MARRIAGE: A Randomized Trial of Moxonidine Versus Ramipril or in Combination With Ramipril in Overweight Patients With Hypertension and Impaired Fasting Glucose or Diabetes Mellitus. Impact on Blood Pressure, Heart Rate and Metabolic Parameters.

BACKGROUND: Moxonidine, an imidazoline I1 receptor agonist, is an effective antihypertensive drug that was shown to improve insulin sensitivity. RAAS-blockers are recommended as first-line therapy in patients with diabetes, alone or in combination with a calcium-channel antagonist or a diuretic. AIMS: This study compared the effects of moxonidine and ramipril on blood pressure (BP) and glucose metabolism in overweight patients with mild-to-moderate hypertension and impaired fasting glucose or type 2 diabetes. METHODS: Treatment-naïve patients for hypertension and dysglycemia were randomized to 12 weeks of double-blind moxonidine 0.4 mg or ramipril 5 mg once-daily treatment. At 12 weeks, for a further 12 weeks non-responders received combination of mox/ram, while responders continued blinded treatment. RESULTS: Moxonidine and ramipril were equivalent in lowering SiDBP and SiSBP at the end of the first 12 weeks. The responder rate was approximately 50% in both groups, with a mean SiDBP and SiSBP decrease of 10 and 15 mm Hg in the responders, respectively. The normalization rate (SiDBP < 85 mm Hg) was non significantly different between treatments groups. Moxonidine reduced heart rate (HR) (average -3.5 bpm, p = 0.017) during monotherapy, and when added to ramipril. HbA1c decreased significantly at Week 12 in both groups. Neither drug affected glucose or insulin response to the oral glucose tolerance test. In non-responders, moxonidine/ramipril combination further reduced BP without compromising metabolic parameters. CONCLUSION: Moxonidine 0.4 mg and ramipril 5 mg were equally effective on BP lowering and were well tolerated and mostly metabolically neutral either as monotherapies or in combination. HR was lowered on moxonidine treatment.

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.

Moxonidine Increases Uptake of Oxidised Low-Density Lipoprotein in Cultured Vascular Smooth Muscle Cells and Inhibits Atherosclerosis in Apolipoprotein E-Deficient Mice.

This study aimed to investigate the effect of the sympatholytic drug moxonidine on atherosclerosis. The effects of moxonidine on oxidised low-density lipoprotein (LDL) uptake, inflammatory gene expression and cellular migration were investigated in vitro in cultured vascular smooth muscle cells (VSMCs). The effect of moxonidine on atherosclerosis was measured by examining aortic arch Sudan IV staining and quantifying the intima-to-media ratio of the left common carotid artery in apolipoprotein E-deficient (ApoE-/-) mice infused with angiotensin II. The levels of circulating lipid hydroperoxides in mouse plasma were measured by ferrous oxidation-xylenol orange assay. Moxonidine administration increased oxidised LDL uptake by VSMCs via activation of α2 adrenoceptors. Moxonidine increased the expression of LDL receptors and the lipid efflux transporter ABCG1. Moxonidine inhibited mRNA expression of inflammatory genes and increased VSMC migration. Moxonidine administration to ApoE-/- mice (18 mg/kg/day) decreased atherosclerosis formation in the aortic arch and left common carotid artery, associated with increased plasma lipid hydroperoxide levels. In conclusion, moxonidine inhibited atherosclerosis in ApoE-/- mice, which was accompanied by an increase in oxidised LDL uptake by VSMCs, VSMC migration, ABCG1 expression in VSMCs and lipid hydroperoxide levels in the plasma.

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.

Assessment of drug-drug interactions between moxonidine and antiepileptic drugs in the maximal electroshock seizure test in mice.

