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Renan B Ferreira, Mariana G de Oliveira, Edson Antunes, Wanda P Almeida, Badr M Ibrahim, Abdel A Abdel-Rahman
2-Aminothiazolines share an isosteric relationship with imidazolines and oxazolines with antihypertensive activity mainly mediated by the imidazoline I1-receptor. In the present work, we have prepared five aminothiazolines, following a previously described synthetic pathway. Aminothiazolines derived from dicyclopropylmethylamine (ATZ1) and cyclohexylamine (3) are unprecedented in the literature. Competitive radioligand assay was carried out with all synthetic compounds, and the I1 receptor affinity in comparison to rilmenidine in PC12 cells was determined...
October 8, 2016: European Journal of Pharmacology
Michel Azizi, Helena Pereira, Idir Hamdidouche, Philippe Gosse, Matthieu Monge, Guillaume Bobrie, Pascal Delsart, Claire Mounier-Véhier, Pierre-Yves Courand, Pierre Lantelme, Thierry Denolle, Caroline Dourmap-Collas, Xavier Girerd, Jean Michel Halimi, Faiez Zannad, Olivier Ormezzano, Bernard Vaïsse, Daniel Herpin, Jean Ribstein, Bernard Chamontin, Jean-Jacques Mourad, Emile Ferrari, Pierre-François Plouin, Vincent Jullien, Marc Sapoval, Gilles Chatellier
BACKGROUND: The DENERHTN trial (Renal Denervation for Hypertension) confirmed the blood pressure-lowering efficacy of renal denervation added to a standardized stepped-care antihypertensive treatment for resistant hypertension at 6 months. We report the influence of adherence to antihypertensive treatment on blood pressure control. METHODS: One hundred six patients with hypertension resistant to 4 weeks of treatment with indapamide 1.5 mg/d, ramipril 10 mg/d (or irbesartan 300 mg/d), and amlodipine 10 mg/d were randomly assigned to renal denervation plus standardized stepped-care antihypertensive treatment, or the same antihypertensive treatment alone...
September 20, 2016: Circulation
Jelica Vucicevic, Tatjana Srdic-Rajic, Marco Pieroni, Jonne M M Laurila, Vladimir Perovic, Sabrina Tassini, Elisa Azzali, Gabriele Costantino, Sanja Glisic, Danica Agbaba, Mika Scheinin, Katarina Nikolic, Marco Radi, Nevena Veljkovic
The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I1-type imidazoline receptors (I1-IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from α2-adrenoceptor activation, rilmenidine cannot be considered a suitable anticancer drug candidate. Here, we report the identification of novel rilmenidine-derived compounds with anticancer potential and devoid of α2-adrenoceptor effects by means of ligand- and structure-based drug design approaches...
July 15, 2016: Bioorganic & Medicinal Chemistry
Alessandro R Nascimento, Marcus V Machado, Fabiana Gomes, Aline B Vieira, Cassiano F Gonçalves-de-Albuquerque, Marcos A Lessa, Pascal Bousquet, Eduardo Tibiriçá
OBJECTIVES: The objective of this study was to investigate the role of the SNS on hemodynamic, metabolic, and microvascular alterations in a rat model of HFD-induced MS with salt supplementation. METHODS: In total, 40 adult male Wistar rats were fed normal chow (n = 10) or a HFD (n = 30) for 20 weeks. Thereafter, the HFD group received the centrally acting sympatho-modulatory drugs clonidine (0.1 mg/kg) or rilmenidine (1 mg/kg) or vehicle (n = 10/group) orally by gavage...
May 2016: Microcirculation: the Official Journal of the Microcirculatory Society, Inc
Tatjana Srdic-Rajic, Katarina Nikolic, Milena Cavic, Ivana Djokic, Branislava Gemovic, Vladimir Perovic, Nevena Veljkovic
Imidazoline I1 receptor signaling is associated with pathways that regulate cell viability leading to varied cell-type specific phenotypes. We demonstrated that the antihypertensive drug rilmenidine, a selective imidazoline I1 receptor agonist, modulates proliferation and stimulates the proapoptotic protein Bax thus inducing the perturbation of the mitochondrial pathway and apoptosis in human leukemic K562 cells. Rilmenidine acts through a mechanism which involves deactivation of Ras/MAP kinases ERK, p38 and JNK...
January 1, 2016: European Journal of Pharmaceutical Sciences
V Forni Ogna, E Pereira, M Sapoval, M Azizi
OBJECTIVE: The French DENERHTN trial has shown that renal denervation (RDN, Symplicity Catheter) in addition to standardized optimal medical treatment (SOMT) decreases ambulatory BP more (6 mmHg) than the same SOMT alone at 6 months in patients (pts) with resistant hypertension (RH). However, some pts did not respond to RDN or SOMT at 6 months. The aim of the study was to determine the prevalence and characteristics of refractory hypertension (RFH) to more than 5 antihypertensive treatments at 6 months in the 2 groups...
