Effects Of Moxonidine Research Articles

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.

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. 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. 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. 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. 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.

Comparative evaluation of renal denervation versus pharmacological treatment on diastolic function in patients with resistant hypertension: three years follow-up

Abstract Background Several recently published sham-controlled trials of high methodological quality confirm the safety and antihypertensive effectiveness of radiofrequency renal denervation. However, special clinical interest represents a suggestion that this type of treatment may improve hypertension-mediated organ damage. Purpose Comparative evaluation of renal denervation versus pharmacological treatment on diastolic function in patients with resistant hypertension. Methods The study enrolled 125 hypertensive patients who, following 4 weeks of standardized treatment with three antihypertensive remedies, one of which were a thiazide-like diuretic in maximum tolerated daily doses (Losartan, Amlodipine and Indapamid) and confirmation of their resistance, were randomly assigned into three groups depending on the treatment supplemented to the previously administered one: group I – Moxonidine, group II – Bisoprolol and group III – renal denervation (RDN). All patients were evaluated by transthoracic echocardiography at baseline, one, two and three years follow-up. A renal denervation was performed in the main renal arteries and their branches. Results At 1-year follow-up Bisoprolol and RDN treatment groups showed an authentic improvement in all diastolic function parameters, while Moxonidine group noted amelioration of only E/A ratio, LAVI and TR velocity. Two years of evaluation were marked by statistically significant changes of all diastolic parameters in all three observational groups. The improvement of diastolic function parameters continued until the end of the study, when the difference in dynamics between groups is evident thanks to the inferior effect of Moxonidine compared to Bisoprolol, RDN demonstrating superiority over both pharmacological treatment groups (Table 1). Conclusions Renal denervation demonstrated efficacy in improving of all parameters of diastolic function starting with 12 months of evaluation, the beneficial effect being maintained until the end of the surveillance period. At the same time, minimally invasive treatment has been shown to be superior to pharmacological treatment with SNS- blockers in improving diastolic function.

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.

Novel non-stimulants rescue hyperactive phenotype in an adgrl3.1 mutant zebrafish model of ADHD

ADHD is a highly prevalent neurodevelopmental disorder. The first-line therapeutic for ADHD, methylphenidate, can cause serious side effects including weight loss, insomnia, and hypertension. Therefore, the development of non-stimulant-based therapeutics has been prioritized. However, many of these also cause other effects, most notably somnolence. Here, we have used a uniquely powerful genetic model and unbiased drug screen to identify novel ADHD non-stimulant therapeutics. We first found that adgrl3.1 null (adgrl3.1−/−) zebrafish larvae showed a robust hyperactive phenotype. Although the hyperactivity was rescued by three ADHD non-stimulant therapeutics, all interfered significantly with sleep. Second, we used wild-type zebrafish larvae to characterize a simple behavioral phenotype generated by atomoxetine and screened the 1200 compound Prestwick Chemical Library® for a matching behavioral profile resulting in 67 hits. These hits were re-assayed in the adgrl3.1−/−. Using the previously identified non-stimulants as a positive control, we identified four compounds that matched the effect of atomoxetine: aceclofenac, amlodipine, doxazosin, and moxonidine. We additionally demonstrated cognitive effects of moxonidine in mice using a T-maze spontaneous alternation task. Moxonidine, has high affinity for imidazoline 1 receptors. We, therefore, assayed a pure imidazoline 1 agonist, LNP599, which generated an effect closely matching other non-stimulant ADHD therapeutics suggesting a role for this receptor system in ADHD. In summary, we introduce a genetic model of ADHD in zebrafish and identify five putative therapeutics. The findings offer a novel tool for understanding the neural circuits of ADHD, suggest a novel mechanism for its etiology, and identify novel therapeutics.

Long-term antihypertensive effect of renal denervation in resistant hypertension: three years follow-up

