Selective Imidazoline Receptor Agonists: redefining the role of centrally acting agents in management of hypertension

Hypertension, often referred to as ‘The silent killer’, is christened so, as it is seldom preceded by any warning signs or symptoms. With the new ACC/AHA guidelines lowering the Blood Pressure (BP) threshold values, it has resulted in a 140% relative increase in the hypertension prevalence in India, which is 3 times higher than that of in United States. Imidazoline receptor agonists control BP effectively with minimal adverse effects of sedation and mental depression that are usually associated with centrally acting antihypertensives. While having a low affinity to the α2-adrenergic receptors, these new generation centrally acting antihypertensive agents are highly selective for imidazoline receptor. Moxonidine, a second-generation centrally acting antihypertensive drug having selective agonist activity on imidazoline I1 receptors and minor activity on imidazoline α2 adrenoceptors, reduces the activity of Sympathetic Nervous System (SNS) by activating I1 imidazoline receptors in Rostral Ventrolateral Medulla (RVLM). Studies of moxonidine have shown equal effectiveness in lowering BP like other well-established antihypertensive drugs such as nifedipine, atenolol or angiotensin-converting enzyme inhibitors, with minimal adverse events. At doses of 0.2-0.6 mg, moxonidine induces satisfactory BP reduction in patients with mild-to-moderate essential hypertension. In patients with mild-to-moderate hypertension, moxonidine (0.2-0.4 mg o.d.) significantly decreased Systolic Blood Pressure/Diastolic Blood Pressure (SBP/DBP), respectively, by 19.5/11.6 mmHg. In obese, non-controlled hypertensive patients, there is a 14% and 13.5% reduction in the mean SBP and DBP, respectively, from the baseline value after moxonidine treatment and during the follow-up with an additional reduction in body weight, plasma leptin levels and Body Mass Index (BMI) (p<0.01). Thus, moxonidine could be considered as a therapeutic option in obese patients with metabolic syndrome.

Effect of I1imidazoline receptor on the expression and function of α2Aadrenergic receptor / 国际药学研究杂志

Objective To investigate the effect of I1imidazoline receptor(I1R)on the expression and function of α2Aadrener-gic receptor(α2AAR)at the cellular level.Methods After sequencing and enzymatic identification,the mouse I1R and α2AAR plas-mids were transfected into CHO cells,respectively.The radioligand receptor binding assay and flow cytometry were used to select sin-gle cell clones,and the CHO cell lines stably expressing the mouse I1R or α2AAR were established.The CHO cell line that stably ex-presses both the mouse I1R and α2AAR were also established by the same technology and strategy.Then,the radioligand receptor bind-ing assay was used to determine the affinity and expression of α2AAR. Further,the effects of I1R on the α2AAR expression and the α2AAR agonist dexmedetomidine(DEX)-induced extracellular regulated protein kinase(ERK)phosphorylation were evaluated by the Western blotting.Results After transfection of mouse I1R and α2AAR plasmids,CHO cells grew normally.In the saturation binding experiments of membrane proteins from the CHO cells that stably expressed α2AAR,the Kdand Bmaxvalues of 3H-RX821002 were(0.96 ± 0.24)nmol/L and(0.29 ± 0.03)nmol/g protein,respectively.The expression levels of I1R were significantly increased in both the CHO cells expressing I1R and the CHO cells co-expressing α2AAR and I1R(P<0.05,P<0.01),when the cells that express exogenous I1R or α2AAR alone were trasfected again with the I1R plasmids.Moreover,in the CHO cells that transfected both I1R and α2AAR sta-bly,the I1R expression upregulated the α2AAR expression(P<0.01),and further increased the ERK phosphorylation induced by DEX through activating α2AAR(P<0.01).Conclusion I1R could upregulate the α2AAR expression and the ERK phosphorylation in-duced by DEX through activating α2AAR in the CHO cells that express exogenous I1R and α2AAR.This study presents a groundwork for further exploration of the relationship between I1R and α2AAR at the molecular level in future.

