Not first-line antihypertensive agents, but still effective-The efficacy and safety of imidazoline receptor agonists: A network meta-analysis.

Cardiovascular disorders are the leading cause of death in the world. Many organ diseases (kidney, heart, and brain) are substantially more prone to develop in people with hypertension. In the treatment of hypertension, first-line medications are recommended, while imidazoline receptor agonists are not first-line antihypertensives. Our goal was to conduct a network meta-analysis to assess the efficacy and safety of imidazoline receptor agonists. The meta-analysis was performed following the PRISMA guidelines using the PICOS format, considering the CONSORT recommendations. Studies were collected from four databases: PubMed, Cochrane Library, Web of Science, and Embase. A total of 5960 articles were found. After filtering, 27 studies remained eligible for network meta-analysis. Moxonidine reduced blood pressure in sitting position statistically significantly after 8 weeks of treatment (SBP MD: 23.80; 95% CI: 17.45-30.15; DBP MD: 10.90; 95% CI: 8.45-13.35) compared to placebo. Moreover, moxonidine reduced blood pressure more effectively than enalapril; however, this difference was not significant (SBP MD: 3.10; 95% CI: -2.60-8.80; DBP MD: 1.30; 95% CI: -1.25-3.85). Dry mouth was experienced as a side effect in the case of all imidazoline receptor agonists. After 8 weeks of treatment, the appearance of dry mouth was highest with clonidine (OR: 9.27 95% CI: 4.70-18.29) and lowest with rilmenidine (OR: 6.46 95% CI: 0.85-49.13) compared to placebo. Somnolence was less frequent with moxonidine compared to rilmenidine (OR: 0.63 95% CI: 0.17-2.31). Imidazoline receptor agonists were nearly as effective as the first-line drugs in the examined studies. However, their utility as antihypertensives is limited due to their side effects. As a result, they are not first-line antihypertensives and should not be used in monotherapy. However, in the case of resistant hypertension, they are a viable option. According to our findings, from the point of view of safety and efficacy, moxonidine appears to be the best choice among imidazoline receptor agonists.

Autophagy and anti-inflammation ameliorate diabetic neuropathy with Rilmenidine

Purpose: To evaluate the neuroprotective effects of Rilmenidine on diabetic peripheral neuropathy (DPN) in a rat model of diabetes induced by streptozotocin (STZ). Methods: STZ (60 mg/kg) was administered to adult Sprague-Dawley rats to induce diabetes. On the 30th day after STZ administration, electromyography (EMG) and motor function tests confirmed the presence of DPN. Group 1: Control (n = 10), Group 2: DM + 0.1 mg/kg Rilmenidine (n = 10), and Group 3: DM + 0.2 mg/kg Rilmenidine (n = 10) were administered via oral lavage for four weeks. EMG, motor function test, biochemical analysis, and histological and immunohistochemical analysis of sciatic nerves were then performed. Results: The administration of Rilmenidine to diabetic rats substantially reduced sciatic nerve inflammation and fibrosis and prevented electrophysiological alterations. Immunohistochemistry of sciatic nerves from saline-treated rats revealed increased perineural thickness, HMGB-1, tumor necrosis factor-α, and a decrease in nerve growth factor (NGF), LC-3. In contrast, Rilmendine significantly inhibited inflammation markers and prevented the reduction in NGF expression. In addition, Rilmenidine significantly decreased malondialdehyde and increased diabetic rats' total antioxidative capacity. Conclusions: The findings of this study suggest that Rilmenidine may have therapeutic effects on DNP by modulating antioxidant and autophagic pathways.

Over-Prescription of the Imidazoline Receptor Agonists: Evidence for Restriction of the Therapeutic Indication.

