DDCI-01,A Novel Long Acting Phospdiesterase-5 Inhibitor Attenuated Monocrotaline-induced Pulmonary Artery Hypertension In Rats

PART Ⅰ EXPLORE THE EFFECTIVE DOSE OF DDCI-01TO INTERVENE PAH IN RATS MODELBackground : Pulmonary arterial hypertension(PAH)is a kind of progressive and fatal cardiopulmonary vascular disease caused by pulmonary arteriole remodeling and increased pulmonary vascular resistance(PVR),which eventually leads to right heart failure and death.At present,as a widely used drug targeting pulmonary hypertension,5-phosphodiesterase(PDE-5)inhibitor has a significant effect on pulmonary hypertension.DDCI-01 is a new type of long-acting PDE-5inhibitor,which has been approved by the China Food and Drug Administration(China Food and Drug Administration,CFDA)and US Food and Drug Administration(Food and Drug Administration,FDA)in clinical trials for the treatment of erectile dysfunction(Erectile dysfunction,ED),but its effects on pulmonary hypertension is still unknown.Objective:To investigate the effect of DDCI-01 on monocrotaline(MCT)-induced PAH in rats and its possible effective dose,to provide experimental evidences for the clinical treatment of PAH.Methods:twenty-five male SD(Spragye-Dawley)rats aged 6-8 weeks and weighing between 200 and 250 g were randomly divided into control group(n = 5)and monocrotaline group(n = 15).Monocrotaline group was subdivided into monocrotaline group(MCT group)and treatment group: 1DDCI-01 group(n = 5),3 DDCI-01 group(n = 5)and 9 DDCI-01 group(n= 5).SD rats in monocrotaline group were intraperitoneally injected with monocrotaline of 50mg/kg,while those in Control group were intraperitoneally injected with the same dose of normal saline.On the seventh day after monocrotaline injection,the monocrotaline group was given DDCI-01 intragastric early treatment,in which the treatment group was given 1mg/kg/day DDCI-01(1 DDCI-01 group),3mg/kg/day DDCI-01(3 DDCI-01 group)and 9mg/kg/day DDCI-01(9 DDCI-01group).The MCT group administration with same volume of vehicle(0.5% CMC.On the 21 st day after intraperitoneal injection of MCT,the mean pulmonary artery pressure(m PAP)and right ventricular systolic pressure(RVSP)of SD rats were measured by right cardiac catheterization to evaluate the effects of different doses of DDCI-01 on pulmonary hypertension.Results : The m PAP and RVSP measured by right cardiac catheterization in MCT group were higher than those in Control group(m PAP: 31.67 ±1.53 mm Hg vs.17.60 ±1.82 mm Hg;RVSP: 57.33 ±3.22 mm Hg vs.34.40 ±2.07 mm Hg,P < 0.01),suggesting that the model of pulmonary hypertension in rats was successful.There were no significant differences(P > 0.05)in m PAP and RVSP between 1 DDCI-01 group and MCT group,but the hemodynamic indexes m PAP and RVSP in 3 DDCI-01 group and 9 DDCI-01 group were significantly lower than those in MCT group(P < 0.01).Conclusion : The animal model of PAH could be successfully established by intraperitoneal injection of 50mg/kg MCT in rats.Compared with the MCT group,1 mg/kg/day DDCI-01 was not enough to have an effective effect on PAH,but the early intervention effect of 3 mg/kg/day and 9 mg/kg/day DDCI-01 was significant.PART Ⅱ DDCI-01 THE EFFECTS OF EARLY TREATMENT IN RATS WITH PAH AND THE COMPARISON WITH TADALAFILBackground:Tadanafil(TDF),a long-acting PDE-5 inhibitor,is one of the targeted drugs that have been used in the clinical treatment of pulmonary hypertension.DDCI-01 is a tritiated analogue of tadanafil,which replaces methyl groups on nitrogen into amino groups and methylene groups on diphenols are replaced by tritium.As a new type of long-acting PDE-5 inhibitor,the pharmacokinetic results of DDCI-01 showed that it might be superior than Tadanafil,such as Maximum concentration(Cmax)and area under the concentration-time curve(AUC).Its half-life was similar to that of Tadanafil in SD rats.Objective : This part of the experiment was further explored the specific efficacy of DDCI-01 on MCT-induced PAH rats from hemodynamic index,histomorphology,ultrasound index,and cyclic guanosine monophosphate(c GMP)concentration,and compared it with TDF.Results:Compared with the MCT group,both MCT+DDCI-01 3 and9mg/kg/day significantly improved in m PAP(MCT: 30.76 ± 2.44 mm Hg;DDCI-01 3mg/kg/day;21.47 ± 1.43 mm Hg;DDCI-01 9mg/kg/day: 17.46 ±1.37 mm Hg,all P < 0.01);RVSP were reduced(MCT: 51.03 ± 3.90 mm Hg;DDCI-01 3mg/kg/day;39.42 ± 1.43 mm Hg;DDCI-01 9mg/kg/day: 32.86 ±3.38 mm Hg,all P < 0.05);attenuated pulmonary artery medial wall thickness(WT%)(MCT: 69.25 ± 12.54%;DDCI-01 3mg/kg/day: 41.78 ±10.76%;DDCI-01 9mg/kg/day: 27.73 ± 8.41%,all P < 0.01).Compared to the MCT group,the right ventricular hypertrophy(RV/LV+S: the ratio of the right ventricle and the left ventricle plus septum)were improved in the groups who received DDCI-01 3 mg/kg/day(0.41 ± 0.05 vs.0.31 ± 0.03,P<0.01)and 9 mg/kg/day(0.41 ± 0.05 vs.0.26 ± 0.06,P<0.01).The echocardiography data also improved,but no dose dependent.(P < 0.01).In addition,Tadalafil(3mg/kg/day,9mg/kg/day)shown the benefits to MCT induced PAH rats.There was no significance in improvement of PAH between DDCI-01 3mg/kg/day and Tadalafil 3mg/kg/day.However,compared DDCI-01 9mg/kg/day with Tadalafil 9mg/kg/day,there were statistical differences in some aspects,such as m PAP(17.46 ±1.37 vs.19.16 ± 1.01,P < 0.01),WT%(27.73 ± 8.41% vs.36.00 ± 6.45%,P < 0.05),lung c GMP level(6.03 ±0.71 vs.5.32 ± 0.78,P < 0.05)and plasma c GMP level(80.91 ± 6.57 vs.71.92 ± 11.69,P < 0.05).Conclusion : DDCI-01 effectively improve hemodynamic index,decrease the m PAP and RVSP,suppress the pulmonary vessels remodeling and right heart failure in MCT-induced PAH rat model.In addition,high dose(9 mg/kg/day)DDCI-01 might be more beneficial than Tadalafil on PAH.