The Time-course Curve Of Pulmonary Artery Contraction Induced By TRPC1 And The Effects Induced By TRPV4 In Monocrotaline-induced Pulmonary Hypertension Rats

Objective: This study aim to discuss the function and the pathophysiology significance of TRPC1 and TRPV4 in monocrotaline (MCT)-induced pulmonary artery hypertension (PAH).Methods: PAH was induced in SD rats by a single intraperitoneal injection of MCT at a dose of 60 mg/kg. The following indexes are measured:①mean right ventricular pressure (mRVP);②right ventricular systolic pressure (RVSP);③systemic Arterial Pressure (SAP);④right ventricular mass index (RVMI) = 100%left ventricle)v septum)r(igh LtV v e+n riecnlet r(iRclVe )(S×;⑤Lung sections (HE stained) are observed under lightmicroscope for pathological right venriclechanges, counting the ratios of cross-sectional area and total area,wall and radius in 50~100μm and 101~150μm;⑥Timetable of cyclopiazonic acid (CPA)-induced PAs contract tensions;⑦4α-PDD dose-dependent relaxation curve;⑧4α-PDD-induced Ca2+ entry transient.Results: In comparison to CON,①mRVP,RVSP and RVMI were markedly elevated in MCT (P<0.01);②In MCT rats, the thickness of pulmonary vascular smooth muscles was increased, the cross-sectional area of PAs is diminished, and the radio was markedly raduced in MCT (P<0.01). But the radio of wall and radius was markedly increased (P<0.01);③The application of CPA caused dramatic increase in PAs contraction. In MCT (P<0.01), its timetable, on the whole, from the third day, the contraction increased strikingly about 1.5 times compare with CON (P<0.01), and reached the peak in the fourteenth day, then sustained on the high level. From the twenty-first day, the increasement began decrease, but the contraction in the twenty-first day was 7.5 times compared with the CON (P<0.01). Application of CPA to deplete Ca2+ stores caused dramatic increase in PAs contraction (P<0.01);④MCT significantly potentiated the effect of 4α-PDD (1 nmol/L~3μmol/L) on PAs vasodilatatioin in a dose-dependent manner,the relaxations were respectively -9.12%±1.58% in 1μmol/L4α-PDD(P<0.01) and -10.08%±1.61% in 3μmol/L 4α-PDD (P<0.01);⑤The ratio of Fluo-3 fluorescence signal induced by 4α-PDD were significantly enhanced in PASMCs, from 0.53±0.21 to 1.69±0.96 (P<0.05) .Conclusion:①In third week MCT can induce PAH and caused right ventricle and PAs remodeling in SD rats. And that different diameters of pulmonary artery , the thickness of smooth muscle was well-distributed proliferation in pulmonary artery hypertension ;②MCT can enhance the function of TRPC1/SOCC mediated vasoconstriction in the early period (in first week);③In third week MCT can increased vascular dose-dependently relaxation response to 4α-PDD/TRPV4. But 4α-PDD- induced [Ca2+]i was markedly increased in MCT PASMCs.This study provides pathophysiological evidences for TRPC1/TRPV4 as targets of treating PAH-related diseases.