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

Hypertension is the most common cardiovascular disease. The discovery of the antihypertensive action of adenosine triphosphate-sensitive potassium (K(ATP)) channel openers was a significant advance in the treatment of hypertension. Iptakalim is a novel K(ATP) channel opener with a unique chemical structure that differs from other K(ATP) openers. Among the 3 different subtypes of K(ATP) channels heterologously expressed in human embryonic kidney cells and Xenopus oocytes, iptakalim exhibits significant selectivity for SUR2B/Kir6.1 channels, mild effects on SUR2A/Kir6.2 channels, and fails to open SUR1/Kir6.2 channels. Iptakalim is a more potent activator of the SUR2B/Kir6.1 subtype of K(ATP) channels than diazoxide and pinacidil, the 2 most commonly studied K(ATP) channel openers. Iptakalim selectively produces arteriolar vasodilation with essentially no effect on the capacitance vessels. It can preferentially relax arterioles and small arteries, without affecting large arteries. Furthermore, iptakalim strongly lowers the blood pressure of hypertensive rodents and humans but has little effect on normotensive rodents and humans. Selective antihypertensive action is not observed with pinacidil or diazoxide and may be due to the high selectivity of iptakalim for the SUR2B/Kir6.1 subtype of K(ATP) channels, as well as its selective relaxation of resistance vessels. In pulmonary arterial smooth muscle cells, iptakalim inhibits the increase of cytoplasmic free Ca2+ concentration, as well as cell proliferation induced by endothelin-1. Furthermore, iptakalim has exerted protective effects against hypertensive damage to target organs in rats and improves endothelial dysfunction associated with cardiovascular diseases by selective activation of the SUR2B/Kir6.1 subtype of K(ATP) channels expressed in the endothelium. Clinical trials of iptakalim in the treatment of mild-moderate hypertension have been completed in China. In additional to strong antihypertensive efficacy, iptakalim seems to have a favorable safety and tolerability profile. Iptakalim is a promising new generation antihypertensive drug.

Topics: Animals; Antihypertensive Agents; Humans; Hypertension; KATP Channels; Potassium Channels, Inwardly Rectifying; Propylamines

To study the relationship between the antihypertensive response of iptakalim and KCNJ11 polymorphisms in Chinese Han hypertensive patients.. One hundred sixty two Chinese Han hypertensive patients were administered iptakalim (5 or 10 mg/d, po) for 8 weeks. Before the treatment and 24 h after completing the treatment blood pressure (BP) was measured. Genotyping was performed using direct sequencing.. Four common A190A, E23K, I337V and 3'UTR +62 G/A polymorphisms were found in KCNJ11. The E23K, I337V and 3'UTR +62 G/A polymorphisms were in complete linkage disequilibrium, and I337V was used as a representative. There were no significant differences in age, body mass index, sex, baseline systolic BP (SBP) and diastolic BP (DBP) among the 3 genotypes for the four polymorphisms. Significant association was found between SBP response and the polymorphisms (adjusted regression coefficient: 3.5 [1.2] mmHg; P=0.003 for the A190A polymorphism; adjusted regression coefficient: 3.1 [1.2] mmHg; P=0.012 for the I337V polymorphism). The patients with TT genotype for A190A polymorphism had higher clinical efficacy than those with CC genotype.. The results suggest the KCNJ11 polymorphisms are associated with the SBP-lowering response of short-term iptakalim therapy in Chinese Han hypertensive patients.

Topics: Adult; Aged; Alleles; Antihypertensive Agents; Asian People; Double-Blind Method; Female; Genotype; Humans; Hypertension; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Single Nucleotide; Potassium Channels, Inwardly Rectifying; Propylamines

