, Hernáiz AHMI. Óxido Nítrico.
Programa de Actualización Continua en Neonatología (PAC- Neonatología-1)
Libro 3. Insuficiencia Respiratoria Neonatal. 2003: 209-214.

[49]  Khan RN, Hamound H, Warren A, Wong LF, Arulkumaran S.
Relaxant action of sildenafil citrate (viagra) on human myometrium of
pregnancy. Am J Obstet Gynecol 2004; 191: 315-321.

[50]  Gobry V, Bouchard G, Carrupt PA, Testa B, Girault HH.
Physicochemical characterization of sildenafil: ionization, lipophilicity
behavior, and ionic-partition diagram studied by two-phase titration and
electrochemistry. Elvetica
Chimica Acta 2000; 83: 1465-1474.

[51]  Sher G. Sildenafil enhances endometrial development.
Fertility Weekly 2002; 2: 10-11.

[52]  Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto
K, Archer S. Oral sildenafil is an effective and specific pulmonary
vasodilator in patients with pulmonary arterial hypertension: Comparison with
inhaled nitric oxide. Circulation 2002; 105: 2398-2403.

[53]  Ghofrani HA, Wiedemann R, Rose F, Olschewski H,
Schermuly RT, Weissmann N,, et al. Combination Therapy with Oral Sildenafil and
inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002;
136: 515-522.

[54]  Sánchez-Aparicio
P, Mota-Rojas D, Nava-Ocampo AA, Trujillo-Ortega ME, Alfaro-Rodríguez A,
Arch E, et al. Effects of sildenafil on the fetal
growth of guinea pigs and their ability to survive induced intrapartum
asphyxia. Am J Obstet Gynecol
2008; 198: 127: e1-e6.

[55]  Shekerdemian LS, Ravn HB, Penny DJ. Intravenous
sildenafil lowers pulmonary vascular resistance in a model of neonatal pulmonary
hypertension. Am J Respir Crit Care Med 2002; 165: 1098-1102.

[56]  Carroll WD, Dhillon R. Sildenafil as a treatment for
pulmonary hypertension. Arch Dis Child 2003; 88: 827-828.

[57]  Lepore JJ, Maroo A, Pereira NL, Ginns LC, Dec GW,
Zapol WM, et al. Effect of sildenafil on the acute pulmonary vasodilator response
to inhaled nitric oxide in adults with primary pulmonary hypertension. Am J
Cardiol 2002; 90: 677-680.

[58]  Rite-García
S, Ruiz-Moreno JA, Sánchez-Jimeno J, Molin-Chica MI, Marco-Tello S,
Rite-Montañes S. Óxido nítrico inhalado en el tratamiento
de la hipertensión pulmonar persistente del recién nacido. Anales
Españoles de Pediatría 1999; 51: 181-185.

[59]  Wareing M, Myers JE, O’Hara M, Baker PN. Sildenafil
citrate (Viagra) enhances vasodilation in fetal growth restriction. J Clin
Endocrinol Metab 2005; 90: 2550-2555.

[60]
Sánchez-Aparicio P,
Mota-Rojas D, Ramírez-Necoechea R, Olmos-Hernández A,
Alonso-Spilsbury M, Villanueva-García D, et al. Systemic
effects of sildenafil citrate on pregnancy and perinatal periods. J Anim Vet Adv 2007; 6: 267-271.

[61]  Shah PS, Ohlsson A. Sildenafil for pulmonary
hypertension in neonates. Cochrane Database Syst Rev 2007; 18: CD005494.

www.premiumreasons.com/JTEP/JTEP.html

© PremiumReasons