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B R Graham - One of the best experts on this subject based on the ideXlab platform.

  • I1 imidazoline agonists. General clinical pharmacology of imidazoline receptors. Implications for the treatment of the elderly
    Drugs & Aging, 2000
    Co-Authors: B. N. C. Prichard, B R Graham
    Abstract:

    In recent years evidence has accumulated for the existence of central imidazoline (I1) receptors that influence blood pressure. While there is some controversy, it has been suggested that clonidine exerts its blood pressure-lowering effect mainly by activation of imidazoline I1 receptors in the rostral ventrolateral medulla, while its sedative effect is mediated by activation of central α2-receptors. Moxonidine and rilmenidine are 2 imidazoline compounds with 30-fold greater specificity for I1 receptors than for α2-receptors. In comparison, clonidine displays a 4-fold specificity for I1 receptors compared with α2 receptors. Moxonidine and rilmenidine lower blood pressure by reducing peripheral resistance. They reduce circulating catecholamine levels and Moxonidine reportedly reduces sympathetic nerve activity in patients with hypertension. Moxonidine and rilmenidine modestly reduce elevated blood glucose levels and Moxonidine has been reported to reduce insulin resistance in hypertensive patients with raised insulin resistance. Small reductions in plasma levels of total cholesterol, low density lipoprotein-cholesterol and triglycerides have been reported with rilmenidine.

  • Moxonidine: a new antiadrenergic antihypertensive agent.
    Journal of Hypertension, 1999
    Co-Authors: Brian N.c. Prichard, B R Graham, C W I Owens
    Abstract:

    Moxonidine is a centrally acting antihypertensive. Its action is mediated by imidazoline I1 receptors located in the rostral ventro-lateral medulla (RVLM). Animal experiments show that much smaller amounts are required to reduce blood pressure (BP) when it is given intracisternally, or injected directly into the RVLM, compared to intravenous dose. Pretreatment with imidazoline I1 blockade from efaroxan abolishes the antihypertensive action of microinjection of Moxonidine into the RVLM in the spontaneously hypertensive rat (SHR), while alpha2 blockade from SKF 86466 is much less effective. Microinjection of efaroxan into the RVLM prevents the fall of BP in the SHR from intravenous Moxonidine. Moxonidine binds with an affinity for the imidazoline I1 receptor that is 33 times more effective than is alpha2-receptor binding. There is only a few fold preference for binding at the imidazoline I1-receptor for clonidine. Moxonidine results in a fall in adrenaline, noradrenaline and renin levels in humans, as might be expected from central inhibition of sympathetic tone. Moxonidine gives a fall of BP due to a decline in systemic vascular resistance, while the heart rate, cardiac output, stroke volume and pulmonary artery pressures are not affected. There is a reduction in left-ventricular end systolic and diastolic volumes. There is a regression of left-ventricular hypertrophy after Moxonidine was given for 6 months. Following oral administration the half-life (Tmax) is about 1 h. Moxonidine is highly bioavailable, approaching 90%. Moxonidine is largely excreted unchanged, biotransformation is unimportant. It has a T(1/2) of 2.5 h, renal insufficiency prolongs the T(1/2). However, suggesting possible retention in the central nervous system (CNS) the antihypertensive effect lasts longer than would be expected from the half-life. Moxonidine has been shown to be suitable for administration once daily. Moxonidine is an effective antihypertensive drug. In the course of its evaluation it has been compared with representatives from each important class of antihypertensive drugs, with diuretics, both alpha- and beta-blocking drugs, clonidine, calcium antagonists and angiotensin-converting enzyme (ACE) inhibitors. These studies have shown that BP control is overall similar with Moxonidine and these other agents. Moxonidine has a favourable side-effect profile, at least in part due to its lack of effect on central alpha2 receptors.

  • Pharmacology and clinical use of Moxonidine, a new centrally acting sympatholytic antihypertensive agent.
    Journal of Human Hypertension, 1997
    Co-Authors: Brian N.c. Prichard, C W I Owens, B R Graham
    Abstract:

    Moxonidine is a centrally acting antihypertensive. Its action is mediated by imidazoline I 1 receptors located in the rostral ventro-lateral medulla (RVLM). Animal experiments show much smaller amounts are required to reduce blood pressure (BP) when it is given intracisternally, or injected directly into the RVLM, compared to intravenous dose. The antihypertensive action of microinjection of Moxonidine into the RVLM in the spontaneously hypertensive rat (SHR) is abolished by pretreatment with imidazoline I 1 blockade from efaroxan, but α 2 blockade from SKF 86466 has much less effect. Similarly the fall of BP in the SHR from intravenous Moxonidine is reversed by the microinjection of efaroxan into the RVLM. Receptor binding studies demonstrate that Moxonidine binds with an affinity for the imidazoline I 1 receptor that is thirty-three times more effective than is α 2 receptor binding, while for clonidine the difference is only four times. Moxonidine reduces adrenaline, noradrenaline and renin levels in man, a finding consistent with central inhibition of sympathetic tone. Acute haemodynamic studies indicate that Moxonidine results in a fall of BP due to a decline in systemic vascular resistance, while the heart rate, cardiac output, stroke volume and pulmonary artery pressures are not affected. Left ventricular end systolic and diastolic volumes are reduced. Left ventricular hypertrophy has been found to regress after 6 months treatment with Moxonidine. After oral administration T max is about 1 h, bioavailability approaches 90%. Moxonidine is mostly excreted unchanged, biotransformation is unimportant. The T 1 /2 is 2.5 h, which is prolonged by renal insufficiency. However, suggesting possible retention in the central nervous system (CNS), the antihypertensive effect lasts longer than would be expected from the half-life, as Moxonidine is suitable for once daily administration. Moxonidine is an effective antihypertensive agent. It has been compared with representatives from each important class of antihypertensive drugs, with clonidine, diuretics, both α- and β-blocking drugs, calcium antagonists and ACE inhibitors. BP control has been similar with Moxonidine and these other agents. The side effect profile of Moxonidine is favourable, its lack of effect on central α 2 receptors is important in this regard.