BACKGROUND: Major antihypertensive drug classes (but not Imidazoline Receptor Agonists) have been demonstrated to reduce cardiovascular morbidity and mortality. In 2017, Latvia and Lithuania had the highest cardiovascular mortality among the Eastern, Central, Northern, and Western Member States of the European Union (EU). Cardiovascular mortality in Estonia is much lower than in Lithuania and Latvia. OBJECTIVE: To evaluate the consumption of Imidazoline Receptor Agonists in the Baltic States and its potential implications. MATERIALS AND METHODS: The study included data on the sales of Imidazoline Receptor Agonists in Lithuania, Latvia, and Estonia; the marketing authorization databases of the competent authorities; the guidelines on the treatment of hypertension, and the reimbursement conditions. RESULTS: The study showed a very high consumption of the Imidazoline Receptor Agonists in Lithuania and Latvia. From 2016 to 2019, the average consumption of Imidazoline Receptor Agonists in Lithuania was 15.5 times higher than in Estonia; in Latvia, it was 8.9 times higher than in Estonia. The guidelines recommend the use of the Imidazoline Receptors Agonists as one of the last options in hypertension therapy, but the marketing authorizations do not restrict their line of therapy. CONCLUSIONS: Consumption of IRAs in Lithuania and Latvia is very high. The authorized use of the IRAs in the EU Member States is not in line with the guidelines on the management of arterial hypertension and therefore patients might be deprived of therapies that reduce the cardiovascular risk. The drug regulatory authorities of the EU should review the data on the safety and efficacy of the IRAs and restrict their therapeutic indications if necessary.

Stimulation of mTOR-independent autophagy and mitophagy by rilmenidine exacerbates the phenotype of transgenic TDP-43 mice.

Autophagy, which mediates the delivery of cytoplasmic substrates to the lysosome for degradation, is essential for maintaining proper cell homeostasis in physiology, ageing, and disease. There is increasing evidence that autophagy is defective in neurodegenerative disorders, including motor neurons affected in amyotrophic lateral sclerosis (ALS). Restoring impaired autophagy in motor neurons may therefore represent a rational approach for ALS. Here, we demonstrate autophagy impairment in spinal cords of mice expressing mutant TDP-43Q331K or co-expressing TDP-43WTxQ331K transgenes. The clinically approved anti-hypertensive drug rilmenidine was used to stimulate mTOR-independent autophagy in double transgenic TDP-43WTxQ331K mice to alleviate impaired autophagy. Although rilmenidine treatment induced robust autophagy in spinal cords, this exacerbated the phenotype of TDP-43WTxQ331K mice, shown by truncated lifespan, accelerated motor neuron loss, and pronounced nuclear TDP-43 clearance. Importantly, rilmenidine significantly promoted mitophagy in spinal cords TDP-43WTxQ331K mice, evidenced by reduced mitochondrial markers and load in spinal motor neurons. These results suggest that autophagy induction accelerates the phenotype of this TDP-43 mouse model of ALS, most likely through excessive mitochondrial clearance in motor neurons. These findings also emphasise the importance of balancing autophagy stimulation with the potential negative consequences of hyperactive mitophagy in ALS and other neurodegenerative diseases.

Protein kinase C-mediated calcium signaling as the basis for cardiomyocyte plasticity.

Protein kinase C is the superfamily of intracellular effector molecules which control crucial cellular functions. Here, we for the first time did the percentage estimation of all known PKC and PKC-related isozymes at the individual cadiomyocyte level. Broad spectrum of PKC transcripts is expressed in the left ventricular myocytes. In addition to the well-known 'heart-specific' PKCα, cardiomyocytes have the high expression levels of PKCN1, PKCδ, PKCD2, PKCε. In general, we detected all PKC isoforms excluding PKCη. In cardiomyocytes PKC activity tonically regulates voltage-gated Ca2+-currents, intracellular Ca2+ level and nitric oxide (NO) production. Imidazoline receptor of the first type (I1R)-mediated induction of the PKC activity positively modulates Ca2+ release through ryanodine receptor (RyR), increasing the Ca2+ leakage in the cytosol. In cardiomyocytes with the Ca2+-overloaded regions of > 9-10 µm size, the local PKC-induced Ca2+ signaling is transformed to global accompanied by spontaneous Ca2+ waves propagation across the entire cell perimeter. Such switching of Ca2+ signaling in cardiac cells can be important for the development of several cardiovascular pathologies and/or myocardial plasticity at the cardiomyocyte level.

