dihydropyridines and Body-Weight

Antihypertensive treatment is frequently needed in type 2 diabetes. In this study we measured the rates of total, oxidative, and nonoxidative glucose disposal, glycogen synthesis, glycolysis, endogenous glucose production, and lipid oxidation using a 4-h euglycemic (approximately 5 mmol/L) hyperinsulinemic (approximately 300 pmol/L) clamp in combination with a dual glucose tracer infusion ([3-(3)H]- and [U-14C] D-glucose) and indirect calorimetry in 40 nonobese subjects with type 2 diabetes. Subjects were studied twice: after a 4-week run-in period and after a 16-week period of double blind, randomized treatment with 4-6 mg/day lacidipine, a calcium channel blocker (n = 19), or 10-20 mg/day lisinopril, an angiotensin-converting enzyme inhibitor (n = 21). Antihypertensive treatment resulted in a significant increase in total glucose disposal during insulin clamp as well as in basal and insulin-stimulated nonoxidative glucose disposal rates. On the contrary, oxidative glucose disposal was significantly decreased by antihypertensive treatment, mainly in the basal state. The changes in glucose disposal rates were not significantly different in subjects treated with lacidipine and in those treated with lisinopril. The suppression of endogenous glucose production during insulin clamp was significantly greater after lacidipine than after lisinopril. These results suggest that treatment of subjects with type 2 diabetes with either lacidipine or lisinopril has no adverse effect on glucose metabolism. Conversely, both drugs seem to improve insulin sensitivity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Body Composition; Body Height; Body Weight; Calcium Channel Blockers; Calorimetry, Indirect; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Fatty Acids, Nonesterified; Female; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Lisinopril; Male; Middle Aged

A short-term trial of isradipine was conducted to assess its effectiveness and tolerability in the treatment of mild-to-moderate hypertension. The study was carried out by general practitioners and involved 2,702 patients, aged 18-70 years, who had diastolic blood pressures (DBP) of 95-114 mm Hg. Patients completed a pretreatment phase of up to 4 weeks for antihypertensive drug washout and placebo run-in, before entering a 12-week active-treatment phase with 1.25 mg of isradipine twice daily, which was increased after 4 weeks to 2.5 mg twice daily, depending on the blood pressure response. At the end of 12 weeks, the mean systolic blood pressure (SBP) and DBP were 148.1 and 86.7 mm Hg compared with 169.0 and 103.0 mm Hg after placebo, respectively. The majority of patients (89.6%) had a DBP reduction greater than 10 mm Hg, and 86.2% had normalized DBP (less than or equal to 90 mm Hg) at the end of treatment. Adverse events were reported by 2.8% of patients, and 90% of patients and general practitioners reported satisfaction with the treatment. Thus, our results indicate that isradipine is effective and well tolerated, and may deserve a place as first-line treatment in mild-to-moderate hypertension.

Topics: Adolescent; Adult; Aged; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Isradipine; Male; Middle Aged; Portugal

The present study was aimed at investigating the safety of Lacidipine (LCDP) loaded nanostructured lipid carriers (NLCs) in Wistar rats. NLCs were formulated using ultrasound dispersion technique. Animals were orally treated once daily with NLCs containing 0.140 mg, 0.350 mg, and 0.875 mg of LCDP as low, medium, and high dose per kg body weight, respectively, during 28 days along with blank formulation and pure LCDP. Control rats were fed with water. Animals were observed throughout experiment period and their body weight was recorded once weekly. Overnight fasted rats were sacrificed on the 29th day. Study revealed no signs or symptoms of toxicity or morbidity. No significant changes in the body weight were observed between treated and control group. Significant increase in left testis weight and liver weight was observed in male and female rats, respectively. Haematological estimation revealed significant decrease in haemoglobin count in male rats while female rats showed significant increase in granulocyte count. All the serum clinical parameters were within the normal range and no gross histopathological changes were observed. No delayed effect was noted in satellite group. The results indicate that developed LCDP loaded NLCs are safe when administered orally in rats.

Topics: Animals; Biomarkers; Body Weight; Chemistry, Pharmaceutical; Dihydropyridines; Drug Carriers; Female; Lipids; Male; Nanocomposites; Organ Size; Rats; Rats, Wistar; Toxicity Tests, Subacute

The in vivo effectiveness of 4-dihydropyridine (bis-1,4-DHP), a new calcium-channel blocker, as a nephroprotector in isolated perfused kidney was evaluated by determining its effects on parameters associated with renal injury in diabetic rats. Diabetes in male Wistar rats, control, diabetic, control + bis-1,4-DHP, and diabetic + bis-1,4-DHP, was induced by a single administration of STZ (55 mg·kg(-1), i.p.). In the drug-treated groups, treatment with bis-1,4-DHP (10 mg·kg(-1)·day(-1)) started one week before diabetes induction; bis-1,4-DHP was dissolved in DMSO (0.3%) and suspended in drinking water with carboxymethyl cellulose (3%). Parameters evaluated were body weight, blood glucose, albuminuria, proteinuria, creatinine, urea excretion, kidney's weight / body weight ratio, and kidney perfusion pressure in all rat groups at different times of diabetes (2, 4, 6, and 10 weeks). Kidney weight of diabetic rats significantly increased vs. control, control + bis-1,4-DHP, and diabetic + bis-1,4-DHP rats at different times of diabetes. The ratios % kidney weight / 100 g body weight were different between control, control + bis-1,4-DHP, and diabetic + bis-1,4-DHP rats vs. diabetic rats (P < 0.05). Kidney perfusion pressure was decreased by diabetes, while it was partially recovered by bis-1,4-DHP treatment in response to phenylephrine. Bis-1,4-DHP had a tendency to decrease hyperglycemia vs. diabetic rats, even though glycemia was too high as compared with controls, and it ameliorated albuminuria, creatinine, and urea excretion, suggesting a favorable effect on renal haemodynamics. Bis-1,4-DHP, by inhibiting Ca(2+) entrance, induced vasodilation in renal vascular bed and thus may have a nephroprotective effect against diabetes-induced renal dysfunction, but does not have significant impact on hyperglycemia.

