dihydropyridines and Cerebrovascular-Disorders

Japanese Society of Hypertension Committee published Guidelines for the Management of Hypertension in 2009 (JSH2009). The first choices of antihypertensive drugs are calcium channel blockers, angiotensin II receptor blockers, angiotensin converting enzyme inhibitors, diuretics, and beta-adrenergic blockers. Because dihydropyridine calcium channel blockers have the greatest hypotensive efficacy without affecting organ blood flow, they are indicated in the patients with complications and the aged. Positive indications of calcium channel blockers are left ventricular hypertrophy, tachycardia (non-dihydropyridine), angina pectoris, chronic phase of cerebrovascular disease, and elderly patients. Patients with bradycardia are contraindicated by non-dihydropyridine calcium channel blockers.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Cerebrovascular Disorders; Coronary Disease; Diabetes Complications; Dihydropyridines; Evidence-Based Medicine; Humans; Hypertension; Kidney Diseases; Practice Guidelines as Topic

Topics: Animals; Brain Ischemia; Calcium Channel Blockers; Calcium Channels; Cerebrovascular Disorders; Dihydropyridines; Flunarizine; Humans; Neuroprotective Agents; Verapamil

The calcium antagonist, manidipine, was developed on the basis of the hypothesis that antihypertensive drugs that act to improve renal hemodynamic alterations will be therapeutically beneficial in hypertensive patients. Manidipine shows long-lasting calcium channel-blocking action in vascular smooth muscle cells and antihypertensive actions in various types of hypertensive models. The drug has high selectivity for resistance vessels, dilates renal vasculature, and inhibits renal vascular constrictions induced by norepinephrine and angiotensin II in spontaneously hypertensive rats. It increases renal blood flow and has a prominent natriuretic action without changing glomerular filtration rate. The coronary dilating effect of the drug is similar to that of nifedipine, but its cardiodepressant effects are less potent than those of other dihydropyridines. Furthermore, manidipine prevents the development of cerebrovascular lesions and inhibits the progression of vascular damage in the brain and kidneys of stroke-prone spontaneously hypertensive rats. The drug also inhibits a proliferative response of the intima to balloon catheter-induced injury in the carotid arteries of spontaneously diabetic rats without affecting plasma lipids or blood pressure. These results suggest that manidipine may be useful for the treatment of hypertensive patients with or without vascular complications.

Topics: Animals; Antihypertensive Agents; Calcium Channel Blockers; Cardiovascular System; Cerebrovascular Disorders; Dihydropyridines; Hemodynamics; Humans; Muscle, Smooth, Vascular; Nitrobenzenes; Piperazines; Renal Circulation

Synthetic calcium channel blockers (Ca2+ entry blockers or antagonists) have been reported to induce relaxation of smooth muscle which is not thought to be mediated by any specific action(s) on receptor sites. In addition, it has been suggested that Ca2+ channel blockers increases blood flow in a number of organ regions, including mesenteric, femoral, renal, cerebral and coronary vasculatures, via a direct action on vascular tone by inhibiting Ca2+ influx across the vascular smooth muscle membranes. Such information has prompted clinical studies with the use of Ca2+ channel blockers in the treatment of a wide variety of cardiovascular disorders. The questions, to be answered, however, are whether any of the newly-designed channel blockers can actively produce vasodilatation of arterioles and venules in regional microvasculatures, and these synthetic agents are safe and therapeutically effective. In addition, can one design site-specific (e.g., cerebral vs. coronary vasodilator) Ca2+ channel blockers. But, since the body has a natural Ca2+ antagonist, viz., magnesium ions (Mg2+), one must ask whether such divalent cations act as peripheral vasodilators and are effective as therapeutic agents. The studies reviewed herein: compare the effects of several different Ca2+ channel blockers on resistance and capacitance vessels in different regional microvasculatures (i.e., mesenteric, skeletal muscle, pial) within a single species, namely the rat, by high-resolution TV microscopy, and demonstrate the rationale, effects and mechanisms of action of Mg2+ on regional blood vessels. These data show some of the new, novel synthetic Ca2+ channel blockers (i.e., nisoldipine, nitrendipine, nimodipine) can: exert effects on both arterioles and venules in certain vasculatures; be designed to exert a wide range of potencies; and be designed to act selectively at regional microvasculatures. In addition, the data presented are consistent with the hypothesis that Mg2+ exerts a regulatory role in vascular tone, vascular reactivity and vascular resistance. Certain vascular diseases associated with a Mg2+-deficiency appear to be amenable to treatment with Mg2+.