The primary object of this fundamental research was to survey the synergistic cardiovascular effects of iptakalim, a novel ATP-sensitive potassium channel (K(ATP)) opener, and clinical first-line antihypertensive drugs, such as calcium antagonists, thiazide diuretics and β receptor blockers by a 2 x 2 factorial-design experiment. It would provide a theoretical basis for the development of new combined antihypertensive therapy program after iptakalim is applied to the clinic. Amlodipine besylate, hydrochlorothiazide and propranolol were chosen as clinical first-line antihypertensive drugs. Blood pressure, heart rate (HR) and cardiac functions were observed in anesthetized normal rats by an eight-channel physiological recorder. The results showed that iptakalim monotherapy in a low dose could produce significant antihypertensive effect. There was no interaction between iptakalim and amlodipine on the maximal changes of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MABP), the left ventricular systolic pressure (LVSP), and the left ventricular end-diastolic pressure (LVEDP) (P > 0.05). However, the effects of combination iptakalim/amlodipine on the maximal changes of SBP, DBP, MABP, LVSP and LVEDP were more obvious than those of iptakalim or amlodipine monotherapy. And there was strong positive interaction between iptakalim and amlodipine on the maximal changes of HR (P>0.05). According to the maximal changes of DBP, MABP, LVSP and LVEDP (P < 0.05) of combination iptakalim with hydrochlorothiazide, there was strong positive interaction between them. But there was no interaction between iptakalim and hydrochlorothiazide on the maximal drop of SBP and HR (P > 0.05). According to the maximal drops of DBP, MABP of combination iptakalim with propranolol, there was strong positive interaction between them (P < 0.05). But there was no interaction between iptakalim and propranolol on the maximal changes of SBP, LVSP, LVEDP and HR (P > 0.05). In conclusion, it was the first time to study the effects of amlodipine, hydrochlorothiazide or propranolol, which had different mechanisms of action from iptakalim, on cardiovascular effects of iptakalim in anesthetized normal rats. This study proved that the combination of iptakalim with hydrochlorothiazide or propranolol respectively had significant synergism on lowering blood pressure, while the combination of iptakalim/amlodipine had additive action on lowering blood pressure. M

Topics: Amlodipine; Animals; Antihypertensive Agents; Blood Pressure; Drug Synergism; Heart Rate; Hydrochlorothiazide; Hypertension; Propranolol; Propylamines; Rats

To investigate the effects of iptakalim on endothelial dysfunction induced by insulin resistance (IR) and to determine whether iptakalim improved IR associated with hypertension in fructose-fed rats (FFRs) and spontaneously hypertensive rats (SHRs).. Human umbilical vein endothelial cells (HUVECs) were used for in vitro study. The levels of endothelial vasoactive mediators and eNOS protein expression were determined using radioimmunoassays, ELISAs, colorimetric assays or Western blotting. Sprague-Dawley rats were fed with a high-fructose diet. In both FFRs and SHRs, tail-cuff method was used to measure systolic blood pressure (SBP), and hyperinsulinemic- euglycemic clamp was used to evaluate IR states.. (1) Cultured HUVECs incubated with the PI3-kinase inhibitor wortmannin (50 nmol/L) and insulin (100 nmol/L) induced endothelial dysfunction characterized by significantly reduced release of NO and expression of eNOS protein, and significantly increased production of ET-1. Pretreatment with iptakalim (0.1-10 μmol/L) could prevent the endothelial dysfunction. (2) In FFRs, the levels of SBP, fasting plasma glucose and insulin were significantly elevated, whereas the glucose infusion rate (GIR) and insulin sensitive index (ISI) were significantly decreased, and the endothelium-dependent vascular relaxation response to ACh was impaired. These changes could be prevented by oral administration of iptakalim (1, 3, or 9 mg·kg(-1)·d(-1), for 4 weeks). The imbalance between serum NO and ET-1 was also ameliorated by iptakalim. (3) In 2-4 month-old SHRs (IR was established at the age of 4 months), oral administration of iptakalim (1, 3, or 9 mg·kg(-1)·d(-1), for 8 weeks) significantly ameliorated hypertension and increased the GIR to the normal level.. These results demonstrate that iptakalim could protect against IR-induced endothelial dysfunction, and ameliorate IR associated with hypertension, possibly via restoring the balance between NO and ET-1 signaling.

Topics: Animals; Cells, Cultured; Endothelium, Vascular; Humans; Hypertension; Insulin Resistance; KATP Channels; Male; Propylamines; Radioimmunoassay; Rats; Rats, Inbred SHR

To study the effects of iptakalim (IPT) on pressure-overload induced cardiac remodeling in rats, and investigate correlation between this protection effects and plasma PGI2 content.. The pressure-overload induced cardiac remodeling model was induced by abdominal aorta constriction for 6 weeks, and the rats were divided into 5 groups repectively: (1) sham group, (2) control group, (3) IPT 3 mg/kg group (IPT 3), (4) indomethacin 2 mg/kg group (Indo 2), (5) indomethacin 2 mg/kg + IPT 3 mg/kg group (Indo 2 + IPT 3). RM6000 eight channel physiological recorder was used to record haemodynamics index, heart weight was weighed and the cardiac remodeling index was calculated, HE stain and Masson's stain were employed to perform histological analysis, colorimetric method was used to detect the hydroxyproline content in cardiac tissue, radioimmunological method was used to measure the plasma PGI2 content.. After 42 days of aortic banding, the hyperdynamic circulation state, cardiac remodeling and decreased plasma PGI2 content were observed in the model group compared with those in the sham group, which were effectively reserved by treatment with IPT 3 mg/kg. Single-use indomethacin led to further deterioration of this pathophysiological changes, however, combination administration of IPT 3 mg/kg prevented these from worsening characteristic by ameliorating hyperdynamic circulation state and cardiac remodeling, augmnent plasma PGI2 content.. IPT can significantly reverse abdominal aorta binding/pressure-overload induced cardiac remodeling, its mechanism may contribute to binding K(ATP) channel in endothelial cells, ameliorating endothelium cells function, augmenting PGI2 synthesis and secretion.