Effect of imidazoline-1 receptor agonists on renal dysfunction in rats associated with chronic, sequential fructose and ethanol administration.

Insulin resistance and chronic alcoholism are risk factors for renal dysfunction. This study investigated the therapeutic effects of two imidazoline-1 receptor (I1R) agonists on renal dysfunction in rats after chronic, sequential fructose and ethanol administration. Daily drinking water was supplemented with fructose (10%, w/v) for 12 weeks and then with ethanol (20%, v/v) for another 8 weeks. Rats were treated with rilmenidine and clonidine in the last two weeks of the study. Blood glucose and serum insulin (sIns) levels, lipid profiles, kidney function and renal histopathology were evaluated at the end of the experiment. Additionally, renal gene expression of nischarin, phosphatidylcholine-specific phospholipase C (PC-PLC) and prostaglandin E2 (PGE2) were measured. Renal levels of superoxide dismutase (SOD), malondialdehyde (MDA), myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS) and total NO (tNO) were detected, and we determined the relative renal gene expression levels of alpha smooth muscle actin (α-SMA), hydroxyproline, interleukin 10 (IL-10), tumour necrosis factor alpha (TNF-α) and caspase-3. The results showed significant deterioration of blood glucose, sIns, lipid profiles, kidney function and renal histopathology in fructose/ethanol-fed rats. Additionally, markers of inflammation, fibrosis, apoptosis and oxidative stress were upregulated. The administration of rilmenidine or clonidine significantly improved blood glucose and sIns levels and reduced renal dysfunction. Our work showed that chronic, sequential fructose and ethanol administration induced fasting hyperglycaemia and renal impairment, and these effects were ameliorated by I1R agonists.

Disturbance of I1-imidazoline receptor signal transduction in cardiomyocytes of Spontaneously Hypertensive Rats.

Imidazoline receptor of the first type (I1R) in addition to the established inhibition of sympathetic neurons may mediate the direct control of myocellular functions. Earlier, we revealed that I1-mediated signaling in the normotensive rat cardiomyocytes suppresses the nitric oxide production by endothelial NO synthase, impairs sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) activity, and elevates intracellular calcium in the cytosol. Also, I1-agonists counteract ß-adrenoceptor stimulation effects in respect to voltage-gated calcium currents. This study ascertains the I1R signal transduction in the normotensive Wistar and SHR cardiomyocytes. Reduction of Ca2+-currents by rilmenidine, a specific agonist of I1R, ensued from the phosphatidylcholine-specific phospholipase C-mediated activation of protein kinase C. There is a stimulation of serine/threonine phosphatase activity. In SHR cardiomyocytes, both the rilmenidine, and putative endogenous ligand, agmatine, almost twofold less effectively reduced L-type of Ca2+-currents. Average mRNA level of Nischarin, established functional component of I1R, is slightly decreased in SHR, as well as the intracellular Nischarin pool immunolabeled in the cytosol of SHR cardiomyocytes. Disturbance of I1R signal transduction in SHR may aggravate the development of this cardiovascular pathology.

Synergism of myocardial ß-adrenoceptor blockade and I1-imidazoline receptor-driven signaling: Kinase-phosphatase switching.

