Sildenafil Can Increase the Response to Inhaled Nitric Oxide

Bigatello, Luca M.; Hess, Dean; Dennehy, Kevin C.; Medoff, Benjamin D.; Hurford, William E.

doi:10.1097/00000542-200006000-00044

Cited by 64 publications

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“…In a recent study, it has been reported that sildenafil, a potent and selective PDE5 inhibitor, potentiates the reduction of PAP induced by nitric oxide inhalation. 36) However, recent findings have demonstrated that pulmonary vasodilation did not cause the amelioration of chronic PH in animal studies. It has been reported that inhaled nitric oxide did not prevent pulmonary vascular remodeling in MCT-induced PH rats.…”

Section: Discussionmentioning

confidence: 96%

Acute and Chronic Effects of T-1032, a Novel Selective Phosphodiesterase Type 5 Inhibitor, on Monocrotaline-Induced Pulmonary Hypertension in Rats.

Inoue

Yano

Noto

et al. 2002

Biological & Pharmaceutical Bulletin

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Pulmonary hypertension (PH) is a fatal disease, characterized by the progressive elevation of pulmonary arterial resistance. Although the causes of this disorder are complicated, abnormal vasoconstriction appears to be a primary factor in the development of PH. 1,2) Although some kinds of vasodilators, such as calcium blockers and prostacyclin, have been used in the treatment of PH, 3,4) they cause several side effects due to systemic vasodilation. Recent studies have demonstrated that nitric oxide inhalation produces selective pulmonary vasodilation without affecting systemic blood pressure in patients with PH. 5,6) However, since the safety of nitric oxide inhalation has not been established, 7) its doses have been restricted. Phosphodiesterases (PDEs) are enzymes, which break down cAMP and/or cGMP, and they play a key role in the regulation of intracellular cyclic nucleotide levels. A phosphodiesterase type 5 (PDE5) is classified as cGMP-bind, cGMP-specific phosphodiesterase. 8,9) PDE5 is abundantly expressed in some specific tissues, including the lung and pulmonary artery.10-12) Therefore, the inhibition of PDE5 is considered to produce an increase in cGMP levels in the lung and pulmonary artery. It has been reported that PDE5 inhibitors such as zaprinast, E-4021 and sildenafil preferably dilate the pulmonary artery in vivo and in vitro experimental conditions. [13][14][15][16][17][18] T-1032 (methyl 2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate) is a novel inhibitor of PDE5 (IC 50 ϭ0.001 mM; canine lung). The selectivity for PDE5 over other PDEs in T-1032 is similar to that of sildenafil (IC 50 : PDE1; 3 mM, PDE2; 9.7 mM, PDE3; Ͼ100 mM, PDE4; 3.3 mM).19) T-1032 shows potentiating effects on the nitric oxide/cGMP signaling pathway in isolated rat aorta and rabbit corpus cavernosum. 20) In addition, an intraduodenal administration of T-1032 potentiates the penile tumescence induced by pelvic nerve stimulation, probably through the blockade of PDE5 in anesthetized dogs.21) These results suggest that T-1032 potentiates a nitric oxide/cGMP pathway inhibitor and is orally active compound in animal studies.The acute hemodynamic effects by PDE5 inhibitors on pulmonary circulation have been examined in animal models with PH. 13,15,18) However, only a few studies have reported whether the chronic treatment is effective for improving cardiac remodeling and its related death in an animal model with PH. 22) In this study, we first examined the hemodynamic properties of T-1032 in MCT-induced PH rats, and we next evaluated the chronic effect of T-1032 on cardiac remodeling and its related death in MCT-induced PH rats. MATERIAL AND METHODSThis study was approved by the Animal Research Committee of Tanabe Seiyaku Co., Ltd.Animal Preparation Monocrotaline (MCT, 70 mg/kg) was subcutaneously administered in male Wistar rats weighing 94-107 g, as described previously. 23)Acute Hemodynamic Effects in MCT Rats Twenty-six days after MCT (70 mg/kg) or vehicle...

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Section: Discussionmentioning

confidence: 96%

Acute and Chronic Effects of T-1032, a Novel Selective Phosphodiesterase Type 5 Inhibitor, on Monocrotaline-Induced Pulmonary Hypertension in Rats.

