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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sympatholytic antihypertensive agent moxonidine, a centrally acting selective I1-imidazoline receptor modulator (putative agonist), may be beneficial in hypertensive patients with insulin resistance. In the present study, the effects of chronic in vivo moxonidine treatment of obese Zucker rats--a model of severe glucose intolerance, hyperinsulinemia and insulin resistance, and dyslipidemia--on whole-body glucose tolerance, plasma lipids, and insulin-stimulated skeletal muscle glucose transport activity (2-deoxyglucose uptake) were investigated. Moxonidine was administered by gavage for 21 consecutive days at 2, 6, or 10 mg/kg body weight. Body weights in control and moxonidine-treated groups were matched, except at the highest dose, at which final body weight was 17% lower in the moxonidine-treated animals compared with controls. The moxonidine-treated (6 and 10 mg/kg) obese animals had significantly lower fasting plasma levels of insulin (17% and 19%, respectively) and free fatty acids (36% and 28%, respectively), whereas plasma glucose was not altered. During an oral glucose tolerance test, the glucose response (area under the curve) was 47% and 67% lower, respectively, in the two highest moxonidine-treated obese groups. Moreover, glucose transport activity in the isolated epitrochlearis muscle stimulated by a maximally effective insulin dose (13.3 nmol/L) was 39% and 70% greater in the 6 and 10 mg/kg moxonidine-treated groups, respectively (P<.05 for all effects). No significant alterations in muscle glucose transport were elicited by 2 mg/kg moxonidine. These findings indicate that in the severely insulin-resistant and dyslipidemic obese Zucker rat, chronic in vivo treatment with moxonidine can significantly improve, in a dose-dependent manner, whole-body glucose tolerance, possibly as a result of enhanced insulin-stimulated skeletal muscle glucose transport activity and reduced circulating free fatty acids.
Hypertension 1997 Dec
PMID:Antihypertensive agent moxonidine enhances muscle glucose transport in insulin-resistant rats. 940 83

Recently we could demonstrate that the imidazoline receptor agonist moxonidine exerts specific renal effects in Sprague Dawley rats [Hohage et al. 1997]. Interestingly, the effects of this compound are attenuated in one kidney-one clip hypertensive rats [Li et al. 1994]. In this study, we therefore investigated the effects of moxonidine as compared to clonidine in genetically determined spontaneously hypertensive rats. Moxonidine in a concentration of 0.5 mg/kg b.w.i.v. induced a significant and long-lasting increase of both urine flow from 11.9 +/- 2.1 microliters/min x 100 g b.w. to 50.3 +/- 12.5 microliters/min x 100 g b.w. and of Na(+)-excretion from 2.2 +/- 0.5 mumol/min x 100 g b.w. to 8.4 +/- 1.9 mumol/min x 100 g b.w. In contrast to moxonidine, the effects of clonidine (0.5 mg/kg b.w.i.v.) on urine flow and Na(+)-excretion were negligible. The antagonists idazoxan, effaroxan and rauwolscine abolished the effects of moxonidine on urine flow and Na(+)-excretion, whereas 4-aminopyridine, phenformine and 1,2,3,4-tetrahydro-9-aminoacridine, which have been described to interact with imidazoline binding sites, had no effect. Addition of the antagonists idazoxan, effaroxan and rauwolscine attenuated the initial blood pressure increase immediately after intravenous application, whereas 4-aminopyridine, phenformine and 1,2,3,4-tetrahydro-9-aminoacridine had no influence on this side-effect. Our results provide further evidence that imidazoline receptor agonists such as moxonidine exhibit renal effects, different from the modulation in urine flow and Na(+)-excretion following renal alpha 2 adrenoceptor stimulation. An upregulation of imidazoline receptors in hypertension may contribute to the effects observed.
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PMID:Renal and blood pressure effects of moxonidine and clonidine in spontaneously hypertensive rats. 943 92