Abstract Background Recent studies have shown proven efficacy of renal denervation in arterial hypertension, but there is a continuing need to assess the duration of antihypertensive effect. Purpose Evaluation of the long-term antihypertensive effect of renal denervation in patients with resistant hypertension. Methods 125 apparently resistant patients without comorbidities after a 3-week standardized treatment with Losartan 100 mg, Amlodipin 10 mg and Indapamid 1.5 mg and confirmation of their resistance were randomly assigned into three groups depending on treatment supplemented to previously administered: group I - selective I1-imidazoline agonist Moxonidine, group II - cardioselective beta-blocker Bisoprolol and group III – renal artery denervation. The compliance to treatment was confirmed using 8-item Morisky Medication Adherence Scale. Renal denervation was performed in the main renal arteries and their branches. Patients were assessed by ambulatory blood pressure monitoring at baseline, 3, 12, 24 and 36 months follow-up. Results The mean 24 hour systolic blood pressure (SBP) at baseline were 179.0±2.02 mmHg in group I versus 177.96±2.44 mmHg in group II and 176.92±1.97 mmHg in group III, p&amp;gt;0.05. A statistically significant reduction in SBP m/24 h was noted in all three groups starting at 3 months, the group of patients undergoing renal denervation showing superiority over both groups of pharmacological treatment: −6.48±0.81 mmHg in group I versus −6.2±0.88 mmHg in group II and −23.28±1.9 mmHg in group III, p&amp;lt;0.001. The progressive improvement continued until the end of the study, so at 3 years of evaluation in observational group supplemented with Moxonidine SBP m/24 h were 146.36±1.36 mmHg with a total reduction of −32.64±1.56 mmHg from baseline, in Bisoprolol group −152.88±1.56 mmHg with a reduction of −25.08±1.65 mmHg and 133.16±0.73 mmHg in renal denervation group with a total reduction of −282±1.30 mmHg in group III, p&amp;lt;0.001. The mean 24 hour diastolic blood pressure (DBP) increased at baseline in all three observational groups (105.52±1.28 mmHg in group I versus 108.6±1.6 mmHg in group II and 107.24±0.92 mmHg in group III, p&amp;gt;0.05) similar with SBP m/24 h noted an authentic reduction at 3 months follow-up. The maximum reduction in DBP m/24 h were registered at 3 years of evaluation, a comparative analyses of dynamics between groups showing a presence of statistical difference due to superiority of renal denervation in amelioration of this parameter: −18.36±1.88 mmHg in group I versus −16.84±1.76 mmHg in group II and −28.2±1.30 mmHg in group III, p&amp;lt;0.001. Conclusions All three regimens have been shown to be effective in reducing SBP and DBP m/24 h in patients with resistant hypertension, with a superior but comparable effect of Moxonidine to Bisoprolol and the absolute superiority of renal denervation treatment, the beneficial effect being maintained for a period of 3 years. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): National Agency for Research and Development

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.

THE POSITIVE EFFECT OF MOXONIDINE ON TELOMERASE ACTIVITY

Objective: To estimate the effect of moxonidine versus bisoprolol on cellular senescence processes in postmenopausal women with arterial hypertension (AH). Design and method: There was an open randomized control study. The study group was represented by 56 women with AH and a mean age of 63 ± 9.217 years, with SBP of 146.72 ± 7.127 mm Hg and DBP of 84.38 ± 7.941 mm Hg, who received moxonidine treatment (average dose 0.515 mg/day [0.4; 0.6]) for 12 months. The control group was comprised of 59 female patients with AH and a mean age of 61 ± 9.117 years, with SBP of 145.59 ± 6.102 mm Hg and DBP of 86.18 ± 6.682 mm Hg, who received treatment with bisoprolol (average dose 5.0 mg/day [5.0; 7.5]) for 12 months. For all patients, the measurement of telomerase activity was performed using genomic DNA real-time PCR at baseline and after 12 months of treatment. Statistical analysis was carried out using the SPSS/PASW Statistics software (version 18, SPSS Inc., Chicago, Illinois, USA). Results: In both groups there was a substantial and significant BP reduction, in the moxonidine treatment group: SBP – 126.93 ± 8.086 mm Hg (p &lt; 0.001), DBP – 73.64 ± 7.522 mm Hg (p &lt; 0.001); in the bisoprolol treatment group: SBP – 125.83 ± 8.097 mm Hg (p &lt; 0.001), DBP – 73.31 ± 7.964 mm Hg (p &lt; 0.001). Patients from the moxonidine treatment group demonstrated a significant reduction of body weight, on average, by 1.89% (from 75.7 ± 12.77 kg to 74.5 ± 11.7 kg,p &lt; 0.001) and of BMI (from 29.359 ± 4.7 kg/m2 to 28.6 ± 4.4 kg/m2, p &lt; 0.001). By contrast, in the bisoprolol treatment group patients’ average body weight increased by 2.22% (from 76.655 ± 13.754 kg to 78.13 ± 13.728 kg, p &lt; 0.001) as well as BMI (from 29.037 ± 4.6 kg/m2 to 29.609 ± 4.7 kg/m2, p &lt; 0.001). TA in the moxonidine treatment group increased from 0.87 [0.16; 1.18] to 1.1 [0.74; 1.5] (p &lt; 0.001), and, conversely in the bisoprolol treatment group TA decreased from 1.1 [0.5; 1.6] to 0.94 [0.56; 1.5] (p &lt; 0.001). Conclusions: The preliminary data suggests that moxonidine can be used as telomerase activator and effective geroprotective agent. Increased TA against the backdrop of moxonidine treatment may be explained by increased insulin sensitivity, decreased body weight, and, consequently, lower intensity of chronic inflammation.

