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

Narrowed afferent arteriolar diameter in young, spontaneously hypertensive rats (SHR) may be a contributor to later development of high blood pressure. Thus, treatment that causes dilation of the afferent arterioles in SHR may inhibit the redevelopment of high blood pressure when treatment is withdrawn. We treated SHR with an ACE inhibitor (cilazapril, 5 to 10 mg/kg per day, high; 1 mg/kg per day, low), a calcium antagonist (mibefradil, 20 to 30 mg/kg per day), and an endothelin receptor antagonist (bosentan, 100 mg/kg per day) from age 4 to 20 weeks. Untreated SHR and Wistar-Kyoto rats were also investigated. At 20 weeks, the rats were killed, and morphology of the afferent arterioles was studied. Other SHR (untreated, high cilazapril, low cilazapril, mibefradil) were treated in exactly the same way and then followed to 32 weeks without treatment. The morphometric studies showed that cilazapril increased the lumen diameter in the afferent arterioles and decreased the media-lumen ratio in a dose-dependent manner. On withdrawal of cilazapril treatment, the reduction in blood pressure persisted. Mibefradil tended to increase afferent arteriolar diameter, whereas it did not alter media-lumen ratio. The persistent effect on blood pressure was only moderate after withdrawal of mibefradil. Bosentan had no effect on renal afferent arteriolar structure or blood pressure. In conclusion, cilazapril was more effective than mibefradil in altering afferent arteriolar structure and caused the most persistent effect on blood pressure after treatment withdrawal. The association of increased afferent arteriolar diameter and lower blood pressure level after withdrawal of treatment may suggest a pathogenic role for afferent arteriolar diameter in the development of high blood pressure in SHR.
Hypertension 1996 Sep
PMID:Effects of an angiotensin-converting enzyme inhibitor, a calcium antagonist, and an endothelin receptor antagonist on renal afferent arteriolar structure. 879 34

Several types of antihypertensive agents, including calcium antagonists, have been reported to prevent stroke and prolong survival in stroke-prone spontaneously hypertensive rats (SHR-SP). We investigated whether mibefradil, a new calcium antagonist acting selectively at the level of T-type calcium channels, would be able to (a) limit or prevent the structural and functional alterations that develop in the cerebral arteries of SHR-SP before stroke and (b) suppress stroke and prolong survival. Mibefradil (30 mg/kg/day) was given orally to young salt-loaded SHR-SP from age 5 weeks to age 20 weeks. Blood pressure (BP) (in conscious animals), diuresis, and proteinuria were determined weekly. After 1012 weeks of treatment, middle cerebral arteries and aortas were removed from randomly selected control and treated SHR-SP. Aortic media thickness and collagen density were evaluated by histomorphometry. Middle cerebral arteries were mounted in a myograph for wall thickness determination and isometric tension recordings. Mibefradil completely prevented stroke and mortality, significantly limited the increase in BP, and opposed the increases in diuresis and proteinuria observed in controls. Simultaneously, mibefradil abolished vascular fibrinoid necrosis formation in the brain and reduced arterial thickening in the cerebral artery as well as in the aorta. The maximal contractile responses of the cerebral arteries to potassium chloride and serotonin were greater in mibefradil-treated animals than in controls, as were the endothelium-dependent relaxant responses. Mibefradil, chronically administered to young SHRSP in a dose that limits the development of hypertension not only prevents stroke and mortality but also affords protection against the vascular structural alterations which develop with age in these animals and preserves or improves the cerebral artery's smooth muscle and endothelial cell functions.
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PMID:Mibefradil, a selective calcium T-channel blocker, in stroke-prone spontaneously hypertensive rats. 885 39

Mibefradil is a novel calcium antagonist that blocks selectively the T-type calcium channels. In this double-blind forced titration study design we compared the effects of mibefradil 50, 100, and 150 mg and nifedipine GITS 30, 60, and 90 mg monotherapies or combined with lisinopril 20 mg in 71 moderate to severe hypertensives (59 men and 12 women) with confirmed ambulatory hypertension. An incremental dose-response effect was observed both in clinic and ambulatory blood pressure parameters during treatment with mibefradil and nifedipine GITS alone and combined with lisinopril. At maximal dosage, patients treated with mibefradil experienced a greater (P < .05) reduction in clinic and ambulatory diastolic blood pressures as well as a greater response rate (86% v 69%). Trough:peak ratios for systolic and diastolic blood pressures were > 90% at each dose level. Significant decrease in baseline heart rate was observed with mibefradil 150 mg alone or combined with lisinopril, but no patients experienced clinically significant atrioventricular conduction abnormalities. Adverse events related to vasodilation were more prevalent in the nifedipine GITS group. Consequently, the results of the present study demonstrate that the novel calcium channel blocker mibefradil, either alone or in combination with lisinopril, is effective in reducing clinic and 24-h blood pressures while decreasing heart rate and is well tolerated in patients with moderate to severe hypertension.
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PMID:The antihypertensive efficacy of the novel calcium antagonist mibefradil in comparison with nifedipine GITS in moderate to severe hypertensives with ambulatory hypertension. 903 27