Topics: Anesthesia; Animals; Arterioles; Blood Pressure; Calcium; Calcium Channel Blockers; Cell Membrane Permeability; Cerebrovascular Circulation; Cerebrovascular Disorders; Coronary Disease; Diabetes Mellitus; Dihydropyridines; Female; Humans; Hypertension; Ketamine; Magnesium; Magnesium Deficiency; Microcirculation; Muscle, Smooth, Vascular; Muscles; Nifedipine; Nisoldipine; Nitrendipine; Nutritional Requirements; Pentobarbital; Pre-Eclampsia; Pregnancy; Pyridines; Rats; Vasoconstrictor Agents; Vasodilator Agents; Venules

It is known that the risk of cerebral stroke recurrence in post-stroke patients is comparatively higher than in normal subjects, and it is suggested that autonomic nervous system dysfunctions elevate this risk. We investigated the anti-hypertensive effects of cilnidipine, a Ca antagonist which suppresses sympathetic nerve activation, in hypertensives with chronic-stage cerebrovascular disease in a comparison with amlodipine.. Amlodipine 5-7.5 mg/day, or cilnidipine 5-10 mg/day was administered to 78 hypertensive subjects (greater than 140 mmHg systolic, or 90 mmHg diastolic) undergoing outpatient treatment. Amlodipine or cilnidipine was also administered similarly, to 30 subjects having hypertension associated with a cerebral infarct which occurred more than one month earlier due to cerebral thrombosis or embolism. After 3 months administration, the subjects' blood pressures and pulse rates were recorded with an ambulatory blood pressure monitor over 24 hours.. No difference was recognized in patient age, gender, and systolic and diastolic blood pressure before treatment between the groups. In the cilnidipine groups, no difference in average 24-hour or waking systolic blood pressure values was seen between cerebrovascular disease (CVD) subjects and non-CVD subjects, although in the amlodipine groups, CVD subjects had significantly higher blood pressure values than non-CVD subjects. In the cilnidipine group, the coefficient of variation values of pulse rate were significantly higher in CVD subjects than in non-CVD subjects (p<0.05).. In patients with recent stroke, a Ca antagonist with no sympathetic nerve suppression had weaker blood pressure-lowering effects. Significantly increased pulse rate variability, shown in the CVD subjects administered cilnidipine, suggests that cilnidipine enhanced the parasympathetic function in hypertensive patients with CVD.

Topics: Aged; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Cerebrovascular Disorders; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged

We determined possible protective effects of benidipine hydrochloride (benidipine), a dihydropyridine calcium antagonist, on cerebrovascular lesions in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). The animals were orally treated with benidipine at 1, 3 and 10 mg/kg daily for 7 weeks, and their neurological symptoms, body weight changes, systolic blood pressure and cerebrovascular lesions on magnetic resonance imaging (MRI) were determined at various time points of treatment. Moreover, the brains of the rats that showed cerebrovascular lesions on MRI in the course of treatment or completed 7-week treatment were examined histopathologically. Control rats presented such symptoms as sedation, ataxia and aggressiveness, while their MRI analysis revealed high signals over wide areas from the occipital to frontal cortex and from the corpus callosum to external capsule. These high signal areas corresponded in location to edematous or softening lesions revealed by the histopathological observation. Treatment with benidipine at 3 and 10 mg/kg ameliorated neurological symptoms, significantly suppressing cerebrovascular damages on MRI. Benidipine at 3 mg/kg significantly decreased blood pressure for the first four weeks but it did not thereafter. These findings demonstrate that benidipine can protect salt-loaded SHRSP from cerebrovascular injury as assessed by MRI.

Topics: Analysis of Variance; Animals; Blood Pressure; Body Weight; Brain; Cerebrovascular Disorders; Dihydropyridines; Disease Models, Animal; Magnetic Resonance Imaging; Male; Psychomotor Performance; Rats; Rats, Inbred SHR; Sodium Chloride, Dietary; Vasodilator Agents

We investigated the protective effect of chronic treatment with AE0047, a dihydropyridine-type calcium channel blocker, on vascular endothelial abnormalities in stroke-prone spontaneously hypertensive rats (SHRSP). Ten-week repeated antihypertensive treatment with AE0047 inhibited blood pressure elevation and improved endothelium-dependent relaxation in response to acetylcholine in aorta isolated from SHRSP. Furthermore, the abnormal production of prostaglandin I2 and thromboxane A2 in the aorta was normalized to a level equivalent to that in Wistar-Kyoto rats. These results suggest that chronic treatment with AE0047 exerts protective effects against endothelial abnormalities associated with the development of hypertension.