  • Pharmacology and clinical use of Moxonidine, a new centrally acting sympatholytic antihypertensive agent.
    Journal of human hypertension, 1997
    Co-Authors: Brian N.c. Prichard, C W I Owens, B R Graham
    Abstract:

    Moxonidine is a centrally acting antihypertensive. Its action is mediated by imidazoline I1 receptors located in the rostral ventro-lateral medulla (RVLM). Animal experiments show much smaller amounts are required to reduce blood pressure (BP) when it is given intracisternally, or injected directly into the RVLM, compared to intravenous dose. The antihypertensive action of microinjection of Moxonidine into the RVLM in the spontaneously hypertensive rat (SHR) is abolished by pretreatment with imidazoline I1 blockade from efaroxan, but alpha(2) blockade from SKF 86466 has much less effect. Similarly the fall of BP in the SHR from intravenous Moxonidine is reversed by the microinjection of efaroxan into the RVLM. Receptor binding studies demonstrate that Moxonidine binds with an affinity for the imidazoline I1 receptor that is thirty-three times more effective than is alpha(2) receptor binding, while for clonidine the difference is only four times. Moxonidine reduces adrenaline, noradrenaline and renin levels in man, a finding consistent with central inhibition of sympathetic tone. Acute haemodynamic studies indicate that Moxonidine results in a fall of BP due to a decline in systemic vascular resistance, while the heart rate, cardiac output, stroke volume and pulmonary artery pressures are not affected. Left ventricular end systolic and diastolic volumes are reduced. Left ventricular hypertrophy has been found to regress after 6 months treatment with Moxonidine. After oral administration Tmax is about 1 h, bioavailability approaches 90%. Moxonidine is mostly excreted unchanged, biotransformation is unimportant. The T1/2 is 2.5 h, which is prolonged by renal insufficiency. However, suggesting possible retention in the central nervous system (CNS), the antihypertensive effect lasts longer than would be expected from the half-life, as Moxonidine is suitable for once daily administration. Moxonidine is an effective antihypertensive agent. It has been compared with representatives from each important class of antihypertensive drugs, with clonidine, diuretics, both alpha- and beta-blocking drugs, calcium antagonists and ACE inhibitors. BP control has been similar with Moxonidine and these other agents. The side effect profile of Moxonidine is favourable, its lack of effect on central alpha(2) receptors is important in this regard.

  • THE USE OF Moxonidine IN THE TREATMENT OF HYPERTENSION
    Journal of hypertension. Supplement : official journal of the International Society of Hypertension, 1997
    Co-Authors: Brian N.c. Prichard, B R Graham
    Abstract:

    BACKGROUND Imidazoline I1-receptor agonism represents a new mode of antihypertensive action to inhibit peripheral alpha-adrenergic tone by a central mechanism. Adrenaline, noradrenaline and renin levels are reduced, a finding consistent with central inhibition of sympathetic tone. Acute haemodynamic studies indicate that Moxonidine results in an acute decrease in blood pressure due to a fall in systemic vascular resistance, whereas the heart rate, cardiac output, stroke volume and pulmonary artery pressures are not affected. Left ventricular end systolic and diastolic volumes are reduced. Left ventricular hypertrophy has been found to regress after 6 months of treatment. PHARMACOKINETICS Following oral administration, maximum concentration is reached at about 1 h, and bioavailability approaches 90%. Moxonidine is mostly excreted unchanged, and biotransformation is unimportant. The half-life of Moxonidine is 2.5 h, which is prolonged by renal insufficiency. However, the antihypertensive effect lasts longer than would be expected from the half-life, suggesting possible retention in the central nervous system. DRUG EFFECTS Decreases of about 20-30 mmHg systolic and 10-20 mmHg diastolic blood pressure have been found in open studies with Moxonidine. The dosage of 0.2-0.4 mg Moxonidine daily controls hypertension in most patients. Moxonidine has been compared with representatives from each important class of antihypertensive drugs, with clonidine, diuretics, both alpha- and beta-blocking drugs, calcium antagonists and angiotensin converting enzyme inhibitors. Blood pressure control has been observed to be similar with Moxonidine and these other agents. Generally, the overall incidence of side-effects has been found to be similar, although the incidence of side-effects with clonidine is greater than that seen with Moxonidine. CONCLUSIONS A meta-analysis of controlled studies with Moxonidine found that Moxonidine gave similar reductions in blood pressure in both men and women, in those aged below 50, 50-60 and over 60 years, and regardless of body weight. As often seen with some other drugs, higher systolic blood pressures are associated with larger reductions in systolic blood pressure and the same appears to be the case with diastolic blood pressure.

