Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Centrally acting antihypertensive drugs, or sympatholytics, (reserpine, methyldopa and clonidine) have a long history of efficacy but are now little used in most countries. One of the most important reasons for this is relatively poor tolerability compared to many newer agents. In the case of clonidine there is also the potential danger of rebound hypertension. The most prominent adverse effects have been dry mouth, sedation, dizziness and oedema. These reactions, especially the first two, are thought to be associated with activation of central nervous system and salivary gland alpha2-adrenergic receptors. In the last 15 years it has become possible to produce drugs with selective agonist effect on another class of brainstem receptors, the imidazoline I1-receptors, which appear to have modulate sympathetic activity and blood pressure without affecting alertness or salivary flow: however, they still have some action on alpha2-receptors. Moxonidine and rilmenidine are moderately selective imidazoline agonists which have been in clinical use for several years in many European countries. Trial evidence and postmarketing surveillance indicate that moxonidine may cause dry mouth or sedation in a minority (<10%) of patients, significantly less than with the older drugs. There is no significant incidence of oedema and unexpected or idiosyncratic adverse effects are extremely rare. Moxonidine may improve aspects of glucose and lipid metabolism. In conclusion, moxonidine is a safe as well as an effective antihypertensive, with considerably improved patient tolerability compared to the older sympatholytics.
 ...
PMID:Moxonidine: a review of safety and tolerability after seven years of clinical experience. 1048 97

Hypertension associated with excessive liberation of circulating and tissue catecholamines is an independent risk factor for further cardiovascular complications and an important predictor of stroke. Moxonidine is a centrally acting anti-hypertensive drug with potent action on I1-imidazoline receptors. It inhibits catecholamine release and is therefore expected to exert an antiadrenergic effect at various levels in the regulation of the cardiovascular system. The aim of this study was to investigate the effect of moxonidine (0.025-0.1 mg/kg, i.v.) on the normal and unilateral carotid occlusion-induced impaired corticocerebral blood flow (cCBF) determined by hydrogen polarography, on mean arterial blood pressure (MABP) and heart rate (HR) in conscious rabbits. Moxonidine produced a reduction of MABP and HR. On the other hand, after administration of the drug, a significant increase in the normal and impaired cCBF was observed. Because the improvement in cCBF was conspicuous in both normal and ischemic conditions, moxonidine might be beneficial not only in the treatment of hypertension but also in the management of cerebral ischemia.
 ...
PMID:Effects of moxonidine on corticocerebral blood flow under normal and ischemic conditions in conscious rabbits. 1071 Jan 27

Moxonidine (Moxon, Solvay Pharma) is the first member of a new class of centrally-acting antihypertensive agents. The selective activation of central I1 imidazoline receptors results in an inhibition of peripheral sympathetic activity and produces arterial vasodilatation. Moxonidine is indicated in the treatment of essential arterial hypertension, at a usual daily dose of 0.4 mg (initial dose of 0.2 mg/day), in one administration per day. Its tolerance profile is better than that of other centrally-acting antihypertensive agents which stimulate alpha-2 adrenergic receptors, and similar to that of medications of other classes. As monotherapy, the antihypertensive efficacy of moxonidine is similar to that of most other antihypertensive agents. In case of insufficient response, moxonidine may be associated with other antihypertensive compounds, which leads to a better efficacy with no deterioration of its good tolerance profile.
 ...
PMID:[Pharma-clinics. Medication of the month. Moxonidine (Moxon)]. 1080 41