Topics: Animals; Antihypertensive Agents; Aorta; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Endothelium, Vascular; Heart Rate; Hypertension; Male; Prostaglandins; Protective Agents; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasoconstriction; Vasodilation

The stroke-prone spontaneously hypertensive rat (SHRSP) is a strain with high incidence of cerebrovascular accidents increased by salt-rich diet and decreased by calcium-antagonist treatment. In the SHRSP rat basilar artery the authors have previously shown reduced contractility and altered structure including regions of smooth muscle cell (SMC) disorganization. The aims of this study have been to analyze (1) the morphology of these abnormal regions, (2) the structural modifications responsible for the reduced function, and (3) the effect of salt and calcium-antagonist treatment on vascular structure and function. Wistar Kyoto and SHRSP rats, untreated or treated from week 8 through 14 with 1% NaCl or 1% NaCl + 1 mg x kg(-1) x d(-1) lacidipine, were used. Function was studied with wire myography. Structure was analyzed in fixed intact arteries with confocal microscopy. Basilar arteries from SHRSP rat showed (1) reduced contractility, (2) discrete foci of SMC disarray with altered proportion of adventitia to SMC, and (3) decreased SMC and increased adventitial cell number. Arteries from salt-loaded SHRSP rats showed a higher degree of SMC disarray and further reduction in contractility. Lacidipine treatment of salt-loaded rats significantly improved structure and function. These data suggest that vascular remodeling can provide an explanation for the observed reduction in vascular contractility of SHRSP rat basilar arteries and might show light on the effects of salt load and calcium-channel blockers in life span and the incidence of cerebrovascular accidents in SHRSP rats.

Topics: Animals; Antihypertensive Agents; Basilar Artery; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Genetic Predisposition to Disease; Hypertension; Microscopy, Confocal; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium Chloride, Dietary

The aim of this study was to investigate the therapeutic effectiveness of lacidipine in stroke-prone spontaneously hypertensive rat (SHRSP) with cerebrovascular lesions in comparison with nicardipine. SHRSP were fed 1% saline as drinking water. After the onset of stroke, saline was replaced with water and each drug was administered orally once a day for 3 weeks. In the drug-untreated group, recurrence of stroke was repeated, deterioration and amelioration of neurological deficits (ND) were repeated, and histological examination and measurement of regional blood flow (rBF) using nonradioactive colored microspheres performed at the end of treatment revealed severe damages and significantly decreased rBF in brain and kidney, respectively. In kidney, not only lacidipine (1 mg/kg) but also nicardipine (30 mg/kg) decreased vascular lesions and ameliorated low-rBF significantly. Both drugs also inhibited the recurrence of stroke completely even at a low dose that did not ameliorate severe hypertension. Neuronal damages and ND in each lacidipine-treated group were ameliorated significantly, whereas those in each nicardipine-treated group were slightly improved. Lacidipine at 1 mg/kg alone ameliorated the cerebral low-rBF significantly even at 24 hr after administration. These results suggest that a long-lasting improvement of low-rBF after stroke may be useful in the treatment of SHRSP with cerebrovascular lesions.

Topics: Animals; Blood Pressure; Body Weight; Brain; Calcium Channel Blockers; Cerebellum; Cerebrovascular Disorders; Dihydropyridines; Hypertension; Kidney; Male; Nicardipine; Rats; Rats, Inbred SHR; Recurrence; Regional Blood Flow; Renal Artery; Systole

Calcium-channel blockers (CCBs) reduce systolic blood pressure and stroke-related mortality in stroke-prone spontaneously hypertensive rats (SPSHR). Brain ischemia is associated with loss of intracellular antioxidants. Increased formation of oxygen radicals and oxidation of LDL may enhance arterial vasoconstriction by various mechanisms. CCBs that also exert antioxidative properties in vitro may therefore be particularly useful. To investigate such antioxidant effects in vivo, we determined several parameters of LDL oxidation in SPSHR treated with two 1,4-dihydropyridine-type (1,4-DHP) CCBs of different lipophilic properties and compared them with antioxidant-treated and untreated controls. We also tested whether these drugs decrease the formation of oxidation-specific epitopes in arteries.. Five groups of 9 to 14 SPSHR each (aged 8 weeks) were treated with 80 mg/kg body wt per day nifedipine, 1 mg or 0.3 mg/kg body wt per day lacidipine, vitamin E (100 IU/d), or carrier for 5 weeks. A group of Wistar-Kyoto rats was used as normotensive control. Plasma samples were taken, and LDL was isolated by ultracentrifugation. Then LDL was exposed to oxygen radicals generated by xanthine/xanthine oxidase reaction (2 mmol/L xanthine+100 mU/mL xanthine oxidase), and several parameters of oxidation were determined. The presence of native apolipoprotein B and oxidation-specific epitopes in the carotid and middle cerebral arteries was determined immunocytochemically.. 1,4-DHP CCBs completely prevented mortality. Normotensive Wistar-Kyoto rats showed less oxidation than control SPSHR. Plasma lipoperoxide levels were 0.87+/-0.27 micromol/L in control SPSHR, 0.69+/-0.19 and 0.63+/-0.20 micromol/L in the groups treated with 0.3 and 1 mg lacidipine, respectively, and 0.68+/-0.23 micromol/L in nifedipine-treated animals (P<0.05 versus control SPSHR for all values). Both CCBs significantly decreased formation of conjugated dienes and prolonged the lag time in LDL exposed to oxygen radicals. Similarly, lipoperoxides and malondialdehyde were significantly reduced (P<0.05). Reduced relative electrophoretic mobility and increased trinitrobenzenesulfonic acid reactivity of LDL from treated rats (P<0.01) also indicated that fewer lysine residues of apolipoprotein B were oxidatively modified in the presence of 1,4-DHP CCBs. Finally, these drugs reduced the intimal presence of apolipoprotein B and oxidized LDL (oxidation-specific epitopes) in carotid and middle cerebral arteries.. In the SPSHR model, 1,4-DHP CCBs reduce plasma and LDL oxidation and formation of oxidation-specific epitopes and prolong survival independently of blood pressure modifications. Our results support the concept that the in vivo protective effect of these drugs on cerebral ischemia and stroke may in part result from inhibition of oxidative processes.