Mibefradil is a recently introduced calcium antagonist that, as a tetralol derivative, is chemically distinct from previous calcium antagonists. This article will review pertinent results from in vitro, animal, and clinical investigations to report the pharmacologic properties that distinguish mibefradil from all of the calcium channel antagonists in use today, all of which operate on the "L-type" calcium channel. Mibefradil's pharmacokinetic profile indicates it can be used as a once-daily oral treatment for hypertension and chronic stable angina pectoris.
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PMID:Pharmacologic and pharmacokinetic profile of mibefradil, a T- and L-type calcium channel antagonist. 928 48

Mibefradil belongs to a new class of calcium antagonists, the tetralol derivatives. It selectively blocks T-type calcium channels in contrast to other calcium antagonists which block only L-type channels. Mibefradil relaxes coronary arteries without suppressing myocardial contractility and causes a dose-related decrease in heart rate. When given orally once daily to patients with hypertension mibefradil produces a dose-related decrease in blood pressure which is sustained for 24 hours and improves exercise performance in patients with stable angina pectoris. In patients with generally mild to moderate hypertension oral mibefradil was superior to nifedipine SR and diltiazem CD, tended to be more effective than nifedipine GITS and had similar efficacy to amlodipine. Mibefradil 50 to 100mg once daily also has antianginal and anti-ischaemic effects. The drug improves the duration of symptom-limited exercise and the time to onset of ischaemia, and reduces the frequency of anginal attacks and consumption of nitroglycerin. Its efficacy is similar to that of diltiazem and tends to be greater than that of amlodipine in patients with stable angina. Mibefradil is generally well tolerated and is associated with a lower incidence of leg oedema than amlodipine and nifedipine. Thus, mibefradil is a calcium antagonist with a predictable cardiovascular profile, which, on the basis of available clinical data, is an effective alternative to other drugs widely used in the treatment of hypertension and stable angina pectoris.
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PMID:Mibefradil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the management of hypertension and angina pectoris. 936 62

Mibefradil is the first of a new class of calcium antagonists with a unique structure and pharmacology. Its novel mechanism of action is characterized by L-type and selective T-type calcium channel blockade. Mibefradil is selective for smooth muscle over cardiac muscle and selectively dilates the coronary vasculature over the peripheral vasculature. In animal studies, mibefradil increases coronary blood flow during induced ischemia. In addition, in vitro studies demonstrated that mibefradil decreases smooth muscle proliferation in response to vascular injury. The most intriguing effects of mibefradil include a lack of negative inotropy and reflex tachycardia, as well as inhibition of pathologic hypertrophy and remodeling in response to vascular injury. In clinical trials, mibefradil (100 mg) was more effective than diltiazem dual-release capsules (360 mg) and as effective as amlodipine (10 mg) in treating mild-to-moderate hypertension; mibefradil (100 mg) also resulted in a greater reduction in sitting diastolic blood pressure than did nifedipine GITS (60 mg) in patients with moderate-to-severe hypertension. In patients with chronic stable angina, mibefradil (100 mg) was as effective as diltiazem SR capsules (120 mg) twice daily and more effective than amlodipine (10 mg) in improving exercise tolerance and reducing ischemic episodes. Mibefradil improved survival in a rat model of heart failure as effectively as the angiotensin-converting enzyme (ACE) inhibitor, cilazapril. The apparent lack of negative inotropic activity and neurohormonal activity with mibefradil, as well as its favorable effects on cardiac remodeling in experimental models, suggest that this agent may be beneficial in congestive heart failure. This hypothesis is being tested in the ongoing Mortality Assessment in Congestive Heart Failure (MACH-1) trial.
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PMID:Mibefradil: a selective T-type calcium antagonist. 937 39

Calcium antagonists (CAs) are widely used in the management of hypertension and chronic stable angina pectoris. Currently available CAs fall into three distinct structural classes--the dihydropyridines, the benzothiazepines, and the phenylalkylamines. The diversity of these agents, even among drugs within a structural group, is apparent in their pharmacology, physiologic effects, and therapeutic uses. Traditional CAs produce their effects through blockade of the L-type calcium channel. Recently, a new CA has been developed. Mibefradil, the first member of a new class of CAs, is a tetralol derivative. It is characterized by its selective blockade of T-type calcium channels. It differs from existing CAs and may offer important therapeutic advantages.
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PMID:Diversity of calcium antagonists. 938 1