Hypertension is a common comorbid condition with epilepsy, and drug interactions between antihypertensive and antiepileptic drugs (AEDs) are likely in patients. Experimental studies showed that centrally active imidazoline compounds belonging to antihypertensive drugs can affect seizure susceptibility. The purpose of this study was to assess the effect of moxonidine, an I1 -imidazoline receptor agonist, on the anticonvulsant efficacy of numerous AEDs (carbamazepine, phenobarbital, valproate, phenytoin, oxcarbazepine, topiramate and lamotrigine) in the mouse model of maximal electroshock. Besides, the combinations of moxonidine and AEDs were investigated for adverse effects in the passive avoidance task and the chimney test. Drugs were administered intraperitoneally (ip). Moxonidine at doses of 1 and 2 mg/kg ip did not affect the convulsive threshold. Among tested AEDs, moxonidine (2 mg/kg) potentiated the protective effect of valproate against maximal electroshock. This interaction could be pharmacodynamic because the brain concentration of valproate was not significantly changed by moxonidine. The antihypertensive drug did not cause adverse effects when combined with AEDs. This study shows that moxonidine may have a neutral or positive effect on the anticonvulsant activity of AEDs in patients with epilepsy. The enhancement of the anticonvulsant action of valproate by moxonidine needs further investigations to elucidate potential mechanisms involved.

Influence of Moxonidine and Bisoprolol on Morphofunctional Condition of Arterial Wall and Telomerase Activity in Postmenopausal Women with Arterial Hypertension and Osteopenia. The Results from a Moscow Randomized Study.

PURPOSE: To compare the effect of 12 months of treatment with moxonidine or bisoprolol on telomerase activity (TA) and parameters characterizing the arterial wall state in postmenopausal women with arterial hypertension (AH) and osteopenia. METHODS: An open-label randomized study with 114 postmenopausal women with hypertension and osteopenia; pulse wave velocity (PWV), intima-media thickness (IMT), and TA were analyzed initially and after 12 months of therapy with moxonidine (n = 57) or bisoprolol (n = 57). RESULTS: Both medications effectively lowered blood pressure (BP) in both groups. After 12 months, the moxonidine group showed a significant increase in TA by 45.5% (from 0.87 to 1.15; p < 0.001), in contrast to the bisoprolol group, where TA decreased by 14.1% (from 0.89 to 0.74; p = 0.001). Within 12 months, in the moxonidine group, PWV decreased by 1.9% (from 10.35 ± 2.56 to 10.05 ± 2.29 m/s; p = 0.039), and in the bisoprolol group it increased by 5.8% (from 10.36 ± 2.47 to 11.26 ± 2.60 m/s; p < 0.001). In the moxonidine group, IMT increased by 3.5% on the right and 1.4% on the left, in the bisoprolol group - by 5.7% on the right and 4.2% on the left. CONCLUSION: A 12-month treatment with moxonidine but not with bisoprolol in postmenopausal women with AH and osteoporosis was associated with a decrease of arterial stiffness seen as statistically significantly reduced PVW and with increased TA.

The use of moxonidine in the treatment of arterial hypertension.

Moxonidine is an oral antihypertensive drug from the group of 2nd generation sympatholytics. In patients with mild to moderate hypertension, moxonidine lowers blood pressure (BP) as effectively as most first-line antihypertensives when used as monotherapy - if appropriate, and is also an effective adjunctive therapy in combination with other antihypertensives. It improves metabolic profile in patients with hypertension and diabetes mellitus or impaired glucose tolerance, is very well tolerated, has a low potential for drug interactions and is administered in a single daily dose. Thus, moxonidine is a good choice especially in the treatment of patients with more severe forms of hypertension, especially as adjunctive therapy in patients with metabolic syndrome or with mental stress.

[Features of antihypertensive therapy and real-world prescription of selective imidazoline receptor agonists in Russia vs other countries: STRAIGHT study data analysis].