Recently identified imidazoline receptors of the first type (I1Rs) on the cardiomyocyte's sarcolemma open a new field in calcium signaling research. In particular, it is interesting to investigate their functional interaction with other well-known systems, such as ß-adrenergic receptors. Here we investigated the effects of I1Rs activation on L-type voltage-gated Ca2+-currents under catecholaminergic stress induced by the application of ß-agonist, isoproterenol. Pharmacological agonist of I1Rs (I1-agonist), rilmenidine, and the putative endogenous I1-ligand, agmatine, have been shown to effectively reduce Ca2+-currents potentiated by isoproterenol. Inhibitory analysis shows that the ability to suppress voltage-gated Ca2+-currents by rilmenidine and agmatine is fully preserved in the presence of the protein kinase A blocker (PKA), which indicates a PKA-independent mechanism of their action. The blockade of NO synthase isoforms with 7NI does not affect the intrinsic effects of agmatine and rilmenidine, which suggests NO-independent signaling pathways triggered by I1Rs. A nonspecific serine/threonine protein phosphatase (STPP) inhibitor, calyculin A, abrogates effects of rilmenidine or agmatine on the isoproterenol-induced Ca2+-currents. Direct measurements of phosphatase activity in the myocardial tissues showed that activation of the I1Rs leads to stimulation of STPP, which could be responsible for the I1-agonist influences. Obtained data clarify peripheral effects that occur during activation of the I1Rs under endogenous catecholaminergic stress, and can be used in clinical practice for more precise control of heart contractility in some cardiovascular pathologies.

Even weak vasoconstriction from rilmenidine can be unmasked in vivo by opening the baroreflex feedback loop.

AIMS: Rilmenidine and moxonidine are centrally acting antihypertensive agents that are more selective for I1-imidazoline receptors than for α2-adrenergic receptors. Moxonidine previously showed a peripheral vasoconstrictive effect stronger than generally recognized, which counteracted an arterial pressure (AP) lowering effect resulting from central sympathoinhibition. We tested whether rilmenidine also showed a significant vasoconstrictive effect that could attenuate its AP lowering effect. MAIN METHODS: Efferent sympathetic nerve activity (SNA) and AP responses to changes in carotid sinus pressure were compared in nine anesthetized Wistar-Kyoto rats before and after low, medium, and high doses (40, 100, and 250 µg/kg, respectively) of intravenous rilmenidine. KEY FINDINGS: High-dose rilmenidine narrowed the range of the SNA response (from 89.6 ±â€¯2.9% to 50.4 ±â€¯7.9%, P < 0.001) and reduced the lower asymptote of SNA (from 13.5 ±â€¯3.0% to 2.7 ±â€¯1.5%, P < 0.001). High-dose rilmenidine significantly increased the intercept (from 57.1 ±â€¯3.8 to 78.2 ±â€¯2.7 mm Hg, P < 0.001) but reduced the slope (from 0.82 ±â€¯0.08 to 0.51 ±â€¯0.07 mm Hg/%, P < 0.001) of the SNA-AP relationship. The reduction in the operating-point AP induced by high-dose rilmenidine did not significantly differ based on whether the peripheral effect was considered (-19.8 ±â€¯2.2 vs. -26.4 ±â€¯5.3 mm Hg, not significant). SIGNIFICANCE: Rilmenidine increased AP in the absence of SNA, which suggests a peripheral vasoconstrictive effect; however, the vasoconstrictive effect was weak and did not significantly counteract the AP-lowering effect through central sympathoinhibition.

Ameliorative effects of clonidine on ethanol induced kidney injury in rats: Potential role for imidazoline-1 receptor.

