n-(1-methylethyl)-1-1-2-trimethylpropylamine and Hypoxia

Hypoxic pulmonary hypertension (HPH) is a serious and potentially devastating chronic disorder of the pulmonary circulation. Attempts to use drugs in the therapy of hypoxic pulmonary hypertension indicated the importance of prevention or reduction of vasoconstriction as well as of the reversal of remodeling within the cardiovascular system. Iptakalim (2,3-dimethyl-N-(1-methylethyl)-2-butylamine), a novel ATP-sensitive potassium channel opener, has the desired effects on hypoxic pulmonary arteries. Iptakalim decreases the elevated mean pressure in pulmonary arteries, and attenuates remodeling in the right ventricle, pulmonary arteries and airways. Moreover, iptakalim has selective antihypertensive effects: it significantly lowers arterial pressure in hypertensive animals, but has little if any effect in normotensive animals. In HPH iptakalim has selective effects on smaller arteries. Long-term iptakalim therapy decreases expression of sulfonylurea receptor 2 and of mRNA of inwardly rectifying potassium channel in smaller arteries of spontaneously hypertensive rats. Iptakalim inhibits the effects of endothelin-1, reduces the intracellular calcium concentration and inhibits the cell cycle in smooth muscle cells of pulmonary arteries. There is no evidence for the development of tolerance to the long-lasting antihypertensive action of iptakalim. At therapeutic doses iptakalim has no effects on the central nervous, respiratory, digestive, or endocrine systems. It has a broad therapeutic range, so that it can be safely used in the therapy of HPH.

Topics: Animals; Antihypertensive Agents; Arteries; Humans; Hypertension, Pulmonary; Hypoxia; KATP Channels; Neovascularization, Pathologic; Potassium Channels, Inwardly Rectifying; Propylamines

To study the selective dilatation effects of iptakalim (Ipt) on basilar and pulmonary arterioles, and endothelial cell function of these arterioles in hypoxic rats.. SD male rats were divided into 2 groups:control and hypoxic group fed in normobaric hypoxic environment (O2 7.8%, 8 h). Arteriole rings about (204 + 5) pm were isolated and the tension of hypoxic arterioles pre-contracted by 6 nmol/L endothelin-1 (ET-1) was observed with wire myograph system model (DMT 610 m). The relaxing response of hypoxic arterioles induced by different concentration of Ipt were detected and endothelial activity was also tested by acetylcholine.. 10(5) mol/L acetylcholine (ACh)-mediated vasodilatation of basilar and pulmonary arterioles was greatly reduced in the hypoxic group than those in control group (P < 0.05). Compared with normal group, a novel ATP-sensitive potassium channel opener Ipt at the concentration ranging from 10(-11) mol/L to 10(3) mol/L, caused stronger dose dependent vasodilatation on hypoxic pulmonary arterioles, and there was no significant difference between control and hypoxic basilar arterioles.. The endothelial function of basilar and pulmonary arterioles was damaged under hypoxic state, and Ipt selectively increased dilatation effects on hypoxic pulmonary arterioles, but not on hypoxic basilar arterioles which could improve high altitude pulmonary edema pathological state and be the novel drug in the treatment of pulmonary hypertension.

Topics: Acetylcholine; Altitude; Altitude Sickness; Animals; Arterioles; Dilatation; Endothelin-1; Hypoxia; KATP Channels; Male; Propylamines; Rats; Vasodilation; Vasodilator Agents

To study the selective dilatation effects of iptakalim (Ipt), a novel ATP-sensitive potassium channel opener, on pulmonary arterioles in hypoxic pulmonary hypertensive rat.. SD male rats were divided into 3 groups, control group, the rest were fed in hypoxic and normobaric environment (O2 10% +/- 0.5%, 8 h/d and 6 d/week) and divided into hypoxia group and hypoxia plus acetazolamide (Acz) group (hypoxic rats were treated with ig acetazolamide (Acz) 80 mg x kg(-1) d(-1)) . After 12 weeks, pulmonary arteriole rings about (197 +/- 4) microm were isolated and the tension of hypoxic pulmonary arterioles pre-contracted by 6 nmol/L endothelin-1 (FT-1) was observed with wire myograph system model (DMT 610 m). The relaxing response of hypoxic pulmonary arterioles induced by different concentration of Ipt were detected and endothelial activity was also tested by acetylcholine.. 10(-5) mol/L acetylcholine (ACh)-mediated vasodilatation was greatly reduced in the hypoxic group than those in control group (P < 0.01) and there was no significant difference between Acz treatment group and control group (P > 0.05). Ipt at the concentration ranging from 10(-11) mol/L to 10(-4) mol/L, caused dose dependent vasodilation on both hypoxic pulmonary arterioles and Acz treatment group (P > 0.05), but not on normal group.. The endothelial function of pulmonary arterioles was damaged under hypoxic pulmonary hypertensive state, and Ipt showed selective dilatation effects on hypoxic pulmonary arterioles. Acz could improve the dysfunction of endothelial cells induced by hypoxic pulmonary hypertensive state, which didn't affect the selective dilatation effects of Ipt on hypoxic pulmonary arterioles.

