Cardiovascular Effects Mediated by Imidazoline Drugs: An Update

Author(s): Luis Cobos-Puc*, Hilda Aguayo-Morales.

Journal Name: Cardiovascular & Hematological Disorders-Drug Targets
(Formerly Current Drug Targets - Cardiovascular & Hematological Disorders)

Volume 19 , Issue 2 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Objective: Clonidine is a centrally acting antihypertensive drug. Hypotensive effect of clonidine is mediated mainly by central α2-adrenoceptors and/or imidazoline receptors located in a complex network of the brainstem. Unfortunately, clonidine produces side effects such as sedation, mouth dry, and depression. Moxonidine and rilmenidine, compounds of the second generation of imidazoline drugs, with fewer side effects, display a higher affinity for the imidazoline receptors compared with α2-adrenoceptors. The antihypertensive action of these drugs is due to inhibition of the sympathetic outflow primarily through central I1-imidazoline receptors in the RVLM, although others anatomical sites and mechanisms/receptors are involved. Agmatine is regarded as the endogenous ligand for imidazoline receptors. This amine modulates the cardiovascular function. Indeed, when administered in the RVLM mimics the hypotension of clonidine.

Results: Recent findings have shown that imidazoline drugs also exert biological response directly on the cardiovascular tissues, which can contribute to their antihypertensive response. Currently, new imidazoline receptors ligands are in development.

Conclusion: In the present review, we provide a brief update on the cardiovascular effects of clonidine, moxonidine, rilmenidine, and the novel imidazoline agents since representing an important therapeutic target for some cardiovascular diseases.

Keywords: Imidazoline, agmatine, nischarin, sympathoinhibition, heart, blood vessels, hypertension, cardiovascular diseases.

Bousquet, P.; Feldman, J.; Schwartz, J. Central cardiovascular effects of alpha adrenergic drugs: Differences between catecholamines and imidazolines. J. Pharmacol. Exp. Ther., 1984, 230(1), 232-236.
Head, G.A.; Mayorov, D.N. Imidazoline receptors, novel agents and therapeutic potential. Cardiovasc. Hematol. Agents Med. Chem., 2006, 4(1), 17-32.
Laurent, S. Antihypertensive drugs. Pharmacol. Res., 2017, 124, 116-125.
Bektas, N.; Nemutlu, D.; Arslan, R. The imidazoline receptors and ligands in pain modulation. Indian J. Pharmacol., 2015, 47(5), 472-478.
Dardonville, C.; Rozas, I. Imidazoline binding sites and their ligands: An overview of the different chemical structures. Med. Res. Rev., 2004, 24(5), 639-661.
Li, J.X. Imidazoline I2 receptors: An update. Pharmacol. Ther., 2017, 178, 48-56.
Mukaddam-Daher, S. An “I” on cardiac hypertrophic remodelling: imidazoline receptors and heart disease. Can. J. Cardiol., 2012, 28(5), 590-598.
Nikolic, K.; Agbaba, D. Imidazoline antihypertensive drugs: Selective I1-imidazoline receptors activation. Cardiovasc. Ther., 2012, 30(4), 209-216.
Sarac, B.; Korkmaz, O.; Altun, A.; Bagcivan, I.; Goksel, S.; Yildirim, S.; Berkan, O. Investigation of the vasorelaxant effects of moxonidine and its relaxation mechanism on the human radial artery when used as a coronary bypass graft. Interact. Cardiovasc. Thorac. Surg., 2015, 21(3), 342-345.
Mar, G.Y.; Chou, M.T.; Chung, H.H.; Chiu, N.H.; Chen, M.F.; Cheng, J.T. Changes of imidazoline receptors in spontaneously hypertensive rats. Int. J. Exp. Pathol., 2013, 94(1), 17-24.
Aceros, H.; Farah, G.; Cobos-Puc, L.; Stabile, A.M.; Noiseux, N.; Mukaddam-Daher, S. Moxonidine improves cardiac structure and performance in SHR through inhibition of cytokines, p38 MAPK and Akt. Br. J. Pharmacol., 2011, 164(3), 946-957.
Aceros, H.; Farah, G.; Noiseux, N.; Mukaddam-Daher, S. Moxonidine modulates cytokine signalling and effects on cardiac cell viability. Eur. J. Pharmacol., 2014, 740, 168-182.