Chronic alcoholism is a risk factor for kidney injury. Clonidine is an α2-adrenergic receptor/imidazoline-1 receptor agonist that can reduce blood pressure and maintain renal functions. This study aims to investigate the possible ameliorative effects of clonidine on ethanol induced kidney injury and its mechanism of action. Kidney injury was induced in rats by adding ethanol to drinking water for eight weeks. Clonidine effects on kidney functions and histopathology were measured. Moreover, phentolamine (α-adrenergic receptor antagonist), efaroxan (imidazoline-1 receptor antagonist) and rilmenidine (imidazoline-1 receptor agonist) were used to clarify the role of imidazoline-1 receptor in mediating renal ameliorative effects. Also, the effect of clonidine on liver functions and metabolic changes, in addition to renal oxidative stress, inflammatory and apoptotic pathways were measured. Results showed that, clonidine improved renal functions and reduced ethanol induced renal inflammation and fibrosis. On the other hand, efaroxan, only, blocked clonidine effects on kidney functions. Rilmenidine decreased kidney injury like clonidine. Both clonidine and rilmenidine increased renal nischarin gene expression. Furthermore, clonidine improved liver functions, increased serum insulin and decreased serum advanced glycation end products (metabolic markers). Also, clonidine reduced renal oxidative stress as reflected by decreased myeloperoxidase, malondialdehyde, inducible nitric oxide synthase and total nitric oxide levels and increased superoxide dismutase level. Moreover, clonidine reduced renal tumor necrosis factor-α (inflammatory marker) and caspase-3 (apoptotic marker) levels, while increased renal prostaglandine E2 and interleukin-10 levels (anti-inflammatory markers). In conclusion, clonidine can reduce ethanol induced kidney injury, at least in part, by stimulating imidazoline-1 receptor signaling.

Rilmenidine promotes MTOR-independent autophagy in the mutant SOD1 mouse model of amyotrophic lateral sclerosis without slowing disease progression.

Macroautophagy/autophagy is the main intracellular catabolic pathway in neurons that eliminates misfolded proteins, aggregates and damaged organelles associated with ageing and neurodegeneration. Autophagy is regulated by both MTOR-dependent and -independent pathways. There is increasing evidence that autophagy is compromised in neurodegenerative disorders, which may contribute to cytoplasmic sequestration of aggregation-prone and toxic proteins in neurons. Genetic or pharmacological modulation of autophagy to promote clearance of misfolded proteins may be a promising therapeutic avenue for these disorders. Here, we demonstrate robust autophagy induction in motor neuronal cells expressing SOD1 or TARDBP/TDP-43 mutants linked to amyotrophic lateral sclerosis (ALS). Treatment of these cells with rilmenidine, an anti-hypertensive agent and imidazoline-1 receptor agonist that induces autophagy, promoted autophagic clearance of mutant SOD1 and efficient mitophagy. Rilmenidine administration to mutant SOD1G93A mice upregulated autophagy and mitophagy in spinal cord, leading to reduced soluble mutant SOD1 levels. Importantly, rilmenidine increased autophagosome abundance in motor neurons of SOD1G93A mice, suggesting a direct action on target cells. Despite robust induction of autophagy in vivo, rilmenidine worsened motor neuron degeneration and symptom progression in SOD1G93A mice. These effects were associated with increased accumulation and aggregation of insoluble and misfolded SOD1 species outside the autophagy pathway, and severe mitochondrial depletion in motor neurons of rilmenidine-treated mice. These findings suggest that rilmenidine treatment may drive disease progression and neurodegeneration in this mouse model due to excessive mitophagy, implying that alternative strategies to beneficially stimulate autophagy are warranted in ALS.

MDMA-induced neurotoxicity of serotonin neurons involves autophagy and rilmenidine is protective against its pathobiology.