Brian N.c. Prichard - One of the best experts on this subject based on the ideXlab platform.

  • I_l Imidazoline Agonists. General Clinical Pharmacology of Imidazoline Receptors
    Drugs & Aging, 2000
    Co-Authors: Brian N.c. Prichard, Barrie R. Graham
    Abstract:

    In recent years evidence has accumulated for the existence of central imidazoline (I_1) receptors that influence blood pressure. While there is some controversy, it has been suggested that clonidine exerts its blood pressure-lowering effect mainly by activation of imidazoline I_1 receptors in the rostral ventrolateral medulla, while its sedative effect is mediated by activation of central α_2-receptors. Moxonidine and rilmenidine are 2 imidazoline compounds with 30-fold greater specificity for I_1 receptors than for α_2-receptors. In comparison, clonidine displays a 4-fold specificity for I_1 receptors compared with α_2 receptors. Moxonidine and rilmenidine lower blood pressure by reducing peripheral resistance. They reduce circulating catecholamine levels and Moxonidine reportedly reduces sympathetic nerve activity in patients with hypertension. Moxonidine and rilmenidine modestly reduce elevated blood glucose levels and Moxonidine has been reported to reduce insulin resistance in hypertensive patients with raised insulin resistance. Small reductions in plasma levels of total cholesterol, low density lipoprotein-cholesterol and triglycerides have been reported with rilmenidine. Both Moxonidine and rilmenidine are well absorbed after oral administration and are eliminated unchanged by the kidneys. The elimination half-life (t½)of rilmenidine and Moxonidine is 8 and 2 hours, respectively, but trough/peak plasma concentration ratios indicate that Moxonidine can be administered once daily, suggesting possible CNS retention. As would be expected, t½ values are increased in patients with reduced renal function, and in elderly individuals. Both drugs have been compared with established antihypertensive drugs from all the major groups. Studies, almost all of which were of a double-blind, parallel-group design, indicate that blood pressure control with Moxonidine or rilmenidine is similar to that with established drugs, i.e. α-blocking drugs, calcium antagonists, ACE inhibitors, β-blocking drugs and diuretic agents. There have been few studies conducted solely in elderly patients. However, evidence clearly suggests that the antihypertensive effect of the imidazoline compounds is not reduced in elderly patients. The overall adverse effect profile of Moxonidine and rilmenidine compares reasonably with established agents. In accord with the receptor-binding studies, drowsiness and dry mouth are observed less often with these drugs than with other centrally acting drugs, although the symptoms occur more often than with placebo. An overshoot of blood pressure was seen when treatment with Clonidine, but not Moxonidine, was abruptly discontinued in conscious, spontaneously hypertensive rats. Clinical evidence of withdrawal reaction with Moxonidine or rilmenidine is scant but caution should be observed pending more formal studies.

  • Moxonidine: a new antiadrenergic antihypertensive agent.
    Journal of Hypertension, 1999
    Co-Authors: Brian N.c. Prichard, B R Graham, C W I Owens
    Abstract:

    Moxonidine is a centrally acting antihypertensive. Its action is mediated by imidazoline I1 receptors located in the rostral ventro-lateral medulla (RVLM). Animal experiments show that much smaller amounts are required to reduce blood pressure (BP) when it is given intracisternally, or injected directly into the RVLM, compared to intravenous dose. Pretreatment with imidazoline I1 blockade from efaroxan abolishes the antihypertensive action of microinjection of Moxonidine into the RVLM in the spontaneously hypertensive rat (SHR), while alpha2 blockade from SKF 86466 is much less effective. Microinjection of efaroxan into the RVLM prevents the fall of BP in the SHR from intravenous Moxonidine. Moxonidine binds with an affinity for the imidazoline I1 receptor that is 33 times more effective than is alpha2-receptor binding. There is only a few fold preference for binding at the imidazoline I1-receptor for clonidine. Moxonidine results in a fall in adrenaline, noradrenaline and renin levels in humans, as might be expected from central inhibition of sympathetic tone. Moxonidine gives a fall of BP due to a decline in systemic vascular resistance, while the heart rate, cardiac output, stroke volume and pulmonary artery pressures are not affected. There is a reduction in left-ventricular end systolic and diastolic volumes. There is a regression of left-ventricular hypertrophy after Moxonidine was given for 6 months. Following oral administration the half-life (Tmax) is about 1 h. Moxonidine is highly bioavailable, approaching 90%. Moxonidine is largely excreted unchanged, biotransformation is unimportant. It has a T(1/2) of 2.5 h, renal insufficiency prolongs the T(1/2). However, suggesting possible retention in the central nervous system (CNS) the antihypertensive effect lasts longer than would be expected from the half-life. Moxonidine has been shown to be suitable for administration once daily. Moxonidine is an effective antihypertensive drug. In the course of its evaluation it has been compared with representatives from each important class of antihypertensive drugs, with diuretics, both alpha- and beta-blocking drugs, clonidine, calcium antagonists and angiotensin-converting enzyme (ACE) inhibitors. These studies have shown that BP control is overall similar with Moxonidine and these other agents. Moxonidine has a favourable side-effect profile, at least in part due to its lack of effect on central alpha2 receptors.

