Antithrombotic Profile of Iloprost in Experimental Models of Arterial and Venous Thrombosis

Witt, Werner; Baldus, B.; Müller, B.

doi:10.1007/978-3-642-71499-3_10

Cited by 8 publications

(12 citation statements)

References 9 publications

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“…When administered from days 14 to 28, this intervention fully normalized pulmonary artery pressure and completely prevented right heart hypertrophy and pulmonary vascular remodeling. For iloprost, such reasoning is well in line with its antithrombotic effects 20 and with in vitro findings of an antiproliferative effect on pulmonary vascular smooth muscle cells. 21 Moreover, recent long-term clinical studies with iloprost inhalation in patients with severe pulmonary artery hypertension strongly support the notion that, next to its pulmonary vasodilatory efficacy, this agent possesses antiremodeling effects in the lung vasculature.…”

Section: Discussionmentioning

confidence: 48%

“…The most effective approach was the combination of iloprost and tolafentrine, which resulted in complete normalization of RVSP (25Ϯ1 mm Hg) with even increased cardiac index. This was also true for right heart hypertrophy, which decreased in response to both iloprost and tolafentrine treatment (ILO [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] Systemic arterial pressure did not change significantly. The decrease in arterial PO 2 in response to MCT treatment was fully normalized in the iloprost/tolafentrine-treated animals ( Figure 2).…”

Section: Treatment From Days 14 To 28mentioning

confidence: 99%

“…A total of 80%, 90%, and 100% of animals survived the 28-day period in the iloprost, tolafentrine, and combined-therapy groups. Protein content of MMP-2 and MMP-9, as well as gelatinolytic activities, decreased in the treatment groups, most impressively in the Tola/ILO 1 [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] group, in which normal values were reached for the MMP-2 and MMP-9 expression ( Figure 5B). As depicted in Figure 4A, a significant decrease in the presence of muscularized peripheral pulmonary arteries was achieved by all treatment protocols.…”

Section: Treatment From Days 14 To 28mentioning

confidence: 99%

“…The following six groups were studied, four with early intervention or sham intervention and two with late intervention or sham intervention: group ILO 14-28 (8.3 ng/kg per minute from day 14 to day 28), group Tola [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] (625 ng/kg per minute), group Tola/ILO 1 [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] (625/8.3 ng/kg per minute), group Tola/ILO 2 [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] (625/8.3 ng/kg per minute from day 28 to 42), group saline 14-28 (5 L/h), and group saline [28][29][30][31][32][33]…”

Section: Experimental Protocolsmentioning

confidence: 99%

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Antiremodeling Effects of Iloprost and the Dual-Selective Phosphodiesterase 3/4 Inhibitor Tolafentrine in Chronic Experimental Pulmonary Hypertension

Schermuly

Kreisselmeier

Ghofrani

et al. 2004

Circulation Research

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Abstract-Severe pulmonary hypertension is a disabling disease with high mortality. We investigated acute and chronic effects of iloprost, a long-acting prostacyclin analogue, and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in monocrotaline-induced pulmonary hypertension in rats. Twenty-eight and 42 days after administration of the alkaloid, right ventricular systolic pressure increased from 25.8Ϯ2.0 to 62.9Ϯ3.4 and 70.5Ϯ7.4 mm Hg, with concomitant decline in cardiac index, central venous oxygen saturation, and arterial oxygenation. Marked right heart hypertrophy was demonstrated by the strongly elevated ratio of right ventricle/left ventricle plus septum weight, and massive thickening of the precapillary artery smooth muscle layer was shown histologically. Western blot analysis demonstrated increased levels of matrix metalloproteinases (MMPs) -2 and -9 and increased gelatinolytic activities in isolated pulmonary arteries. In these animals, both intravenous iloprost and tolafentrine displayed characteristic features of pulmonary vasodilators. When chronically infused from days 14 to 28, both agents significantly attenuated all monocrotaline-induced hemodynamic and gas exchange abnormalities as well as right heart hypertrophy. Full normalization of all variables including right ventricle size was achieved on combined administration of both agents during this period. This was also true for MMP-2 and MMP-9 expression and activity. Moreover, when iloprost plus tolafentrine was used for late therapeutic intervention, with infusion from days 28 to 42 after full establishment of severe pulmonary hypertension and cor pulmonale, hemodynamic, gas exchange, and cardiac and pulmonary vascular remodeling changes were significantly reversed. We conclude that the combined administration of iloprost and a dual-selective phosphodiesterase 3/4 inhibitor prevents and reverses the development of pulmonary hypertension and cor pulmonale in response to monocrotaline in rats. This regimen may therefore offer a possible antiremodeling therapy in severe pulmonary hypertension. Key Words: iloprost Ⅲ pulmonary hypertension Ⅲ monocrotaline Ⅲ phosphodiesterase Ⅲ tolafentrine P ulmonary arterial hypertension (PAH) is a severe disabling disease characterized by elevation of pulmonary artery pressure and death attributable to circulatory failure. 1,2 Predominant features of the pathology of PAH include intimal lesions, medial hypertrophy, and adventitial thickening of precapillary pulmonary arteries and right ventricular hypertrophy. Imbalances of vasodilatory and vasoconstrictor agents have been implicated in both the predominance of increased vasomotor tone and the chronic remodeling of resistance vessels, including vascular smooth muscle cell growth. In patients with primary pulmonary hypertension, a reduced excretion of prostaglandin and an enhanced excretion of thromboxane metabolites has been noted. 3 Moreover, enhanced activities of phosphodiesterases (PDEs), which hydrolyze the prostaglandin-and NO-induced second mes...