Sympathetic renal denervation treatment in resistant hypertension: one-year follow-up

Abstract Aims A comparison influence of renal denervation versus pharmacological treatment with sympathetic nervous system blockers on blood pressure in patients with resistant hypertension. Methods 125 patients with resistant hypertension without comorbidities after a 3-week standardized treatment with Losartan 100 mg, Amlodipine 10 mg and Indapamid 1,5 mg and confirmation of their resistance were randomly assigned into three groups, depending on medication supplemented to previously administered: IM group – selective I1-imidazoline agonist Moxonidine, IIB group – cardioselective beta-blocker Bisoprolol and IIID group – renal artery denervation. Patients were assessed by ambulatory blood pressure monitoring at baseline, 3, 6 and 12 month follow-up. The compliance to drug treatment was confirmed by 8-item Morisky Medication Adherence Scale. Renal denervation was performed with a Symplicity Spyral catheter. Results The mean 24 hour systolic blood pressure (SBP m/24 h) at baseline were 179.0±2.02 mmHg in IM group versus 177.96±2.44 mmHg in IIB group and 176.92±1.97 mmHg in IIID group, p&amp;gt;0.05. Statistically significant dynamics was recorded starting with 3 months of evaluation in all three groups, the group of patients undergoing denervation of the renal arteries demonstrating a net superior effect compared with pharmacological treatment: −6.48±0.81 mmHg in I M group versus −6.2±0.88 mmHg in II B group and −23.28±1.9 mmHg in III D group, p&amp;lt;0.001. The beneficial effect was maintained until the end of the study, when in observational group supplemented with Moxonidine SBP m/24 h were 159.6±1.72 mmHg with a total reduction of −19.9±0.7 mmHg from baseline, in Bisoprolol group −164.08±1.93 mmHg with a reduction of −13.88±1.13 mmHg and 141.76±0.77 mmHg in renal denervation group with a total reduction of −35.16±2.23 mmHg, p&amp;lt;0.001. The mean 24 hour diastolic blood pressure (DBP m/24 h) increased at baseline in all three groups (105.52±1.28 mmHg in IM versus 108.6±1.6 mmHg in IIB and 107.24±0.92 mmHg in IIID, p&amp;gt;0.05) similar to SBP m/24 h noted a significantly reduction at 3 month follow-up: −4.8±0.96 mmHg in IM group versus −3.64±0.47 mmHg in IIB group and −12.08±0.63 mmHg in IIID group, p&amp;lt;0.001. The maximum reduction in DBP m/24 h were registered at 12 month follow-up, a comparative analyses of dynamics between groups showing a presence of statistical difference due to superiority of renal denervation treatment in amelioration of this parameter: −13.68±0.83 mmHg in IM group versus −10.72±0.64 mmHg in IIB group and −20.2±1.28 mmHg in IIID group, p&amp;lt;0.001. Conclusions The application of all three treatment regimens has been shown to be effective in reducing SBP and DBP values m/24 hours in patients with resistant hypertension, with a superior but comparable effect of Moxonidine to Bisoprolol and the absolute superiority of renal denervation treatment versus both pharmacological treatment regimens. Funding Acknowledgement Type of funding source: None

Vegetotropic and emotional-behavioral effects of moxonidine in normotensive rats

Vegetotropic and emotional-behavioral effects of moxonidine in normotensive rats

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)

Новые возможности использования моксонидина в контроле артериального давления у пациенток с остеопенией

To assess the effect of moxonidine on bone metabolism and bone mineral density (BMD) in postmenopausal patients with arterial hypertension (AH) and osteopenia. 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. 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. 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.

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

AimsMoxonidine 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 methodsIn 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 findingsMoxonidine 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). SignificanceMoxonidine 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.

Effects of Moxonidine and Low-Calorie Diet: Cardiometabolic Benefits from Combination of Both Therapies.