Analysis of routine clinical practice of hypertensive patient management represents one of the important tools in the search for further ways to minimize hypertension-associated cardiovascular and renal adverse outcomes. AIM: To compare the strategies for hypertension management and features of clinical use of I1-imidazoline receptor (I1-IR) agonists in the Russian Federation and other countries where the STRAIGHT (Selective imidazoline receptor agonists Treatment Recommendation and Action In Global management of HyperTension) study was conducted. MATERIALS AND METHODS: It was a cross-sectional online study involving physicians of various specializations. The study was conducted from January 18 to July 1, 2019, in seven countries with a high rate of I1-IR agonist prescription, including Russia. RESULTS: A total of 125 (4.5%) responders filled out the survey in the Russian Federation, which was somewhat lower than in other countries (6.8%). The participants were mostly general practitioners (54.0%) and cardiologists (42.0%), while in other countries greater diversity was seen. Most Russian physicians (83.0%) seemed to rely on national clinical guidelines in their routine practice, while in other countries the US guidelines were more popular (66.0%). The majority of responders stated that they took into account the traditional risk factors of hypertension when initiating the therapy; every second responder noted if sleep apnea was present. Awareness of I1-IR agonists, their prescription rate and their preference were higher in Russia. The main reported benefits of I1-IR agonists were their efficacy, including in resistant hypertension, and their metabolic effects (in Russia). Most participants preferred I1-IR agonists as third-line therapy (65.0% in Russia vs 60.0% in other countries) and in combination with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blockers (ARB) (55.0% in Russia vs 54.0% in other countries). Compared to responders from other countries, Russian physicians prescribe I1-IR agonists as first-line (15.0% vs 5.0%) and second-line (48.0% vs 21.0%) therapy more often. CONCLUSION: Russian physicians were the most aware of I1-IR agonists and tended to prescribe drugs of this class for hypertension management more often, and I1-IR agonist combination with ACEi was preferable compared to physician responders from other countries. Antihypertensive efficacy and metabolic effects were reported as the major benefits of I1-IR agonist therapy.

Quantitative analysis by reversed-phase high-performance liquid chromatography and retinal neuroprotection after topical administration of moxonidine.

AIM: To determine moxonidine in aqueous humor and iris-ciliary body by reversed-phase high performance liquid chromatography (RP-HPLC), and to evaluate the retinal neuroprotective effect after topical administration with moxonidine in a high intraocular pressure (IOP) model. METHODS: The eyes of albino rabbits were administered topically and ipsilaterally with 0.2% moxonidine. A RP-HPLC method was employed for the identification and quantification of moxonidine between 2 and 480min, which presented in the aqueous humor and iris-ciliary body. Flash electroretinography (F-ERG) amplitude and superoxide dismutase (SOD) level were measured between day 1 and day 15 after topical administration with moxonidine in a rabbit model of high IOP. Histological and ultrastructural observation underwent to analyze the changes of retinal morphology, the inner retinal layers (IRL) thickness, and retinal ganglion cell (RGC) counting. RESULTS: Moxonidine was detectable between 2 and 480min after administration, and the peak concentration developed both in the two tissues at 30min, 0.51 µg/mL in aqueous humor and 1.03 µg/g in iris-ciliary body. In comparison to control, F-ERG b-wave amplitude in moxonidine eyes were significantly differences between day 3 and day 15 (P<0.01) in the high IOP model; SOD levels were significantly higher at all time-points (P<0.01) with a maximum level of 20.29 U/mgprot at day 15; and RGCs were significantly higher (P<0.05). CONCLUSION: Moxonidine is a viable neuroprotective agent with application to high IOP model. All layers of retina, including RGC layer, retinal nerve fiber layer and INL, are more preserved after moxonidine administration. SOD plays a neuroprotective role in ocular hypertension-mediated RGC death.

Moxonidine inhibits excitatory inputs to airway vagal preganglionic neurons via activation of both α2-adrenoceptors and imidazoline I1 receptors.