Effect of agmatine co-administration with yohimbine on morphine-induced behavioral sensitization in mice / 国际药学研究杂志

Objective To investigate the effect of agmatine or agmatine combined with yohimbine on morphine-induced psychological dependence in mice. Methods 1. Testing the effect of agmatine or agmatin combined with yohimbine on basal locomotor activity in 60 minutes. C57BL/6J male mice were divided into four groups: control group, agmatine (1,10,20,40 and 80 mg/kg) groups, yohimbine (0.3,1,2 and 8 mg/kg) groups and yohimbine (2 mg/kg) + agmatine (80 mg/kg) group. 2. Testing theeffects of drug pretreatment on morphine-induced hyperlocomotion in 60 minutes. Mice were divided into five groups: control group, morphine (10 mg/kg) group, agmatine (1,20 and 80 mg/kg) + morphine (10 mg/kg) group,yohimbine (2 mg/kg) + morphine (10 mg/kg) group and yohimbine (2 mg/kg) + agmatine (80 mg/kg) + morphine (10 mg/kg) group. 3. Observing the effects of agmatine or agmatine combined with yohimbine on morphine induced behavioral sensitization. The mice were administrated with morphine (10 mg/kg) on the 1st , 4th and 7th day and the locomotor activity of mice was recorded for 60 minutes. Mice were divided into four groups: control group, morphine (10 mg/kg) group, agmatine (1,20 and 80 mg/kg) + morphine (10 mg/kg) groups and yohimbine (2 mg/kg) + agmatine (80 mg/kg) + morphine (10 mg/kg) group. Results Our present study showed that agmatine (1-80 mg/kg) or yohimbine (0.3-2 mg/kg), a selective antagonist of a2-adrenoceptor, had no significant effect on basal locomotor and acute morphine-induced hyperlocomotion compared with those of control group. However, the distance in the group of agmatine combined with yohimbine followed by morphine for 60 min was (22 581.6&11 694.0) cm, which was significantly lower than the acute morphine group(37 577.9±9 657.4) cm(#<0.05). In the mophine-induced behavioral sensitization model, agmatine (1,20 and 80 mg/kg) alone had no effect on morphine-induced development of behavioral sensitization in mice. But, the combination of the two drugs significantly attenuated morphine-induced behavioral sensitization. The locomotor activities in the combination treatment groups were (21 112.7±5 586.7) cm, (37 672.7±10 518.8) cm and 47 681.0±15 845.3 cm, which were lower than those of morphine group (31 156.4&8 010.5) cm(#<0.01), (51 724.9&11 364.51) cm (P<0.05) and (63 572.2&12 151.2) cm (P<0.05) on the 1st , 4th and 7th day of experiment, respectively. Conclusion Our current results demonstrated that agmatine combined with yohimbine could decrease morphine-induced psychological dependence in mice. It may provide a new strategy for psychological dependence of morphine.

Effect of agmatine co-administration with yohimbine on morphine-induced behavioral sensitization in mice / 国际药学研究杂志

Objective To investigate the effect of agmatine or agmatine combined with yohimbine on morphine-induced psychological dependence in mice. Methods 1. Testing the effect of agmatine or agmatin combined with yohimbine on basal locomotor activity in 60 minutes. C57BL/6J male mice were divided into four groups:control group, agmatine (1,10,20,40 and 80 mg/kg) groups, yohimbine(0.3,1,2 and 8 mg/kg) groups and yohimbine(2 mg/kg)+ agmatine(80 mg/kg) group. 2. Testing the effects of drug pretreatment on morphine-induced hyperlocomotion in 60 minutes. Mice were divided into five groups: control group, morphine(10 mg/kg) group, agmatine(1,20 and 80 mg/kg)+ morphine(10 mg/kg) group,yohimbine(2 mg/kg)+ morphine(10 mg/kg) group and yohimbine(2 mg/kg)+ agmatine(80 mg/kg)+ morphine(10 mg/kg) group. 3. Observing the effects of agmatine or agmatine combined with yohimbine on morphine induced behavioral sensitization. The mice were administrated with morphine(10 mg/kg) on the 1st , 4th and 7th day and the locomotor activity of mice was recorded for 60 minutes. Mice were divided into four groups: control group, morphine(10 mg/kg) group, agmatine(1,20 and 80 mg/kg) + morphine(10 mg/kg) groups and yohimbine (2 mg/kg)+ agmatine(80 mg/kg)+ morphine(10 mg/kg) group. Results Our present study showed that agmatine(1-80 mg/kg) or yohimbine (0.3-2 mg/kg), a selective antagonist of α2-adrenoceptor, had no significant effect on basal locomotor and acute morphine-induced hyperlocomotion compared with those of control group. However, the distance in the group of agmatine combined with yohimbine followed by morphine for 60 min was(22 581.6±11 694.0) cm,which was significantly lower than the acute morphine group(37 577.9±9 657.4)cm(P<0.05). In the mophine-induced behavioral sensitization model, agmatine(1,20 and 80 mg/kg) alone had no effect on morphine-induced development of behavioral sensitization in mice. But, the combination of the two drugs significantly attenuated morphine-induced behavioral sensitization. The locomotor activities in the combination treatment groups were (21 112.7±5 586.7)cm,(37 672.7±10 518.8)cm and(47 681.0±15 845.3)cm, which were lower than those of morphine group (31 156.4±8 010.5) cm(P<0.01),(51 724.9±11 364.51)cm(P<0.05) and(63 572.2±12 151.2) cm(P<0.05) on the 1st , 4th and 7th day of experiment, respectively. Conclusion Our current results demonstrated that agmatine combined with yohimbine could decrease morphine-induced psychological dependence in mice. It may provide a new strategy for psychological dependence of morphine.