Because sympathetic nervous system activity plays a detrimental role in metabolic and cardiovascular health, this study compared the effects of a centrally acting sympatholytic agent, the effects of a weight loss (WL) program using a low-calorie diet, and the effects of a combination of both. Young (18-30 years) male subjects with overweight (BMI > 25 kg/m2 ) were allocated to a WL program (n = 10), a moxonidine treatment course (M; n = 10, 0.4 mg/d), a combination of both (WL + M; n = 11), or to a control (C) group (n = 6) for 6 months. Muscle sympathetic nerve activity (MSNA), endothelial function, renal function (Cockcroft-Gault formula), and the metabolic profile were assessed before and after intervention. WL occurred in the WL and WL + M groups (-7.6 ± 1.9 kg, P < 0.001 in both). MSNA and systolic blood pressure decreased similarly in the WL, M, and WL + M groups (by ∼10 bursts/min, P < 0.001, and by ∼9 mm Hg, P < 0.05). All other parameters for the WL, C, and M groups remained unchanged. In the WL + M group, decreased total cholesterol (-0.78 ± 0.23 mmol/L, P < 0.001), decreased low-density lipoprotein cholesterol (-0.49 ± 0.16 mmol/L, P < 0.01), decreased insulin (-6.5 ± 2.8 mmol/L, P < 0.05), and attenuated glomerular hyperfiltration (-19 ± 5 mL/min, P < 0.01) occurred. The combination of moxonidine with a WL program has beneficial effects on aspects of the metabolic profile and end organ damage in young males with overweight.

Effect of Moxonidine on the Aldosterone/Renin Ratio in Healthy Male Volunteers.

The most popular screening test for primary aldosteronism is the plasma aldosterone/renin ratio (ARR). Medications, dietary sodium, posture, and time of day all affect renin and aldosterone levels and can result in false-negative or false-positive ARRs if not controlled. Most antihypertensive medications affect the ARR and can interfere with interpretation of results. To our knowledge, no study has been undertaken to evaluate the effects of moxonidine on the ARR. Normotensive, nonmedicated male volunteers (n = 20) underwent measurement (seated, midmorning) of plasma aldosterone (by high-performance liquid chromatography-tandem mass spectrometry), direct renin concentration (DRC), plasma renin activity (PRA), cortisol, electrolytes and creatinine; and urinary aldosterone, cortisol, electrolytes and creatinine at baseline and after 1 week of moxonidine at 0.2 mg/d and a further 5 weeks at 0.4 mg/d. Compared with baseline, despite the expected significant falls in both systolic and diastolic blood pressure, levels of plasma aldosterone [median, 134 (range, 90 to 535) pmol/L], DRC [20 (10 to 37) mU/L], PRA [2.2 (1.0-3.8) ng/mL/h], and ARR using either DRC [8.0 (4.4 to 14.4)] or PRA [73 (36 to 218)] were not significantly changed after either 1 [135 (98-550) pmol/L, 20 (11-35) mU/L, 2.0 (1.2-4.1) ng/mL/h, 8.8 (4.2 to 15.9), and 73 (32-194), respectively] or 6 weeks [130 (90-500) pmol/L, 22 (8 to 40) mU/L, 2.1 (1.0 to 3.2) ng/mL/h, 7.7 (4.3 to 22.4), and 84 (32 to 192), respectively] of moxonidine. There were no changes in any urinary measurements. Moxonidine was associated with no significant change in the ARR and may therefore be a good option for maintaining control of hypertension when screening for primary aldosteronism.

The effect of moxonidine on lipid profile of patients with arterial hypertension, grade 1 and 2

The effect of moxonidine on lipid profile of patients with arterial hypertension, grade 1 and 2

Inhibitory effects of imidazoline receptor ligands on basal and kainic acid-induced neurotoxic signalling in mice.