As an imidazoline I1 receptor agonist with very weak binding affinity for α2-adrenoceptors, moxonidine is commonly used in the treatment of hypertension. Moxonidine also has been implicated to act centrally to reduce airway vagal outflow. However, it is unknown at which central sites moxonidine acts to affect airway vagal activity, and how moxonidine takes effect at synaptic and receptor levels. In this study, airway vagal preganglionic neurons (AVPNs) were retrogradely labeled in neonatal rats from the intrathoracic trachea; retrogradely labeled AVPNs in the external formation of the nucleus ambiguus (NA) were identified in rhythmically active medullary slices using whole-cell patch-clamp techniques; and the effects of moxonidine on the spontaneous excitatory postsynaptic currents (EPSCs) of AVPNs were observed at synaptic level. The results show that moxonidine (10 µmol·L-1) significantly inhibited the frequency of spontaneous EPSCs in both inspiratory-activated and inspiratory-inhibited AVPNs. This effect was partially blocked by SKF-86466 (10 µmol·L-1), a highly selective antagonist of α2-adrenoceptors, or AGN-192403, a selective antagonist of imidazoline I1 receptors, and was completely blocked by efaroxan (10 µmol·L-1), an antagonist of both α2-adrenoceptors and imidazoline I1 receptors. These results demonstrate that moxonidine inhibits the excitatory inputs to AVPNs via activation of both α2-adrenoceptors and imidazoline I1 receptors, and suggest that physiologically both of these two types of receptors are involved in the central regulation of airway vagal activity at preganglionic level. Moxonidine might be potentially useful in diseases with aberrant airway vagal activity such as asthma and chronic obstructive diseases.

Effect of Central Sympathoinhibition With Moxonidine on Sympathetic Nervous Activity in Polycystic Ovary Syndrome-A Randomized Controlled Trial.

Sympathetic nervous system (SNS) activity is increased in polycystic ovary syndrome (PCOS). Moxonidine is a centrally acting sympatholytic drug with known beneficial effects on hypertension, insulin sensitivity, dyslipidemia and inflammation. In this double-blind placebo controlled randomized clinical trial we examined the effect of moxonidine on modulating sympathetic activity and downstream metabolic abnormalities in 48 pre-menopausal women with PCOS (Rotterdam diagnostic criteria), recruited from the community (January 2013-August 2015). Participants received moxonidine (0.2 mg daily initially, up titrated to 0.4 mg daily in 2 weeks) (n = 23) or placebo (n = 25) for 12 weeks. Multiunit muscle sympathetic activity (by microneurography) and plasma noradrenaline levels were measured (primary outcomes). Fasting lipids, insulin resistance, serum androgens, and inflammatory markers were measured as secondary outcomes. Forty three women completed the trial (19 moxonidine, 24 placebo). Mean change in burst frequency (-3 ± 7 vs. -3 ± 8 per minute) and burst incidence (-3 ± 10 vs. -4 ± 12 per 100 heartbeat) did not differ significantly between moxonidine and placebo groups. Women on moxonidine had a significant reduction in hs-CRP compared to placebo group (-0.92 ± 2.3 vs. -0.04 ± 1.5) which did not persist post Bonferroni correction. There was a significant association between markers of insulin resistance at baseline and reduction in sympathetic activity with moxonidine. Moxonidine was not effective in modulating sympathetic activity in PCOS. Anti-inflammatory effects of moxonidine and a relationship between insulin resistance and sympathetic response to moxonidine are suggested which need to be further explored. Clinical Trial Registration Number: (NCT01504321).

[New possibilities of using moxonidin for blood pressure control in female patients with osteopenia].

OBJECTIVE: To assess the effect of moxonidine on bone metabolism and bone mineral density (BMD) in postmenopausal patients with arterial hypertension (AH) and osteopenia. MATERIALS AND METHODS: A randomized, open, clinical trial included 114 postmenopausal patients with AH. All participants were evaluated bone metabolism), BMD, telomerase activity (TA). Randomization was carried out into 2 groups (moxonidine and bisoprolol therapy) using simple envelopes. After 12 months of therapy, a dynamic examination was performed. RESULTS: Both groups showed a positive effect of both moxonidine and bisoprolol on hypertension during treatment both as monotherapy and in the group of patients receiving combined antihypertensive therapy: a decrease in SBP and DBP in the 1st group was 13.6% and 12.8% respectively, and in the 2nd group - 13.7% and 15% respectively, while achieving normal values. In most patients of group 1, normalization of body weight was noted in comparison with group 2 (23.4% and 17.4%, respectively, p = 0.043), delta of body weight in the moxonidine group was -1.89%. The increase in the processes of bone formation in the form of increased markers of OC and Osteoprotegerin and a statistically signifcant increase in TA in patients receiving moxonidine were revealed, while in women who took bisoprolol there were no dynamic changes in bone metabolism rates, there was a tendency for a decrease in BMD and a signifcant decrease in AT. CONCLUSIONS: Te detected pleiotropic effect of moxonidine on bone metabolism and replicative cell aging processes will reduce the risk of development or progression of osteopenia and osteoporosis in postmenopausal women with AH.