Topics: Animals; Antioxidants; Apolipoproteins B; Arteries; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Epitopes; Genetic Predisposition to Disease; Immunohistochemistry; Lipoproteins, LDL; Male; Oxidation-Reduction; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reference Values; Vitamin E

1. The potential of AE0047, a novel calcium antagonist, to remedy brain damage of stroke-prone spontaneously hypertensive rats (SHRSPs) with signs of stroke was compared with those of nicardipine and hydralazine. 2. AE0047 (1 and 3 mg/kg/day) given daily to diseased SHRSPs prevented mortality and improved neurological symptoms. Histological examination also supported the effectiveness of AE0047 against the progression of the disease. 3. Nicardipine (10 mg/kg/day) and hydralazine (10 mg/kg/day) were less effective than AE0047 in a dose equal to or more than the hypotensive dose, respectively. 4. AE0047 may be beneficial for treating the acute stage of stroke in humans by virtue of its long-lasting hypotensive action and undefined direct actions on the cerebral vasculature.

Topics: Animals; Brain; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Hydralazine; Male; Nicardipine; Rats; Rats, Inbred SHR; Vasodilator Agents

To analyze the effect of the long-acting calcium channel blocker lacidipine on cardiovascular remodeling induced by salt loading in a genetic model of hypertension.. We examined the influence of threshold doses of lacidipine, with little blood-pressure lowering effect, on cardiac weight and gene expression in stroke-prone spontaneously hypertensive rats (SHRSP).. SHRSPs (8-week-old) were randomly allocated to four groups: control, salt-loaded SHRSP and salt-loaded SHRSP treated with lacidipine at 0.3 and 1 mg/kg per day. Systolic blood pressure was measured by the tail-cuff method. At the end of 6 weeks of treatment, ventricles were collected and weighed. Ventricular messenger RNA was extracted and subjected to Northern blot analysis.. Lacidipine (0.3 mg/kg per day) not only prevented the salt-dependent cardiac hypertrophy and the slight increase in systolic blood pressure induced by salt, but also prevented, largely or completely, salt-dependent increases in ventricular levels of several gene products: skeletal and cardiac alpha-actin, beta-myosin heavy chain (beta-MHC), type I collagen, long-lasting (L)-type calcium channel and preproendothelin-1. At a higher dose of 1 mg/kg per day, lacidipine further decreased systolic blood pressure below the level of control SHRSP, completely prevented salt-dependent overexpression of the beta-MHC gene and markedly attenuated salt-dependent overexpression of the transforming growth factor-beta1 gene.. Lacidipine prevents the cardiac remodeling and enhanced gene expression induced by salt loading in SHRSP at doses that only minimally affect the high systolic blood pressure.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cardiomegaly; Cerebrovascular Disorders; Dihydropyridines; Follow-Up Studies; Gene Expression; Hypertension; Male; Myosin Heavy Chains; Random Allocation; Rats; Rats, Inbred SHR; RNA, Messenger; Sodium Chloride; Ventricular Remodeling

Effects of benidipine hydrochloride or triple therapy (hydralazine, reserpine, and hydrochlorothiazide) on renal cortical and medullary intrinsic antioxidant enzyme (AOE) activity were evaluated in stroke-prone spontaneously hypertensive rats (SHR-SP) as an animal model for human essential hypertension with cerebral stroke. This study showed a significant decrease of renal intrinsic glutathione peroxidase (GSH-Px) activity in untreated SHR-SP. Renal GSH-Px activity in untreated SHR-SP was significantly lower than that in Wister Kyoto rats (WKY) as a normotensive reference strain. GSH-Px activity in SHR-SP was significantly improved after benidipine hydrochloride therapy. Levels of urinary albumin excretion or creatinine clearance (Ccr) in SHR-SP were also improved after the therapy. Glomerular sclerosis index was slightly improved in SHR-SP treated with benidipine hydrochloride according to light microscopic analysis. It appears that hypertension may influence the renal intrinsic GSH-Px activity, albuminuria, and Ccr in SHR-SP. Thus it is indicated that control of blood pressure may improve the GSH-Px activity in SHR-SP.