June 2015: Journal of Hypertension
Michel Azizi, Marc Sapoval, Philippe Gosse, Matthieu Monge, Guillaume Bobrie, Pascal Delsart, Marco Midulla, Claire Mounier-Véhier, Pierre-Yves Courand, Pierre Lantelme, Thierry Denolle, Caroline Dourmap-Collas, Hervé Trillaud, Helena Pereira, Pierre-François Plouin, Gilles Chatellier
BACKGROUND: Conflicting blood pressure-lowering effects of catheter-based renal artery denervation have been reported in patients with resistant hypertension. We compared the ambulatory blood pressure-lowering efficacy and safety of radiofrequency-based renal denervation added to a standardised stepped-care antihypertensive treatment (SSAHT) with the same SSAHT alone in patients with resistant hypertension. METHODS: The Renal Denervation for Hypertension (DENERHTN) trial was a prospective, open-label randomised controlled trial with blinded endpoint evaluation in patients with resistant hypertension, done in 15 French tertiary care centres specialised in hypertension management...
May 16, 2015: Lancet
Haya Abu Ghazaleh, Maggie D Lalies, David J Nutt, Alan L Hudson
Harmane is an active component of clonidine displacing substance and a candidate endogenous ligand for imidazoline binding sites. The neurochemistry of tritiated harmane was investigated in the present study examining its uptake and release properties in the rat brain central nervous system (CNS) in vitro. At physiological temperature, [(3)H]harmane was shown to be taken up in rat brain cortex. Further investigations demonstrated that treatment with monoamine uptake blockers (citalopram, nomifensine and nisoxetine) did not alter [(3)H]harmane uptake implicating that the route of [(3)H]harmane transport was distinct from the monoamine uptake systems...
March 17, 2015: Neuroscience Letters
Suleyman Salman, Serkan Kumbasar, Nesrin Gursan, Yakup Kumtepe, Bunyamin Borekci, Beyzagul Polat, Hamit Hakan Alp, Mustafa Talip Sener, Halis Suleyman
BACKGROUND: In this study, we investigated the effects of treatment with chronic antihypertensive drugs (clonidine, methyldopa, amlodipine, ramipril and rilmenidine) on oxidant-antioxidant parameters and toxic effects on DNA in rat uterus tissue. In addition, uterus tissues were examined histopathologically. MATERIALS AND METHODS: A total of 36 albino Wistar rats were divided into the following six groups: 0.075 mg/kg clonidine group; 100 mg/kg methyldopa group; 2 mg/kg amlodipine group; 2...
July 2011: International Journal of Fertility & Sterility
Kristy L Jackson, Kesia Palma-Rigo, Thu-Phuc Nguyen-Huu, Pamela J Davern, Geoffrey A Head
OBJECTIVE: BPH/2J hypertensive mice have an exaggerated sympathetic contribution to blood pressure (BP). Premotor sympathetic neurons within the rostroventrolateral medulla (RVLM) are a major source of sympathetic vasomotor tone and major site of action of the centrally acting sympatholytic agent, rilmenidine. The relative cardiovascular effect of rilmenidine in BPH/2J versus normotensive BPN/3J mice was used as an indicator of the involvement of the RVLM in the sympathetic contribution to hypertension in BPH/2J mice...
March 2014: Journal of Hypertension
H H Chung, J- T Cheng
Imidazoline I1-receptor (I1R) is known to regulate the blood pressure, and rilmenidine, as the agonist, is used to treat hypertension in clinics. However, the role of I1R in obesity is still unclear. In the present study, we investigated the changes of obesity by activation of I1R in high fat diet (HFD)-fed mice. Chronic administration of rilmenidine into HFD-fed mice for 8 weeks significantly reduced body weight, which was reversed by efaroxan at the dose sufficient to block I1R. Also, rilmenidine significantly decreased the energy intake of HFD-fed mice...
August 2013: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
Zoltán S Zádori, Ágnes Fehér, Mahmoud Al-Khrasani, Erzsébet Lackó, Viktória E Tóth, Serena B Brancati, Lutz Hein, Péter Mátyus, Klára Gyires
Several lines of evidence suggest that imidazoline receptors mediate various physiological processes. It is rather difficult, however, to distinguish the imidazoline receptor-mediated effects from the alpha₂-adrenoceptor-mediated ones due to the reasonable affinity of most imidazoline ligands for the alpha₂-adrenoceptors. In the present study the effects of different imidazoline ligands were tested on the electrical field stimulation (EFS)-induced gastric contractions in wild-type (WT), alpha₂A-, alpha₂B- and alpha₂C-adrenoceptor knockout (KO) mice in order to analyze, whether imidazoline I₁ and I₂ receptors take part in the regulation of gastric motor activity...
April 5, 2013: European Journal of Pharmacology
L-Y Wang, P-M Ku, S-H Chen, L-J Chen, Y-M Yu, J-T Cheng
Specific antibodies are essential in the study of receptor protein. Gene matching shows that Nischarin (NISCH) is a mouse homologue of human imidazoline receptor antisera-selective (IRAS) protein, a viable candidate for imidazoline I-1 receptor. However, selectivity of this antibody against imidazoline I-2 or imidazoline I-3 receptors remained obscure. At first, an intracerebroventricular (ICV) injection of anti-NISCH antibody blocked the blood pressure lowering action of rilmenidine (I-1 receptor agonist) in spontaneous hypertensive rat (SHR)...