Topics: Albuminuria; Animals; Body Weight; Calcium Channel Blockers; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dihydropyridines; In Vitro Techniques; Kidney; Male; Organ Size; Perfusion; Proteinuria; Rats; Rats, Wistar; Streptozocin; Vasodilation

Cilnidipine is an L- and N-type calcium channel blocker (CCB), and amlodipine is an L-type CCB. Valsartan (10 mg kg(-1)), valsartan (10 mg kg(-1)) and amlodipine (1 mg kg(-1)), and valsartan (10 mg kg(-1)) and cilnidipine (1 mg kg(-1)) were administered once daily for 2 weeks to stroke-prone, spontaneously hypertensive rats (SHR-SPs). Blood pressure was significantly reduced by valsartan, and it was further reduced by the combination therapies. Vascular endothelial dysfunction was significantly attenuated in all therapeutic groups, and further significant attenuation was observed in the valsartan+cilnidipine-treated group, but not in the valsartan+amlodipine-treated group. Vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NOX1 gene expression was significantly attenuated in all therapeutic groups, and significantly greater attenuation was observed in the valsartan+cilnidipine-treated group than in the valsartan-treated group. Compared with the valsartan-treated group, the positive areas for 4-hydroxy-2-nonenal were significantly lower only in the valsartan+cilnidipine-treated group. Plasma renin activity was significantly augmented in the valsartan-treated group, and it was significantly attenuated in the valsartan+cilnidipine-treated group. A significant increase in the ratio of plasma angiotensin-(1-7) to angiotensin II was observed only in the valsartan+cilnidipine-treated group. Vascular angiotensin-converting enzyme (ACE) gene expression was significantly attenuated only in the valsartan+cilnidipine-treated group, but ACE2 gene expression was significantly higher in all of the therapeutic groups. Thus, valsartan and cilnidipine combination therapy might have a powerful protective effect in the vascular tissues via increases in the angiotensin-(1-7)/angiotensin II ratio in plasma.

Topics: Aldehydes; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Carotid Arteries; Cysteine Proteinase Inhibitors; Dihydropyridines; Heart; Immunohistochemistry; Male; Muscle Relaxation; Muscle, Smooth, Vascular; NADH, NADPH Oxidoreductases; NADPH Oxidase 1; Nitric Oxide Synthase Type III; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Real-Time Polymerase Chain Reaction; Tetrazoles; Valine; Valsartan; Vascular Diseases

Many studies have aimed to identify anti-atherogenic agents in cardiovascular medicine. We have recently demonstrated that the combination therapy with olmesartan (OLM), an angiotensin II receptor blocker, and azelnidipine (AZL), a dihydroprydine calcium-channel blocker, improves endothelial function in diabetic Apolipoprotein-deficient (ApoE(-/-)) mice. In the present study, we examined whether this combination therapy also inhibits atherosclerosis in mice. We used male control and streptozocin-induced diabetic ApoE(-/-) mice. Diabetic ApoE(-/-) mice were orally treated for 5 weeks with vehicle (Untreated), OLM (30 mg/kg/day), AZL (10 mg/kg/day), their combination (OLM+AZL), or hydralazine (HYD, 5 mg/kg/day) as an antihypertensive control. At 5 weeks, systolic blood pressure was significantly elevated in Untreated but was normalized in OLM+AZL and HYD. The atherosclerosis area in the thoracic aorta, perivascular fibrosis and medial thickness of the coronary arteries were increased in Untreated and were ameliorated in OLM+AZL but not in HYD. Staining with a fluorescent probe dihydroethidium showed that production of reactive oxygen species was increased in Untreated, and ameliorated in OLM+AZL. Consistent with these findings, macrophage infiltration in the kidney and the expression of receptor for advanced glycation end-products in the heart, kidney and liver were increased in Untreated and were all ameliorated in OLM+AZL, associated with up-regulation of endothelial NO syntheses (eNOS). In conclusion, the combination therapy with OLM and AZL exerts anti-atherogenic effect in diabetic ApoE(-/-) mice through suppression of oxidative stress and activation of eNOS, independent of its blood pressure-lowering effects. Clinically, this combination therapy may be useful for patients with hypertension, hyperlipidemia and diabetes.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Aorta, Thoracic; Apolipoproteins E; Atherosclerosis; Azetidinecarboxylic Acid; Azo Compounds; Blood Pressure; Body Weight; Calcium Channel Blockers; Coronary Vessels; Diabetes Mellitus, Experimental; Dihydropyridines; Drug Therapy, Combination; Imidazoles; Macrophages; Male; Mice; Mice, Inbred C57BL; Models, Biological; Myocytes, Cardiac; Nitric Oxide Synthase Type III; Oxidative Stress; Phosphorylation; Systole; Tetrazoles

The vascular remodeling associated with hypertension involves oxidative stress and enhanced matrix metalloproteinases (MMPs) expression/activity, especially MMP-2. While previous work showed that lercanidipine, a third-generation dihydropyridine calcium channel blocker (CCB), attenuated the oxidative stress and increased MMP-2 expression/activity in two-kidney, one-clip (2K1C) hypertension, no previous study has examined whether first- or second-generation dihydropyridines produce similar effects. We compared the effects of nifedipine, nimodipine, and amlodipine on 2K1C hypertension-induced changes in systolic blood pressure (SBP), vascular remodeling, oxidative stress, and MMPs levels/activity. Sham-operated and 2K1C rats were treated with water, nifedipine 10 mg/kg/day, nimodipine 15 mg/kg/day, or amlodipine 10 mg/kg/day by gavage, starting 3 weeks after hypertension was induced. SBP was monitored weekly. After 6 weeks of treatment, quantitative morphometry of structural changes in the aortic wall was studied in hematoxylin/eosin-stained sections. Aortic and systemic reactive oxygen species levels were measured by using dihydroethidine and thiobarbituric acid-reactive substances (TBARs), respectively. Aortic MMP-2 levels and activity were determined by gelatin zymography, in situ zymography, and immunofluorescence. Nifedipine, nimodipine, or amlodipine attenuated the increases in SBP in hypertensive rats by approximately 17% (P < 0.05) and prevented vascular hypertrophy (P < 0.05). These CCBs blunted 2K1C-induced increases in vascular oxidative stress and plasma TBARs concentrations (P < 0.05). All dihydropyridines attenuated the increases in aortic MMP-2 levels and activity associated with 2K1C hypertension. These findings suggest lack of superiority of one particular dihydropyridine, at least with respect to antioxidant effects, MMPs downregulation, and inhibition of vascular remodeling in hypertension.

Topics: Amlodipine; Animals; Antioxidants; Aorta, Thoracic; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Down-Regulation; Gelatinases; Hypertension, Renovascular; Hypertrophy; Lipid Peroxides; Male; Matrix Metalloproteinase 2; Nifedipine; Nimodipine; Rats; Rats, Wistar; Reactive Oxygen Species; Tunica Media

Clinical studies have indicated the beneficial effect of an L/N-type calcium channel blocker (CCB), cilnidipine, on the progression of proteinuria in hypertensive patients compared with an L-type CCB, amlodipine. In the present study, we examined the effects of cilnidipine and amlodipine on the renal injury in spontaneously hypertensive rat/ND mcr-cp (SHR/ND) and their underlying mechanism.. SHR/ND were treated with vehicle (nU10), cilnidipine [33 mg/kg per day, orally (p.o.); nU11] or amlodipine (20 mg/kg per day, p.o.; nU9) for 20 weeks. SHR/ND developed proteinuria in an age-dependent manner. Cilnidipine suppressed the proteinuria greater than amlodipine did. The immunohistochemical analysis showed that N-type calcium channel and Wilm's tumor factor, a marker of podocyte, were co-expressed. SHR/ND had significantly greater desmin staining, an indicator of podocyte injury, with lower podocin and nephrin expression in the glomeruli than Wistar-Kyoto rat or SHR. Cilnidipine significantly prevented the increase in desmin staining and restored the glomerular podocin and nephrin expression compared with amlodipine. Cilnidipine also prevented the increase in renal angiotensin II content, the expression and membrane translocation of NADPH oxidase subunits and dihydroethidium staining in SHR/ND. In contrast, amlodipine failed to change these renal parameters.. These data suggest that cilnidipine suppressed the development of proteinuria greater than amlodipine possibly through inhibiting N-type calcium channel-dependent podocyte injury in SHR/ND.