Topics: Animals; Antioxidants; Blood Pressure; Calcium Channel Blockers; Catalase; Cerebrovascular Disorders; Creatine; Dihydropyridines; Drug Therapy, Combination; Glutathione Peroxidase; Hydralazine; Hydrochlorothiazide; Hypertension; Kidney; Male; Organ Size; Oxidoreductases; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reserpine; Superoxide Dismutase

These studies were designed to investigate the protective effects of the new angiotensin II receptors antagonist BAY 10-6734 (6-n-butyl-4-methoxycarbonyl-2-oxo-1[(2'-(1H-tetrazol-5-yl) -3-fluorobiphenyl-4-yl)methyl] 1,2-dihydropyridine, CAS 156001-18-2) on haemodynamic, hormonal, renal, and structural parameters in renin transgenic rats (TGR(mRen2)27), salt-loaded Dahl S and R rats, and salt-loaded stroke-prone spontaneously hypertensive rats (SHR-SP) in long-term trials. Study 1: In SHR-SP the development of blood pressure, cardiac hypertrophy, and the deleterious effects of salt loading on kidney structure and kidney function was prevented by BAY 10-6734. Study 2: In salt-loaded Dahl S rats with a suppressed plasma renin activity treatment with BAY 10-6734 did not delay the increase in blood pressure but prevented cardiac hypertrophy and the increase in plasma ANP (Atrial natriuretic peptide). Study 3: TGR develop malignant hypertension associated with cardiac hypertrophy, elevated left-ventricular end-diastolic pressure and increased plasma ANP. After 6 weeks of treatment with BAY 10-6734 (30 mg/kg p.o. bid) cardiac pump function was improved and cardiac hypertrophy was reversed in this angiotension dependent form of hypertension. The beneficial effects of BAY 10-6734 in these different animal hypertension models are also emphasized by a reduction in mortality.

Topics: Aldosterone; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Animals, Genetically Modified; Antihypertensive Agents; Atrial Natriuretic Factor; Body Weight; Cerebrovascular Disorders; Cyclic GMP; Dihydropyridines; Hemodynamics; Hormones; Hypertension; Kidney; Rats; Rats, Inbred SHR; Renin; Tetrazoles

To test for evidence of stroke-preventive action, we initially examined the effect on salt-loaded stroke-prone spontaneously hypertensive rats of chronic treatment with 4-(4-benzhy-drylpiperazino)phenethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate dihydrochloride (AE0047), a novel calcium antagonist with slow onset and long-lasting hypotensive effect, and compared its efficacy with that of the calcium antagonist nicardipine and the vasodilator hydralazine. We then used radioactive microspheres to study the effects of these three agents on hemodynamic impairment to clarify the mechanism of the test drug's putative preventive action. In a 12-week repeated-administration study using animals of initial age 9 weeks; all vehicle-treated subjects died within 37 days as a result of severe hypertension and stroke, whereas those treated with AE0047, at doses of 1 or 3 mg/kg/day, remained free of stroke and showed no signs of hemorrhage, brain softening or the cerebrovascular lesions typical in this animal model. Significant suppression of the development of hypertension was not noted at the lower of these doses nor at a nicardipine dose of 10 mg/kg/day, which failed to prevent stroke in most cases. A 10-mg/kg/day dose of hydralazine did suppress the development of hypertension but failed to prevent death in half of all cases. In the hemodynamic study, 4-week treatment with AE0047 averted the marked decreases in cardiac output and blood flow in the brain, heart, kidneys and adrenal glands observed in the control group, as well as the accompanying rise in total peripheral resistance before and after stroke.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Hemodynamics; Hypertension; Male; Rats; Rats, Inbred SHR