Topics: Animals; Aorta, Abdominal; Constriction; Endothelium, Vascular; Epoprostenol; Hypertension; KATP Channels; Male; Propylamines; Rats; Ventricular Remodeling

We investigated the effects of iptakalim, a new ATP-sensitive potassium channel (K(ATP)) opener providing endothelial protection, on the progression of cardiac hypertrophy to failure in a rat model of pressure overloading caused by abdominal aortic banding (AAB). Endothelial dysfunction is central to cardiac hypertrophy and failure induced by pressure overload. It would be useful to clarify whether iptakalim could prevent this.. The effects of pressure overload were assessed in male Sprague-Dawley rats 6 weeks after AAB using progression of cardiac hypertrophy to heart failure as the endpoint. The AAB-treated rats had significantly elevated blood pressure, systolic and diastolic cardiac dysfunction, evidence of left ventricular hypertrophy (LVH), and transition to heart failure. LVH was characterized by increases in the ratios of heart and left ventricular weights to body weight, increased myocyte cross-sectional areas, myocardial and perivascular fibrosis, and elevated cardiac hydroxyproline. These could be prevented by treatment with iptakalim at daily oral doses of 1, 3, and 9 mg/kg for 6 weeks. Progression to cardiac failure, demonstrated by increases in relative lung and right ventricular weights, cardiac function disorders and overexpression of atrial and B-type natriuretic peptide mRNA, could also be prevented. The downregulated nitric oxide signalling system was enhanced, whereas the upregulated endothelin signalling system was inhibited, resulting in normalization of the balance between these two systems.. Iptakalim protected the endothelium and prevented progression of cardiac hypertrophy to failure induced by a pressure overload.

Topics: Animals; Aorta, Abdominal; Atrial Natriuretic Factor; Blood Pressure; Cardiovascular Agents; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Fibrosis; Heart Failure; Heart Rate; Hydroxyproline; Hypertension; Hypertrophy, Left Ventricular; KATP Channels; Male; Myocardium; Natriuretic Peptide, Brain; Nitric Oxide; Propylamines; Rats; Rats, Sprague-Dawley; Signal Transduction; Time Factors; Ventricular Remodeling

Topics: Animals; Cardiovascular Agents; Disease Progression; Endothelin-1; Endothelium, Vascular; Fibrosis; Heart Failure; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; KATP Channels; Mice; Myocardium; Nitric Oxide; Propylamines; Signal Transduction; Ventricular Remodeling

It has been demonstrated that hyperuricemia induces reno-cardiovascular damage resulting in hypertension and renal injury because of vascular endothelial dysfunction. The pathogenesis of hyperuricemia, endothelial dysfunction, hypertension, and renal injury is progressive, and develops into a vicious cycle. It is reasonable to suggest that an antihypertensive drug with endothelial protection may block this vicious cycle. Iptakalim, a novel antihypertensive drug undergoing phase-three clinical trials, is a new ATP-sensitive potassium channel opener and can ameliorate endothelial dysfunction. We hypothesized that iptakalim could prevent hypertension and retard the pathogenesis of endothelial dysfunction and renal injury in hyperuricemic rats.. In rats with hyperuricemia induced by 2% oxonic acid and 0.1 mmol/l uric acid, iptakalim prevented increases in systolic blood pressure, reduced the impairment of endothelial vasodilator function, and attenuated renal dysfunction and pathological changes in glomerular and renal interstitial tissue at 0.5, 1.5, and 4.5 mg/kg orally daily for 4 weeks. Serum levels of nitric oxide and prostacyclin, and gene expression of endothelial nitric oxide synthase in the aortic and intrarenal tissue, were increased, whereas the serum levels of endothelin-1 and gene expression of endothelin-1 in aortic and intrarenal tissue were decreased. However, serum levels of angiotensin II and renin remained unchanged in the hyperuricemic rats treated with iptakalim. In cultured rat aortic endothelial cells, amelioration of endothelial dysfunction by iptakalim was suggested by inhibition of the overexpression of intercellular adhesive molecule-1, vascular cell adhesive molecule-1, and monocyte chemoattractant protein-1 mRNA induced by uric acid, and reversal of the inhibitory effects of uric acid on nitric oxide release in a concentration-dependent manner, which could be abolished by pretreatment with glibenclamide, an ATP-sensitive potassium channel blocker. Iptakalim ameliorated hyperuricemia in this rat model by decreasing renal damage through its antihypertensive and endothelial protective properties, and it had no direct effects on anabolism, catabolism and excretion of uric acid.. These findings suggest that the activation of ATP-sensitive potassium channels by iptakalim can protect endothelial function against hypertension and renal injury induced by hyperuricemia. Iptakalim is suitable for use in hypertensive individuals with hyperuricemia.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin II; Angiotensins; Animals; Cells, Cultured; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Hypertension; Hyperuricemia; KATP Channels; Kidney; Kidney Diseases; Male; Nitric Oxide; Oxonic Acid; Propylamines; Rats; Rats, Sprague-Dawley; Urate Oxidase; Uric Acid; Xanthine Oxidase