Effects of Intra-articular Injection of Agmatine and Clonidine into the Knee Joint Cavity on the Induction and Maintenance of Arthritic Pain in Rats / 대한마취과학회지

BACKGROUND: Previous studies suggest that systemic administration of agmatine, endogenous ligand for imidazoline receptors has anti-hypernociceptive effects in experimental animal. However the peripheral effects of agmatine on inflammatory pain have not yet been elucidated. Here we examined the effects of intra-articular injection of agmatine in the induction and maintenance phase of arthritic pain. In addition, we sought to determine the potential contribution of imidazoline and alpha(2)-adrenergic receptors to the antinociceptive effects using clonidine which is mixed alpha(2)-adrenoceptor and imidazoline receptor agonist. METHODS: To induce arthritis in rats, 2% lambda-carrageenan (50microliter, in saline) was injected into the joint of the right hind limb under enflurane anesthesia. Either agmatine (10, 50, 100microgram/40microliter) or clonidine (10, 50, 100microgram/40microliter) was injected into the knee joint cavity immediately before or 4 hr after carrageenan injection. Weight load tests were performed to measure pain-related behavior in freely walking rats. RESULTS: The intraarticular injection of agmatine into the knee joint had no effects in the both phase of induction and maintenance of arthritic pain at any dose tested. However, injection of clonidine reversed arthritic pain, when injected 4 h after carrageenan injection. CONCLUSIONS: In rats, agmatine has no peripheral effect on inflammatory pain and imidazoline receptors in the periphery may not contribute to the anti-inflammatory pain.

Monoaminergic Activity by Drugs Acting on Adrenergic alpha2-receptors in Rat Hippocampus and Primary Visual Cortex / 대한정신약물학회지

OBJECTIVE: The aim of the this study was to compare the effects of clonidine (a alpha2-adrenoceptor and imidazoline receptor agonist), yohimbine (a selective alpha2-adrenoceptor antagonist) and idazoxan (a alpha2-adrenoceptor and imidazoline receptor antagonist) on extracellular monoamines and their metabolites by using the awakening animal microdialysis and high-performance liquid chromatography with electrochemical detection (HPLC-ECD) in brain regions, which are suggested to have regulatory role in depression. METHODS: We used intracerebral microdialysis in awakening rats by inserting probe through the dorsal hippocampus and occipital cortex especially in primary visual cortex, We studied respective effects of 2.0 mg/kg of clonidine, 5.0 mg/kg of yohimbine, and 5.0 mg/kg of idazoxan on the release of MHPG (a major metabolite of norepinephrine), norepinephrine (NE), DOPAC (a major metabolite of dopamine), and 5-HIAA (a main metabolite of serotonin) by intraperitoneal administration. RESULTS: Clonidine decreased the release of MHPG, NE, DOPAC, and 5-HIAA in both dorsal hippocampus and occipital cortex regions, and there were no significant differences in releasing pattern of all monoamines and their metabolites. Both yohimbine and idazoxan enhanced the release of MHPG, NE, DOPAC, and 5-HIAA in both brain regions, but there were significant differences in releasing pattern of NE and 5-HIAA. Idazoxan induced the delayed and higher efflux of NE and 5-HIAA in the primary visual cortex than yohimbine, but not in the hippocampus. CONCLUSION: This study shows that the selective alpha2-adrenoceptor antagonists increase basal monoamine output and enhance the metabolism of them in the hippocampus and primary visual cortex, and the imidazoline receptor has modulatory role in the regulation of monoamine release in primary visual cortex than hippocampus. It also suggests that high turnover rate of serotonin and norepinephrine in primary visual cortex may contribute to the pathophysiological role in depression.

