| The hypoxic pulmonary hypertension (HPH) has been demonstrated to be the key event in the process chronic obstructive pulmonary disease (COPD) to chronic cor pulmonale. It is very important to elucidate the mechanism of HPH and search for new classed of treatment for this debilitating disease. Endothelin-1 (ET-1) may be a crucial mediator in the development of HPH/vascular wall remodeling. Endogenous ET-1 plays a major role in hypoxic pulmonary vasoconstriction/hypertension, right ventricle hypertrophy, and pulmonary vascular remodeling, but further understanding of the molecular mechanism underlying ET-1 remains to be fully established. In addition, potassium channel has been considered to be a useful therapeutic target for management of HPH. However, no desired drugs to date have developed thatATP-sensitive potassium channel opener (KATpCO) is effective in treatment for HPH. Iptkalim hydrochloride (Ipt) is a novel KATPCO supported by pharmacological, biochemical and binding studies. In the present study, the effects of Ipt on ET-1-induced PH and chronic hypoxic pulmonary hypertension (HPH) in rats were investigated so as to evaluate thetherapeutic value and elucidate the mechanism of PH. The study included 3 experiments.Part 1. The effect of KATP opener Iptkalim hydrochloride (Ipt) on pulmonary artery (PA) ring constriction induced by ET-1.AIM: To examine the role of KATpCO activation in ET-1-induced constriction of rat small pulmonary arteries ring with Ipt (a novel KATPCO), Pin (a specific KATPCO) and Gli (a specific KATPCO) antagonist. To support the correlativity of KATP in ET-1-induced constriction of pulmonary artery rings, and investigate the effect of KATp on the pathogenesis of pulmonary hypertension.METHODS: Normal male Sprague-Dawley rats were decapitated, The main pulmonary arteries (PA) were dissected free from connective tissues and cut into cylindrical segments (2-3 mm in width). Then the PA rings were mounted on two stainless steel hooks suspended in Krebs-Henseleit(K-H) solution (composition in mol-L-1: NaCl 122, KC14.73, MgCl2 1.19, NaHCO3 15.5, KH2PO42.25, CaCl2 2.49, and Glucose 11.5, pH 7.4) oxygenated continuously with 95%O2-5%CO2 gas mixture at 37℃ and connected to a force-displacement transducer for tension recording with a resting tension of 800mg and were equilibrated for Ih before the beginning of each experiment. Vascular effects to ET-1 were examined by cumulative application of increasing concentrations of ET-1 in the range 0.05-50nmol-L-1, and concentration-response curves10were obtained. For the study of dilatory responses, PA rings were preconstricted with ET-1, then exposed to cumulative concentrations of Ipt or Pin(10-13 ~ 10-3 mol-L"1) or Gli(10~6 mol-L-1), a specific KAipCO antagonist.Vasodilatory responses to KATPCOs (Ipt or Pin) and Gli were expressed as relaxation percentage of the preconstricted values. EC5o of ET-1 , KATpCOs (Ipt or Pin) and 95% confidence limits(L95), slope B(b), standard error of B(Sb), and correlation coefficient(r) were estimated by Bliss method. Data were presented as mean ?S, and Statistical significance analysis was determined using the analysis of variance (ANOVA)(a p-value<0.05 was considered significant).RESULTS: The concentration-dependent PA constriction was evoked by different ET-1 concentrations in the range 0.05 -50 nmoL-L-1, EC50 values were 10.48 nmoL-L-1. At this concentration, latent period of PA rings constriction was 1.33 ± 0.75 min, the time of reaching peak was 9.5±1.67 min, the time of peak lasting was 12.08 ± 3.54 min. Both Ipt and Pin antagonized vasoconstriction induced by ET-1 with the concentration of 10-1~10-3 nmol-L-1 in a concentration -dependent manner, the EC50 values for dilating PA rings-preconstricted with ET-1 were 5.84 and 3.93 nmol-L-1, while the maximum rate of vasodilatory were 57.36±15.6% and 96.01±8.1%, respectively. There is no difference in the dilating effect between Ipt and Pin in the concentration of 10-13-10-5mol-L-1 (P>0.05), but there is significant difference between...
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