Topics: Amlodipine; Animals; Base Sequence; Blood Glucose; Blood Pressure; Body Weight; Calcium Channel Blockers; Calcium Channels, N-Type; Creatinine; Dihydropyridines; Disease Models, Animal; DNA Primers; Humans; Kidney; Male; Metabolic Syndrome; Oxidative Stress; Podocytes; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin-Angiotensin System; RNA, Messenger; RNA, Small Interfering; Triglycerides

Recent in-vitro studies demonstrated that dihydropyridine calcium channel blockers have direct mineralocorticoid receptor antagonistic activity. The present study was conducted to examine the effects of a dihydropyridine calcium channel blocker, azelnidipine, on aldosterone-induced oxidative stress and renal injury.. Uninephrectomized rats subjected to 6 weeks treatment with aldosterone (0.75 microg/h, subcutaneous) and 1% NaCl (in drinking water) showed higher systolic blood pressure (SBP), urinary excretion of protein (UproteinV), glomerular cell proliferation and renal interstitial fibrosis than vehicle (2% ethanol)-infused rats. Aldosterone-induced renal injury was associated with increased renal cortical content of thiobarbituric acid-reactive substances (TBARS), NAD(P)H oxidase complex formation and mRNA expression of NAD(P)H oxidase membrane components (p22 and gp91). Administration of azelnidipine [3 mg/kg per day, orally (p.o.)] markedly attenuated the aldosterone-induced increases in SBP, UproteinV, renal cortical tissues TBARS content, NAD(P)H oxidase complex formation, mRNA levels of p22 and gp91, and morphological changes. In aldosterone-infused rats, treatment with a nonspecific vasodilator, hydralazine (5 mg/kg per day in drinking water) resulted in a reduction in SBP similar to azelnidipine; however, it did not affect any renal parameters. Treatment with azelnidipine suppressed aldosterone/mineralocorticoid receptor-dependent but not mineralocorticoid receptor-independent superoxide production in cultured rat mesangial cells.. These data suggest that dihydropyridine calcium channel blockers may elicit marked amelioration of aldosterone-induced renal injury through their inhibitory effects on NAD(P)H oxidase-dependent oxidative stress.

Topics: Aldosterone; Animals; Azetidinecarboxylic Acid; Blood Pressure; Body Weight; Calcium Channel Blockers; Collagen Type IV; Connective Tissue Growth Factor; Creatinine; Dihydropyridines; Ethidium; Gene Expression; Kidney; Kidney Diseases; Male; Mesangial Cells; NADPH Oxidases; Organ Size; Proteinuria; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Thiobarbituric Acid Reactive Substances; Transforming Growth Factor beta

Pharmacological interventions for prevention of sudden arrhythmic death in patients with chronic heart failure remain limited. Accumulating evidence suggests increased ventricular expression of T-type Ca(2+) channels contributes to the progression of heart failure. The ability of T-type Ca(2+) channel blockade to prevent lethal arrhythmias associated with heart failure has never been tested, however.. We compared the effects of efonidipine and mibefradil, dual T- and L-type Ca(2+) channel blockers, with those of nitrendipine, a selective L-type Ca(2+) channel blocker, on survival and arrhythmogenicity in a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor transgenic mice (dnNRSF-Tg), which is a useful mouse model of dilated cardiomyopathy leading to sudden death. Efonidipine, but not nitrendipine, substantially improved survival among dnNRSF-Tg mice. Arrhythmogenicity was dramatically reduced in dnNRSF-Tg mice treated with efonidipine or mibefradil. Efonidipine acted by reversing depolarization of the resting membrane potential otherwise seen in ventricular myocytes from dnNRSF-Tg mice and by correcting cardiac autonomic nervous system imbalance. Moreover, the R(-)-isomer of efonidipine, a recently identified, highly selective T-type Ca(2+) channel blocker, similarly improved survival among dnNRSF-Tg mice. Efonidipine also reduced the incidence of sudden death and arrhythmogenicity in mice with acute myocardial infarction.. T-type Ca(2+) channel blockade reduced arrhythmias in a mouse model of dilated cardiomyopathy by repolarizing the resting membrane potential and improving cardiac autonomic nervous system imbalance. T-type Ca(2+) channel blockade also prevented sudden death in mice with myocardial infarction. Our findings suggest T-type Ca(2+) channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure.

Topics: Animals; Arrhythmias, Cardiac; Autonomic Nervous System; Blood Pressure; Body Weight; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Cardiomyopathy, Dilated; Death, Sudden, Cardiac; Dihydropyridines; Disease Models, Animal; Female; Mibefradil; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Infarction; Myocytes, Cardiac; Nitrendipine; Nitrophenols; Organophosphorus Compounds; Patch-Clamp Techniques

Type 2 diabetes is associated with obesity, insulin resistance, hyperglycemia, hyperphagia, polyuria, body weight gain, excessive secretion of glucocorticoids (GCs), thymus involution, adrenal gland hypertrophy, diabetic nephropathy, etc. We examined the effect of cerebrocrast, a new antidiabetic agent (synthesized in the Latvian Institute of Organic Synthesis), on body weight, food and water intake, urine output, and on changes of organ weight: that is, kidney, thymus, adrenal gland of normal rats. Cerebrocrast was administered at doses of 0.05 and 0.5 mg kg(-1) per os (p.o.) once a day for three consecutive days, and its effects were observed from 3 to 27 days after the last administration. Cerebrocrast, during the experimental period, decreased body weight by an average of approximately 32.3%, food intake by about 10-15% at the beginning of the experiments and by 22.6% at the end of the experiments, especially at a dose of 0.5 mg kg(-1). Water intake and urine output in comparison with controls were decreased. The daily food intake decreased about 1.0 and 2.1 g by administering single cerebrocrast doses of 0.05 and 0.5 mg kg(-1) body weight (b.w.), respectively, but by administering for three consecutive days, food intake decreased by about 2.2 and 3.4 g, respectively. The weekly body weight gain decreased by administering a single dose of cerebrocrast by 2.61 and 2.51 g, respectively, and by triple administration it decreased by 4.36 and 3.07 g, respectively. Cerebrocrast has long-lasting effects on these parameters and on thymus and adrenal gland weight. As cerebrocrast decreased glucose levels in normal and streptozotocin (STZ)-induced diabetic rats, it also promoted glucose uptake by the brain, intensified insulin action and formation de novo of insulin receptors. We can conclude that cerebrocrast may regulate food intake and body weight through glucose sensing by proopiomelanocortin (POMC) neurons, that are involved in control of glucose homeostasis, stimulation of alpha-melanocyte-stimulating hormone (alpha-MSH) secretion, activation of MC4-Rs and inhibition of neuropeptide Y (NPY) in the ARC of the hypothalamus, affecting the kidney, and causing decreased urine output and water intake. Moreover, it could stimulate secretion of vasopressin. By administration of cerebrocrast thymus mass was increased, thereby preventing the action of GCs. As cerebrocrast inhibited L- and T-type calcium channels, it can prevent vasoconstriction of kidney arterioles

