Suppressive Effect of Prostaglandin E1 on Pulmonary Hypertension Induced by Monocrotaline in Rats

Abstract

The effect of administering prostaglandin E1 (PGE1) on the extent of monocrotaline (MCT)-induced pulmonary hypertension and cytokine production [interleukins (IL) 1 and 6 and tumor necrosis factor (TNF)] by macrophages during MCT induction of pulmonary hypertension was studied. Right ventricle/left ventricle plus septum weight ratios (RV/LV + S) were used as an index of the development of pulmonary hypertension. Administering PGE1 at a dose of 0.2 mg/kg/day for 4 weeks reduced significantly the RV/LV + S ratio from 0.428 +/- 0.070 to 0.243 +/- 0.059 (p < 0.01) and decreased the production of these cytokines: IL-1, from 4.675 +/- 3.558 to 1.800 +/- 0.722 units; IL-6, from 0.322 +/- 0.121 to 0.060 +/- 0.039 units; and TNF, from 0.578 +/- 0.369 to 0.004 +/- 0.004 units. In another series of experiments, a significant reduction of the RV/LV + S ratio was noted for only 1 week when we administered PGE1 immediately after the injection of MCT. We confirmed that histopathologic improvements of lungs were noted by administering 0. 2 mg/kg PGE1 for 4 weeks. In another experiment, PGE1 at a concentration of 2 microg/ml suppressed a rise in the cytosolic Ca2+ concentration of lipopolysaccharide-stimulated peritoneal macrophages of rats in vitro, suggesting that PGE1 suppressed cytokine production by macrophages through the suppression of the Ca2+ influx. These results suggest that administering PGE1 may be effective in the treatment of some forms of pulmonary hypertension in humans.

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

“…In contrast to previous investigations, which investigated the influence of an endothelin antagonist, 16 prostaglandin E 1 , 17 or a PDE 5 inhibitor 19 by coapplication with MCT, we started therapeutic interventions when the development of pulmonary hypertension had already commenced, from weeks 2 to 4, by implantation of osmotic minipumps to deliver agents intravenously. Under these conditions, both iloprost and tolafentrine markedly attenuated the degree of pulmonary hypertension evolving in response to pyrrolizidine.…”

“…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).…”

“…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]…”

“…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.…”

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

“…MCT has repeatedly been employed for inducing chronic PAH in rats, and this model is suitable for testing chronic antiremodelling effects of vasoactive and anti-proliferative agents [29][30][31][32]. Similar to the abnormalities observed in human PAH, MCT provokes proliferation and hypercontraction of vascular SMCs, in particular in small intra-acinary pulmonary arteries and inflammatory sequelae [33,34].…”