Inoue

Yano

Noto

et al. 2002

Biological & Pharmaceutical Bulletin

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“…Prostaciclina (PGI2) en infusión o en aerosol y la inhalación de óxido nítrico se han descrito como tratamientos efectivos de la hipertensión pulmonar (13,14), y han sido utilizados con éxito en la gestación asociada a hipertensión pulmonar primaria (14)(15)(16)(17)(18)(19). Más recientemente, ha aparecido las primeras comunicaciones sobre casos aislados, beneficiados por una intervención dirigida a aumentar la disponibilidad de guanosina monofosfato cíclica (cGMP), el mensajero intracelular de NO, mediante el inhibidor de fosfodiesterasa sildenafil (20)(21)(22)(23)(24); este ha sido empleado como droga única (22,23) o en asociación a NO inhalado (24). No se describen efectos deletéreos ni en la madre ni en el feto (25), L-arginina ha sido administrada a mujeres preeclám-pticas y a mujeres con fetos con restricción del crecimiento intrauterino, con buena tolerancia y efectos benéficos en las presiones maternas y en el flujo útero placentario (26).…”

Section: Discussionunclassified

Síndrome De Eisenmenger Y Embarazo

et al. 2007

Rev. chil. obstet. ginecol.

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INTRODUCCIÓNEl desarrollo de hipertensión pulmonar (HP) secundaria a cardiopatías congénitas con defectos septales, habitualmente ocurren en la cuarta déca-da de la vida (1). Sin embargo, hay numerosas publicaciones de mujeres embarazadas con este síndrome (2-4). Corresponde a una cardiopatía congénita del tipo de la comunicación interauricular (CIA), interventricular (CIV) y ductus persistente en las que se ha producido inversión del shunt de izquierda a derecha, lo que da como resultado un incremento progresivo de la resistencia vascular pulmonar, falla ventricular derecha y muerte (5).En embarazos normales el gasto cardíaco se incrementa entre un 30-50%, la volemia en un 40%, y el consumo de oxígeno en un 20%, modificaciones fisiológicas a las cuales el corazón sano se adapta. La función sistólica izquierda decrece en el último período del embarazo, y durante el parto las contracciones uterinas inducen una elevación adicional del gasto cardíaco de 40% aproximadamente (6). Todos estos cambios fisiológicos hacen que la hipertensión pulmonar sea pobremente tole- RESUMENAntecedentes: El embarazo está contraindicado en toda paciente con hipertensión pulmonar, y particularmente en aquellas con síndrome de Eisenmenger. Objetivo: Describir 3 casos de embarazadas con síndrome de Eisenmenger, tratadas con sildenafil. Resultados: El desarrollo del embarazo se complicó en las tres pacientes con parto prematuro, a las 30, 28 y 35 semanas, respectivamente. En 2 pacientes el parto se resolvió mediante operación cesárea. No hubo mortalidad materna ni perinatal. Conclusión: El síndrome de Eisenmenger es de alto riesgo de morbimortalidad materno-perinatal y el manejo multidisciplinario optimiza los resultados. Se describe el uso de sildenafil.PALABRAS CLAVE: Síndrome de Eisenmenger y embarazo, sildenafil SUMMARY Background: Pregnancy in contraindicated in patient with pulmonary hypertension, especially in dose with Eisenmenger syndrome. Objective: To present 3 cases of pregnancy in patients with Eisenmenger syndrome treated with sildenafil. Results: The pregnancy becomes complicated in the 3 cases, with premature delivery at 30, 28 and 35 weeks respectively. Cesarean delivery was performed in two cases. There was no maternal or perinatal mortality. Conclusion: The Eisenmenger syndrome is a high risk condition of maternal-perinatal morbimortality and the multidisciplinary handling optimizes the results. The sildenafil use is described.