Effects of clonidine on the expression of myocardial Gi? after severe scald in rats / 第三军医大学学报

Objective To investigate the effects of clonidine on the expression of myocardial ? subunit of inhibitory G protein (Gi?) in severely scalded rats and the mechanisms. Methods A scald model of 30% total body surface area Ⅲdegree burn on the back of rats was established. The basal and Gpp (NH) p, forsklin stimulated activity of adenylate cyclase (AC), and Gi? in cardiac myocytes were determined by indirect enzyme radiochemical assay and Western blotting, respectively. Results Clonidine at the dosage of 1-3 mg?kg -1 inhibited significantly the increase in the myocardial Gi? levels. Clonidine at the dosage of 0.3-3 mg?kg -1 partially reversed the decrease in the basal activity, and clonidine at the dosage of 1-3 mg?kg -1 showed the similar effect on the decrease in the Gpp (NH) p stimulated activity. Efaroxan, an I 1 imidazoline receptor antagonist, could partially reverse the inhibitory effect of clonidine on myocardial Gi? levels. Conclusion Clonidine can inhibit the elevation of myocardial Gi? levels, and the mechanisms of the inhibition may possibly be associated with the stimulatory effect of clonidine on I 1 imidazoline receptors.

Progress in study of a novel protein Nischarin / 中国药理学通报

Nischarin is a novel protein interacting with integrin ?5 subunit.A series of studies have indicated that Nischarin plays an important role in inhibiting tumor cells migration and invasion.Meanwhile it may also serve as the functional I1-imidazoline receptor.To study this protein will be in favour of understanding the biological mechanisms of inhibiting cell migration and developing novel drugs such as inhibitors for tumor invasion.The article mainly reviews the recent progress in studies on Nischarin.

The analgesic effect of agmatine on inflammatory pain and its influence on the analgesic effect of morphine / 中国药理学通报

Aim To evaluate the analgesic effect of agmatine on inflammatory pain and its influence on the analgesic effect of morphine. To investigate whether the mechanism of analgesic effect of agmatine is related to activation of imidazoline receptor or to affect the release of endogenous glutamate and gamma-aminobutyric acid (GABA) from rat spinal cord slices. Methods The formalin test in rats was used as a long-lasting inflammatory pain model. Effects of agmatine on basal and K+ evoked release of endogenous glutamate and GABA from rat spinal cord slices were determined by high performance liquid chromatography (HPLC). Results Pretreatment with agmatine (ip or sc) inhibited the second phase of the nociceptive response of rats and potentiated the analgesic effect of morphine in phase 2, but not in phase 1. Idazoxan did not attenuate the analgesic effect of agmatine. Agmatine (1, 10, 100, 1000 ?mol?L -1 ) had no effect on the basal release of glutamate and GABA from spinal cord slices, nor did it affect the K+ (50 mmol?L -1 ) evoked release of glutamate and GABA contents. Conclusions Agmatine has an analgesic effect and enhances morphine analgesia in the second but not the first phase of formalin-induced nociception. Its analgesic effect does not likely involve imidazoline receptor. The mechanism of the analgesic effect of agmatine may not be associated with inhibiting glutamate release nor increasing the GABA content.

The Effect of Intradermal Norepinephrine on Allodynia in a Neuropathic Pain Rat Model / 대한마취과학회지

BACKGROUND: A spinal nerve ligation (SNL) injury may produce a neuropathic pain syndrome that includes tactile allodynia. This pain state may be diminished by sympathectomy. Intradermal (I.D.) injection of norepinephrine (NE) evokes pain in patients with sympathetically maintained pain. Recently, we reported the effect of intrathecal (I.T.) brimonidine and rilmenidine on the sympathetic nervous system. Therefore, we conducted a behavioral test to investigate the effects of sympathetic stimulation by I.D. NE on mechanical allodynia in rats with a SNL injury. METHODS: Male SD rats were prepared with ligation of the left lumbar 5th and 6th spinal nerves and lumbar I.T. catheter implantation. NE 10ng I.D. was administered in normal and SNL rats to investigate the change of cutaneous sensitivity to tactile stimuli. NE 30ng I.D. was administered before and after I.T. injection of brimonidine 3ng and rilmenidine 30ng in SNL rats. Using a von Frey hair (VFH) test, we examined the effects of NE on the withdrawal threshold. Allodynic thresholds for the withdrawal response of the lesioned hindpaw to VFH stimuli were assessed. RESULTS: Intradermal NE produced a reduction of the withdrawal threshold in normal and allodynic rats. An allodynic state induced by a SNL was aggravated by NE. In allodynic rats, the baseline threshold of a lesioned left hindpaw was markedly low and such a state was maintained during the behavioral experiment. The antiallodynic effects of I.T. brimonidine and rilmenidine were produced in both pre- and post-treatment of NE. CONCLUSIONS: The results suggest that a sympathetic component is likely involved in the mechanism of mechanical allodynia produced by a SNL injury.