Maltsev, A.V.; Kokoz, Y.M.; Evdokimovskii, E.V.; Pimenov, O.Y.; Reyes, S.; Alekseev, A.E. Alpha-2 adrenoceptors and imidazoline receptors in cardiomyocytes mediate counterbalancing effect of agmatine on NO synthesis and intracellular calcium handling. J. Mol. Cell. Cardiol., 2014, 68, 66-74.
Maltsev, A.V.; Nenov, M.N.; Pimenov, O.Y.; Kokoz, Y.M. Modulation of L-type Ca2+ currents and intracellular calcium by agmatine in rat cardiomyocytes. Biol. Membrany,, 2013, 30(2), 92-104.
Laube, G.; Bernstein, H.G. Agmatine: Multifunctional arginine metabolite and magic bullet in clinical neuroscience? Biochem. J., 2017, 474(15), 2619-2640.
Neis, V.B.; Rosa, P.B.; Olescowicz, G.; Rodrigues, A.L.S. Therapeutic potential of agmatine for CNS disorders. Neurochem. Int., 2017, 108, 318-331.
Molderings, G.J.; Haenisch, B. Agmatine (decarboxylated L-arginine): Physiological role and therapeutic potential. Pharmacol. Ther., 2012, 133(3), 351-365.
Wehrwein, E.A.; Orer, H.S.; Barman, S.M. Overview of the anatomy, physiology, and pharmacology of the autonomic nervous system. Compr. Physiol., 2016, 6(3), 1239-1278.
Sorota, S. The sympathetic nervous system as a target for the treatment of hypertension and cardiometabolic diseases. J. Cardiovasc. Pharmacol., 2014, 6(5), 466-476.
Dampney, R.A. Central neural control of the cardiovascular system: Current perspectives. Adv. Physiol. Educ., 2016, 40(3), 283-296.
Lim, K.; van den Buuse, M.; Head, G.A. Effect of endothelin-1 on baroreflexes and the cardiovascular action of clonidine in conscious rabbits. Front. Physiol., 2016, 7, 321.
Nik Yusoff, N.S.; Mustapha, Z.; Govindasamy, C.; Sirajudeen, K.N. Effect of clonidine (an antihypertensive drug) treatment on oxidative stress markers in the heart of spontaneously hypertensive rats. Oxid. Med. Cell. Longev., 2013, 2013, 927214.
Lee, H.M.; Ruggoo, V.; Graudins, A. Intrathecal clonidine pump failure causing acute withdrawal syndrome with ‘stress-induced’ cardiomyopathy. J. Med. Toxicol., 2016, 12(1), 134-138.
Lowry, J.A.; Brown, J.T. Significance of the imidazoline receptors in toxicology. Clin. Toxicol. (Phila.), 2014, 52(5), 454-469.
Edwards, L.P.; Brown-Bryan, T.A.; McLean, L.; Ernsberger, P. Pharmacological properties of the central antihypertensive agent, moxonidine. Cardiovasc. Ther., 2012, 30(4), 199-208.
Karlafti, E.F.; Hatzitolios, A.I.; Karlaftis, A.F.; Baltatzi, M.S.; Koliakos, G.G.; Savopoulos, C.G. Effects of moxonidine on sympathetic nervous system activity: An update on metabolism, cardio, and other target-organ protection. J. Pharm. Bioallied Sci., 2013, 5(4), 253-256.
Deftereos, S.; Giannopoulos, G.; Kossyvakis, C.; Efremidis, M.; Panagopoulou, V.; Raisakis, K.; Kaoukis, A.; Karageorgiou, S.; Bouras, G.; Katsivas, A.; Pyrgakis, V.; Stefanadis, C. Effectiveness of moxonidine to reduce atrial fibrillation burden in hypertensive patients. Am. J. Cardiol., 2013, 112(5), 684-687.
Reid, J.L. Update on rilmenidine: clinical benefits. Am. J. Hypertens., 2001, 14(11 Pt 2), 322S-324S.
Benitez, J.; Garcia, D.; Romero, N.; Gonzalez, A.; Martinez, J.; Figueroa, M.; Salas, M.; Lopez, V.; Dodd, P.R.; Schenk, G.; Carvajal, N.; Uribe, E. Metabolic strategies for the degradation of the neuromodulator agmatine in mammals. Metabolism, 2018, 81, 35-44.
Shopsin, B. The clinical antidepressant effect of exogenous agmatine is not reversed by parachlorophenylalanine: A pilot study. Acta Neuropsychiatr., 2013, 25(2), 113-118.
Uzbay, T.; Goktalay, G.; Kayir, H.; Eker, S.S.; Sarandol, A.; Oral, S.; Buyukuysal, L.; Ulusoy, G.; Kirli, S. Increased plasma agmatine levels in patients with schizophrenia. J. Psychiatr. Res., 2013, 47(8), 1054-1060.