This in vivo study assessed the potential of the imidazoline receptor (IR) ligands moxonidine (selective I1-IR), BU224 (selective I2-IR) and LSL61122 (mixed I1/I2-IR) to dampen excitotoxic signalling induced by kainic acid (KA; 45 mg/kg) in the mouse brain (hippocampus and cerebral cortex). KA triggered a strong behavioural syndrome (seizures; maximal at 60-90 minutes) and sustained stimulation (at 72 hours with otherwise normal mouse behaviour) of pro-apoptotic c-Jun-N-terminal kinases (JNK) and calpain with increased cleavage of p35 into neurotoxic p25 (cyclin-dependent kinase 5 [Cdk5] activators) in mouse hippocampus. Pretreatment (five days) with LSL61122 (10 mg/kg), but not moxonidine (1 mg/kg) or BU224 (20 mg/kg), attenuated the KA-induced behavioural syndrome, and all three IR ligands inhibited JNK and calpain activation, as well as p35/p25 cleavage after KA in the hippocampus (effects also observed after acute IR drug treatments). Efaroxan (I1-IR, 10 mg/kg) and idazoxan (I2-IR, 10 mg/kg), postulated IR antagonists, did not antagonise the effects of moxonidine and LSL61122 on KA targets (these IR ligands showed agonistic properties inhibiting pro-apoptotic JNK). Brain subcellular preparations revealed reduced synaptosomal postsynaptic density-95 protein contents (a mediator of JNK activation) and indicated increased p35/Cdk5 complexes (with pro-survival functions) after treatment with moxonidine, BU224 and LSL61122. These results showed that I1- and I2-IR ligands (moxonidine and BU224), and especially the mixed I1/I2-IR ligand LSL61122, are partly neuroprotective against KA-induced excitotoxic signalling. These findings suggest a therapeutic potential of IR drugs in disorders associated with glutamate-mediated neurodegeneration.

Centrally acting drug moxonidine decreases reactive oxygen species via inactivation of the phosphoinositide-3 kinase signaling in the rostral ventrolateral medulla in hypertensive rats.

Centrally acting antihypertensive action of moxonidine is a result of activation of Imidazoline-1 receptor (I1R) in the rostral ventrolateral medulla (RVLM). Hypertension shows an increase in reactive oxygen species (ROS) in the RVLM. The present objective was to determine the phosphoinositide-3 kinase (PI3K) signaling pathway involved in the effect of moxonidine on ROS generation in the RVLM of spontaneously hypertensive rat (SHR). Wistar-Kyoto rats and SHR received intracisternal infusion (2 weeks) of tested agents which were subjected to subsequent experiments. In-situ ROS in the RVLM was evaluated by the oxidative fluorescence dye. Western blot and PCR analysis were performed to detect the expression levels of PI3K signaling pathway. Lentivirus was injected bilaterally into the RVLM for silencing PI3K signaling. ROS production in the RVLM was dose-dependently reduced in SHRs treated with infusion of moxonidine (20 nmol/day), which was prevented by the I1R antagonist efaroxan but not by the α2-adrenoceptor antagonist yohimbine. Moxonidine pretreatment significantly blunted cardiovascular sensitivity to injection of tempol (5 nmol) or angiotensin II (10 pmol) into the RVLM in SHR. Expression levels of PI3K/Akt, nuclear factor kappa-B (NFκB), NADPHase (NOX4), and angiotensin type I receptor (AT1R) in the RVLM were markedly decreased in SHR treated with moxonidine. Infection of lentivirus containing PI3K shRNA in the RVLM effectively prevented effects of moxonidine on cardiovascular activity and expression levels of Akt, NFκB, NOX4, and AT1R. The centrally antihypertensive drug moxonidine decreases ROS production in the RVLM through inactivation of the PI3K/Akt signaling pathway in hypertension.

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.

GABA mechanisms of the nucleus of the solitary tract regulates the cardiovascular and sympathetic effects of moxonidine

The antihypertensive drugs moxonidine and clonidine are α2-adrenoceptor and imidazoline (I1) agonists. Previous results from our laboratory have shown that moxonidine can act in the commissural nucleus of the solitary tract (commNTS). In addition, some studies have shown that GABA or glutamate receptor blockade in the RVLM blunted the hypotension produced by these antihypertensive agents in spontaneously hypertensive rats. Therefore, in the present study we verify whether the cardiovascular and sympathetic effects produced by moxonidine in the commNTS are dependent on GABAergic or glutamatergic mechanisms. Mean arterial pressure (MAP) and splanchnic sympathetic nerve activity (sSNA) were recorded in urethane-anesthetized, and artificially-ventilated male Wistar rats (250-350 g). Injection of the GABAA antagonist bicuculline (25 pmol/50 nL) into the commNTS reduced the hypotension as well as the sympathoinhibition elicited by moxonidine. Prior injection of the glutamate receptor antagonist kynurenic acid (2.5 nmol/50 nL) into the commNTS was not effective in reducing the hypotension and sympathoinhibition elicited by moxonidine. Therefore, we conclude that the hypotensive and sympathoinhibitory effects elicited by microinjection of moxonidine into the commNTS are dependent on GABA receptors, but not ionotropic glutamate receptors.