Pharmacotherapeutic strategies for treating hypertension in patients with obesity.

INTRODUCTION: Hypertension and obesity are important health challenges that independently increase cardiovascular morbidity and mortality. There is a lack of randomized controlled trials to clearly inform on preferred drug choices to be adopted in clinical practice for the treatment of obesity-related hypertension (OHT). Adequate differentiation of drug classes for preferential use in obesity or the metabolic syndrome aimed at avoiding adverse effects on body weight and the metabolic profile is neglected in this population, at least in part due to the lack of specific pharmacologic recommendations in hypertension guidelines. AREAS COVERED: The authors summarize and suggest pharmacotherapeutic strategies based on pathophysiologic rationale to achieve blood pressure (BP) control and avoid adverse metabolic consequences in OHT. EXPERT OPINION: Combinations of various pharmacologic antihypertensive approaches are required in the management of OHT. It is recommended that targeting sympathetic overactivity with a centrally acting sympatholytic agent such as moxonidine should be considered as a preferred second line treatment choice in combination with renin angiotensin system (RAS) blockade, the current first line choice. Though not all obese subjects have sympathetic overdrive, this approach is likely to provide effective control of blood pressure and improve the metabolic profile of patients with OHT along with positive implications for cardiovascular risk reduction.

Peripheral versus central effect of intravenous moxonidine on rat carotid sinus baroreflex-mediated sympathetic arterial pressure regulation.

AIMS: Moxonidine is a centrally acting antihypertensive agent with a selectivity to I1-imidazoline receptors higher than that to α2-adrenergic receptors. The present study aimed to quantify a peripheral effect of moxonidine on carotid sinus baroreflex-mediated sympathetic arterial pressure (AP) regulation separately from its central effect. MAIN METHODS: In eight anesthetized Wistar rats, changes in efferent sympathetic nerve activity (SNA) and AP in response to a carotid sinus pressure input were compared before and during an intravenous administration of moxonidine (100µgkg-1 bolus followed by a continuous infusion at 200µg·kg-1·h-1). KEY FINDINGS: Moxonidine significantly narrowed the range of the AP response (55.3±5.8 to 39.1±6.1mmHg, P<0.05) without changing the minimum AP (77.2±6.4 to 80.7±5.1mmHg, not significant). In the neural arc, moxonidine reduced the minimum SNA (56.6±5.9 to 29.7±6.2%, P<0.05) without affecting the range of the SNA response (45.3±5.5 to 40.2±5.0%, not significant). In the peripheral arc, moxonidine increased the intercept (3.0±8.5 to 51.1±7.2mmHg, P<0.01) and reduced the slope (1.28±0.06 to 0.92±0.15mmHg/%, P<0.05). SIGNIFICANCE: Moxonidine increased AP at any given SNA, suggesting that the peripheral vasoconstrictive effect is stronger than generally recognized. The peripheral vasoconstrictive effect of moxonidine may partly offset the vasodilatory effect attained by centrally-mediated sympathoinhibition.

Pharmacological analysis of the inhibition produced by moxonidine and agmatine on the vasodepressor sensory CGRPergic outflow in pithed rats.