  • Pharmacology and clinical use of Moxonidine, a new centrally acting sympatholytic antihypertensive agent.
    Journal of Human Hypertension, 1997
    Co-Authors: Brian N.c. Prichard, C W I Owens, B R Graham
    Abstract:

    Moxonidine is a centrally acting antihypertensive. Its action is mediated by imidazoline I 1 receptors located in the rostral ventro-lateral medulla (RVLM). Animal experiments show much smaller amounts are required to reduce blood pressure (BP) when it is given intracisternally, or injected directly into the RVLM, compared to intravenous dose. The antihypertensive action of microinjection of Moxonidine into the RVLM in the spontaneously hypertensive rat (SHR) is abolished by pretreatment with imidazoline I 1 blockade from efaroxan, but α 2 blockade from SKF 86466 has much less effect. Similarly the fall of BP in the SHR from intravenous Moxonidine is reversed by the microinjection of efaroxan into the RVLM. Receptor binding studies demonstrate that Moxonidine binds with an affinity for the imidazoline I 1 receptor that is thirty-three times more effective than is α 2 receptor binding, while for clonidine the difference is only four times. Moxonidine reduces adrenaline, noradrenaline and renin levels in man, a finding consistent with central inhibition of sympathetic tone. Acute haemodynamic studies indicate that Moxonidine results in a fall of BP due to a decline in systemic vascular resistance, while the heart rate, cardiac output, stroke volume and pulmonary artery pressures are not affected. Left ventricular end systolic and diastolic volumes are reduced. Left ventricular hypertrophy has been found to regress after 6 months treatment with Moxonidine. After oral administration T max is about 1 h, bioavailability approaches 90%. Moxonidine is mostly excreted unchanged, biotransformation is unimportant. The T 1 /2 is 2.5 h, which is prolonged by renal insufficiency. However, suggesting possible retention in the central nervous system (CNS), the antihypertensive effect lasts longer than would be expected from the half-life, as Moxonidine is suitable for once daily administration. Moxonidine is an effective antihypertensive agent. It has been compared with representatives from each important class of antihypertensive drugs, with clonidine, diuretics, both α- and β-blocking drugs, calcium antagonists and ACE inhibitors. BP control has been similar with Moxonidine and these other agents. The side effect profile of Moxonidine is favourable, its lack of effect on central α 2 receptors is important in this regard.

  • Pharmacology and clinical use of Moxonidine, a new centrally acting sympatholytic antihypertensive agent.
    Journal of human hypertension, 1997
    Co-Authors: Brian N.c. Prichard, C W I Owens, B R Graham
    Abstract:

    Moxonidine is a centrally acting antihypertensive. Its action is mediated by imidazoline I1 receptors located in the rostral ventro-lateral medulla (RVLM). Animal experiments show much smaller amounts are required to reduce blood pressure (BP) when it is given intracisternally, or injected directly into the RVLM, compared to intravenous dose. The antihypertensive action of microinjection of Moxonidine into the RVLM in the spontaneously hypertensive rat (SHR) is abolished by pretreatment with imidazoline I1 blockade from efaroxan, but alpha(2) blockade from SKF 86466 has much less effect. Similarly the fall of BP in the SHR from intravenous Moxonidine is reversed by the microinjection of efaroxan into the RVLM. Receptor binding studies demonstrate that Moxonidine binds with an affinity for the imidazoline I1 receptor that is thirty-three times more effective than is alpha(2) receptor binding, while for clonidine the difference is only four times. Moxonidine reduces adrenaline, noradrenaline and renin levels in man, a finding consistent with central inhibition of sympathetic tone. Acute haemodynamic studies indicate that Moxonidine results in a fall of BP due to a decline in systemic vascular resistance, while the heart rate, cardiac output, stroke volume and pulmonary artery pressures are not affected. Left ventricular end systolic and diastolic volumes are reduced. Left ventricular hypertrophy has been found to regress after 6 months treatment with Moxonidine. After oral administration Tmax is about 1 h, bioavailability approaches 90%. Moxonidine is mostly excreted unchanged, biotransformation is unimportant. The T1/2 is 2.5 h, which is prolonged by renal insufficiency. However, suggesting possible retention in the central nervous system (CNS), the antihypertensive effect lasts longer than would be expected from the half-life, as Moxonidine is suitable for once daily administration. Moxonidine is an effective antihypertensive agent. It has been compared with representatives from each important class of antihypertensive drugs, with clonidine, diuretics, both alpha- and beta-blocking drugs, calcium antagonists and ACE inhibitors. BP control has been similar with Moxonidine and these other agents. The side effect profile of Moxonidine is favourable, its lack of effect on central alpha(2) receptors is important in this regard.