Topics: Animals; Blood Glucose; Body Weight; Dihydropyridines; Drinking; Eating; Hypoglycemic Agents; Male; Organ Size; Rats; Rats, Wistar; Urine

To examine whether benidipine hydrochloride, one of the calcium channel blockers, up-regulate uncoupling protein 3 (UCP3) expression in two skeletal muscles (gastrocnemius and soleus) in rats. Wistar rats were treated orally with benidipine hydrochloride at 4 mg/kg for 7 days. Blood pressure was measured after 4 days. At the end of experiments, the rats were weighed, and brown adipose tissue (BAT) and skeletal muscles (gastrocnemius and soleus muscles) were removed. The mRNA levels of uncoupling protein 1 (UCP1) and UCP3 were measured using the real-time quantitative reverse transcription-polymerase chain reaction method. Benidipine reduced body weight and also had a hypotensive effect. In rats treated with benidipine, UCP1 mRNA levels were significantly increased 1.4-fold in BAT, and UCP3 mRNA levels in BAT and gastrocnemius muscle were significantly increased 1.7 and 3.0-fold, respectively, compared with the control rats. There was no difference in UCP3 mRNA levels in soleus muscle between the two groups. We concluded that benidipine up-regulates not only UCP1 gene expression in BAT but also UCP3 gene expression in BAT and gastrocnemius muscle, which may contribute to thermogenesis in rats.

Topics: Adipose Tissue, Brown; Animals; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Gene Expression; Hydrochloric Acid; Hypertension; Ion Channels; Male; Mitochondrial Proteins; Muscle, Skeletal; Rats; Rats, Inbred SHR; Rats, Wistar; Thermogenesis; Uncoupling Protein 1; Uncoupling Protein 3; Up-Regulation

L-type Ca(2+) channel-mediated, Ca(2+)-induced Ca(2+) release (CICR) is the dominant mode of excitation-contraction (E-C) coupling in the mature mammalian myocardium but is thought to be absent in the fetal and newborn mammalian myocardium. Furthermore, the characteristics and contributors of E-C coupling at the earliest developmental stages are poorly understood. In this study, we measured [(3)H](+)PN200-110 dihydropyridine binding capacity, functionality and expression of the L-type Ca(2+) channel, and cytosolic [Ca(2+)] ([Ca(2+)](i)) at various developmental stages (3, 6, 10, 20, and 56 days old) to characterize ontogenetic changes in E-C coupling. We found that 1) the whole cell L-type Ca(2+) channel peak current (I(Ca)) density increased slightly in parallel with cell growth, but the current-voltage relationship, the steady-state activation, and the maximum DHP binding and binding affinity did not exhibit significant developmental changes; 2) sarcoplasmic reticulum Ca(2+) dependence of inactivation rates of L-type Ca(2+) channel and peak of I(Ca) density were only observed after 10 days of age, which temporally coincides with transverse (T)-tubule formation; 3) the relationship between [Ca(2+)](i) and voltage changed from a linear relationship at the earliest developmental stages to a "bell-shaped" relationship at the later developmental stages, presumably corresponding to a switch from reverse-mode Na/Ca exchange-dependent to I(Ca)-dependent E-C coupling; and 4) the expression of two different splice variants of Ca(V)1.2, IVS3A and IVS3B, switched from predominantly IVS3A at the earliest stages to IVS3B at the later developmental stages. Our data suggest that whereas the density of functional dihydropyridine receptors (DHPRs) increases only slightly during ontogeny, the enhancement of functional coupling between DHPR and ryanodine receptor is dramatic between the second and third weeks after birth. Furthermore, we found that the differential expression of splice variants during development temporally correlated with the appearance of I(Ca)-dependent E-C coupling and T-tubule formation.

Topics: Aging; Amino Acid Sequence; Animals; Animals, Newborn; Body Weight; Calcium Channels, L-Type; Calcium Signaling; Cell Membrane; Dihydropyridines; Electrophysiology; Female; Heart Ventricles; In Vitro Techniques; Male; Molecular Sequence Data; Myocytes, Cardiac; Patch-Clamp Techniques; Rabbits; Reverse Transcriptase Polymerase Chain Reaction; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum

A decrease in renal synthesis of nitric oxide (NO) in the progression of diabetic nephropathy has been documented. As (6R)-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor of NO synthase, we investigated whether BH4 deficiency is involved in the pathogenesis of nephropathy. Ten-week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats were used as a type II diabetic model, and Long-Evans Tokushima Otsuka (LETO) rats as the healthy controls. OLETF rats were orally treated with BH4 (10 mg/kg daily) or with water from 10 to 61 weeks of age. In another experiment, OLETF rats were treated orally with a calcium channel blocker, benidipine (5 mg/kg daily), or with 0.3% carboxymethyl cellulose (nontreated) from 10 to 52 weeks of age. Proteinuria was observed periodically, and at the end of the study, BH4 level and GTP cyclohydrolase I (GTPCH) activity in the kidney were measured. Proteinuria was observed at 13 weeks of age in the OLETF rats, and deteriorated until 61 weeks of age. Supplemental BH4 reduced the proteinuria. At 52 weeks of age, GTPCH activity and the BH4 level were decreased in the plasma and kidneys of OLETF rats, whereas they were significantly higher in the benidipine group than in the nontreated group. Proteinuria was milder in the benidipine group than in the nontreated group, without a concomitant decrease in blood pressure. Histologically observed glomerulosclerosis was mild in the BH4 and benidipine groups. In type II diabetic rats, renal BH4 is considered to play a crucial role in the pathogenesis of diabetic nephropathy. Benidipine was found to preserve BH4 levels, suggesting therapeutic renoprotective effects.

Topics: Animals; Biopterins; Blood Glucose; Blood Pressure; Body Weight; Calcium Channel Blockers; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Kidney; Male; Nitric Oxide; Proteinuria; Rats; Rats, Inbred OLETF; Rats, Long-Evans

Effects of a new lipophilic L-type calcium channel blocker, azelnidipine, on the expression of molecular components of the renin-angiotensin-aldosterone system (RAAS) were assessed. Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of diabetes with hypertension, and their lean littermates, Long-Evans Tokushima Otsuka (LETO) rats, were treated with azelnidipine for 2 weeks. The renal cortical mineralocorticoid receptor mRNA in OLETF was higher than in LETO, but was suppressed (P<0.05) by azelnidipine. Renal cortical angiotensin-converting enzyme mRNA of OLETF was lower than that of LETO rats, and it was further suppressed by azelnidipine (P<0.05). Azelnidipine can down-regulate the gene expression of molecular components of RAAS.