Toxicity of 3,4-methylenedioxymethamphetamine (MDMA) towards biogenic amine neurons is well documented and in primate brain predominantly affects serotonin (5-HT) neurons. MDMA induces damage of 5-HT axons and nerve fibres and intracytoplasmic inclusions. Whilst its pathobiology involves mitochondrially-mediated oxidative stress, we hypothesised MDMA possessed the capacity to activate autophagy, a proteostatic mechanism for degradation of cellular debris. We established a culture of ventral pons from embryonic murine brain enriched in 5-HT neurons to explore mechanisms of MDMA neurotoxicity and recruitment of autophagy, and evaluated possible neuroprotective actions of the clinically approved agent rilmenidine. MDMA (100 µM-1 mM) reduced cell viability, like rapamycin (RM) and hydrogen peroxide (H2O2), in a concentration- and time-dependent manner. Immunocytochemistry revealed dieback of 5-HT arbour: MDMA-induced injury was slower than for RM and H2O2, neuritic blebbing occurred at 48 and 72 h and Hoechst labelling revealed nuclear fragmentation with 100 µM MDMA. MDMA effected concentration-dependent inhibition of [3H]5-HT uptake with 500 µM MDMA totally blocking transport. Western immunoblotting for microtubule associated protein light chain 3 (LC3) revealed autophagosome formation after treatment with MDMA. Confocal analyses and immunocytochemistry for 5-HT, Hoechst and LC3 confirmed MDMA induced autophagy with abundant LC3-positive puncta within 5-HT neurons. Rilmenidine (1 µM) protected against MDMA-induced injury and image analysis showed full preservation of 5-HT arbours. MDMA had no effect on GABA neurons, indicating specificity of action at 5-HT neurons. MDMA-induced neurotoxicity involves autophagy induction in 5-HT neurons, and rilmenidine via beneficial actions against toxic intracellular events represents a potential treatment for its pathobiology in sustained usage.

Comparison in Conscious Rabbits of the Baroreceptor-Heart Rate Reflex Effects of Chronic Treatment with Rilmenidine, Moxonidine, and Clonidine.

We investigated the effects of chronic subcutaneous treatment with centrally-acting antihypertensive agents moxonidine, rilmenidine, and clonidine on the baroreflex control of heart rate (HR) in conscious normotensive rabbits over 3 weeks. Infusions of phenylephrine and nitroprusside were performed at week 0 and at weeks 1 and 3 of treatment to determine mean arterial pressure (MAP)-HR baroreflex relationships. A second curve was performed after intravenous methscopolamine to determine the sympathetic baroreflex relationship. The vagal component of the reflex was determined by subtracting the sympathetic curve from the intact curve. Clonidine and moxonidine (both 1 mg/kg/day), and rilmenidine (5 mg/kg/day), reduced MAP by 13 ± 3, 15 ± 2, and 13 ± 2 mmHg, respectively, but had no effect on HR over the 3-week treatment period. Whilst all three antihypertensive agents shifted baroreflex curves to the left, parallel to the degree of hypotension, moxonidine and rilmenidine decreased the vagal contribution to the baroreflex by decreasing the HR range of the reflex but moxonidine also increased sympathetic baroreflex range and sensitivity. By contrast clonidine had little chronic effect on the cardiac baroreflex. The present study shows that second generation agents moxonidine and rilmenidine but not first generation agent clonidine chronically shift the balance of baroreflex control of HR toward greater sympathetic and lesser vagal influences. These changes if translated to hypertensive subjects, may not be particularly helpful in view of the already reduced vagal contribution in hypertension.

A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin.

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. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to α2-adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers.

Rilmenidine suppresses proliferation and promotes apoptosis via the mitochondrial pathway in human leukemic K562 cells.

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. Moreover, rilmenidine renders K562 cells, which are particularly resistant to chemotherapeutic agents, susceptible to the DNA damaging drug doxorubicin. The rilmenidine co-treatment with doxorubicin reverses G2/M arrest and triggers apoptotic response to DNA damage. Our data offer new insights into the pathways associated with imidazoline I1 receptor activation in K562 cells suggesting rilmenidine as a valuable tool to deepen our understanding of imidazoline I1 receptor signaling in hematologic malignancies and to search for medicinally active agents.

Prediction of blood-brain barrier permeation of α-adrenergic and imidazoline receptor ligands using PAMPA technique and quantitative-structure permeability relationship analysis.