  • THE USE OF Moxonidine IN THE TREATMENT OF HYPERTENSION
    Journal of hypertension. Supplement : official journal of the International Society of Hypertension, 1997
    Co-Authors: Brian N.c. Prichard, B R Graham
    Abstract:

    BACKGROUND Imidazoline I1-receptor agonism represents a new mode of antihypertensive action to inhibit peripheral alpha-adrenergic tone by a central mechanism. Adrenaline, noradrenaline and renin levels are reduced, a finding consistent with central inhibition of sympathetic tone. Acute haemodynamic studies indicate that Moxonidine results in an acute decrease in blood pressure due to a fall in systemic vascular resistance, whereas the heart rate, cardiac output, stroke volume and pulmonary artery pressures are not affected. Left ventricular end systolic and diastolic volumes are reduced. Left ventricular hypertrophy has been found to regress after 6 months of treatment. PHARMACOKINETICS Following oral administration, maximum concentration is reached at about 1 h, and bioavailability approaches 90%. Moxonidine is mostly excreted unchanged, and biotransformation is unimportant. The half-life of Moxonidine is 2.5 h, which is prolonged by renal insufficiency. However, the antihypertensive effect lasts longer than would be expected from the half-life, suggesting possible retention in the central nervous system. DRUG EFFECTS Decreases of about 20-30 mmHg systolic and 10-20 mmHg diastolic blood pressure have been found in open studies with Moxonidine. The dosage of 0.2-0.4 mg Moxonidine daily controls hypertension in most patients. Moxonidine has been compared with representatives from each important class of antihypertensive drugs, with clonidine, diuretics, both alpha- and beta-blocking drugs, calcium antagonists and angiotensin converting enzyme inhibitors. Blood pressure control has been observed to be similar with Moxonidine and these other agents. Generally, the overall incidence of side-effects has been found to be similar, although the incidence of side-effects with clonidine is greater than that seen with Moxonidine. CONCLUSIONS A meta-analysis of controlled studies with Moxonidine found that Moxonidine gave similar reductions in blood pressure in both men and women, in those aged below 50, 50-60 and over 60 years, and regardless of body weight. As often seen with some other drugs, higher systolic blood pressures are associated with larger reductions in systolic blood pressure and the same appears to be the case with diastolic blood pressure.

Paul Ernsberger - One of the best experts on this subject based on the ideXlab platform.

  • Cardiac Effects of Moxonidine in Spontaneously Hypertensive Obese Rats
    Annals of the New York Academy of Sciences, 2003
    Co-Authors: Suhayla Mukaddam-daher, Rouwayda El-ayoubi, Ahmed Menaouar, Jolanta Gutkowska, Rodney A Velliquette, Marek Jankowski, Paul Ernsberger
    Abstract:

    Moxonidine, an imidazoline receptor agonist that acts centrally to inhibit sympathetic activity, has been shown to reduce effectively blood pressure, fasting insulin levels, and free fatty acids. In this study, we investigated the long-term effects of Moxonidine treatment on cardiac natriuretic peptides (ANP and BNP) in Spontaneously Hypertensive Obese Rats (SHROBs), a rat model that resembles human Syndrome X. SHROBs expressing spontaneous hypertension, insulin resistance, and genetic obesity (weight 590 6 20 g, at 30 weeks) received Moxonidine in chow at 4 mg/kg/day for 15 days. Moxonidine significantly reduced not only systolic blood pressure (187 6 6 versus 156 6 5 mm Hg, P < 0.05) but also plasma ANP (1595 6 371 versus 793 6 131 pg/mL, P < 0.05) and BNP (22 6 3 versus 14 6 1 pg/mL, P < 0.04), without influencing cardiac content of either peptide. Semi-quantitative PCR revealed that atrial ANPmRNA/GAPDHmRNA decreased to 39% 6 10% of pair-fed controls, P < 0.03. In left ventricles, Moxonidine also decreased ANP mRNA to 69% 6 7% and BNP mRNA to 74% 6 6% of control, P < 0.02, but right ventricular ANP and BNP mRNA were not affected. These findings indicate that chronic inhibition of sympathetic activity with Moxonidine in SHROB is associated with decreased ventricular natriuretic peptide transcription, consistent with the cardioprotective effects of Moxonidine given the role of ANP and BNP as markers of cadiac disease. Moxonidine also improves the metabolic profile in these rats, thus it may be considered the drug of choice in treatment of metabolic syndrome X

  • Mechanisms of Antihyperglycemic Effects of Moxonidine in the Obese Spontaneously Hypertensive Koletsky Rat (SHROB)
    The Journal of pharmacology and experimental therapeutics, 1999
    Co-Authors: Paul Ernsberger, Tatsuya Ishizuka, Sha Liu, Craig J. Farrell, David Bedol, Richard J. Koletsky, Jacob E. Friedman
    Abstract:

    Increased activity of the sympathetic nervous system may be a critical factor in the development of impaired insulin secretion and insulin resistance. We studied the chronic effects of sympathetic inhibition with Moxonidine on glucose metabolism in the spontaneously hypertensive genetically obese rat (SHROB). This unique animal model closely resembles human syndrome X, expressing insulin resistance, genetic obesity, spontaneous hypertension, and hyperlipoproteinemia. Moxonidine, a selective imidazoline receptor agonist, was administered to lean spontaneous hypertensive rats (SHR) and SHROBs for 90 days in food at 8 mg/kg/day and significantly reduced mean blood pressure. Moxonidine treatment reduced fasting insulin levels by 71% in SHROB and lowered plasma free fatty acids by 25%. In SHR, Moxonidine treatment decreased free fatty acids by 17% compared with controls. During an oral glucose tolerance test, blood glucose levels in Moxonidine-treated SHROB were reduced relative to untreated controls from 60 min onwards. Insulin secretion was facilitated at 30 min (83% greater) and 60 min (67% greater) postchallenge compared with control SHROB. In skeletal muscle, Moxonidine treatment increased the expression of the insulin receptor β subunit by 19% in SHROB but was without effect in SHR. The level of insulin receptor substrate-1 (IRS-1) protein was decreased by 60% in control SHROB compared with lean SHR. Moxonidine treatment enhanced the expression and insulin-stimulated phosphorylation of IRS-1 protein in skeletal muscle in SHROB by 74 and 27%, respectively, and in SHR by 40 and 56%, respectively. Moxonidine increased the levels of expression of IRS-1 protein in liver in SHR by 275% and in SHROB by 260%. These findings indicate that chronic inhibition of sympathetic activity with Moxonidine therapy can lower free fatty acids and significantly improve insulin secretion, glucose disposal, and expression of key insulin signaling intermediates in an animal model of obese hypertension.