We investigated the effects of the combination of idebenone, an energy metabolism enhancer, and manidipine 2HCl, a dihydropyridine-derivative calcium antagonist, on neurological deficits and histological changes in the brain and kidneys of stroke-prone spontaneously hypertensive rats (SHRSP) with cerebrovascular lesions (stroke). The SHRSP were kept on a 1% NaCl solution as their drinking water to synchronize the onset of stroke. After the onset of stroke symptoms, the salt solution was replaced with tap water. On the day following the onset of stroke, idebenone (50 mg/kg), manidipine 2HCl (2 mg/kg) or a combination of idebenone (50 mg/kg) and manidipine 2HCl (2 mg/kg) was administered orally once a day for 3 weeks. In the combination group and manidipine 2HCl-treated group, the neurological deficits after the onset of stroke were ameliorated during the entire experimentalperiod. Especially, the combination significantly decreased the number of days with severe neurological deficits as compared to the control group. The combination and manidipine 2HCl significantly recovered the decrease in body weight and ameliorated the increase of brain weight, which was mainly caused by edema, significantly as compared to the control group. Manidipine 2HCl ameliorated the histological changes in the brain. In the combination group, the histological changes in both the brain and the kidneys were ameliorated. In conclusion, the combination of idebenone and manidipine 2HCl significantly ameliorated the neurological deficits and the histological changes in the brain and the kidney of SHRSP with stroke as compared to each individual treatment. We concluded that manidipine 2HCl enhances the therapeutic effect of idebenone in the treatment of cerebrovascular diseases.

Topics: Administration, Oral; Animals; Benzoquinones; Brain; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Drug Combinations; Drug Synergism; Drug Therapy, Combination; Kidney; Male; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Ubiquinone

1. Malignant or precocious stroke-prone spontaneously hypertensive rats (M-SHRSP) showed hypertensive ocular fundus changes with severe hypertension, but various anti-hypertensive drugs given over a proper period improved funduscopic findings. 2. We treated a M-SHRSP with SQ29,852 (an angiotensin converting enzyme inhibitor, ACEI) or manidipine (a calcium antagonist) and observed hypertensive vascular changes in the fundus. 3. The M-SHRSP treated with anti-hypertensive drugs lived longer and the hypertensive fundic changes improved in both groups. But there were some differences of histochemical staining reaction on the endothelial cell-surface and mucopolysaccharides accumulations between the treated group of ACEI and the group treated with the calcium antagonist. 4. In the treated group with calcium antagonist, the anionic ion functions of the endothelial cell-surface were impaired and organic retinal or choroidal damages appeared to have deteriorated.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Arterioles; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Fundus Oculi; Histocytochemistry; Hypertension; Male; Nitrobenzenes; Organophosphorus Compounds; Piperazines; Proline; Rats; Rats, Inbred SHR; Rats, Inbred WKY

1. The effects of benidipine hydrochloride (benidipine), a long-acting dihydropyridine calcium antagonist, on the development of hypertension and renal lesions were examined in stroke-prone spontaneously hypertensive rats (SHRSP). 2. SHRSP were fed with 8% NaCl diet for 3 weeks from 13 weeks of age, and benidipine (1 or 3 mg/kg per day) was orally administered during the same period. 3. The high salt diet accelerated an increase in urinary excretions of total protein and albumin, and caused marked arteriole, glomerular and tubular lesions in the kidney. 4. Benidipine significantly inhibited these changes, and also suppressed the elevation of blood pressure in salt-loaded SHRSP. 5. These results reveal that benidipine has protective effects against the development of hypertension and the progression of renal lesions induced by the high salt diet in SHRSP.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Hypertension; Kidney; Male; Organ Size; Rats; Rats, Inbred SHR

1. We evaluated the protective effects of manidipine on spermatogenic damage induced by the hypertensive vascular changes in stroke-prone spontaneously hypertensive rats (SHRSP). 2. Blood pressure reached more than 250 mmHg in SHRSP at 15 weeks of age, and thereafter the hypertensive changes in testicular arterioles developed. Manidipine reduced both the blood pressure and the hypertensive vascular changes. 3. Although immature and mature spermatids greatly diminished in SHRSP at 23 weeks of age, manidipine could preserve almost normal spermatogenesis even at 23 weeks of age. Transferrin concentration in testicular cytosol, which was considered to be indicative of the Sertoli cell function, in SHRSP with manidipine administration was significantly higher than that in SHRSP with no treatment at 23 weeks of age. 4. In conclusion, manidipine could prevent the development of the hypertensive changes in intratesticular arterioles and maintain normal Sertoli cell function. As a result, manidipine protected spermatogenic damage in SHRSP.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Disorders; Cytosol; Dihydropyridines; Hypertension; Male; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Regional Blood Flow; Spermatogenesis; Testis

