A Combination of Oral Sildenafil and Beraprost Ameliorates Pulmonary Hypertension in Rats

Itoh, Takefumi; Nagaya, Noritoshi; Fujii, Takafumi; Igarashi, Takashi; Nakanishi, Norifumi; Hamada, Kaoru; Kangawa, Kenji; Kimura, Hiroshi

doi:10.1164/rccm.200303-346oc

Cited by 94 publications

(71 citation statements)

References 26 publications

(23 reference statements)

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“…As shown in Figure 4, the phosphodiesterase type V inhibitor sildenafil (5 mg/kg/day) did not show any significant inhibitory effects on RVSP, RV/(LV+S) and Lung/BW in monocrotaline-induced pulmonary hypertensive rats. Monotherapy with sildenafil (25 or 75 mg/kg/day) attenuates the elevation of pulmonary artery pressure and vascular remodeling in hypoxia-induced pulmonary hypertension [36], whereas combination therapy with sildenafil (25 mg/kg/day) and beraprost (100 µg/kg/day) attenuates the development of monocrotaline-induced pulmonary hypertension [37]. Sildenafil (100 mg/kg/day) was efficacious in rats with pulmonary hypertension, and the combination therapy of sildenafil and bosentan showed an additional effect for decreasing pulmonary arterial pressure, maintaining body weight, and reducing mortality [38].…”

Section: Discussionmentioning

confidence: 99%

3-Hydroxy-3-Methylglutaryl-COA Reductase Inhibitors and Phosphodiesterase Type V Inhibitors Attenuate Right Ventricular Pressure and Remodeling in a Rat Model of Pulmonary Hypertension

Satoh

Satoh²

2009

J Pharm Pharm Sci

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-Purpose. We examined the inhibitory effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, a prostacyclin analogue and a phosphodiesterase type V inhibitor on hemodynamic function and cardiac remodeling in rats with monocrotaline-induced pulmonary hypertension. Methods. The rat model of pulmonary hypertension was created by administration of monocrotaline (70 mg/kg, s.c.) to male Wistar rats. A polyethylene tube was introduced into a left carotid artery for measurement of mean arterial pressure (MAP), another into the right ventricle via the right jugular vein for measurement of right ventricular systolic pressure (RVSP).Results. Repeated administration of atorvastatin (2 mg/kg/day, p.o. 0 -28 days) and simvastatin (2 mg/kg/day, p.o. 0 -28 days) significantly reduced RVSP and right ventricular weight (RV)/left ventricular + septum weight (LV + S) without a change in MAP and heart rate. However, repeated administration of pravastatin (4 mg/kg/day, p.o. 0 -28 days) did not reduce the monocrotaline-induced elevation of RVSP and RV/(LV + S) significantly. The reduction of RVSP and RV/(LV + S) induced by a combination of a prostacyclin analogue, beraprost (100 µg/kg/day, 0 -28 days) and simvastatin (2 mg/kg/day, 0 -28 days), was more potent than the effect induced by each drug alone. Sildenafil (5 mg/kg/day, 0 -28 days) tended to reduce RVSP and RV/(LV + S). Repeated combined administration of atorvastatin (2 mg/kg/day, p.o. 0 -28 days) + sildenafil (5 mg/kg/day, p.o. 0 -28 days) significantly reduced lung/body weight. Conclusion. Our present results suggest that repeated administration of the lipophilic HMG-CoA reductase inhibitors, atorvastatin and simvastatin, selectively attenuates the elevation of RVSP, development of pulmonary hypertension and right ventricular remodeling in rats with monocrotaline-induced pulmonary hypertension, and that a combination of HMG-CoA reductase inhibitor and beraprost has a more potent effect than each agent alone. Although the significant inhibitory effect of sildenafil (5mg/kg/day) alone were not observed, higher dosage of sildenafil might attenuate the elevation of RVSP, development of pulmonary hypertension and right ventricular remodeling in rats with monocrotaline-induced pulmonary hypertension. INTRODUCTIONPulmonary hypertension is a serious disease, characterized by progressive elevation of pulmonary arterial resistance, leading to right ventricular failure and death [1]. Although the causes of this disorder are complicated, abnormal vasoconstriction by vascular endothelial injury in pulmonary arterioles, smooth muscle cell proliferation and hypertrophy, contraction of arterioles and remodeling appear to be primary factors. It is reported that release of the vasodilators prostacyclin [2] and nitric oxide [3] decreases, on the other hand, the release of the vasoconstrictor thromboxane A 2 [4] and the expression of endothelin-1 from vascular endothelial cells [5] increases. Therefore, a prostacyclin analogue, epoprostenol, has been administered by cont...