  • Anti-hyperglycemic activity of Moxonidine: metabolic and molecular effects in obese spontaneously hypertensive rats.
    Blood pressure. Supplement, 1998
    Co-Authors: Jacob E. Friedman, Tatsuya Ishizuka, Sha Liu, Craig J. Farrell, David Bedol, Richard J. Koletsky, Paul Ernsberger
    Abstract:

    Hypertension and insulin resistance are often part of a complex set of abnormalities including obesity, hyperlipidemia, and glucose intolerance, described as syndrome X. Besides a common genetic basis, insulin resistance and hypertension might be linked by excessive activity of the sympathetic nervous system. We studied the effects of chronic inhibition of sympathetic activity with the antihypertensive agent Moxonidine on glucose metabolism in the genetically obese SHR Koletsky rat (SHROB), a unique animal model which closely resembles human syndrome X, expressing genetic obesity, hypertension, and hyperlipidemia. Moxonidine, a selective I1-imidazoline receptor agonist, was administered to SHROB and SHR for 90 days in food at 8 mg/kg/day. Moxonidine not only lowered blood pressure, but also reduced fasting insulin levels by 49% in SHROB, and reduced plasma free fatty acids by 30%. In lean SHR, Moxonidine treatment decreased circulating free fatty acids by 33% compared to controls. During oral glucose tolerance tests, blood glucose levels in Moxonidine-treated SHROB were reduced from 60 min onwards, and there was a sharply higher insulin secretion post-challenge compared to control SHROB. Western blot analysis of insulin signaling proteins showed that IRS-1 was decreased 42% in control SHROB compared with SHR. Moxonidine treatment enhanced the expression of IRS-1 protein in skeletal muscle by 74% in SHROB and 40% in SHR. Moxonidine increased expression of IRS-1 protein in liver by 245% in SHROB and 268% in SHR. Long-term inhibition of sympathetic activity with Moxonidine therapy lowered free fatty acids and significantly improved insulin secretion, glucose disposal, and expression of key insulin signaling intermediates. Thus, Moxonidine should be considered for the treatment of multiple metabolic and cardiovascular abnormalities associated with syndrome X.

  • pharmacology of Moxonidine an i1 imidazoline receptor agonist
    Journal of Cardiovascular Pharmacology, 1996
    Co-Authors: D Ziegler, M A Haxhiu, E C Kaan, Julius Gy Papp, Paul Ernsberger
    Abstract:

    Moxonidine is a second-generation, centrally acting antihypertensive drug with a distinctive mode of action. Moxonidine activates I 1 -imidazoline receptors (I 1 -receptors) in the rostroventrolateral medulla (RVLM), thereby reducing the activity of the sympathetic nervous system. Moxonidine leads to a pronounced and long-lasting blood pressure reduction in different animal models of hypertension, e.g., spontaneously hypertensive rats, renal hypertensive rats, and renal hypertensive dogs. Blood pressure reduction with Moxonidine is usually accompanied by a reduction in heart rate which, however, in most studies is of shorter duration and lesser magnitude than the fall in blood pressure. Chronic administration of Moxonidine to SHRs with established hypertension causes normalization of myocardial fibrosis, capillarization, and regressive changes in myocytes, in parallel with the reduction of blood pressure. Left ventricular hypertrophy and renal glomerulosclerosis are also significantly reduced. After withdrawal of chronic Moxonidine treatment, blood pressure gradually rises to pretreatment values. Direct injection of Moxonidine into the vertebral artery of cats elicits a more pronounced fall in blood pressure compared with i.v. injection of an equivalent dose. This observation and others clearly indicate that Moxonidine's antihypertensive activity is centrally mediated. The RVLM is the site of action within the CNS that mediates pronounced blood pressure reduction after direct administration of Moxonidine into the RVLM of anesthetized SHRs. Selective I 1 -receptor antagonists introduced into this area abolish the action of systemic Moxonidine. Receptor binding studies have shown high and selective affinity of Moxonidine for I 1 -receptors vs. α 2 -adrenergic receptors. In vivo studies using a variety of selective I 1 or α 2 -adrenergic agonists and antagonists have confirmed the primary role of I 1 -receptors in blood pressure regulation by Moxonidine. In addition to lowering blood pressure, Moxonidine possesses further properties that appear likely to be relevant in its therapeutic application in the hypertensive syndrome. Moxonidine increases urine flow rate and sodium excretion after central and direct intrarenal administration. It is active against ventricular arrhythmias in a variety of experimental settings. It lacks the respiratory depressant effects attributed to central α 2 activation. It exerts beneficial effects on glucose metabolism and blood lipids in genetically hypertensive obese rats. It exhibits anti-ulcer activity. And, finally, Moxonidine lowers intraocular pressure, suggesting a possible benefit in glaucoma. Therefore, Moxonidine, by its novel mode of action, represents a new therapeutic principle in the treatment of hypertension. Because of its unique profile, Moxonidine may prove to be effective in slowing progression of the disease by providing protective effects beyond merely blood pressure reduction. Further studies are needed to verify this potential.