Topics: Animals; Aorta, Thoracic; Azetidinecarboxylic Acid; Blood Pressure; Body Weight; Calcium Channel Blockers; Diabetes Mellitus, Experimental; Dihydropyridines; Down-Regulation; Heart; Hypertension; Kidney Cortex; Male; Myocardium; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Inbred Strains; Receptors, Mineralocorticoid; Renin-Angiotensin System; RNA, Messenger

Long-acting dihydropyridine calcium channel blockades have been shown to limit the progression of atherosclerosis and decrease the incidence of cardiovascular events in humans and animals. To investigate the vasoprotective effects beyond the blood pressure-lowering effects of these agents, amlodipine (20 mg/kg/ day) and manidipine (10 mg/kg/day) were administered by gavage to N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats for 2 weeks. L-NAME treatment (0.7 mg/ml in drinking water) significantly decreased the gene and protein expression of endothelial nitric oxide synthase (eNOS) and increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, vascular cell adhesion molecule-1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1) mRNA levels in the aorta, as determined by Western blotting and reverse transcription (RT)-polymerase chain reaction (PCR). Amlodipine and manidipine normalized the decreased expression of eNOS gene and protein, and attenuated the overexpression of NADPH oxidase, VCAM-1, and MCP-1 mRNA. Furthermore, amlodipine and manidipine prevented the L-NAME-induced increase in the angiotensin converting enzyme (ACE) mRNA content, thereby restoring control levels in the aorta. On the other hand, hydralazine treatment had no such effect in L-NAME treated rats. Furthermore, the increased expression of manganese superoxide dismutase (Mn-SOD) by L-NAME treatment was not affected by amlodipine, manidipine, or hydralazine. We concluded that the direct anti-inflammatory and antioxidative effects of calcium channel blockades in the aorta of rats with L-NAME-induced hypertension were not likely to have been mediated by the blood pressure-lowering action of these agents, but instead these beneficial effects appear to have been mediated by an augmentation of eNOS expression and by the inhibition of the expression of ACE.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents; Antihypertensive Agents; Antioxidants; Aorta; Blood Pressure; Body Weight; Calcium Channel Blockers; Chemokine CCL2; Dihydropyridines; Enzyme Inhibitors; Gene Expression Regulation; Heart Rate; Hypertension; Inflammation; Male; NADPH Oxidases; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type III; Nitrobenzenes; Oxidative Stress; Peptidyl-Dipeptidase A; Piperazines; Polymerase Chain Reaction; Rats; Rats, Wistar; RNA, Messenger; Vascular Cell Adhesion Molecule-1

The influence of treatment with the dihydropyridine-type Ca2+ antagonist lercanidipine on heart and coronary microanatomic changes was investigated in spontaneously hypertensive rats, Cohen-diabetic rats, and Cohen-Rosenthal diabetic hypertensive rats. At 12 weeks of age, animals were left untreated (control groups) or were treated for 8 weeks with an oral dose of 3 mg/kg per day of lercanidipine. Wistar-Kyoto rats were used as a normotensive reference group. In spontaneously hypertensive rats and diabetic hypertensive rats, systolic blood pressure was higher in comparison with Wistar-Kyoto rats. Augmented pressure values were decreased by lercanidipine treatment. Systolic blood pressure was slightly higher in Cohen-diabetic rats than in Wistar-Kyoto rats, and this increase was countered by treatment with lercanidipine. In spontaneously hypertensive rats, diabetic rats, and diabetic hypertensive rats, the thickness of left ventricle and cardiocyte area were increased. Focal connective tissue areas and diffuse accumulation of connective tissue were observed in the left ventricle of spontaneously hypertensive and Cohen-diabetic rats, respectively. Pharmacological treatment countered left ventricle thickening and restored cardiocyte area values in subendocardium. An increased thickness of tunica media accompanied by luminal narrowing was found in coronary artery branches of control spontaneously hypertensive and diabetic hypertensive rats. Treatment with lercanidipine countered vascular changes primarily in small-sized coronary arteries. These results indicate that hypertensive, diabetic, and diabetic hypertensive rats undergo cardiac hypertrophy and vascular changes affecting small-sized coronary arteries. Treatment with lercanidipine countered hypertension-related cardiac and coronary changes, suggesting that this dihydropyridine-type Ca2+ antagonist may improve heart and coronary structure in diabetes associated with hypertension.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Calcium Channel Blockers; Coronary Vessels; Diabetes Mellitus, Type 2; Dihydropyridines; Heart; Hypertension; Male; Myocardium; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY

We examined the effects of the angiotensin II type 1 receptor blocker candesartan, the calcium channel blockers benidipine and amlodipine, hydralazine, and the combination of candesartan and benidipine or amlodipine on blood pressure and renal function in Dahl salt-sensitive (DS) hypertensive rats. Male DS rats (5 weeks of age) were fed a high-salt (8% NaCl) diet, resulting in hypertension accompanied by glomerular sclerosis and an increased urinary albumin excretion. Drugs were orally administered from 2 to 6 weeks after the start of the feeding. Although candesartan (1 or 10 mg/kg) had little effect on the blood pressure, benidipine (4 mg/kg), amlodipine (4 mg/kg) and hydralazine (5 mg/kg) had similar hypotensive effects. Benidipine, but not amlodipine, hydralazine, or candesartan, significantly inhibited the increase in the albuminuria and glomerular sclerosis. The combination of candesartan (1 mg/kg) and benidipine (4 mg/kg) lowered the levels of blood pressure and albuminuria more effectively than the combination of candesartan (1 mg/kg) and amlodipine (4 mg/kg). These results indicate that benidipine is effective in preventing the impairment of renal function in DS hypertensive rats, and suggest that additional benefits can be expected by combination therapy with benidipine and an angiotensin II type 1 receptor blocker.

Topics: Albuminuria; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Body Weight; Calcium Channel Blockers; Creatinine; Dihydropyridines; Drug Therapy, Combination; Hypertension, Renal; Kidney; Male; Rats; Rats, Inbred Dahl; Tetrazoles

Efonidipine, a calcium antagonist, has been reported to dilate not only afferent but also efferent arterioles, thereby reducing glomerular hydrostatic pressure. We investigated the effect of chronic treatment with efonidipine or lisinopril on the afferent and efferent arteriolar diameters by the vascular cast technique. Four-week-old spontaneously hypertensive rats (SHR) were divided into three groups: untreated, efonidipine (25 mg/kg/day)-treated, and lisinopril (3 mg/kg/day)-treated. At 22 weeks of age, the renal vasculatures were fixed at the maximally dilated condition. The morphometrical measurements showed that the treatments with efonidipine and lisinopril caused structural alteration of the vasculature, resulting in significantly greater efferent arteriolar diameters than in untreated SHR. In addition, lisinopril-treated rats had wider afferent lumina. The renoprotective effect of efonidipine and lisinopril might be partly due to the structurally larger efferent arteriolar lumen.