Esnafoglu, E.; Irende, I. Decreased plasma agmatine levels in autistic subjects. J. Neural Transm. (Vienna), 2018, 125(4), 735-740.
Gilad, G.M.; Gilad, V.H. Long-term (5 years), high daily dosage of dietary agmatine-evidence of safety: A case report. J. Med. Food, 2014, 17(11), 1256-1259.
Isbister, G.K.; Heppell, S.P.; Page, C.B.; Ryan, N.M. Adult clonidine overdose: Prolonged bradycardia and central nervous system depression, but not severe toxicity. Clin. Toxicol. (Phila.), 2017, 55(3), 187-192.
Lindesay, G.; Ragonnet, C.; Chimenti, S.; Villeneuve, N.; Vayssettes-Courchay, C. Age and hypertension strongly induce aortic stiffening in rats at basal and matched blood pressure. levels. Physiol. Rep, 2016, 4, 10, e12805.
Buttgereit, J.; Shanks, J.; Li, D.; Hao, G.; Athwal, A.; Langenickel, T.H.; Wright, H.; da Costa Goncalves, A.C.; Monti, J.; Plehm, R.; Popova, E.; Qadri, F.; Lapidus, I.; Ryan, B.; Ozcelik, C.; Paterson, D.J.; Bader, M.; Herring, N. C-type natriuretic peptide and natriuretic peptide receptor B signalling inhibits cardiac sympathetic neurotransmission and autonomic function. Cardiovasc. Res., 2016, 112(3), 637-644.
Mohammed, M.; Kulasekara, K.; Ootsuka, Y.; Blessing, W.W. Locus coeruleus noradrenergic innervation of the amygdala facilitates alerting-induced constriction of the rat tail artery. Am. J. Physiol. Regul. Integr. Comp. Physiol., 2016, 310(11), R1109-R1119.
Hanafusa, N.; Okamoto, K.; Takatori, S.; Kawasaki, H. Involvement of hypothalamic periventricular GABAergic nerves in the central pressor response to clonidine in freely-moving conscious rats. J. Pharmacol. Sci., 2012, 118(3), 382-390.
Parkin, M.L.; Lim, K.; Burke, S.L.; Head, G.A. Comparison in conscious rabbits of the baroreceptor-heart rate reflex effects of chronic treatment with rilmenidine, moxonidine, and clonidine. Front. Physiol., 2016, 7, 522.
Monroy-Ordonez, E.B.; Villalon, C.M.; Cobos-Puc, L.E.; Marquez-Conde, J.A.; Sanchez-Lopez, A.; Centurion, D. Evidence that some imidazoline derivatives inhibit peripherally the vasopressor sympathetic outflow in pithed rats. Auton. Neurosci., 2008, 143(1-2), 40-45.
Situmorang, J.H.; Lin, H.H.; Lo, H.; Lai, C.C. Role of neuronal nitric oxide synthase (nNOS) at medulla in tachycardia induced by repeated administration of ethanol in conscious rats. J. Biomed. Sci., 2018, 25(1), 8.
Peng, J.; Wang, Y.K.; Wang, L.G.; Yuan, W.J.; Su, D.F.; Ni, X.; Deng, X.M.; Wang, W.Z. Sympathoinhibitory mechanism of moxonidine: Role of the inducible nitric oxide synthase in the rostral ventrolateral medulla. Cardiovasc. Res., 2009, 84(2), 283-291.
Shinohara, K.; Hirooka, Y.; Kishi, T.; Sunagawa, K. Reduction of nitric oxide-mediated γ-amino butyric acid release in rostral ventrolateral medulla is involved in superoxide-induced sympathoexcitation of hypertensive rats. Circ. J., 2012, 76(12), 2814-2821.
Peng, J.F.; Wu, Z.T.; Wang, Y.K.; Yuan, W.J.; Sun, T.; Ni, X.; Su, D.F.; Wang, W.; Xu, M.J.; Wang, W.Z. GABAergic mechanism in the rostral ventrolateral medulla contributes to the hypotension of moxonidine. Cardiovasc. Res., 2011, 89(2), 473-481.
Alves, T.B.; Totola, L.T.; Takakura, A.C.; Colombari, E.; Moreira, T.S. GABA mechanisms of the nucleus of the solitary tract regulates the cardiovascular and sympathetic effects of moxonidine. Auton. Neurosci., 2016, 194, 1-7.