  • Moxonidine, a centrally acting antihypertensive agent, is a selective ligand for I1-imidazoline sites.
    The Journal of pharmacology and experimental therapeutics, 1993
    Co-Authors: Paul Ernsberger, Timothy H. Damon, Lynette M. Graff, S. G. Schafer, M. O. Christen
    Abstract:

    Both the hypotension and the sedation elicited by centrally acting antihypertensive agents are traditionally attributed to activation of alpha 2 adrenergic receptors. Second-generation centrally acting agents such as Moxonidine are less sedating but retain antihypertensive efficacy. A novel receptor which recognizes imidazolines may contribute to their vasodepressor action in the ventrolateral medulla (VLM). We sought to determine whether Moxonidine was a selective ligand for these putative I1-imidazoline receptors in different species and tissues. Moxonidine inhibited [3H]clonidine binding to bovine VLM membranes in a heterogeneous manner, showing 40-fold selectivity for one component. Masking studies using selective inhibitors to block either I1-imidazoline or alpha 2 sites established that the population of sites showing high affinity for Moxonidine were I1-imidazoline sites. Moxonidine also showed 70-fold selectivity for I1-imidazoline sites labeled by [125I]p-iodoclonidine in the VLM. Moxonidine competitively inhibited [3H]clonidine binding to I1-imidazoline sites at concentrations that failed to inhibit alpha 2 binding. In the rat renal medulla, Moxonidine showed almost 700-fold selectivity for I1-imidazoline sites relative to the alpha 2B receptor subtype. The high affinity of Moxonidine for I1 sites was confirmed by using membranes prepared from bovine adrenomedullary cells, which lack alpha 2 adrenergic receptors. Among centrally acting antihypertensives, clinical potency correlated with binding affinity at bovine VLM I1-imidazoline sites (r = 0.996, N = 4), but not with alpha 2 adrenergic affinity (r = -0.239, N = 6). The potent action of Moxonidine on I1-imidazoline receptors may account for its antihypertensive efficacy.

Seungsoo Chung - One of the best experts on this subject based on the ideXlab platform.

  • modulation of n type ca2 currents by Moxonidine via imidazoline i1 receptor activation in rat superior cervical ganglion neurons
    Biochemical and Biophysical Research Communications, 2011
    Co-Authors: Seungsoo Chung
    Abstract:

    Abstract Moxonidine, an imidazoline deriviatives, suppress the vasopressor sympathetic outflow to produce hypotension. This effect has been known to be mediated in part by suppressing sympathetic outflow via acting imidazoline I1 receptors (IR1) at postganglionic sympathetic neurons. But, the cellular mechanism of IR1-induced inhibition of noradrenaline (NA) release is still unknown. We therefore, investigated the effect of IR1 activation on voltage-dependent Ca2+ channels which is known to play an pivotal role in regulating NA in rat superior cervical ganglion (SCG) neurons, using the conventional whole-cell patch-clamp method. In the presence of rauwolscine (3 μΜ), which blocks α2-adrenoceptor (Rα2), Moxonidine inhibited voltage-dependent Ca2+ current (ICa) by about 30%. This Moxonidine-induced inhibition was almost completely prevented by efaroxan (10 μΜ) which blocks IR1 as well as Rα2. In addition, ω-conotoxin (CgTx) GVIA (1 μΜ) occluded Moxonidine-induced inhibition of ICa, but, Moxonidine-induced ICa inhibition was not affected by pertussis toxin (PTX) nor shows any characteristics of voltage-dependent inhibition. These data suggest that Moxonidine inhibit voltage-dependent N-type Ca2+ current (ICa–N) via activating IR1. Finally, Moxonidine significantly decreased the frequency of AP firing in a partially reversible manner. This inhibition of AP firing was almost completely occluded in the presence of ω-CgTx. Taken together, our results suggest that activation of IR1 in SCG neurons reduced ICa–N in a PTX-and voltage-insensitive pathway, and this inhibition attenuated repetitive AP firing in SCG neurons.