Calcitonin gene-related peptide (CGRP) plays a role in several (patho)physiological functions, and modulation of its release is considered a therapeutic target. In this respect, electrical spinal (T9--T12) stimulation of the perivascular sensory outflow in pithed rats produces vasodepressor responses mediated by CGRP release. This study investigated the role of imidazoline I1 and I2 receptors in the inhibition by moxonidine and agmatine of these vasodepressor responses. Male Wistar pithed rats (pretreated i.v. with 25mg/kg gallamine and 2mg/kg⋅min hexamethonium) received i.v. continuous infusions of methoxamine (20µg/kg⋅min) followed by physiological saline (0.02ml/min), moxonidine (1, 3, 10 or 30µg/kg⋅min) or agmatine (1000 or 3000µg/kg⋅min). Under these conditions, electrical stimulation (0.56-5.6Hz; 50V; 2ms) of the spinal cord (T9-T12) produced frequency-dependent vasodepressor responses which were: (i) unchanged during saline infusion; and (ii) inhibited during the above infusions of moxonidine or agmatine. Moreover, using i.v. administrations, the inhibition by 3µg/kg⋅min moxonidine or 3000µg/kg⋅min agmatine (which failed to inhibit the vasodepressor responses by α-CGRP; 0.1-1µg/kg) was: (i) unaltered after saline (1ml/kg), rauwolscine (300µg/kg; α2-adrenoceptor antagonist) or BU224 (300µg/kg; imidazoline I2 receptor antagonist); and (ii) reversed after AGN 192403 (3000µg/kg; imidazoline I1 receptor antagonist). This reversion was relatively more pronounced after AGN 192403 plus rauwolscine. These blocking doses of antagonists lacked any effects on the electrically-induced vasodepressor responses. Therefore, the inhibition of the vasodepressor sensory CGRPergic outflow by moxonidine and agmatine is mainly mediated by prejunctional imidazoline I1 receptors on perivascular sensory nerves.

Activation of imidazoline I1 receptor by moxonidine regulates the progression of liver fibrosis in the Nrf2-dependent pathway.

Imidazoline I1 receptor (I1R) has been recognized as a promising target in the treatment of many diseases, but little is known about its function in liver fibrogenesis. This study aimed to investigate the effect of I1R activation on the development and progression of liver fibrosis. The results showed that I1R expression was decreased in the livers of both patients and mice with liver fibrosis, and in TGF-ß-treated hepatic stellate cells (HSCs). Activation of I1R by moxonidine (MOX) significantly inhibited the progression of liver fibrosis in carbon tetrachloride-induced mice and attenuated the activation of HSCs and kupffer cells. MOX also suppressed the activation of TLR4/NF-κB and TGF-ß/Smad signaling, however, knockdown of I1R abrogated the inhibitory effects of MOX. Additionally, MOX activated Nrf2 signaling in vivo and in vitro, but knockout or knockdown of Nrf2 ameliorated the anti-inflammatory and anti-fibrotic effects of MOX. Taken together, activation of I1R negatively regulates the progression of liver fibrosis in the Nrf2-dependent pathway, which suggests that specifically targeting I1R may be a potential therapeutic strategy for the treatment of liver fibrosis.

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.

Pharmacological analysis of the cardiac sympatho-inhibitory actions of moxonidine and agmatine in pithed spontaneously hypertensive rats.

This study shows that in spontaneously hypertensive rats (SHR) of 14-weeks-old, the sympathetically-induced, but not noradrenaline-induced tachycardic response are higher than age-matched Wistar normotensive rats. Furthermore, in SHR the sympathetically-induced tachycardic response was: (1) unaffected by moxonidine (3µg/kgmin); (2) partially inhibited by B-HT 933 (30µg/kgmin), both at the lowest doses; and (3) completely inhibited by the highest doses of B-HT 933 (100µg/kgmin), moxonidine (10µg/kgmin) or agmatine (1000 and 3000µg/kgmin) while the noradrenaline-induced tachycardic responses remained unaffected by the above compounds, except by 3000µg/kgmin agmatine. In SHR, 300µg/kg rauwolscine failed to block the sympatho-inhibition to 100µg/kgmin B-HT 933 or 10µg/kgmin moxonidine, but 1000µg/kg rauwolscine abolished, partially antagonized, and did not modify the sympatho-inhibition to the highest doses of B-HT 933, moxonidine, and agmatine, respectively, 3000µg/kg AGN 192403 or 300µg/kg BU224 given alone had no effect in the moxonidine- or agmatine-induced sympatho-inhibition, and the combination rauwolscine plus AGN 192403 but not plus BU224, abolished the sympatho-inhibition to the highest doses of moxonidine and agmatine. In conclusion, the sympathetically-induced tachycardic responses in SHR are inhibited by moxonidine and agmatine. The inhibition of moxonidine is mainly mediated by prejunctional α2-adrenoceptors and to a lesser extent by I1-imidazoline receptors, while the inhibition of agmatine is mediated by prejunctional α2-adrenoceptors and I1-imidazoline receptors at the same extent. Notwithstanding, the inhibitory function of α2-adrenoceptors seems to be altered in SHR compared with Wistar normotensive rats.