Totola, L.T.; Alves, T.B.; Takakura, A.C.; Ferreira-Neto, H.C.; Antunes, V.R.; Menani, J.V.; Colombari, E.; Moreira, T.S. Commissural nucleus of the solitary tract regulates the antihypertensive effects elicited by moxonidine. Neuroscience, 2013, 250, 80-91.
Cobos-Puc, L.E.; Aguayo-Morales, H.; Silva-Belmares, Y.; Gonzalez-Zavala, M.A.; Centurion, D. alpha2A-adrenoceptors, but not nitric oxide, mediate the peripheral cardiac sympatho-inhibition of moxonidine. Eur. J. Pharmacol., 2016, 782, 35-43.
Sear, J.W. Chapter 23 Antihypertensive drugs and vasodilators A2 - Hemmings, Hugh C.In: Pharmacology and Physiology for Anesthesia; Egan, T.D., Ed.; W.B. Saunders: Philadelphia, 2013, pp. 405-425.
Kim, Y.H.; Nam, T.S.; Ahn, D.S.; Chung, S. Modulation of N-type Ca(2)(+) currents by moxonidine via imidazoline I(1) receptor activation in rat superior cervical ganglion neurons. Biochem. Biophys. Res. Commun., 2011, 409(4), 645-650.
Martin, S.W.; Butcher, A.J.; Berrow, N.S.; Richards, M.W.; Paddon, R.E.; Turner, D.J.; Dolphin, A.C.; Sihra, T.S.; Fitzgerald, E.M. Phosphorylation sites on calcium channel alpha1 and beta subunits regulate ERK-dependent modulation of neuronal N-type calcium channels. Cell Calcium, 2006, 39(3), 275-292.
Cobos-Puc, L.E.; Sanchez-Lopez, A.; Centurion, D. Pharmacological analysis of the cardiac sympatho-inhibitory actions of moxonidine and agmatine in pithed spontaneously hypertensive rats. Eur. J. Pharmacol., 2016, 791, 25-36.
Gulati, A. Down-regulation of alpha 2 adrenoceptors in ventrolateral medulla of spontaneously hypertensive rats. Life Sci., 1991, 48(12), 1199-1206.
Zhang, J.; Abdel-Rahman, A.A. Inhibition of nischarin expression attenuates rilmenidine-evoked hypotension and phosphorylated extracellular signal-regulated kinase 1/2 production in the rostral ventrolateral medulla of rats. J. Pharmacol. Exp. Ther., 2008, 324(1), 72-78.
Maziveyi, M.; Dong, S.; Baranwal, S.; Alahari, S.K. Nischarin regulates focal adhesion and Invadopodia formation in breast cancer cells. Mol. Cancer, 2018, 17(1), 21.
Dong, S.; Baranwal, S.; Garcia, A.; Serrano-Gomez, S.J.; Eastlack, S.; Iwakuma, T.; Mercante, D.; Mauvais-Jarvis, F.; Alahari, S.K. Nischarin inhibition alters energy metabolism by activating AMP-activated protein kinase. J. Biol. Chem., 2017, 292(41), 16833-16846.
Jain, P.; Baranwal, S.; Dong, S.; Struckhoff, A.P.; Worthylake, R.A.; Alahari, S.K. Integrin-binding protein nischarin interacts with tumor suppressor liver kinase B1 (LKB1) to regulate cell migration of breast epithelial cells. J. Biol. Chem., 2013, 288(22), 15495-15509.
Marei, H.; Malliri, A. Rac1 in human diseases: The therapeutic potential of targeting Rac1 signaling regulatory mechanisms. Small GTPases, 2017, 8(3), 139-163.
Wang, Y.; Wang, S.; Lei, M.; Boyett, M.; Tsui, H.; Liu, W.; Wang, X. The p21-activated kinase 1 (Pak1) signalling pathway in cardiac disease: From mechanistic study to therapeutic exploration. Br. J. Pharmacol., 2018, 175(8), 1362-1374.
Salt, I.P.; Hardie, D.G. AMP-activated protein kinase: An ubiquitous signaling pathway with key roles in the cardiovascular system. Circ. Res., 2017, 120(11), 1825-1841.
Zhang, W.; Wang, Q.; Wu, Y.; Moriasi, C.; Liu, Z.; Dai, X.; Wang, Q.; Liu, W.; Yuan, Z.Y.; Zou, M.H. Endothelial cell-specific liver kinase B1 deletion causes endothelial dysfunction and hypertension in mice in vivo. Circulation, 2014, 129(13), 1428-1439.