Heart rate is a key determinant of myocardial oxygen consumption. Several lines of evidence support a consistent association between heart rate and cardiovascular mortality. Increments in heart rate are positively related to cardiovascular and sudden death in patients with hypertension or previous myocardial infarction and in the elderly with heart disease. This relationship is important because a number of commonly used cardiovascular agents, such as beta-blockers and calcium antagonists (CAs), can affect heart rate. Beta-blockers decrease heart rate and reduce morbidity and mortality in post-myocardial infarction patients. The CAs are a structurally diverse group of agents with different physiologic effects. The dihydropyridine CAs are not associated with a reduction in heart rate. In fact, often they can cause reflex tachycardia as a result of potent systemic vasodilator action, which may provoke angina, especially in patients with ischemic heart disease. The nondihydropyridine CAs verapamil and diltiazem reduce heart rate but are associated with negative inotropy. Mibefradil, the first member of a new class of CAs, reduces heart rate and is not associated with negative inotropic effects. This unique pharmacologic profile may be of great value in treating hypertensive patients, particularly those with coexisting ischemic heart disease, and also patients with angina pectoris alone. However, the clinical benefit of pharmacologically reducing heart rate with mibefradil needs to be demonstrated in controlled trials.
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PMID:Reappraisal of the importance of heart rate as a risk factor for cardiovascular morbidity and mortality. 938 4

PROTECTIVE EFFECTS OF ANTIHYPERTENSIVE DRUGS: Treatment of hypertension has been shown to reduce cardiovascular morbidity and mortality. This is especially true for the beneficial effect against stroke. The protective effects against coronary heart disease have also been significant but numerically less impressive than the effect against stroke. It is conceivable that a modern drug should possess cardioprotective properties in order to achieve a better protection against coronary heart disease. EFFECTS OF MIBEFRADIL: The novel calcium antagonist mibefradil, which blocks both transient (T) and long-lasting (L) calcium channels, has a hemodynamic profile which may have cardioprotective properties. Mibefradil reduces arterial pressure by a vasodilating effect with little or no effect on cardiac output. Recently reported effects of antihypertensive treatment with a calcium antagonist on stroke morbidity in the European trial on systolic hypertension (Syst-Eur) have confirmed previous findings with a calcium antagonist in the Shanghai Trial Of Nifedipine in the Elderly (STONE). Thus the pharmacodynamic profile of mibefradil might offer additional cardioprotective benefit. This possibility deserves assessment in a proper prospective intervention study.
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PMID:Should a modern antihypertensive drug possess cardioprotective properties? 948 15

Low-voltage-activated T-type Ca2+ channels are present in most excitable tissues including the heart (mainly pacemaker cells), smooth muscle, central and peripheral nervous systems, and endocrine tissues, but also in non-excitable cells, such as osteoblasts, fibroblasts, glial cells, etc. Although they comprise a slightly heterogeneous population, these channels share many defining characteristics: small conductance (< 10 pS), similar Ca2+ and Ba2+ permeabilities, slow deactivation, and a voltage-dependent inactivation rate. In addition, activation at low voltages, rapid inactivation, and blockade by Ni2+ are classical properties of T-type Ca2+ channels, which are less specific. T-type Ca2+ channels are weakly blocked by standard Ca2+ antagonists. Pharmacological blockers are scarce and often lack specificity and/or potency. The physiological modulation of T-type Ca2+ currents is complex: they are enhanced by endothelin-1, angiotensin II (AT1-receptor), ATP, and isoproterenol (cAMP-independent), but are reduced by angiotensin II (AT2-receptor), somatostatin and atrial natriuretic peptide. Norepinephrine enhances these currents in some cells but decreases them in others. T-type Ca2+ currents have many known or suggested physiological and pathophysiological roles in growth (protein synthesis, cell differentiation, and proliferation), neuronal firing regulation, some aspects of genetic hypertension, cardiac hypertrophy, cardiac fibrosis, cardiac rhythm (normal and abnormal), and atherosclerosis. Mibefradil is a new Ca2+ antagonist that is effective in hypertension and angina pectoris. Its favorable pharmacological profile and limited side effects appear to be related to selective block of T-type Ca2+ channels: mibefradil reduces vascular resistance and heart rate without negative inotropy or neurohormonal stimulation, and it also has significant antiproliferative actions.
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PMID:T-type Ca2+ channels and pharmacological blockade: potential pathophysiological relevance. 951 67


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