We investigated the effect on cardiac hypertrophy of a once-daily treatment with lacidipine, at doses that do not reduce systolic blood pressure. Spontaneously hypertensive stroke-prone rats (SHR-SP) were fed a 1% NaCl enriched diet and treated daily by gastric gavage with lacidipine at doses of 0.3, 1, or 3 mg/kg/die or vehicle. At 15 weeks of age the rats were sacrificed. The heart was removed, weighed and processed for transmission electron microscopy, scanning electron microscopy and ultrastructural morphometry. Though the treatment did not reduce systolic blood pressure, heart weight and heart weight/body weight ratio were lower in the lacidipine-treated rats than in those treated with vehicle alone. Medial and subendothelial lesions were visible in coronaries of vehicle-treated SHR-SP but not in animals treated with lacidipine. In the cardiocytes of the lacidipine-treated rats, the myofibrils had a more regular arrangement and the intercalated discs did not show the irregular course and infoldings seen in the vehicle-treated rats. Morphometry showed a significantly higher density of mitochondria in the cardiocytes of lacidipine-treated SHR-SP. Scanning electron microscopy identified a decrease in the width of cardiocytes and in the number and length of lateral branches following lacidipine-treatment. The cardio-protective action of this calcium-antagonist at doses that do not reduce systolic blood pressure is attributable both to its vascular activity and to improvement in cytoplasmic organization of cardiocytes.

Topics: Animals; Calcium Channel Blockers; Cardiomegaly; Cerebrovascular Disorders; Coronary Vessels; Dihydropyridines; Disease Models, Animal; Hypertension; Male; Microscopy, Electron; Microscopy, Electron, Scanning; Myocardium; Rats; Rats, Inbred SHR

Calcium channel antagonists have gained widespread acceptance for treatment of a variety of cardiovascular disorders. Newer drugs of the dihydropyridine class are especially attractive for treating hypertension and angina because of their increased vascular selectivity, favorable side-effect profile, and pharmacokinetics that allow once-daily dosing. In the future, calcium channel antagonists may also play a role in antiatherogenic therapy and in treatment of congestive heart failure and cerebrovascular disease as results of prospective studies become available and new agents are developed.

Topics: Arteriosclerosis; Calcium Channel Blockers; Cardiovascular Diseases; Cerebrovascular Disorders; Dihydropyridines; Diltiazem; Heart Failure; Humans; Verapamil

Hypotensive and antihypertensive effects of S-312-d (S-(+)-methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2, 3- b]pyridine-5-carboxylate, CAS 120056-57-7) in Wistar Kyoto rat (WKY), spontaneously hypertensive rat (SHR), stroke-prone SHR (SHRSP), and DOCA-salt hypertensive rat (DOCA-HR) were compared with those of other representative calcium antagonists. The minimal effective hypotensive dose of S-312-d in WKY was 3 mg/kg p.o. and those in SHR, SHRSP, and DOCA-HR were 1 mg/kg p.o. in gum arabic suspension. The minimal antihypertensive dose of S-312-d in polyethylene glycol solution was 0.3 mg/kg p.o. in SHRSP. The antihypertensive effects of S-312-d was the most potent and long-lasting compared with the calcium antagonists, nifedipine, nicardipine, nimodipine, nilvadipine, and flunarizine. In conscious two-kidney Goldblatt-type hypertensive dogs, a significant antihypertensive effect and concomitant increases of heart rate with S-312-d at 1 mg/kg lasted for 4 to 6 h after oral administration. Determination of the plasma concentration of S-312-d by HPLC showed that more than 4.3 ng/ml of S-312-d is required for a significant antihypertensive effect. Subcutaneous administration of atenolol at 20 mg/kg 30 min before S-312-d significantly inhibited the tachycardia with S-312-d at 1 mg/kg p.o. but not its antihypertensive effect. S-312-d is considered useful for the treatment of essential hypertension and related organ disorders.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Disorders; Desoxycorticosterone; Dihydropyridines; Dogs; Female; Heart Rate; Hypertension; Hypertension, Renal; Hypertension, Renovascular; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Renin