Guo, C.A.; Guo, S. Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure. J. Endocrinol., 2017, 233(3), R131-R143.
Jackson, K.L.; Palma-Rigo, K.; Nguyen-Huu, T.P.; Davern, P.J.; Head, G.A. Actions of rilmenidine on neurogenic hypertension in BPH/2J genetically hypertensive mice. J. Hypertens., 2014, 32(3), 575-586.
Burke, S.L.; Evans, R.G.; Head, G.A. Effects of chronic sympatho-inhibition on renal excretory function in renovascular hypertension. J. Hypertens., 2011, 29(5), 945-952.
Yang, J.; Wang, W.Z.; Shen, F.M.; Su, D.F. Cardiovascular effects of agmatine within the rostral ventrolateral medulla are similar to those of clonidine in anesthetized rats. Exp. Brain Res., 2005, 160(4), 467-472.
Raasch, W.; Schafer, U.; Qadri, F.; Dominiak, P. Agmatine, an endogenous ligand at imidazoline binding sites, does not antagonize the clonidine-mediated blood pressure reaction. Br. J. Pharmacol., 2002, 135(3), 663-672.
Zhao, D.; Ren, L.M. Non-adrenergic inhibition at prejunctional sites by agmatine of purinergic vasoconstriction in rabbit saphenous artery. Neuropharmacology, 2005, 48(4), 597-606.
Santos, W.C.; Smaili, S.S.; Jurkiewicz, A.; Picarro, I.; Garcez-do-Carmo, L. Dual effect of agmatine in the bisected rat vas deferens. J. Pharm. Pharmacol., 2003, 55(3), 373-380.
Torok, J.; Zemancikova, A. Agmatine modulation of noradrenergic neurotransmission in isolated rat blood vessels. Chin. J. Physiol., 2016, 59(3), 131-138.
Kim, Y.H.; Jeong, J.H.; Ahn, D.S.; Chung, S. Agmatine suppresses peripheral sympathetic tone by inhibiting N-type Ca(2+) channel activity via imidazoline I2 receptor activation. Biochem. Biophys. Res. Commun., 2016, 477(3), 406-412.
Kim, Y.H.; Jeong, J.H.; Ahn, D.S.; Chung, S. Phospholipase C-dependent hydrolysis of phosphatidylinositol 4,5-bisphosphate underlies agmatine-induced suppression of N-type Ca2+ channel in rat celiac ganglion neurons. Biochem. Biophys. Res. Commun., 2017, 484(2), 342-347.
Cobos-Puc, L.; Aguayo-Morales, H.; Ventura-Sobrevilla, J.; Luque-Contreras, D.; Chin-Chan, M. Further analysis of the inhibition by agmatine on the cardiac sympathetic outflow: Role of the alpha(2)-adrenoceptor subtypes. Eur. J. Pharmacol., 2017, 805, 75-83.
Sugiura, T.; Kobuchi, S.; Tsutsui, H.; Takaoka, M.; Fujii, T.; Hayashi, K.; Matsumura, Y. Preventive mechanisms of agmatine against ischemic acute kidney injury in rats. Eur. J. Pharmacol., 2009, 603(1-3), 108-113.
Tagashira, H.; Matsumoto, T.; Taguchi, K.; Zhang, C.; Han, F.; Ishida, K.; Nemoto, S.; Kobayashi, T.; Fukunaga, K. Vascular endothelial sigma1-receptor stimulation with SA4503 rescues aortic relaxation via Akt/eNOS signaling in ovariectomized rats with aortic banding. Circ. J., 2013, 77(11), 2831-2840.
Taguchi, K.; Matsumoto, T.; Kamata, K.; Kobayashi, T. Suppressed G-protein-coupled receptor kinase 2 activity protects female diabetic-mouse aorta against endothelial dysfunction. Acta Physiol. (Oxf.), 2013, 207(1), 142-155.
Enouri, S.; Monteith, G.; Johnson, R. Functional characteristics of alpha adrenergic and endothelinergic receptors in pressurized rat mesenteric veins. Can. J. Physiol. Pharmacol., 2013, 91(7), 538-546.
Broadley, K.J.; Fehler, M.; Ford, W.R.; Kidd, E.J. Functional evaluation of the receptors mediating vasoconstriction of rat aorta by trace amines and amphetamines. Eur. J. Pharmacol., 2013, 715(1-3), 370-380.