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“…Sildenafil is rapidly absorbed through the gastrointestinal tract, even in critically ill patients 6 . High doses (400 mg, 4 times a day) of sildenafil are well tolerated and have few significant side effects (hypotension, significant cephalea) 11 .…”

Section: Discussionmentioning

confidence: 99%

“…Sildenafil is a specific inhibitor of PDE5 that increases the pulmonary vasodilating effect of inhaled nitric oxide [5][6][7][8] , prevents pulmonary hypertensive crises after weaning of nitric oxide in patients with severe pulmonary hypertension 5,9 , and has its own pulmonary vasodilating effect 10,11 by increasing the GMPc levels 12 .…”

Section: Case Reportmentioning

confidence: 99%

Sildenafil melhora a função ventricular direita no receptor de transplante cardíaco

Paez¹,

Araujo²,

Hossne³

et al. 2005

Arq. Bras. Cardiol.

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The use of a female donor for a male recipient is known to have a greater early mortality (OR=1.11, P=0.3), similarly to that of a recipient using vasoactive drugs and waiting in the intensive care unit (OR=2.51, P<0.0001) [13][14][15] .We report the case of a patient undergoing orthotopic cardiac transplantation, who experienced cardiogenic shock due to right ventricular dysfunction secondary to pulmonary hypertension associated with vasoplegia. Because the recipient's clinical condition was critical, a marginal donor was used.In the national literature, we did not find reports of the use of sildenafil for pulmonary hypertension in the postoperative period. The objective of this report is to propose a new and safe manner to treat right ventricular failure secondary to pulmonary hypertension in the postoperative period of cardiac transplantation. Case ReportThe patient was a 33-year-old man with idiopathic dilated cardiomyopathy, who had been in NYHA functional class IV for the preceding 2 years and was hospitalized with low cardiac output and was using catecholamines (dobutamine, 6.6 mcg/kg/min, and dopamine, 8 mcg/kg/min). The patient was hypotensive (blood pressure of 70x40 mmHg), slightly dyspneic at rest, and had hepatomegaly and pulmonary congestion (basal rales in both bases).The patient underwent orthotopic cardiac transplantation on 08/02/2003. Due to his rapid clinical worsening, a marginal organ was used. The marginal donor was a 60-kg female, who had experienced cardiac arrest for 15 minutes 3 days before, was using 12 mcg/kg/min of dopamine, and, on the echocardiogram, had diffuse, mild hypokinesia and preserved overall function.The transplantation was performed according to the bicaval technique with 165 minutes of extracorporeal circulation and 117 minutes of anoxia, under mild hypothermia (32 o C) and use of intermittent anterograde blood cardioplegia. The patient was removed from the extracorporeal circulation after the third attempt and sent to the ICU receiving 0.11 mcg/kg/min of isoproterenol, 0.75 mcg/ kg/min milrinone, and 20mcg/kg/min of dobutamine. His mean blood pressure was 40 mmHg and mean pulmonary arterial pressure was 45 mmHg. His right ventricular contractility was very poor, and he received adrenaline in bolus during transportation and in the first hours at the ICU. Twelve hours after transplantation, the patient was receiving 10mcg/kg/min of dobutamine, 0.96 mcg/kg/min of adrenaline, 0.13 mcg/kg/min of isoproterenol, and 0.41 mcg/kg/ The use of inhaled nitric oxide reduces pulmonary artery pressure, increasing the production of guanosine 3',5'-cyclic monophosphate (GMPc) in the smooth muscle cells of the lung 1 . Specific inhibitors of GMPc phosphodiesterase (PDE5), which hydrolyzes GMPc in vascular smooth muscle, cause pulmonary vasodilation 2-4 .Sildenafil is a specific inhibitor of PDE5 that increases the pulmonary vasodilating effect of inhaled nitric oxide 5-8 , prevents pulmonary hypertensive crises after weaning of nitric oxide in patients with severe pulmonary hypertensio...

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Sildenafil Can Increase the Response to Inhaled Nitric Oxide

Cited by 64 publications

References 0 publications

Acute and Chronic Effects of T-1032, a Novel Selective Phosphodiesterase Type 5 Inhibitor, on Monocrotaline-Induced Pulmonary Hypertension in Rats.

Acute and Chronic Effects of T-1032, a Novel Selective Phosphodiesterase Type 5 Inhibitor, on Monocrotaline-Induced Pulmonary Hypertension in Rats.

Síndrome De Eisenmenger Y Embarazo

Sildenafil melhora a função ventricular direita no receptor de transplante cardíaco

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