  • modulation of n type ca currents by Moxonidine via imidazoline i receptor activation in rat superior cervical ganglion neurons
    Biochemical and Biophysical Research Communications, 2011
    Co-Authors: Younghwan Kim, Taick Sang Nam, Duck Sun Ahn, Seungsoo Chung
    Abstract:

    Abstract Moxonidine, an imidazoline deriviatives, suppress the vasopressor sympathetic outflow to produce hypotension. This effect has been known to be mediated in part by suppressing sympathetic outflow via acting imidazoline I1 receptors (IR1) at postganglionic sympathetic neurons. But, the cellular mechanism of IR1-induced inhibition of noradrenaline (NA) release is still unknown. We therefore, investigated the effect of IR1 activation on voltage-dependent Ca2+ channels which is known to play an pivotal role in regulating NA in rat superior cervical ganglion (SCG) neurons, using the conventional whole-cell patch-clamp method. In the presence of rauwolscine (3 μΜ), which blocks α2-adrenoceptor (Rα2), Moxonidine inhibited voltage-dependent Ca2+ current (ICa) by about 30%. This Moxonidine-induced inhibition was almost completely prevented by efaroxan (10 μΜ) which blocks IR1 as well as Rα2. In addition, ω-conotoxin (CgTx) GVIA (1 μΜ) occluded Moxonidine-induced inhibition of ICa, but, Moxonidine-induced ICa inhibition was not affected by pertussis toxin (PTX) nor shows any characteristics of voltage-dependent inhibition. These data suggest that Moxonidine inhibit voltage-dependent N-type Ca2+ current (ICa–N) via activating IR1. Finally, Moxonidine significantly decreased the frequency of AP firing in a partially reversible manner. This inhibition of AP firing was almost completely occluded in the presence of ω-CgTx. Taken together, our results suggest that activation of IR1 in SCG neurons reduced ICa–N in a PTX-and voltage-insensitive pathway, and this inhibition attenuated repetitive AP firing in SCG neurons.

Wei-zhong Wang - One of the best experts on this subject based on the ideXlab platform.

  • GABAergic mechanism in the rostral ventrolateral medulla contributes to the hypotension of Moxonidine
    Cardiovascular research, 2010
    Co-Authors: Jun-feng Peng, Wu Zhaotang, Wang Yangkai, Wen-jun Yuan, Tao Sun, Wei Wang, Wei-zhong Wang
    Abstract:

    Aims The depressor action of the centrally antihypertensive drug Moxonidine has been attributed to activation of I1-imidazoline receptor in the rostral ventrolateral medulla (RVLM). The objective of this study was to determine the role of the γ-aminobutyric acid (GABA) mechanisms in the RVLM in mediating the effect of Moxonidine in anaesthetized normotensive rats. Methods and results The relationship between the effects of microinjection or picoinjection of Moxonidine and the functional state of GABA receptors at the level of the RVLM or pre-sympathetic neuron was determined. Microdialysis was performed to detect the effect of Moxonidine on the release of GABA in the RVLM. Western blot analysis was carried out to test the effect of chronic intracerebroventricular injection of Moxonidine on the protein expression of GABA receptors in the RVLM. Pre-treatment with the GABAA or GABAB receptor antagonist bicuculline (5 pmol) or CGP35348 (200 pmol), respectively, microinjected into the RVLM significantly attenuated the decrease in blood pressure and renal sympathetic nerve activity induced by Moxonidine. In 22 Moxonidine-sensitive pre-sympathetic neurons in the RVLM, picoinjection of bicuculline (100 fmol/5 nL) significantly attenuated the neuronal inhibition evoked by Moxonidine (100 pmol/5 nL). The release of GABA in the RVLM was increased after intravenous Moxonidine (50 μg/kg). Central infusion of Moxonidine upregulated the protein expression of both GABAA and GABAB receptors in the RVLM. Conclusion The current data demonstrate that GABAergic mechanisms in the RVLM are responsible for the hypotension and sympathoinhibition of Moxonidine.

  • Sympathoinhibitory mechanism of Moxonidine: role of the inducible nitric oxide synthase in the rostral ventrolateral medulla
    Cardiovascular research, 2009
    Co-Authors: Jie Peng, Wang Yangkai, Wen-jun Yuan, Li-gang Wang, Xiao-ming Deng, Wei-zhong Wang
    Abstract:

    Aims The central antihypertensive drug Moxonidine lowers blood pressure (BP) through stimulating an imidazoline receptor within the rostral ventrolateral medulla (RVLM). Nitric oxide (NO) generated by the inducible NO synthase (iNOS) in the RVLM has been suggested to be involved in tonic sympathetic inhibition. The aim of this study was to determine the role of NO generated by iNOS in mediating Moxonidine-induced cardiovascular inhibition in rats. Methods and results In anaesthetized rats, the cardiovascular response to local or systemic injection of Moxonidine was observed after treatment with the selective iNOS inhibitor S -methylisothiourea (SMT) in the brain. Using immunohistochemical staining and western blot techniques, the protein expression of iNOS in the RVLM was measured in the Moxonidine-infused rats. Intracerebroventricular (ICV) injection of SMT (1–100 nmol) dose-dependently attenuated the Moxonidine (20 nmol, ICV)-induced decrease in BP and heart rate. Prior injection of SMT (20 and 200 pmol) into the RVLM also dose-dependently prevented the decrease in BP and renal sympathetic nerve activity evoked by RVLM microinjection of Moxonidine (5 nmol) or intravenous injection of Moxonidine (50 µg/kg). We further found that expression of iNOS protein following chronic ICV infusion of Moxonidine (20 nmol, 2 weeks) is selectively upregulated in the RVLM but not in the nucleus tractus solitarius. Conclusion The present data suggest that an NO mechanism generated by iNOS in the RVLM plays an important role in mediating the sympathetic inhibition of the centrally acting drug Moxonidine.