The prophylactic and therapeutic effects of S-312-d (S-(+)-methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2, 3- b]pyridine-5-carboxylate, CAS 120056-57-7) were compared with those of nimodipine or nicardipine using male stroke-prone spontaneously hypertensive rats (SHRSP). The survival rate of SHRSP was dose-dependently increased by once a day oral administration of S-312-d (0.3, 1, and 3 mg/kg) or nimodipine (10 mg/kg), while all non-treated SHRSP fed with high Na+ diet died within 40 days after the start of the experiment. All SHRSP treated with 3 mg/kg S-312-d survived during the 60-day experiment periods. Marked decreases of body weights and various neurological symptoms were also inhibited with S-312-d or nimodipine. Moderate diuretic effects were observed with S-312-d at doses of 1 and 3 mg/kg. The appearance of urinary occult blood in control SHRSP was markedly inhibited with S-312-d at 1 mg/kg and nimodipine at 10 mg/kg. Histological examination of the brain of SHRSP showed that cerebral stroke lesion including edema, hemorrhage, and/or softening was dose-dependently inhibited with S-312-d. Once a day oral administration of S-312-d (1, 3, or 10 mg/kg) dose-dependently increased the body weights and improved the neurological symptoms of diseased SHRSP. The appearance of proteinuria and of occult blood in the urine of SHRSP were also markedly inhibited with S-312-d or nicardipine. Histological examination of the brain of SHRSP showed that the arbitrary neurotoxic index (ANI) for stroke lesion dose-dependently decreased with S-312-d at 1, 3, and 10 mg/kg as follows: 4.8, 3.0, 2.3. The ANI for non-treated SHRSP was 7.6. The therapeutic effects of nicardipine (ANI 3.9) at 10 mg/kg corresponded to those of S-312-d at 3 mg/kg. Thus, S-312-d can be recommended for the treatment of cerebral insufficiency or vasospasm following stroke as well as in essential hypertension.

Topics: Animals; Behavior, Animal; Blood Pressure; Body Weight; Brain; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Drinking; Eating; Heart Rate; Hypertension; Life Expectancy; Male; Nicardipine; Nimodipine; Organ Size; Rats; Rats, Inbred SHR; Sodium, Dietary

The effect of a calcium antagonist, manidipine, on blood pressure and proteinuria induced by the inhibition of endothelial-derived relaxation factor (EDRF) formation was examined. Manidipine attenuated the increase in blood pressure and prevented proteinuria caused by renal damage associated with the inhibition of EDRF formation in stroke-prone spontaneously hypertensive rat (SHRSP) and Wistar Kyoto (WKY) rats.

Topics: Animals; Arginine; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Hypertension; Male; Nitric Oxide; Nitroarginine; Nitrobenzenes; Piperazines; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY

In a rat model of embolic stroke (permanent occlusion of the left middle cerebral artery [MCAO]), various 1,4-dihydropyridine calcium antagonists have been shown to attenuate brain damage and the resultant functional impairment when administered after MCAO. Dose-response curves reveal that isradipine is one of the most potent and efficacious representatives of this class of compounds, reducing the infarct size by more than 60%. These results suggest that isradipine, when administered shortly after stroke onset, may have beneficial effects in patients suffering from brain ischemia. When isradipine is used to normalize the high blood pressure in spontaneously hypertensive rats, it will, in addition, also protect the brain from damage engendered by a subsequent stroke. This is not the case if blood pressure is controlled with a calcium antagonist which does not cross the blood-brain barrier, suggesting that the brain protection seen with isradipine is not due to blood pressure normalization. Isradipine, when used as an antihypertensive, appears to have an additional beneficial effect within the brain itself. As high blood pressure is a major risk factor for stroke, such an additional benefit with isradipine would be particularly valuable in antihypertensive therapy.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Brain Damage, Chronic; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension; Isradipine; Male; Prognosis; Pyridines; Rats; Rats, Inbred SHR

Renal effects of CV-4093, a newly developed dihydropyridine calcium channel blocker, were examined using anesthetized stroke-prone spontaneously hypertensive rats, and the findings were compared with those of nicardipine. An intravenous injection of CV-4093 (2 micrograms/kg) produced long-lasting hypotension with a slow-onset accompanied by moderate renal vasodilation. There were no appreciable alterations in glomerular filtration rate (GFR) and urine formation, except that urine flow (UF) increased significantly during the first 10 min after injection. When CV-4093 was administered at 10 micrograms/kg, the hypotensive action was markedly augmented. Eighty minutes after the injection, a decrease in mean arterial pressure of about 45 mmHg was observed. Simultaneously, renal blood flow increased significantly from the control value of 5.76 +/- 0.46 ml/g.min to 6.94 +/- 0.28 ml/g.min. Renal vascular resistance decreased immediately after the injection, and the response lasted for over 3 hr, thereby indicating the marked and sustained renal vasodilating effect of CV-4093. GFR was constant throughout the experiment, but UF and urinary excretion of sodium were increased significantly. Fractional excretion of sodium was also elevated, thereby suggesting an inhibitory action of CV-4093 on renal tubular reabsorption of sodium. Nicardipine at a dose of 10 micrograms/kg, a dose producing an effective hypotensive action, caused no significant increases in RBF and urine formation. The renal vasodilating and diuretic actions of CV-4093 may provide a beneficial effect in the treatment of hypertension.

Topics: Animals; Body Weight; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Hemodynamics; Hypertension; Injections, Intravenous; Kidney Function Tests; Male; Nicardipine; Nitrobenzenes; Organ Size; Piperazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Urodynamics