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Section: Discussionmentioning

confidence: 48%

Section: Treatment From Days 14 To 28mentioning

confidence: 99%

Section: Treatment From Days 14 To 28mentioning

confidence: 99%

Section: Experimental Protocolsmentioning

confidence: 99%

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Antiremodeling Effects of Iloprost and the Dual-Selective Phosphodiesterase 3/4 Inhibitor Tolafentrine in Chronic Experimental Pulmonary Hypertension

Schermuly

Kreisselmeier

Ghofrani

et al. 2004

Circulation Research

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“…The mixed selective PDE-3/4 inhibitor tolafentrine was particularly potent in this respect, and long-term infusion of tolafentrine in combination with the prostacyclin mimetic iloprost was shown to suppress the pulmonary artery pressure increase in response to monocrotaline (MCT) in rats [4]. However, since iloprost is a stable prostacyclin analogue with strong vasodilatory [23] and antithrombotic [24] properties it is impossible to differentiate the effects on vascular remodelling between the two compounds. In the present study, these investigations were extended further by asking whether the sole prolonged administration of the orally bioavailable combined selective PDE-3/4 inhibitor pumafentrine would reverse pulmonary hypertension in the MCT model.…”

mentioning

confidence: 99%

Partial reversal of experimental pulmonary hypertension by phosphodiesterase-3/4 inhibition

Dony¹,

Lai²,

Dumitrascu³

et al. 2008

European Respiratory Journal

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Phosphodiesterase (PDE) inhibitors are currently under investigation for the therapy of pulmonary hypertension.The present study was designed to investigate chronic effects of oral pumafentrine, a mixed selective PDE-3/4 inhibitor, in monocrotaline (MCT)-induced pulmonary hypertension in rats.Treatment with pumafentrine (10 mg?kg -1 daily) from week 4 to 6 after a single injection of MCT (60 mg?kg -1 ) partially reversed pulmonary hypertension and right heart hypertrophy in rats. In addition, small pulmonary arterial muscularisation, media hypertrophy and decrease in lumen area were largely reversed. Inhibition of smooth muscle proliferation under pumafentrine was demonstrated in vivo as was a pro-apoptotic effect of pumafentrine on vascular cells. Moreover, pumafentrine dose-dependently increased cyclic adenosine monophosphate levels and inhibited proliferation of cultured pulmonary arterial smooth muscle cells.In conclusion, oral pumafentrine partially reverses monocrotaline-induced pulmonary hypertension, lung vascular remodelling and right heart hypertrophy in rats.

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New approaches for the assessment of platelet activation status in thrombus under flow condition using confocal microscopy

Marcińczyk

Golaszewska

Misztal

et al. 2019

Naunyn-Schmiedeberg's Arch Pharmacol

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Antithrombotic Profile of Iloprost in Experimental Models of Arterial and Venous Thrombosis

Cited by 8 publications

References 9 publications

Antiremodeling Effects of Iloprost and the Dual-Selective Phosphodiesterase 3/4 Inhibitor Tolafentrine in Chronic Experimental Pulmonary Hypertension

Antiremodeling Effects of Iloprost and the Dual-Selective Phosphodiesterase 3/4 Inhibitor Tolafentrine in Chronic Experimental Pulmonary Hypertension

Partial reversal of experimental pulmonary hypertension by phosphodiesterase-3/4 inhibition

New approaches for the assessment of platelet activation status in thrombus under flow condition using confocal microscopy

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