Topics: Acetazolamide; Animals; Arterioles; Hypertension, Pulmonary; Hypoxia; Male; Propylamines; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Vasodilator Agents

Hypoxic pulmonary hypertension (HPH) is a syndrome characterized by the increase of pulmonary vascular tone and the structural remodeling of peripheral pulmonary arteries. The aim of specific therapies for hypoxic pulmonary hypertension is to reduce pulmonary vascular resistance, reverse pulmonary vascular remodeling, and thereby improving right ventricular function. Iptakalim, a lipophilic para-amino compound with a low molecular weight, has been demonstrated to be a new selective ATP-sensitive potassium (K(ATP)) channel opener via pharmacological, electrophysiological, biochemical studies, and receptor binding tests. In hypoxia-induced animal models, iptakalim decreases the elevated mean pressure in pulmonary arteries, and attenuates remodeling in the right ventricle, pulmonary arteries and airways. Furthermore, iptakalim has selective antihypertensive effects, selective vasorelaxation effects on smaller arteries, and protective effects on endothelial cells, but no effects on the central nervous, respiratory, digestive or endocrine systems at therapeutic dose. Our previous studies demonstrated that iptakalim inhibited the effects of endothelin-1, reduced the intracellular calcium concentration and inhibited the proliferation of pulmonary artery smooth muscle cells. Since iptakalim has been shown safe and effective in both experimental animal models and phase I clinical trials, it can be a potential candidate of HPH in the future.

Topics: Animals; Antihypertensive Agents; Calcium; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Hypoxia; KATP Channels; Myocytes, Smooth Muscle; Propylamines; Pulmonary Artery

To explore the effects of iptkalim on myocardial enzymes and free radicals metabolism with hypoxic pulmonary hypertension (HPH), in order to provide evidence for the mechanism of iptkalim on clinical treat.. 110 young men stayed at high altitude above 5 000 m were divided into iptkalim group (n = 74) and placebo group (n = 36), aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (gamma-GT), creatine kinase (CK), lactate dehydrogenase (LDH), superoxide dismutase (SOD), malonaldehyde (MDA), nitric oxide(NO) and nitric oxide synthase(NOS) were detected before and after took medicines for 6 mouths.. After took medication for 6 mouths, ALT, AST, gamma-GT, CK and LDH were reduced, SOD, NO, and NOS were increased, MDA were reduced, there were very significant difference (P < 0.05).. Oxygen free radicals have taken part in the process of HPH, iptkalim have the effect of anti-peroxidation of lipid and protect myocardial cells stress injured by hypoxia which related with mitochondrial membrane and cell membrane's K(ATP) channel activation.

Topics: Adolescent; Adult; Altitude; Creatine Kinase; Free Radicals; Humans; Hypertension, Pulmonary; Hypoxia; L-Lactate Dehydrogenase; Male; Myocardium; Potassium Channels; Propylamines; Young Adult

Topics: Animals; Blood Glucose; Body Weight; Chronic Disease; Female; Hypoxia; KATP Channels; Male; Propylamines; Protective Agents; Rats; Rats, Sprague-Dawley

To investigate whether pulmonary vascular remodeling in hypoxic pulmonary hypertensive rats could be prevented by treatment with a selective K(ATP)CO, iptkalim (Ipt).. Rats were fed in hypoxic and normobaric environment (10% +/- 0.5% O2, 8 h/day and 6 day/week) and divided into control group, hypoxia group (hypoxic rat treated with ig NS 5.0 ml x kg(-1) x d(-1)), treated group I (hypoxic rat treated with ig Ipt 0.75 mg x kg(-1) x d(-1)), treated group II (hypoxic rat treated with ig Ipt 1.5 mg x kg(-1) x d(-1)). After 4 wk, the mean pulmonary arterial pressure (mPAP), right ventricle/left ventricle and septum [RV/(LV + S)] were measured, and the small pulmonary arterial morphologic changes were observed with morphometric analysis under microscopes in four groups.. The level of mPAP and RV/(LV+ S) was significantly higher in the hypoxic group than those in control group (P < 0.01). Morphometric analysis revealed that the ratio of vascular medial wall thickness to external diameter (MT%) and the ratio of vascular medial cross-sectional area to total arterial cross-sectional area (MA%) were also significantly increased in the hypoxic group than those in control group (P < 0.01) and the ratio of vessel lumen cross-sectional area to total arterial cross-sectional area (VA%) was significantly lower in the hypoxic group than those in control group (P < 0.01). Ipt 0.75 mg x kg(-1) x d(-1) or 1.5 mg x kg(-1) x d(-1) decreased the level of mPAP(mmHg), RV/(LV+ S), and inhibited the small pulmonary arterial remodeling significantly. Ipt 1.5 mg x kg(-1) x d(-1) reversed all pathological indices.. K(ATP)CO iptkalim can be a very promising candidate for the treatment of hypoxic pulmonary hypertension.

Topics: Animals; Hypertension, Pulmonary; Hypoxia; KATP Channels; Male; Propylamines; Rats; Rats, Sprague-Dawley