The SHROB rat is a unique strain with genetic obesity, hypertriglyceridemia, hyperinsulinemia, renal disease with proteinuria, and genetically determined hypertension, characteristics paralleling human Syndrome X. The obese phenotype results from a single homozygous recessive trait, designated faK, and is allelic with the Zucker fatty trait (fa), but of distinct origin. The faK mutation is a premature stop codon in the extracellular domain of the leptin receptor, resulting in a natural receptor knockout. The SHROB are glucose intolerant compared to heterozygous or wild-type SHR, but retain fasting euglycemia even on a high sucrose diet, suggesting that diabetes requires polygenic interaction with additional modifier genes. Insulin-stimulated phosphorylation of tyrosine residues on the insulin receptor and on the associated docking protein IRS-1 are reduced in skeletal muscle and liver compared to SHR, due mainly to diminished expression of insulin receptor and IRS-1 proteins. Despite multiple metabolic derangements and severe insulin resistance, hypertension is not exacerbated in SHROB compared to SHR. Thus, insulin resistance and hypertension are independent in this model. Increased activity of the sympathetic nervous system may be a common factor leading by separate pathways to hypertension and to insulin resistance. We studied the chronic effects of sympathetic inhibition with moxonidine on glucose metabolism in SHROB. Moxonidine (8 mg/kg/day), a selective I1-imidazoline receptor agonist, not only reduced blood pressure but also ameliorated glucose intolerance. Moxonidine reduced fasting insulin by 47% and plasma free fatty acids by 30%. Moxonidine enhanced expression and insulin-stimulated phosphorylation of IRS-1 in skeletal muscle by 74 and 27%, respectively. Thus, central sympatholytic therapy not only counters hypertension but also insulin resistance, glucose tolerance, and hyperlipidemia in the SHROB model of Syndrome X.
 ...
PMID:Molecular pathology in the obese spontaneous hypertensive Koletsky rat: a model of syndrome X. 1084 68

Moxonidine, an antihypertensive imidazoline compound, reduces blood pressure by selective activation of central imidazoline I(1)-receptors and inhibition of sympathetic nerve activity and by direct actions on the kidney, with both mechanisms resulting in diuresis and natriuresis. We hypothesized that the hypotensive and renal actions of moxonidine may be mediated by atrial natriuretic peptide (ANP), a cardiac peptide involved in pressure and volume homeostasis through its vasodilatory, diuretic, and natriuretic actions. Renal parameters were measured on an hourly basis over a period of 4 hours in conscious rats that received bolus intravenous injections of moxonidine (1 to 150 microg/300 microL saline). During the first hour, moxonidine dose-dependently stimulated diuresis, natriuresis, kaliuresis, and urinary cGMP, the index of ANP activity. Moxonidine (50 microg) significantly (P<0.001) stimulated urinary volume (0.35+/-0.04 versus 1.05+/-0.09 mL/h per 100 g), sodium (14. 3+/-2.5 versus 51.8+/-6.5 micromol/h per 100 g), potassium (10.5+/-2. 3 versus 32.3+/-3.2 micromol/h per 100 g), and cGMP (325+/-52 versus 744+/-120 pmol/h per 100 g). Pretreatment with a selective imidazoline receptor antagonist, efaroxan, dose-dependently inhibited moxonidine-stimulated renal parameters. Efaroxan (25 microg per rat) significantly inhibited moxonidine-stimulated diuretic and natriuretic effects and urinary cGMP excretion (744+/-120 versus 381+/-137 pmol/h per 100 g, P<0.02). The alpha(2)-adrenoceptor antagonist yohimbine (50 microg per rat) partially yet significantly inhibited moxonidine-stimulated diuresis and natriuresis but not cGMP excretion. Plasma ANP was dose-dependently increased by moxonidine and was inhibited by pretreatment with efaroxan (220.8+/-36.9 versus 100.3+/-31.7 pg/mL, P<0.03) but not by yohimbine. In conclusion, selective in vivo activation of imidazoline receptors by moxonidine is associated with dose-dependent diuresis, natriuresis, and kaliuresis as well as stimulated plasma ANP and urinary cGMP excretion, thus implicating ANP in the renal actions of moxonidine.
Hypertension 2000 Jun
PMID:Atrial natriuretic peptide is involved in renal actions of moxonidine. 1085 66