The effects of iptakalim, a new ATP-sensitive potassium channel opener, were studied in spontaneously hypertensive rats (SHR). Treatment of 12-week-old male SHR (six animals in each group) with iptakalim by gastric lavage at doses of 1, 3, or 9 mg/kg/day for 12 weeks resulted in a lowering of blood pressure. Iptakalim provided significant renoprotection to SHR rats as measured by decreased proteinuria and improved renal function. Histological evidence demonstrated that iptakalim could reverse renal vascular remodeling (of afferent arterioles, arcuate arteries, or interlobular arteries), and improve pathological changes of glomerular, renal interstitial, and glomerular filtration membranes. These effects were accompanied by the decreased circulation and intrarenal concentrations of endothelin 1 and transforming growth factor beta1 (TGF-beta1), and down-regulated overexpression of genes for ET-1, endothelin-converting enzyme 1, TGF-beta1, and the subunits of ATP-sensitive potassium channels (K(ATP)), Kir1.1 and Kir6.1, in the kidney during hypertension. Abnormal expression of matrix components [collagen IV, fibronectin, matrix metalloproteinase 9 (MMP-9) and MMP tissue inhibitor 1 (TIMP-1)] was also significantly reversed by iptakalim. Our results demonstrate that chronic treatment with iptakalim not only reduces blood pressure but also preserves renal structure and function in SHR. In addition to reducing blood pressure, the renoprotective of iptakalim may be involved in inhibiting the circulation and intrarenal concentrations of endothelin 1 and TGF-beta1, regulating the expression of K(ATP) genes and correcting MMP-9/TIMP-1 imbalance in renal tissue, which may result in reducing the accumulation of extracellular matrix molecules.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; ATP-Binding Cassette Transporters; Benzazepines; Endothelin-1; Extracellular Matrix; Hemodynamics; Hypertension; Immunohistochemistry; KATP Channels; Kidney; Kidney Diseases; Kidney Function Tests; Potassium Channels, Inwardly Rectifying; Propylamines; Rats; Rats, Inbred SHR; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta; Transforming Growth Factor beta1

To investigate the experimental therapeutic effects of iptakalim hydrochloride (Ipt) on renoprotection in spontaneously hypertensive rats.. 30 SHR were treated ig with Ipt 1, 3, 9 mg.kg(-1).d(-1), benazepril 3 mg.kg(-1).d(-1) once a day for 12 weeks. Age-matched WKY rats were used as normal control. The blood pressure, heart rates, proteinuria were assessed, and renal tissues were examined by light microscopy. The levels of blood and renal tissue ET-1 and TGF-beta1 were detected respectively by radioimmunoanalysis and enzyme linked immune absorption assay (ELISA).. During 12 weeks experimental period, the systolic blood pressure (SBP) and heart rates (HR) of the untreated SHR were increased progressively. Ipt (3, 9 mg.kg(-1).d(-1)) could decrease effectively and inhibit the increasing tendency of HR. In addition, Ipt (1, 3, 9 mg.kg(-1).d(-1)) reduced urinary proteinuria, alleviated obviously the small vascular remodeling of renal and decreased the levels blood and renal ET-1 and TGF-beta1. Ipt (3, 9 mg.kg(-1).d(-1)) alleviated obviously the small vascular remodeling of renal compared with Ipt (1 mg.kg(-1).d(-1)).. Ipt (1, 3, 9 mg.kg(-1).d(-1)) decreased SBP and protected the kidney of SHR. The renoprotection of Ipt may be involved in inhibiting of blood and renal tissue ET-1 and TGF-beta1.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Endothelin-1; Female; Heart Rate; Hypertension; Kidney; Male; Propylamines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Transforming Growth Factor beta