Topics: Animals; Arterioles; Blood Pressure; Body Weight; Calcium Channel Blockers; Corrosion Casting; Dihydropyridines; Hypertension, Renal; Kidney Glomerulus; Male; Nitrophenols; Organophosphorus Compounds; Rats; Rats, Inbred SHR; Renal Circulation

We tested the hypothesis that long-term application of a Ca2+ channel blocker would ameliorate the functional and morphological deterioration of the cerebral arteries during hypertension. Male spontaneously hypertensive rats (SHR) were fed a standard rat chow, containing a low (3 mg/kg/day) or high dose (6 mg/kg/day) of benidipine, a Ca2+ channel blocker, for 2 months. Using a cranial window, we examined responses of the basilar artery to acetylcholine, sodium nitroprusside, (-)-(3S,4R)-4-(N-acetyl-N-hydroxyamino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol (Y-26763; an opener of ATP-sensitive K+ channels), and (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide (Y-27632; an inhibitor of Rho-associated kinase). Mean arterial pressure of the control group was 193+/-5 mm Hg (mean+/-S.E.M.), while that of the low-dose benidipine group was 183+/-5 mm Hg and that of the high-dose group was 159+/-4 mm Hg. Dilator responses of the basilar artery to acetylcholine and Y-26763 were impaired in SHR compared with those of normotensive Wistar-Kyoto (WKY) rats and treatment with benidipine enhanced the vasodilator responses to acetylcholine and Y-26763 in SHR. Y-27632-induced dilatation of the basilar artery was enhanced in SHR compared to that in WKY rats and the vasodilatation was reduced by benidipine in SHR. Sodium nitroprusside caused similar dilatation of the basilar artery, in both WKY rats and the SHR control group, and benidipine did not affect nitroprusside-induced dilatation of the artery in SHR. The wall of the basilar artery was significantly thicker in SHR than in WKY rats and benidipine treatment reduced the wall thickness of the artery in SHR. These findings suggest that chronic treatment with a Ca2+ channel blocker may enhance the dilator capacity and reduce contractility of the basilar artery during hypertension. Benidipine may also ameliorate the morphological changes of the basilar artery in hypertension.

Topics: Acetylcholine; Amides; Animals; Basilar Artery; Body Weight; Calcium Channel Blockers; Cerebral Arteries; Dihydropyridines; Dose-Response Relationship, Drug; Hypertension; Male; Muscle Relaxants, Central; Nitric Oxide Donors; Nitroprusside; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Time Factors; Vasodilation; Vasodilator Agents

We evaluated the effects of cilnidipine, a long-acting Ca(2+) channel antagonist, on endothelial nitric oxide synthase (eNOS), preproendothelin-1 and endothelin ETA receptor expression in the left ventricle, and evaluated the relations between these effects and coronary microvascular remodeling and extracellular signal-regulated kinases belonging to one subfamily of mitogen-activated protein kinases in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Cilnidipine (DOCA-cilnidipine, 1 mg/kg/day, subdepressor dose) or vehicle (DOCA-vehicle) was given after induction of DOCA-salt hypertension for 5 weeks. The eNOS mRNA and protein expression in the left ventricle was significantly lower in DOCA-vehicle than in control rats and significantly higher in DOCA-cilnidipine than in DOCA-vehicle rats. Preproendothelin-1 and endothelin ETA receptor expression levels and phospho-p42/p44 extracellular signal-regulated kinase activities were significantly increased in DOCA-vehicle compared with control rats and significantly suppressed in DOCA-cilnidipine compared with DOCA-vehicle rats. DOCA-vehicle rats showed a significant increase in the wall-to-lumen ratio, perivascular fibrosis and myocardial fibrosis, with all these parameters being significantly improved by cilnidipine. These results led us to conclude that phospho-p42/p44 extracellular signal-regulated kinase activities may contribute to the coronary microvascular remodeling of DOCA rats and that protective effects of cilnidipine on cardiovascular remodeling may be at least in part mediated by an increased eNOS expression and a decreased endothelin-1 and endothelin ETA receptor expression in the left ventricle.

Topics: Animals; Blotting, Western; Body Weight; Calcium Channel Blockers; Coronary Vessels; Dihydropyridines; Endothelin-1; Endothelins; Gene Expression Regulation; Heart Ventricles; Hemodynamics; Hypertension; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Organ Size; Protein Precursors; Rats; Rats, Wistar; Receptor, Endothelin A; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Treatment with the angiotensin-converting enzyme inhibitor, quinapril, has been shown to normalize increased dihydropyridine sensitivity and impaired potassium relaxation, characteristic features of arterial smooth muscle in spontaneously hypertensive rats, and also reduce the concentration of plasma digoxin-like immunoreactivity in these animals. However, whether angiotensin II receptor blocker therapy can beneficially influence these variables is not known. Therefore, we compared the effects of 10-week losartan and enalapril treatments (15 and 4 mg/kg/day, respectively) on functional responses of mesenteric arterial rings in spontaneously hypertensive rats and Wistar-Kyoto rats. Both losartan and enalapril normalized blood pressure, cardiac mass, and media to lumen ratio without significantly changing the media cross-sectional area in the mesenteric artery of spontaneously hypertensive rats (i.e. induced outward remodelling). The inhibitory effect of the calcium entry blocker nifedipine on calcium-evoked contractions was similar and less marked in arterial preparations from Wistar-Kyoto rats and losartan- and enalapril-treated spontaneously hypertensive rats than in those from untreated spontaneously hypertensive rats. Furthermore, the relaxations of arterial rings induced by the return of potassium to the organ bath (upon precontractions elicited by potassium-free solution) were used to evaluate the function of vascular Na+,K+-ATPase. The rate of potassium relaxation was faster in losartan- and enalapril-treated spontaneously hypertensive rats and all Wistar-Kyoto groups than in untreated spontaneously hypertensive rats, and the response was effectively inhibited by the sodium pump inhibitor ouabain. Both treatments especially augmented the ouabain-sensitive part of the potassium-relaxation in spontaneously hypertensive rats, indicating the involvement of the sodium pump in this response. However, no significant changes in plasma digoxin-like immunoreactivity were observed. In conclusion, the outward remodelling following long-term AT1-receptor blockade and angiotensin-converting enzyme inhibition in spontaneously hypertensive rats was associated with normalization of the increased dihydropyridine sensitivity of arteries. Both losartan and enalapril treatments also augmented arterial potassium relaxation in spontaneously hypertensive rats, suggesting enhanced function of Na+,K+-ATPase, but this effect could not be attributed to changes in circulating s

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Cardiomegaly; Digoxin; Dihydropyridines; Enalapril; Heart; Hypertension; Losartan; Male; Mesenteric Arteries; Muscle, Smooth, Vascular; Nifedipine; Organ Size; Potassium Chloride; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Sodium-Potassium-Exchanging ATPase; Tunica Media