Imidazoline receptor ligands are a numerous family of biologically active compounds known to produce central hypotensive effect by interaction with both α2-adrenoreceptors (α2-AR) and imidazoline receptors (IRs). Recent hypotheses connect those ligands with several neurological disorders. Therefore some IRs ligands are examined as novel centrally acting antihypertensives and drug candidates for treatment of various neurological diseases. Effective Blood-Brain Barrier (BBB) permeability (P(e)) of 18 IRs/α-ARs ligands and 22 Central Nervous System (CNS) drugs was experimentally determined using Parallel Artificial Membrane Permeability Assay (PAMPA) and studied by the Quantitative-Structure-Permeability Relationship (QSPR) methodology. The dominant molecules/cations species of compounds have been calculated at pH = 7.4. The analyzed ligands were optimized using Density Functional Theory (B3LYP/6-31G(d,p)) included in ChemBio3D Ultra 13.0 program and molecule descriptors for optimized compounds were calculated using ChemBio3D Ultra 13.0, Dragon 6.0 and ADMET predictor 6.5 software. Effective permeability of compounds was used as dependent variable (Y), while calculated molecular parametres were used as independent variables (X) in the QSPR study. SIMCA P+ 12.0 was used for Partial Least Square (PLS) analysis, while the stepwise Multiple Linear Regression (MLR) and Artificial Neural Networks (ANN) modeling were performed using STASTICA Neural Networks 4.0. Predictive potential of the formed models was confirmed by Leave-One-Out Cross- and external-validation and the most reliable models were selected. The descriptors that are important for model building are identified as well as their influence on BBB permeability. Results of the QSPR studies could be used as time and cost efficient screening tools for evaluation of BBB permeation of novel α-adrenergic/imidazoline receptor ligands, as promising drug candidates for treatment of hypertension or neurological diseases.

Comparison of antiallodynic effect of intrathecal morphine, brimonidine and rilmenidine between neuritis and ligation injury induced neuropathic pain.

BACKGROUND: Mechanical allodynia is generally resulted from nerve damage by direct injury or inflammation. Thus, this study was designed to compare the antiallodynic effect of morphine, brimonidine and rilmenidine in two models of neuropathic pain, that is, induced by nerve ligation and neuritis. METHODS: Rats were prepared with tight ligation of the L5/L6 spinal nerves (SNL group) or with Freund's complete adjuvant (FCA) administration evoked sciatic inflammatory neuritis (SIN group). Antiallodynic effects by intrathecal morphine, brimonidine and rilmenidine were measured by applying von Frey filaments to the lesioned hind paw. Thresholds for withdrawal response were assessed and converted to % MPE to obtain an effective dose 50% (ED 50) and a dose response curve. RESULTS: Either SNL group or SIN group showed marked mechanical allodynia in the lesioned hind paw. Antiallodynic effects of morphine were different between two groups. That is ED 50 was 0.16 microgram (SIN) and 8.12 microgram (SNL), and dose response curve of the SIN group shifted left from that of the SNL group. The difference between SIN and SNL groups was statistically significant (P < 0.05). With the brimonidine or rilmenidine administration, ED 50 s were 0.12 microgram (SNL) and 0.37 microgram (SIN) and 2.16 microgram (SIN) and 11.46 microgram (SNL), respectively. And the shift to left of dose response curve from the SNL group is more prominent with rilmenidine administration. CONCLUSIONS: These results suggest morphine and rilmenidine showed a better effect on reducing the mechanical allodynia induced by FCA administration.

Comparison of antiallodynic effect of intrathecal morphine, brimonidine and rilmenidine between neuritis and ligation injury induced neuropathic pain / 대한마취과학회지