Contribution of imidazoline receptors in caudal ventrolateral medulla to central depressor effect of clonidine / 第二军医大学学报

Objective:To explore the roles of the caudal ventrolateral medulla(CVLM) in the central anti-hypertensive mechanism. Methods : In 20 urethane-anesthetized SD rats, the effects of I1-imidazoline receptor and ?2-adrenceptor antagonists (microinjection into the CVLM) on the cardiovascular responses induced by intravenous clonidine were observed. Results: Prior bilateral microinjection of mixed antagonist idazoxan (I1-imidazoline receptor and a2-adrenceptor) into the CVLM not only decreased the mean arterial pressure [(-17. 3 ? 6. 9) mmHg, 1 mmHg = 0. 133 kPa, P

Complicated and diverse effects of agmatine on central nervous system / 中国药理学通报

Agmatine was first identified and characterized as a candidate for CDS (clonidine displacing substance) in the bovine brain in 1994. The following researches demonstrated that agmatine was a widely distributed endogenous substance and performed a lot of biological functions in the central nervous system. The evidences revealed its targets were diverse and its mechanisms were complicated. Now it is well accepted that agmatine is a new neurotransmitter and/or neuromodulator and it might be an endogenous ligand of imidazoline receptor.

Imidazoline binding sites and receptors related with cardiovascular functions / 中国药理学通报

I 2 Imidazoline binding sites have been shown to exist on cardiac myocytes of human beings and rat. Both of I 1 and I 2 imidazoline binding sites have been identified on vascular smooth muscle cells of various species. Vascular I 2 imidazoline binding sites may participate in vascular smooth muscle proliferation. The sympathetic nerves supplying the cardiovascular system are endowed with presynaptic inhibitory imidazoline receptors. Being different from most of the imidazolines, moxonidine does not activate presynaptic imidazoline receptors, but SR141716A, which is considered as a selective antagonist at cannabinoid receptors, antagonizes presynaptic imidazoline receptors. It has been shown that imidazolines exhibit antiarrhythmic action. Agamatine, which is endogenous ligand at imidazoline receptors, not only decreases the rate of pacemaker firing in sinoatrial node of animal, prolongs action potential duration on cardiac myocytes of human beings and animal, but also inhibits afterdepolarizations induced by isoproterenol. On the other hand, imidazolines and guanidines inhibit the cardiovascular K ATP channel in a noncompetitive manner, those effects might interfere with the cardioprotective effects of K ATP channel.

Mechanism of aqueous humor through uveoscleral outflow in rabbits with topical administration of moxonidine / 西安交通大学学报(医学版)

Objective To investigate the changes of uveoscleral pathway by an I1 receptor agonist,moxonidine,and with pretreatment of antagonists topical administration,and to study the mechanism that moxonidine improves uveoscleral outflow.Methods Moxonidine was administered unilaterally and topically to rabbits and with pretreatment of the antagonists,namely,prazosin,yohimbine and efaroxan.FITC-BSA,a tracer agent,was injected into the anterior chamber after moxonidine treatment or with pretreatment of the antagonists.Frozen sections were undertaken at different time points between 2 to 10 h.Fluorescence intensity was observed in the sites of uveoscleral pathway in the sections by fluorescence microscopy.Results Bilateral fluorescence intensity treated with moxonidine was more intense than that with placebo,and the most intense regions of fluorescence were ciliary body and superchoroidal space.Fluorescence intensity by prazosin pretreatment was not significantly different compared to that by moxonidine,while yohimbine and efaroxan pretreatment decreased the intensity compared with moxonidine(P

The effect of imidazoline receptor agonist-moxonidine on the His bundle electrogram in vivo / 西安交通大学学报(医学版)

Objective To study the effect of moxonidine (Mox) on the His bundle electrogram (HBE) of normal rabbits. Methods A total of 24 healthy rabbits were randomly divided into four groups: control group, small dose of Mox (0.1 mg?kg -1), medium dose of Mox (0.3 mg?kg -1) and large dose of Mox (0.9 mg?kg -1). The electrode catheter was inserted from the right carotid artery to record the HBE. The HBE and the synchronism surface ECG were recorded before and after intravenous injection. Results In normal rabbits, the R-R interphase, P-R interphase of the ECG and the H-V interphase of the HBE were prolonged in a dose-dependent manner after intravenous injection of Mox. Mox exerted no significant influence on the A-H interphase. Conclusion ① Mox decreases the heart rate of rabbits in a dose-dependent manner in vivo. ② Mox dose-dependently prolongs the P-R interphase of the surface ECG and the H-V interphase of HBE. This indicates that Mox mainly acts on the intraventricular conducting system.