Evidence exists for a state of sympathetic hyperactivity in essential hypertension, and moxonidine, a new central sympathetic inhibitor, has been introduced for its treatment. Acute administration of moxonidine lowers peripheral sympathetic neural output. This study examined the effect of chronic moxonidine therapy, at increasing therapeutic doses, on resting peripheral sympathetic activity and vascular resistance and their responses to physiological reflex maneuvers. Twelve newly diagnosed patients with essential hypertension were studied sequentially at least 1 month apart, initially on no therapy, then on 200 microg, and finally on 400 microg of oral moxonidine daily. Changes in heart rate, arterial blood pressure, calf vascular resistance, and peripheral sympathetic drive were assessed at rest and during reflex maneuvers. Peroneal microneurography was used to quantify peripheral sympathetic vasoconstrictor activity by single-unit and multiunit techniques. Moxonidine therapy progressively reduced resting mean arterial pressure (P<0.0001) without affecting heart rate. At 200 microg daily, there was a significant reduction in sympathetic nerve activity (P<0.001) and calf vascular resistance (P<0.01). At 400 microg daily, further reductions were smaller and insignificant. Responses to cold stimulus and isometric handgrip exercise showed a similar pattern, with the greatest magnitude of change at 200 microg daily. In patients with essential hypertension, chronic moxonidine therapy inhibited resting sympathetic vasoconstrictor drive and also its reflex responses. The magnitude of inhibition became less as the therapeutic dose was increased, suggesting that moxonidine may be more effective under conditions of high sympathetic activity.
Hypertension 2000 Jun
PMID:Chronic I(1)-imidazoline agonism : sympathetic mechanisms in hypertension. 1085 75

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 alpha2-receptors. Moxonidine and rilmenidine are 2 imidazoline compounds with 30-fold greater specificity for I1 receptors than for alpha2-receptors. In comparison, clonidine displays a 4-fold specificity for I1 receptors compared with alpha2 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 (t(1/2)) 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, t(1/2) 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. alpha-blocking drugs, calcium antagonists, ACE inhibitors, beta-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.
 ...
PMID:I1 imidazoline agonists. General clinical pharmacology of imidazoline receptors: implications for the treatment of the elderly. 1098 1

Classic centrally acting drugs such as clonidine and alpha-methyldopa induce peripheral sympatho-inhibition via the stimulation of alpha(2)-adrenoceptors in the brainstem. From a haemodynamic point of view this appears to be a useful mechanism to lower elevated blood pressure in hypertensives. Although not known in full detail, a complex relationship exists between the sympathetic nervous system and hypertensive disease; sympathetic inhibition therefore appears to be a logical target of antihypertensive drug treatment. Numerous attempts have been made to improve the unfavourable side-effect profile of the centrally actingalpha(2)-adrenoceptor stimulants. None of these attempts were successful, since both the central antihypertensive activity and the major side-effects (sedation, dry mouth) are mediated by alpha(2)-adrenoceptors. A new approach in this field has been offered by the introduction of centrally acting antihypertensives which interact with central imidazoline (I(1))-receptors and thus cause peripheral sympatho-inhibition. As such they offer haemodynamic benefits similar to those of the classic alpha(2)-adrenoceptor agonists. However, it is hoped that their side-effect profile will be more favourable because of their much weaker affinity for alpha(2)-adrenoceptors. Moxonidine and rilmenidine are the prototypes of centrally acting I(1)-receptor stimulants. The antihypertensive activity of these agents is caused by vasodilatation and a reduction of peripheral vascular resistance. Left ventricular end-diastolic and end-systolic volumes are reduced, whereas heart rate, stroke volume, cardiac output and pulmonary artery pressures are largely unchanged. Left ventricular hypertrophy (LVH) is reduced in the long term. 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 antihypertensives in controlled trials and have been found to be equally effective with respect to blood pressure control. The incidence and severity of side-effects is lower than for clonidine, in particular with respect to sedation. A rebound (withdrawal) phenomenon has so far not been reported for moxonidine and rilmenidine. In conclusion, I(1)-receptor stimulants appear to offer the potential to be developed as centrally acting agents with a better side-effect profile than the classic alpha(2)-adrenoceptor stimulants, but with similar haemodynamic properties.
 ...
PMID:Renewed interest in centrally acting antihypertensive drugs. 1144 83