BACKGROUND: Mechanical allodynia is generally resulted from nerve damage by direct injury or inflammation. Thus, this study was designed to compare the antiallodynic effect of morphine, brimonidine and rilmenidine in two models of neuropathic pain, that is, induced by nerve ligation and neuritis. METHODS: Rats were prepared with tight ligation of the L5/L6 spinal nerves (SNL group) or with Freund's complete adjuvant (FCA) administration evoked sciatic inflammatory neuritis (SIN group). Antiallodynic effects by intrathecal morphine, brimonidine and rilmenidine were measured by applying von Frey filaments to the lesioned hind paw. Thresholds for withdrawal response were assessed and converted to % MPE to obtain an effective dose 50% (ED 50) and a dose response curve. RESULTS: Either SNL group or SIN group showed marked mechanical allodynia in the lesioned hind paw. Antiallodynic effects of morphine were different between two groups. That is ED 50 was 0.16 microgram (SIN) and 8.12 microgram (SNL), and dose response curve of the SIN group shifted left from that of the SNL group. The difference between SIN and SNL groups was statistically significant (P < 0.05). With the brimonidine or rilmenidine administration, ED 50 s were 0.12 microgram (SNL) and 0.37 microgram (SIN) and 2.16 microgram (SIN) and 11.46 microgram (SNL), respectively. And the shift to left of dose response curve from the SNL group is more prominent with rilmenidine administration. CONCLUSIONS: These results suggest morphine and rilmenidine showed a better effect on reducing the mechanical allodynia induced by FCA administration.

The Effect of Rilmenidine Pretreatment on the Cardiovascular Toxicity Caused by Intravenous Bupivacaine by Autonomic Nervous System Analysis in Anesthetized Cats / 대한마취과학회지

BACKGROUND: This study was designed to assess the effects of rilmenidine on the autonomic nervous system, and to evaluate whether it prevents bupivacaine-induced cardiovascular toxicity during intravenous bupivacaine infusion in anesthetized cats. METHODS: Thirty male cats were randomly divided into a control group (n = 15) and a rilmenidine group (n = 15). Following the injection of rilmenidine (10microgram/kg), systolic blood pressures (SBP) and R-R intervals (RRI) were recorded for 5 minutes. Then power spectral analyses of the SBP and RRI, and transfer function analysis were conducted to evaluate the autonomic nervous system. During the infusion of bupivacaine (0.5 mg/kg/min), blood pressures, heart rates, times to reach each events, and bupivacaine doses were measured at the first QRS modification, the first dysrhythmia, at 25% (HR25) and 50% reductions in baseline heart rate, and at 25% and 50% reductions in baseline mean arterial pressure and at final systole. RESULTS: The high frequency (HF) power of heart rate variability (HRV) was significantly elevated in the rilmenidine group versus the control group. Magnitude HF was significantly higher in the rilmenidine group than in the control group. The onset of dysrhythmia correlated significantly with the HFs of HRV and baroreflex sensitivity (BRS). Except for HR25, the rilmenidine group showed significantly higher bupivacaine doses and delayed event onsets versus the control group. CONCLUSIONS: We suggest that pretreatment with rilmenidine delays the onset of dysrhythmia by increasing vagal tone and BRS and by reducing cardiovascular toxicity when bupivacaine is infused continuously to isoflurane anesthetized cats.

Participação do óxido nítrico no efeito sedativo e antinociceptivo dos agonistas alfa 2 - adrenérgicos / nvolvement of nitric oxide in the sedative and antinociceptive alpha 2 agonist - adrenergic

O mecanismo do efeito sedativo da clonidina (CLO), um agonista alfa2 adrenérgico não é claro. Como a ativação dps receptores alfa2 adrenérgico induz a liberação de óxido nítrico (NO) das células endoteliais, restamos a hipótese de que o efeito sedativo e antinociceptivo da CLO sistêmica dependeria de mecanismos relacionados a via NOGMPc. P 7NI reduziu significativamente o tempo de sono induzido pela clonidina...A CLO (3-120 mg/kg) and RIL induziram efeito antinociceptivo dose-dependente no teste das contorções abdominais e TFL. O efeito antinociceptivo da CLO foi significativamente reduzido pela inibição da NO syntase and guanylyl ciclase. O efeito da RIL também foi reduzido pelo 7-NI. O efeito antinociceptivo da morfina foi inibido pela naloxona, que não inibiu o efeito da CLO. Nossos resultados sugerem que o efeito da CLO sistêmica não envolve receptor opióide e é modulado por uma via NO-GMPc.