Cystathionine-γ lyase-derived hydrogen sulfide mediates the cardiovascular protective effects of moxonidine in diabetic rats.

Blunted cystathionine-γ lyase (CSE) activity (reduced endogenous H2S-level) is implicated in hypertension and myocardial dysfunction in diabetes. Here, we tested the hypothesis that CSE derived H2S mediates the cardiovascular protection conferred by the imidazoline I1 receptor agonist moxonidine in a diabetic rat model. We utilized streptozotocin (STZ; 55mg/kg i.p) to induce diabetes in male Wistar rats. Four weeks later, STZ-treated rats received vehicle, moxonidine (2 or 6mg/kg; gavage), CSE inhibitor DL-propargylglycine, (37.5mg/kg i.p) or DL-propargylglycine with moxonidine (6mg/kg) for 3 weeks. Moxonidine improved the glycemic state, and reversed myocardial hypertrophy, hypertension and baroreflex dysfunction in STZ-treated rats. Ex vivo studies revealed that STZ caused reductions in CSE expression/activity, H2S and nitric oxide (NO) levels and serum adiponectin and elevations in myocardial imidazoline I1 receptor expression, p38 and extracellular signal-regulated kinase, ERK1/2, phosphorylation and lipid peroxidation (expressed as malondialdehyde). Moxonidine reversed these biochemical responses, and suppressed the expression of death associated protein kinase-3. Finally, pharmacologic CSE inhibition (DL-propargylglycine) abrogated the favorable cardiovascular, glycemic and biochemical responses elicited by moxonidine. These findings present the first evidence for a mechanistic role for CSE derived H2S in the glycemic control and in the favorable cardiovascular effects conferred by imidazoline I1 receptor activation (moxonidine) in a diabetic rat model.

α2A-adrenoceptors, but not nitric oxide, mediate the peripheral cardiac sympatho-inhibition of moxonidine.

Moxonidine centrally inhibits the sympathetic activity through the I1-imidazoline receptor and nitric oxide. In addition, inhibits the peripheral cardiac sympathetic outflow by α2-adrenoceptors/I1-imidazoline receptors, although the role of α2-adrenoceptor subtypes or nitric oxide in the cardiac sympatho-inhibition induced by moxonidine are unknown. Therefore, the cardiac sympatho-inhibition induced by moxonidine (10µg/kgmin) was evaluated before and after of the treatment with the following antagonists/inhibitor: (1) BRL 44408, (300µg/kg, α2A), imiloxan, (3000µg/kg, α2B), and JP-1302, (300µg/kg, α2C), in animals pretreated with AGN 192403 (3000µg/kg, I1 antagonist); (2) N(ω)-nitro-l-arginine methyl ester (l-NAME; 34, 100, and 340µg/kgmin); and (3) the combinations of the highest dose of l-NAME plus AGN 192403 or BRL 44408. Additionally, the expression of the neuronal (nNOS) and inducible (iNOS) nitric oxide synthase in the stellate ganglion was determined after treatment with moxonidine (i.p. 0.56mg/kg daily, during one week). The cardiac sympatho-inhibition of 10µg/kgmin moxonidine was: (1) unaffected by imiloxan and JP-1302, under pretreatment with AGN 192403, or l-NAME (34, 100 and 340µg/kgmin) given alone; (2) partially antagonized by the combination of 340 µg/kgmin l-NAME plus BRL 44408; and (3) abolished by BRL 44408 under treatment with AGN 192403. Furthermore, moxonidine did not modify the nNOS or iNOS protein expression in the stellate ganglion, the main source of postganglionic sympathetic neurons innervating the heart. In conclusion, our results suggest that the peripheral cardiac sympatho-inhibition induced by moxonidine is mediated by α2A-adrenoceptor subtype but not by nitric oxide.