Study On Experimental Therapeutics Of Novel ATP-sensitive Potassium Channel Opener, Iptakalim, In Pulmonary Hypertension

Chronic obstructive pulmonary disease (COPD) and hypoxic pulmonary hypertension (HPH) are the common cause of hospital admissions. HPH has been demonstrated to be the key event in the process of COPD to chronic cor pulmonale. There is still no ideal treatment for HPH and alternatives are still required. It is very important to elucidate the mechanism of HPH and search for one new treatment for this debilitating disease. The plasmalemmal K channels in pulmonary arterial smooth muscle cells (SMCs) may play a unique and important role in the regulation of pulmonary vasoconstriction and vascular remodeling.There are at least three types of K channels in pulmonary arterial SMCs: (1) voltage-gated K (Kv) channels, (2) Ca-activated K(Kca ) channels, and (3) ATP-sensitive K(KATP ) channels. Among them, KATP channels are now thought to play an important role as mediators of the response of vascular smooth muscle to a variety of pharmacological and endogenous vasodilators. They play important roles in the physiology and pathophysiology of vascular SMCs by coupling the metabolic state of the cell to its electrical activity.Nitric oxide relaxes vascular SMCs by activation of KATP channels. The cellular signalling pathway in this case presumably involves GMP, which activates PKG. Other endogenous vasodilators such as prostacylin, calcitonin gene-related peptide, vasoactive intestinal polypeptide, adrenomedullin and adenosine activate KATP channels by stimulating the formation of cAMP and increasing the activity of PKA. Part of the mechanism of contraction of endogenous vasoconstrictors such as endothelin-1, angiotensin II and vasopressin is due to inhibition of KATP channels via PKC activity. Furthermore, vasoconstrictors may inhibit KATP channels by inhibiting PKA activity.KATP channels represent potential therapeutic targets for control of abnormal vascular contractility. Although KATP channel openers are considered as a trend in management of HPH, there are no desired candidates with selective effects on pulmonary arterial SMCs. Iptakalim designed and synthesized by native researchers is a fatty para-amino compound with low molecular weight. It has been confirmed by substantial pharmacological, biochemical, and electrophysiological studies as well as receptor-combining test as a newly selective KATP channel opener. In the present study, the effects of iptakalim on pulmonary hypertension were explored so as to evaluate its therapeutic value and elucidate the mechanism of pulmonary hypertension. The study included following 5 experiments.Part I The effects of iptakalim on pulmonary hypertensioninduced by ET-1 in ratsAIM To investigate the effects of iptakalim on ET-1-induced pulmonary hypertension in rats. METHODS The effects of iptakalim, administered by cumulative method, on vasoconstriction mediated by ET-1 were studied in pulmonary arterial rings from rats. The rat model of pulmonary hypertension was prepared by infusing ET-1 through pulmonary artery. The mean pulmonary arterial pressure (mPAP), heart rate (HR) and systemic blood pressure were monitored by a polygraph. RESULTS ET-1 0.05 ~ 50 nmol.L-1 induced constriction of pulmonary arterial rings in a concentration-dependent manner, EC50 values (95% confidence limits) were 10.48 (9.07-12.11) nmol.L-1 . Slope B and standard error of B were 0.82 and 0.085, respectively. The correlation coefficient of cumulative concentration-response curve was 0.97. Iptakalim antagonized vasoconstriction induced by ET-1 in a concentration-dependent manner. The IC50 value for dilating pulmonary arterial rings-preconstricted with ET-1 was 5.84 nmol.L-1, while the IC95 value was 2.65 nmolL. ET-1 infused by pulmonary artery induced acute pulmonary hypertension. Pre-treatment rats with iptakalim (1.0 mg-kg or 0.5 mgkg) blocked pulmonary hypertension. The prevention of ET-1-induced pulmonary hypertension afforded by iptakalim was abolished by glibenclimide, a KATP channel inhibitor. After-treatment rats with iptakalim (1.0 mgkg) inhibited pulmonary hypertension induced by ET-1. CONCL...