Chlopicki, S.; Kozlovski, V.I.; Gryglewski, R.J. Clonidine-induced coronary vasodilatation in isolated guinea pig heart is not mediated by endothelial alpha(2) adrenoceptors. J. Physiol. Pharmacol., 2003, 54(4), 511-521.
Vidal, C.; Grassin-Delyle, S.; Devillier, P.; Naline, E.; Lansac, E.; Menasche, P.; Faisy, C. Effect of severe acidosis on vasoactive effects of epinephrine and norepinephrine in human distal mammary artery. J. Thorac. Cardiovasc. Surg., 2014, 147(5), 1698-1705.
de Souza Rossignoli, P.; Yamamoto, F.Z.; Pereira, O.C.; Chies, A.B. Norepinephrine responses in rat renal and femoral veins are reinforced by vasoconstrictor prostanoids. Vascul. Pharmacol., 2015, 72, 93-100.
Tugrul, I.; Dost, T.; Demir, O.; Gokalp, F.; Oz, O.; Girit, N.; Birincioglu, M. Effects of a PPAR-gamma receptor agonist and an angiotensin receptor antagonist on aortic contractile responses to alpha receptor agonists in diabetic and/or hypertensive rats. Cardiovasc. J. Afr., 2016, 27(3), 164-169.
Moreira, T.S.; Takakura, A.C.; Menani, J.V.; Colombari, E. Involvement of central alpha1- and alpha2-adrenoceptors on cardiovascular responses to moxonidine. Eur. J. Pharmacol., 2007, 563(1-3), 164-171.
Zhao, D.; Ren, L.M.; Lu, H.G.; Zhang, X. Potentiation by yohimbine of alpha-adrenoceptor-mediated vasoconstriction in response to clonidine in the rabbit ear vein. Eur. J. Pharmacol., 2008, 589(1-3), 201-205.
Mukaddam-Daher, S.; Menaouar, A.; Gutkowska, J. Receptors involved in moxonidine-stimulated atrial natriuretic peptide release from isolated normotensive rat hearts. Eur. J. Pharmacol., 2006, 541(1-2), 73-79.
Kawada, T.; Shimizu, S.; Yamamoto, H.; Miyamoto, T.; Shishido, T.; Sugimachi, M. Peripheral versus central effect of intravenous moxonidine on rat carotid sinus baroreflex-mediated sympathetic arterial pressure regulation. Life Sci., 2017, 190, 103-109.
Artigues-Varin, C.; Richard, V.; Varin, R.; Mulder, P.; Thuillez, C. Alpha2-adrenoceptor ligands inhibit alpha1-adrenoceptor-mediated contraction of isolated rat arteries. Fundam. Clin. Pharmacol., 2002, 16(4), 281-287.
Marsault, R.; Taddei, S.; Boulanger, C.M.; Illiano, S.; Vanhoutte, P.M. Rilmenidine activates postjunctional alpha 1- and alpha 2-adrenoceptors in the canine saphenous vein. Fundam. Clin. Pharmacol., 1996, 10(4), 379-386.
Gadkari, T.V.; Cortes, N.; Madrasi, K.; Tsoukias, N.M.; Joshi, M.S. Agmatine induced NO dependent rat mesenteric artery relaxation and its impairment in salt-sensitive hypertension. Nitric Oxide, 2013, 35, 65-71.
Musgrave, I.F.; Van Der Zypp, A.; Grigg, M.; Barrow, C.J. Endogenous imidazoline receptor ligands relax rat aorta by an endothelium-dependent mechanism. Ann. N. Y. Acad. Sci., 2003, 1009, 222-227.
Nader, M.A.; Gamiel, N.M.; El-Kashef, H.; Zaghloul, M.S. Effect of agmatine on experimental vascular endothelial dysfunction. Hum. Exp. Toxicol., 2016, 35(5), 573-582.
El-Awady, M.S.; Suddek, G.M. Agmatine ameliorates atherosclerosis progression and endothelial dysfunction in high cholesterol-fed rabbits. J. Pharm. Pharmacol., 2014, 66(6), 835-843.
Lee, L.M.; Lin, C.H.; Chung, H.H.; Cheng, J.T.; Chen, I.H.; Tong, Y.C. Agmatine induces rat prostate relaxation through activation of peripheral imidazoline I2-Receptors. Low. Urin. Tract Symptoms, 2013, 5(1), 39-43.
Lee, L.M.; Tsai, T.C.; Chung, H.H.; Tong, Y.C.; Cheng, J.T. Prostatic relaxation induced by agmatine is decreased in spontaneously hypertensive rats. BJU Int., 2012, 110(6B), E253-E258.