July 2013: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
Katarina Nikolic, Nevena Veljkovic, Branislava Gemovic, Tatjana Srdic-Rajic, Danica Agbaba
The group of imidazoline-1 receptors (I(1)-IR) agonists encompasses drugs are currently used in treatment of high blood pressure and hyperglycemia. The I(1)-IR protein structures have not been determined yet, but Nischarin protein that binds numerous imidazoline ligands inducing initiation of various cell-signaling cascades, including apoptosis, is identified as strong I(1)-IR candidate. In this study we examined apoptotic activity of rilmenidine (potent I(1)-IR agonist), moxonidine (moderate I(1)-IR agonist), and efaroxan (I(1)-IR partial agonist) on cancer cell line (K562) expressing Nischarin...
May 2013: Combinatorial Chemistry & High Throughput Screening
H H Chung, T T Yang, M F Chen, M T Chou, J T Cheng
Imidazoline I1-receptors (I1R) are known to regulate blood pressure and rilmenidine, an agonist, is widely used as antihypertensive agent in clinic. However, the role of I1R in feeding behavior is still unclear. In the present study, we used the agonist of I1R to investigate the effect on hyperphagia in streptozotocin (STZ)-induced diabetic mice. Rilmenidine decreased the food intake of STZ-diabetic mice in a dose-dependent manner. The reduction of food intake was abolished by pretreatment with efaroxan at the dose sufficient to block I1R...
September 2012: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
Sam D Perez, Brooke Kozic, Christine A Molinaro, Srinivasan Thyagarajan, Mark Ghamsary, Cheri L Lubahn, Dianne Lorton, Denise L Bellinger
In the present study, we investigated how increased sympathetic tone during middle-age affects the splenic sympathetic neurotransmission. Fifteen-month-old (M) F344 rats received rilmenidine (0, 0.5 or 1.5mg/kg/day, i.p. for 90 days) to lower sympathetic tone. Controls for age were untreated 3 or 18M rats. We report that rilmenidine (1) reduced plasma and splenic norepinephrine concentrations and splenic norepinephrine turnover, and partially reversed the sympathetic nerve loss; and (2) increased β-adrenergic receptor (β-AR) density and β-AR-stimulated cAMP production...
June 15, 2012: Journal of Neuroimmunology
Gianfranco Parati, Murray Esler
Evidence assembled in this review indicates that sympathetic nervous system dysfunction is crucial in the development of heart failure and essential hypertension. This takes the form of persistent and adverse activation of sympathetic outflows to the heart and kidneys in both conditions. An important goal for clinical scientists is translation of the knowledge of pathophysiology, such as this, into better treatment for patients. The achievement of this 'mechanisms to management' transition is at different stages of development with regard to the two disorders...
May 2012: European Heart Journal
Po-Sheng Yang, Hung-Tsung Wu, Hsien-Hui Chung, Chun-Ta Chen, Chin-Wen Chi, Ching-Hua Yeh, Juei-Tang Cheng
The nuclear receptor farnesoid X receptor (FXR) regulates pathways in lipid, glucose, and energy metabolism. Activation of FXR in mice significantly improved high-fat diet-induced hepatic steatosis. It has been reported that activation of imidazoline I-1 receptor by rilmenidine increases the expression of FXR in human hepatoma cell line, Hep G2 cell, to regulate the target genes relating to lipid metabolism; activation of FXR by rilmenidine exerts an antihyperlipidemic action. However, signals for this action of rilmenidine are still unknown...
January 2012: Naunyn-Schmiedeberg's Archives of Pharmacology
Lincoln P Edwards, Terry A Brown-Bryan, Lancelot McLean, Paul Ernsberger
The sympathetic nervous system plays a central role in the pathophysiology not only of hypertension and other cardiovascular diseases but also metabolic disorders including disturbances of glucose and lipid homeostasis. A centrally acting sympathetic agent is therefore attractive not only for lowering blood pressure, but also intervening with multiple disease processes. Older agents such as clonidine and guanabenz have numerous side effects, including sedation and dry mouth that limit their acceptability to patients...
August 2012: Cardiovascular Therapeutics
C-S Niu, H-T Wu, K-C Cheng, K-C Lin, C-T Chen, J-T Cheng
The imidazoline I-1 receptor (I-1 R) agonists are widely used to lower blood pressure, but their effects on hyperlipidemia are still obscure. The present study is aimed to evaluate the possible mechanism(s) of I-1 R in the regulation of lipid homeostasis. Farnesoid X receptor (FXR) plays an important role in blood lipid homeostasis; however, the role of FXR in rilmenidine-induced blood lipid lowering action is still unknown. Thus, we administered rilmenidine, a selective agonist of I-1 R, into high fat diet-fed (HFD) mice showing hypertriglyceridemia and hypercholesterolemia...
June 2011: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
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