Ischemic acute renal failure is associated with vascular endothelial dysfunction. We examined whether vasodilatory antihypertensive agents would improve endothelial function in rats with ischemia/reperfusion renal injury. Rat kidneys were isolated and perfused after clipping of the bilateral renal arteries for 45 min and reperfusion for 24 h, and renal perfusion pressure and nitric oxide concentration in the venous effluent (chemiluminescence assay) were monitored. Preischemic administration of celiprolol (a beta-blocker; 100 mg/kg p.o.), benidipine (a calcium channel blocker; 1 mg/kg p.o.), or imidapril (an angiotensin converting-enzyme inhibitor; 3 mg/kg p.o.) restored endothelial function in rats subjected to acute renal ischemia (deltarenal perfusion pressure [10(-8) M acetylcholine]: sham -42+/-3%, ischemia -31+/-1%, ischemia +celiprolol -39+/-1%*, ischemia+benidipine -38+/-2%*, ischemia+imidapril -42+/-2%*; *p<0.05 vs. ischemia). Serum urea nitrogen and creatinine levels were also lower in the treated groups. Furthermore, ischemia-induced decreases in the response to acetylcholine and renal excretory function were smaller in SHR than in deoxycorticosterone-salt hypertensive rats, in which endothelial damage was marked. These results suggest that preischemic endothelial function may influence the degree of ischemic renal injury. Calcium channel blockers, converting-enzyme inhibitors, and endothelial NO synthase-activating beta-blockers had beneficial effects on renovascular endothelial dysfunction due to ischemia.

Topics: Acetylcholine; Acute Kidney Injury; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Blood Urea Nitrogen; Body Weight; Calcium Channel Blockers; Celiprolol; Creatinine; Desoxycorticosterone; Dihydropyridines; Endothelium, Vascular; Imidazoles; Imidazolidines; Male; Nitric Oxide; Rats; Rats, Inbred SHR; Rats, Wistar; Reperfusion Injury; Vasodilator Agents

The effect of long-term administration of amlodipine and cilnidipine was examined on the histopathology and 1,4-dihydropyridine (DHP) calcium channel antagonist receptors in the left ventricle of BIO TO-2 hamsters, a model of dilated cardiomyopathy (DCM). Oral administration of amlodipine (3 and 10 mg/kg/d, 19 weeks) in 7 week-old BIO TO-2 hamsters produced a significant reduction in calcium deposition and necrosis with little change in the cavity area and fibrosis. A reduction of calcium deposition and necrosis in the myocardium of BIO TO-2 hamsters was also seen following similar administration of cilnidipine (10 mg/kg/d). The long-term administration of amlodipine (3 and 10 mg/kg/d) caused a significant increase (36.6 and 21.7%, respectively) in the Bmax for specific (+)-[3H]PN 200-110 binding in the myocardium from BIO TO-2 hamsters, compared with that in control hamsters. In conclusion, the present study has shown that long-term administration of amlodipine and cilnidipine improves calcium deposition and necrosis in the myocardium from BIO TO-2 hamsters. Thus, these data suggest that both agents may be effective pharmacological treatments of DCM.

Topics: Amlodipine; Animals; Animals, Inbred Strains; Body Weight; Calcium Channel Blockers; Calcium Channels, L-Type; Cardiomyopathies; Cricetinae; Dihydropyridines; Heart; Kinetics; Male; Mesocricetus; Myocardium; Organ Size

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

Although the renoprotective effect of calcium-channel blockers (CCBs) has been examined in several models of hypertensive nephropathy, it remains unclear. It also remains to be clarified whether CCBs prevent the progression to end-stage renal failure in chronic progressive glomerulonephritis (GN). A new rat model of progressive mesangioproliferative GN was used to study the effect of benidipine hydrochloride, a long-acting dihydropyridine CCB, on the clinical features and morphological lesions.. This animal model of progressive GN was induced by a single intravenous injection of anti-Thy-1 monoclonal antibody (MoAb 1-22-3) two weeks after unilateral nephrectomy. After 10 weeks of treatment with benidipine (1, 3, and 5 mg/kg body weight, p.o.) or hydralazine (5 mg/kg body weight, p.o.), systolic blood pressure (SBP), urinary protein excretion, creatinine clearance, glomerulosclerosis index, tubulointerstitial lesion index, glomerular cross-sectional area, and glomerular expression of transforming growth factor-beta (TGF-beta) and alpha-smooth muscle actin (alpha-SMA) were measured.. Untreated rats developed hypertension, massive proteinuria, renal dysfunction, severe glomerular and tubulointerstitial injury, higher glomerular size, and marked glomerular staining for TGF-beta and alpha-SMA, while uninephrectomized control rats did not. Each dose of benidipine and hydralazine equally reduced SBP to uninephrectomized control levels. Three and five mg/kg/day of benidipine increased creatinine clearance, ameliorated glomerular and tubulointerstitial injury, and reduced glomerular staining for TGF-beta and alpha-SMA, but 1 mg/kg/day of benidipine and hydralazine failed. Only a dose of 5 mg/kg/day of benidipine reduced glomerular size, although it did not reduce the size to control levels.. These results indicate that in a rat model of progressive mesangioproliferative GN, benidipine prevents the progression to end-stage renal failure in a dose-dependent manner. This renoprotective action is associated with the suppression of glomerular expression of TGF-beta and alpha-SMA.

Topics: Actins; Animals; Blood Pressure; Body Weight; Calcium Channel Blockers; Creatinine; Dihydropyridines; Disease Models, Animal; Disease Progression; Fluorescent Antibody Technique; Glomerulonephritis, Membranoproliferative; Hydralazine; Kidney Failure, Chronic; Kidney Glomerulus; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Transforming Growth Factor beta; Vasodilator Agents

Normotensive rats fed a high-fructose diet (HFD) develop hypertriglyceridemia, hyperinsulinemia, and hypertension. The glomerular changes observed in the kidneys of these animals are similar to those observed in diabetic rats. The aim of this study was to evaluate whether lacidipine, a calcium antagonist, could have a protective effect with this animal model. Forty male Wistar-Kyoto (WKY) rats were divided into four groups treated with HFD + placebo; HFD + lacidipine, 0.3 mg/kg/day; HFD + lacidipine, 3 mg/kg/day; or standard diet + placebo for 4 weeks. Urinary excretion of the stable metabolic products of nitric oxide (NO) was determined, because this vasoactive agent has been found to cause hemodynamic changes in the diabetic kidney. Glomerular size was determined by means of morphometric analysis. The results of this study show that lacidipine prevents (a) the HFD-induced increase in blood pressure in a dose-dependent manner; (b) the HFD-induced increase in glomerular size and fibronectin synthesis; and (c) the increase of collagen III synthesis in the heart. The drug had no effect on the increased urinary excretion of the stable metabolic products of NO. These data suggest that lacidipine might be useful in preventing the renal and cardiac damage caused by hypertension and non-insulin-dependent diabetes mellitus.