Tsai, T.C.; Lin, C.H.; Chung, H.H.; Cheng, J.T.; Chen, I.H.; Tong, Y.C. Urinary bladder relaxation through activation of imidazoline receptors induced by agmatine is increased in diabetic rats. Low. Urin. Tract Symptoms, 2014, 6(2), 117-123.
El-Awady, M.S.; Nader, M.A.; Sharawy, M.H. The inhibition of inducible nitric oxide synthase and oxidative stress by agmatine attenuates vascular dysfunction in rat acute endotoxemic model. Environ. Toxicol. Pharmacol., 2017, 55, 74-80.
Zefirov, T.L.; Ziyatdinova, N.I.; Khisamieva, L.I.; Zefirov, A.L. Effect of alpha2-adrenoceptor stimulation on cardiac activity in rats. Bull. Exp. Biol. Med., 2014, 157(2), 194-197.
Knaus, A.; Zong, X.; Beetz, N.; Jahns, R.; Lohse, M.J.; Biel, M.; Hein, L. Direct inhibition of cardiac hyperpolarization-activated cyclic nucleotide-gated pacemaker channels by clonidine. Circulation, 2007, 115(7), 872-880.
Radwanska, A.; Dlugokecka, J.; Wasilewski, R.; Kaliszan, R. Testing conception of engagement of imidazoline receptors in imidazoline drugs effects on isolated rat heart atria. J. Physiol. Pharmacol., 2009, 60(1), 131-142.
Stabile, A.M.; Aceros, H.; Stockmeyer, K.; Abdel Rahman, A.A.; Noiseux, N.; Mukaddam-Daher, S. Functional and molecular effects of imidazoline receptor activation in heart failure. Life Sci., 2011, 88(11-12), 493-503.
Yarmohmmadi, F.; Rahimi, N.; Faghir-Ghanesefat, H.; Javadian, N.; Abdollahi, A.; Pasalar, P.; Jazayeri, F.; Ejtemaeemehr, S.; Dehpour, A.R. Protective effects of agmatine on doxorubicin-induced chronic cardiotoxicity in rat. Eur. J. Pharmacol., 2017, 796, 39-44.
El-Sayed, S.S.; Zakaria, M.N.; Abdel-Ghany, R.H.; Abdel-Rahman, A.A. Cystathionine-gamma lyase-derived hydrogen sulfide mediates the cardiovascular protective effects of moxonidine in diabetic rats. Eur. J. Pharmacol., 2016, 783, 73-84.
Li, T.; Jiang, S.; Yang, Z.; Ma, Z.; Yi, W.; Wang, D.; Yang, Y. Targeting the energy guardian AMPK: Another avenue for treating cardiomyopathy? Cell. Mol. Life Sci., 2017, 74(8), 1413-1429.
Lambert, E.A.; Sari, C.I.; Eikelis, N.; Phillips, S.E.; Grima, M.; Straznicky, N.E.; Dixon, J.B.; Esler, M.; Schlaich, M.P.; Head, G.A.; Lambert, G.W. Effects of moxonidine and low-calorie diet: cardiometabolic benefits from combination of both therapies. Obesity (Silver Spring), 2017, 25(11), 1894-1902.
Schrover, I.M.; Dorresteijn, J.A.N.; Smits, J.E.; Danser, A.H.J.; Visseren, F.L.J.; Spiering, W. Identifying treatment response to antihypertensives in patients with obesity-related hypertension. Clin. Hypertens., 2017, 23, 20.
Nascimento, A.R.; Machado, M.V.; Gomes, F.; Vieira, A.B.; Goncalves-de-Albuquerque, C.F.; Lessa, M.A.; Bousquet, P.; Tibirica, E. Central sympathetic modulation reverses microvascular alterations in a rat model of high-fat diet-induced metabolic syndrome. Microcirculation, 2016, 23(4), 320-329.
Wang, Y.K.; Yu, Q.; Tan, X.; Wu, Z.T.; Zhang, R.W.; Yang, Y.H.; Yuan, W.J.; Hu, Q.K.; Wang, W.Z. Centrally acting drug moxonidine decreases reactive oxygen species via inactivation of the phosphoinositide-3 kinase signaling in the rostral ventrolateral medulla in hypertensive rats. J. Hypertens., 2016, 34(5), 993-1004.
Honda, N.; Hirooka, Y.; Ito, K.; Matsukawa, R.; Shinohara, K.; Kishi, T.; Yasukawa, K.; Utsumi, H.; Sunagawa, K. Moxonidine-induced central sympathoinhibition improves prognosis in rats with hypertensive heart failure. J. Hypertens., 2013, 31(11), 2300-2308 discussion 2308.