Classical centrally acting antihypertensive agents lower blood pressure by reducing excessive sympathetic tone; however, their clinical use is limited by an adverse effect profile resulting from alpha2-adrenoceptor agonism. Moxonidine is a new centrally acting agent showing selective agonism of imidazoline I1 receptors, but very little alpha2-adrenoceptor agonism. The safety and tolerability of moxonidine was reviewed over an 8-year period (1989 to 1997), including 74 clinical trials and an estimated 370000 patient-years of exposure. Dry mouth and somnolence were the most frequently reported adverse events, followed by headache and dizziness. In phase II to IV controlled studies in patients with hypertension (n = 1460), the incidence of dry mouth was 8 to 9%, somnolence 5 to 8% and headache 6%, as recorded by spontaneous reporting; the percentage of patients discontinuing treatment because of adverse events did not exceed 4%. Subgroup analyses revealed no differences in adverse events related to age or gender. Moxonidine did not exacerbate concomitant conditions such as diabetes mellitus or chronic obstructive pulmonary disease, or interact pharmacokinetically with concurrent medications such as hydrochlorothiazide, digoxin and glibenclamide (glyburide). Coadministration of moxonidine with lorazepam resulted in small additional impairments in tasks requiring attention. A similar distribution of adverse events was observed in uncontrolled studies (n = 1058). The incidence and severity of dry mouth and somnolence were found to decrease with increasing exposure to moxonidine over a period of up to 2 years. Serious adverse events were rare in all trials and could not be attributed to administration of moxonidine. Post-marketing surveillance of the adverse effect profile of moxonidine detected 2 additional adverse effects: nausea and allergic skin reactions. The safety profile of moxonidine, combined with proven antihypertensive efficacy, suggests that it may have an important role to play in the management of mild-to-moderate hypertension.
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PMID:Safety and tolerability of moxonidine in the treatment of hypertension. 974 66

Disorders in peripheral microcirculation are observed in arterial hypertension and may be improved by antihypertensive treatment. In this pilot study the authors measured capillary blood cell velocity in the finger nailfold in 14 patients (mean age 50 +/- 14 years, range 30-71 years; 9 men, 5 women) with mild-to-moderate essential hypertension. After a 3-week placebo period, patients received double-blind randomized treatment with either 0.2- to 0.4-mg moxonidine (n=7) or 2.5- to 5.0-mg cilazapril (n=7). Finger nailfold video capillaroscopy was performed at baseline and after 8 weeks of treatment. Blood pressure was measured by conventional office technique. Capillary blood cell velocity, 1 minute after local finger cooling, increased in the Moxonidine group (0.65 +/- 0.53 mm/sec to 1.13 +/- 0.77 mm/sec; p<0.05) after 8 weeks treatment compared to the baseline. The increase in the Cilazapril group from 0.79 +/- 0.45 mm/sec to 0.93 +/- 1.03 mm/sec did not reach a level of statistical significance. Blood pressure decreased from 151 +/- 8/101 +/- 5 to 147 +/- 6/98 +/- 7 mmHg in the Moxonidine group and from 164 +/- 12/102 +/- 6 to 140 +/- 9/93 +/- 9 mmHg in the cilazapril group. Moxonidine increased nailfold capillary blood cell velocity 1 minute after local finger cooling in patients with mild-to-moderate hypertension. This improvement of the peripheral microcirculation may be associated with reversal of vascular dysfunction in hypertension.
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PMID:Effect of moxonidine and cilazapril on microcirculation as assessed by finger nailfold capillaroscopy in mild-to-moderate hypertension. 982 45

Moxonidine is an I1-imidazoline receptor agonist that reduces blood pressure in hypertensives. Experimental data suggest that moxonidine inhibits central sympathetic activity. However, whether such a mechanism is involved in vivo in humans is still unclear. We investigated the effects of 0.4 mg moxonidine orally on muscle sympathetic nerve activity and heart rate in an open study in 8 healthy volunteers. Furthermore, we studied the effects of 0.4 mg moxonidine on muscle sympathetic nerve activity, heart rate, blood pressure, 24-hour blood pressure profile, and hormone plasma levels in 25 untreated hypertensives in a double-blind, placebo-controlled study. Moxonidine decreased muscle sympathetic nerve activity in both healthy volunteers (P<0.05 versus baseline) and hypertensives (P<0.02 versus placebo). Plasma norepinephrine also decreased (P<0. 01), whereas plasma epinephrine and renin levels did not change (P=NS). Furthermore, moxonidine decreased systolic (P<0.0001) and diastolic (P<0.001) blood pressure. Heart rate decreased after moxonidine in healthy subjects (P<0.05); in hypertensives, heart rate decreased during the night hours (P<0.05) but not during daytime (P=NS). Plasma levels of LDL, HDL, and total cholesterol were not influenced by the drug (P=NS). Moxonidine decreases systolic and diastolic blood pressure by inhibiting central nervous sympathetic activity. This makes this new drug suitable for the treatment of human hypertension and possibly for other cardiovascular diseases with increased sympathetic nerve activity, ie, ischemic heart disease and heart failure.
Hypertension 1998 Dec
PMID:I1-imidazoline agonist moxonidine decreases sympathetic nerve activity and blood pressure in hypertensives. 985 67

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 beta 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.
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PMID:Mechanisms of antihyperglycemic effects of moxonidine in the obese spontaneously hypertensive Koletsky rat (SHROB). 986 64