Moxonidine is a new centrally active imidazoline-receptor agonist being effectively applied in the treatment of arterial hypertension due to its sympathicolytic potency. This is the first investigation regarding the effects of moxonidine on coronary and systemic hemodynamics, metabolic markers of ischemia and neurohumoral parameters in patients with essential hypertension (WHO I-II). We studied moxonidine (single dose of 0.4 mg p.o.) in 22 patients with left ventricular (LV) hypertrophy, ST segment depressions during exercise, pectanginal complaints and negative coronarograms. Assessments included arterial blood pressure, cardiac output, pulmonary artery pressure mean (PAPm), pulmonary capillary wedge pressure (PCWP) and coronary sinus flow (CSF) by intravascular Doppler technique. The moxonidine-induced parameter changes 2 hours later were as follows: a decrease in systolic/diastolic pressure by 28/10 mmHg, and in heart rate by 5 bpm, associated with a decline of PAPm by 17% and of PCWP by 26%. LV work was reduced by 26%, MVO2 by 18% and CSF by 16%. Average peak velocity in CS fell by 18% and coronary flow reserve (with adenosine) increased by 12%. CS-O2 saturation rose by 4%, accompanied by an increase in lactate extraction by 17%, a decrease in norepinephrine spillover by 30% and in arterial endotheline by 20%. In conclusion, moxonidine produces clinically relevant sympathicolysis with beneficial effects on hemodynamics, coronary circulation and neurohumoral parameters.
 ...
PMID:[Effect of the imidazoline receptor agonist moxonidine on hemodynamics, coronary circulation, metabolic ischemia markers and the neurohumoral system in patients with essential hypertension. Effects of moxonidine on coronary circulation]. 1182 37

Moxonidine is a centrally-active imidazoline compound with preferential affinity for imidazoline receptors (IR) over alpha(2)-adrenoceptors (alpha(2)AR). Clinically, moxonidine has proven advantageous for treating hypertension over pure alpha(2)-adrenergic agonists (i.e., guanabenz) due to its lowered incidence of sedative side effects. The present experiments reveal divergent behavioral effects of low doses of moxonidine and guanabenz in C57Bl/6 mice in an exploratory arena. Low-dose moxonidine (0.05 mg kg(-1) i.p.) elicited an increase in novel object contacts (+36%) and more movement into central space (+56%; P<0.01) compared to saline-injected controls; whereas guanabenz induced only dose-responsive sedative-like behaviors in the same paradigm. Yet, the two agonists were indistinguishable in terms of blood pressure changes over a similar dose range (0.025-0.1 mg kg(-1) i.p.) in consciously free-moving mice (Delta mean+/-S.E.M.=-12.3+/-3.2 mm Hg for moxonidine versus -13.5+/-1.9 mm Hg for guanabenz). As expected of alpha(2)AR involvement, the sedative-like effects of guanabenz were completely blocked by pretreatment with the non-imidazoline alpha(2)AR-antagonist, SKF86466 (0.5 or 1.0 mg kg(-1) i.p.). However, the pro-exploratory effects of low doses of moxonidine (0.05 or 0.1 mg kg(-1)) were not antagonized by SKF86466. These results suggest that moxonidine acts preferentially through a non-adrenergic mechanism, possibly IR-mediated, to elicit pro-exploratory behavior.
 ...
PMID:Non-adrenergic exploratory behavior induced by moxonidine at mildly hypotensive doses. 1257 8


<< Previous 1 2 3 4 5 6 Next >>