Saczewski, F.; Kornicka, A.; Rybczynska, A.; Hudson, A.L.; Miao, S.S.; Gdaniec, M.; Boblewski, K.; Lehmann, A. 1-[(Imidazolidin-2-yl)imino]indazole. Highly alpha 2/I1 selective agonist: Synthesis, X-ray structure, and biological activity. J. Med. Chem., 2008, 51(12), 3599-3608.
Kornicka, A.; Wasilewska, A.; Saczewski, J.; Hudson, A.L.; Boblewski, K.; Lehmann, A.; Gzella, K.; Belka, M.; Saczewski, F.; Gdaniec, M.; Rybczynska, A.; Baczek, T. 1-[(Imidazolidin-2-yl)imino]-1H-indoles as new hypotensive agents: synthesis and in vitro and in vivo biological studies. Chem. Biol. Drug Des., 2017, 89(3), 400-410.
Saczewski, F.; Kornicka, A.; Hudson, A.L.; Laird, S.; Scheinin, M.; Laurila, J.M.; Rybczynska, A.; Boblewski, K.; Lehmann, A.; Gdaniec, M. 3-[(Imidazolidin-2-yl)imino]indazole ligands with selectivity for the alpha(2)-adrenoceptor compared to the imidazoline I(1) receptor. Bioorg. Med. Chem., 2011, 19(1), 321-329.
Saczewski, J.; Hudson, A.; Scheinin, M.; Rybczynska, A.; Ma, D.; Saczewski, F.; Laird, S.; Laurila, J.M.; Boblewski, K.; Lehmann, A.; Gu, J.; Watts, H. Synthesis and biological activities of 2-[(heteroaryl)methyl]imidazolines. Bioorg. Med. Chem., 2012, 20(1), 108-116.
Boblewski, K.; Lehmann, A.; Saczewski, F.; Saczewski, J.; Kornicka, A.; Marchwinska, A.; Rybczynska, A. Circulatory effect of TCS-80, a new imidazoline compound, in rats. Pharmacol. Rep., 2016, 68(4), 715-719.
Schann, S.; Bruban, V.; Pompermayer, K.; Feldman, J.; Pfeiffer, B.; Renard, P.; Scalbert, E.; Bousquet, P.; Ehrhardt, J.D. Synthesis and biological evaluation of pyrrolinic isosteres of rilmenidine. Discovery of cis-/trans-dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H-pyrrol-2-yl)-amine (LNP 509), an I1 imidazoline receptor selective ligand with hypotensive activity. J. Med. Chem., 2001, 44(10), 1588-1593.
Schann, S.; Greney, H.; Gasparik, V.; Dontenwill, M.; Rascente, C.; Lacroix, G.; Monassier, L.; Bruban, V.; Feldman, J.; Ehrhardt, J.D.; Bousquet, P. Methylation of imidazoline related compounds leads to loss of alpha(2)-adrenoceptor affinity. Synthesis and biological evaluation of selective I(1) imidazoline receptor ligands. Bioorg. Med. Chem., 2012, 20(15), 4710-4715.
Gasparik, V.; Greney, H.; Schann, S.; Feldman, J.; Fellmann, L.; Ehrhardt, J.D.; Bousquet, P. Synthesis and biological evaluation of 2-aryliminopyrrolidines as selective ligands for I1 imidazoline receptors: Discovery of new sympatho-inhibitory hypotensive agents with potential beneficial effects in metabolic syndrome. J. Med. Chem., 2015, 58(2), 878-887.
Ferreira, R.B.; de Oliveira, M.G.; Antunes, E.; Almeida, W.P.; Ibrahim, B.M.; Abdel-Rahman, A.A. New 2-Aminothiazoline derivatives lower blood pressure of spontaneously hypertensive rats (SHR) via I1-imidazoline and alpha-2 adrenergic receptors activation. Eur. J. Pharmacol., 2016, 791, 803-810.
Abas, S.; Erdozain, A.M.; Keller, B.; Rodriguez-Arevalo, S.; Callado, L.F.; Garcia-Sevilla, J.A.; Escolano, C. Neuroprotective effects of a structurally new family of high affinity imidazoline I2 receptor ligands. ACS Chem. Neurosci., 2017, 8(4), 737-742.

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Year: 2019
Page: [95 - 108]
Pages: 14
DOI: 10.2174/1871529X18666180629170336
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