Treatment of arterial hypertension is known to reduce cardiovascular morbidity and mortality and has a positive effect against stroke, where benefit is strongly linked to reduction in blood pressure per se. The protective effects against coronary heart disease (CHD) have also been significant but numerically less impressive than the effect against stroke. It is conceivable that this due to the fact that not just blood pressure, but also a number of metabolic variables need to be considered in this context. The insight that hypertension is often just one of the components of the so-called metabolic syndrome suggests that a modern antihypertensive drug should not only lower blood pressure; to exert optimal cardioprotective properties it should also have a neutral or even positive metabolic profile as regards its effects on lipids, glucose and insulin in order to achieve a better protection against CHD. Against this background the centrally acting selective imidazoline receptor (I1) agonist moxonidine is of considerable interest. Moxonidine has been shown to improve glucose tolerance in man, probably by two different mechanisms, i.e. by augmenting insulin sensitivity in peripheral tissues and by enhancing glucose-stimulated insulin release from the pancreas. By employing a therapeutic intervention against hypertension that not only lowers elevated arterial pressure but also positively affects some of the frequently occurring concomitant metabolic disturbances, it appears that today's standard of antihypertensive therapy may be surpassed in tomorrow's perspective.
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PMID:Therapy of hypertension and metabolic syndrome: today's standard and tomorrow's perspectives. 1032 50

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.
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PMID:Anti-hyperglycemic activity of moxonidine: metabolic and molecular effects in obese spontaneously hypertensive rats. 1032 53

alpha2-Adrenergic receptor (AR)-selective compounds produce antihypertensive and antinociceptive effects. Moxonidine alleviates hypertension in multiple species, including humans. This study demonstrates that intrathecally administered moxonidine produces antinociception in mice. Antinociception was detected via the (52.5 degrees C) tail-flick and Substance P (SP) nociceptive tests. Moxonidine was intrathecally administered to ICR, mixed C57BL/6 x 129/Sv [wild type (WT)], or C57BL/6 x 129/Sv mice with dysfunctional alpha2aARs (D79N-alpha2a). The alpha2AR-selective antagonist SK&F 86466 and the mixed I1/alpha2AR-selective antagonist efaroxan were tested for inhibition of moxonidine-induced antinociception. Moxonidine prolonged tail-flick latencies in ICR (ED50 = 0.5 nmol; 0. 3-0.7), WT (0.17 nmol; 0.09-0.32), and D79N-alpha2a (0.32 nmol; 0. 074-1.6) mice. Moxonidine inhibited SP-elicited behavior in ICR (0. 04 nmol; 0.03-0.07), WT (0.4 nmol; 0.3-0.5), and D79N-alpha2a (1.1 nmol; 0.7-1.7) mice. Clonidine produced antinociception in WT but not D79N-alpha2a mice. SK&F 86466 and efaroxan both antagonized moxonidine-induced inhibition of SP-elicited behavior in all mouse lines. SK&F 86466 antagonism of moxonidine-induced antinociception implicates the participation of alpha2ARs. The comparable moxonidine potency between D79N-alpha2a and WT mice suggests that receptors other than alpha2a mediate moxonidine-induced antinociception. Conversely, absence of clonidine efficacy in D79N-alpha2a mice implies that alpha2aAR activation enables clonidine-induced antinociception. When clinically administered, moxonidine induces fewer side effects relative to clonidine; moxonidine-induced antinociception appears to involve a different alpha2AR subtype than clonidine-induced antinociception. Therefore, moxonidine may prove to be an effective treatment for pain with an improved side effect profile.
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PMID:Moxonidine, a selective alpha2-adrenergic and imidazoline receptor agonist, produces spinal antinociception in mice. 1038 6

Moxonidine and rilmenidine are moderately selective I1-receptor stimulants. The imidazoline (I1) agonists cause peripheral sympathoinhibition, triggered at the level of central nervous imidazoline receptors. Imidazoline receptor stimulants are effective antihypertensive agents with a hemodynamic profile that is attractive from a pathophysiologic point of view. The antihypertensive activity of these agents is caused by vasodilatation and reduced peripheral vascular resistance. Left ventricular end-diastolic and end-systolic volume is reduced, whereas heart rate, stroke volume, cardiac output, and pulmonary artery pressures are largely unchanged. Long-term left ventricular hypertrophy is reduced. Both drugs, when applied in a once-daily dosage schedule, appear to control hypertension in most patients. Both drugs have been compared with representative agents from the major classes of antihypertensive drugs in controlled trials and found to be equally effective in blood pressure control. The incidence and severity of side effects are lower than those for clonidine, particularly with respect to sedation. A rebound (withdrawal) phenomenon has so far not been reported for moxonidine and rilmenidine. Therefore, I1-receptor stimulants offer the possibility of developing centrally acting agents with a better side-effect profile than do the classic alpha 2-adrenoceptor stimulants.
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PMID:Central I1-imidazoline receptors as targets of centrally acting antihypertensive drugs. Clinical pharmacology of moxonidine and rilmenidine. 1041 46


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