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Section: Discussionmentioning

confidence: 99%

3-Hydroxy-3-Methylglutaryl-COA Reductase Inhibitors and Phosphodiesterase Type V Inhibitors Attenuate Right Ventricular Pressure and Remodeling in a Rat Model of Pulmonary Hypertension

Satoh

Satoh²

2009

J Pharm Pharm Sci

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“…In these studies, rats that received both a prostacyclin analog and a PDE5 inhibitor showed increased survival. 1 In summary, we present evidence for the first time that the prostacyclin analog UT-15C and PDE5 inhibitors interact to augment cAMP accumulation and ATP release from erythrocytes of humans with PAH. Some of the beneficial effects of the administration of these drugs in combination in PAH patients may be explained by the release of this potent vasodilator and stimulus for nitric oxide synthesis in the pulmonary vasculature.…”

Section: Discussionmentioning

confidence: 72%

Phosphodiesterase 5 inhibitors augment UT-15C-stimulated ATP release from erythrocytes of humans with pulmonary arterial hypertension

Bowles

Moody

Yeragunta

et al. 2014

Exp Biol Med (Maywood)

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Both prostacyclin analogs and phosphodiesterase 5 (PDE5) inhibitors are effective treatments for pulmonary arterial hypertension (PAH). In addition to direct effects on vascular smooth muscle, prostacyclin analogs increase cAMP levels and ATP release from healthy human erythrocytes. We hypothesized that UT-15C, an orally available form of the prostacyclin analog, treprostinil, would stimulate ATP release from erythrocytes of humans with PAH and that this release would be augmented by PDE5 inhibitors. Erythrocytes were isolated and the effect of UT-15C on cAMP levels and ATP release were measured in the presence and absence of the PDE5 inhibitors, zaprinast or tadalafil. In addition, the ability of a soluble guanylyl cyclase inhibitor to prevent the effects of tadalafil was determined. Erythrocytes of healthy humans and humans with PAH respond to UT-15C with increases in cAMP levels and ATP release. In both groups, UT-15C-induced ATP release was potentiated by zaprinast and tadalafil. The effect of tadalafil was prevented by pre-treatment with an inhibitor of soluble guanylyl cyclase in healthy human erythrocytes. Importantly, UT-15C-induced ATP release was greater in PAH erythrocytes than in healthy human erythrocytes in both the presence and the absence of PDE5 inhibitors. The finding that prostacyclin analogs and PDE5 inhibitors work synergistically to enhance release of the potent vasodilator ATP from PAH erythrocytes provides a new rationale for the co-administration of these drugs in this disease. Moreover, these results suggest that the erythrocyte is a novel target for future drug development for the treatment of PAH.

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“…The mechanism underlying the augmented response with sildenafil and prostanoids is incompletely understood, but these findings suggest significant cross talk between the cyclic nucleotides. Itoh, et al 13) also demonstrated the additive effect of sildenafil and beraprost using an animal model of PAH.…”

Section: Discussionmentioning

confidence: 94%

Combination Therapy With Oral Sildenafil and Beraprost for Pulmonary Arterial Hypertension Associated With CREST Syndrome

et al. 2007

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SUMMARYPulmonary arterial hypertension (PAH) is commonly associated with CREST (Calcinosis, Raynaud phenomenon, Esophageal motility disorders, Sclerodactyly, and Telangiectasia) syndrome. Sildenafil, an oral phosphodiesterase type-5 inhibitor, may offer benefits in the pharmacological management of PAH. However, little is known about the long-term hemodynamic effects of sildenafil, and the potential role of sildenafil in longterm combination with beraprost, an oral prostacyclin analogue, remains unclear. We therefore examined the hemodynamic effect of oral sildenafil alone and when coadministered with beraprost in a patient with PAH associated with CREST syndrome.Traces of the acute hemodynamic effects of beraprost (20 µg) disappeared after 2 hours. In contrast, the acute hemodynamic effects of sildenafil (50 mg) produced a greater reduction in PAP (31%) and PVR (40%), and these effects also disappeared after 5 hours.After 1 month of combination therapy of sildenafil (25 mg) twice daily and beraprost (20 µg) 3 times daily, the fall in pulmonary artery pressure and pulmonary vascular resistance was sustained (31% in both). Furthermore, the patient had significantly improved her 3-minute walk test and NYHA function class without significant adverse effects at the reported doses. The findings indicate that oral sildenafil is a potent pulmonary vasodilator that appears to act synergistically with oral beraprost to cause sustained pulmonary vasodilatation in a patient with PAH associated with CREST syndrome. (Int Heart J 2007; 48: 417-422) Key words: Pulmonary artery hypertension, CREST syndrome, Sildenafil, Beraprost PULMONARY artery hypertension (PAH) is a life-threatening disease characterized by progressive pulmonary hypertension that leads to right ventricular failure and death. 1) PAH comprises idiopathic PAH and PAH in the setting of collagen disease (eg, in localized cutaneous systemic sclerosis, also known as the From the

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A Combination of Oral Sildenafil and Beraprost Ameliorates Pulmonary Hypertension in Rats

Cited by 94 publications

References 26 publications

3-Hydroxy-3-Methylglutaryl-COA Reductase Inhibitors and Phosphodiesterase Type V Inhibitors Attenuate Right Ventricular Pressure and Remodeling in a Rat Model of Pulmonary Hypertension

3-Hydroxy-3-Methylglutaryl-COA Reductase Inhibitors and Phosphodiesterase Type V Inhibitors Attenuate Right Ventricular Pressure and Remodeling in a Rat Model of Pulmonary Hypertension

Phosphodiesterase 5 inhibitors augment UT-15C-stimulated ATP release from erythrocytes of humans with pulmonary arterial hypertension

Combination Therapy With Oral Sildenafil and Beraprost for Pulmonary Arterial Hypertension Associated With CREST Syndrome

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