Topics: Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Body Weight; Collagen; Creatinine; Dietary Carbohydrates; Dihydropyridines; Dose-Response Relationship, Drug; Fibronectins; Fructose; Heart Diseases; Hypertension; Insulin; Kidney; Kidney Diseases; Kidney Glomerulus; Male; Myocardium; Nitric Oxide; Organ Size; Rats; Rats, Inbred WKY; Triglycerides

Toxicological studies on wild animals play an important role in the ecotoxicological examination of pesticides. The applied model tests enable the assessment of toxicological consequences with particular regard to the life and nutrition of wild animals in the ploughed field among plants treated with pesticides. The application of different pesticide formulations on plough-land may pose a simultaneous chemical burden to wild birds. In this model study, manifestations of the interaction between an insecticide and a herbicide were studied in pheasants. The birds were placed on lucerne in cages (48 m2) and sprayed once. The applied doses were: Sumithion 50 EC 1 litre/ha + Fusilade S 6 litres/ha (practical doses) and Sumithion 50 EC 5 litres/ha + Fusilade S 30 litres/ha. The analytically determined pesticide concentration of the lucerne was taken as a basis in the further treatment of fodder. The fodder of pheasants contained the following chemicals: 85 mg/kg Sumithion 50 EC + 510 mg/kg Fusilade S and 425 mg/kg Sumithion 50 EC + 2250 mg/kg Fusilade S. Sporadic deaths observed among the pheasants were of traumatic origin and not due to a toxic effect. The decrease of body weight was significant only at the higher dose levels. Acetylcholinesterase (AChE) activity of the blood decreased significantly in both dose groups. On the basis of the results obtained it can be established that at the dose level used in the practice the pesticides studied do not give rise to a toxic interaction in pheasants.

Topics: Acetylcholinesterase; Animals; Birds; Body Weight; Chromatography, Gas; Dihydropyridines; Female; Fenitrothion; Herbicides; Insecticides; Male; Medicago sativa; Random Allocation

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

Among the antihypertensive drugs, fast-acting Ca2+ antagonists have been reported to worsen insulin sensitivity. This effect may be attributable to reflex increases in sympathetic activity. On the other hand, however, it has been reported that long-acting, dihydropiridine Ca2+ antagonists improve insulin-resistance. The purpose of this study was to investigate whether cilnidipine, another long-acting dihydropidine Ca2+ antagonist, improves insulin sensitivity in Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of spontaneous NIDDM. 25 weeks OLETF rats were divided into the following groups; normal-diet group, cilnidipine-supplemented group (cilnidipine 3 mg/kg/day) and angiotensin II receptor antagonist CS-866-supplemented group (CS-866 1 mg/kg/day). As a non-diabetic control, we used Long-Evans-Tokushima-Otsuka rats (non-diabetic rats). Glucose infusion rate (GIR), an index of insulin resistance, as measured by the hyperinsulinemic euglycemic clamp technique was significantly decreased in OLETF rats. Cilnidipine-treatment partially but significantly improved insulin sensitivity in addition to systolic blood pressure in OLETF rats at 30 weeks of age, although it did not decrease accumulation of abdominal fat or serum levels of glucose or insulin. CS-866, an angiotensin II receptor antagonist, which lowers blood pressure through a different mechanism, did not improve insulin resistant states in OLETF rats. These results suggest that cilnidipine has a beneficial effect on insulin-resistance together with the antihypertensive effect.

Topics: Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Body Weight; Calcium Channel Blockers; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dihydropyridines; Glucose Tolerance Test; Imidazoles; Insulin; Insulin Resistance; Lipid Metabolism; Male; Olmesartan Medoxomil; Rats; Rats, Inbred OLETF; Tetrazoles; Time Factors

1. The present study was designed to investigate the anti-atherosclerotic effect of AE0047, a calcium channel blocker, and to compare it with that of nilvadipine in cholesterol-fed rabbits. Furthermore, the effects of AE0047 on low-density lipoprotein (LDL) oxidation were studied in vitro. 2. A 7 week treatment period with AE0047 (3 and 10 mg/kg, p.o.) led to a dose-dependent reduction in the lipid deposition area by Oil Red-O staining (surface index) without affecting serum lipid levels. There was no reduction in the surface index following treatment with the same dose of nilvadipine (10 mg/kg). 3. In a vehicle-administered high-fat diet group of rabbits, levels of total cholesterol (TC) and esterified cholesterol (EC) and calcium content in the aorta were increased approximately two- to three-fold over those of the normal diet group. Increased levels of TC and EC and calcium content were reduced to the same levels as the normal diet group by AE0047 treatment, whereas nilvadipine did not affect TC and EC levels. 4. In an in vitro study, AE0047 (10 micromol/L) inhibited LDL oxidation and the aggregation of apolipoprotein (Apo) B-100 induced by Cu2+. Furthermore, AE0047 inhibited the degradation of oxidized LDL by macrophages. In contrast, the same dose of nilvadipine (10 micromol/L) did not inhibit either LDL oxidation or the aggregation of ApoB-100. 5. In summary, AE0047 inhibited LDL oxidation, resulting in a decrease of its uptake into macrophages and an inhibition of cholesterol esterification. This leads to an anti-atherosclerotic effect of AE0047. Thus, AE0047 may have therapeutic potential in preventing cardiovascular disease in hypertensive patients.

Topics: Animals; Aorta, Thoracic; Arteriosclerosis; Body Weight; Calcium; Calcium Channel Blockers; Cholesterol, Dietary; Diet; Diet, Atherogenic; Dihydropyridines; Lipids; Lipoproteins, LDL; Male; Oxidation-Reduction; Rabbits

We examined the effect of a calcium antagonist, manidipine hydrochloride, on cardiac hypertrophy and the expression of the atrial natriuretic peptide (ANP), transforming growth factor beta 1 (TGF-beta 1), and extracellular matrix protein genes in rats with isoproterenol-induced cardiac hypertrophy. Rats were continuously infused with saline or isoproterenol (0.5 mg/kg per day) for 7 days using an osmotic minipump. Treatment with manidipine hydrochloride (once a day at 3 mg/kg) began 1 day before minipump implantation and continued until the end of the experiments (each group; n = 6). After treatment, left ventricular weight was measured and mRNA was extracted and analyzed by Northern blot hybridization. Isoproterenol increased left ventricular weight (2.40 +/- 0.04 g/kg; p < 0.01) without increasing blood pressure. ANP, collagen type I and type III, and fibronectin mRNAs were increased 1.5-(p < 0.01), 1.9- (p < 0.01), 2.7- (p < 0.01), and 3.2-fold (p < 0.01), respectively, by isoproterenol infusion. However, TGF-beta 1, collagen type IV, and laminin B1 and B2 mRNA levels were unchanged by isoproterenol. Manidipine hydrochloride prevented isoproterenol-induced left ventricular hypertrophy (2.26 +/- 0.02 g/kg; p < 0.01) and expression of mRNA of ANP (0.9-fold of the control value; p < 0.01), collagen types I (1.1-fold; p < 0.01) and type III (1.6-fold; p < 0.01), and fibronectin (1.1-fold; p < 0.01). Thus, manidipine hydrochloride prevented cardiac hypertrophy and changes in the expression of genes for ANP and interstitial components of extracellular matrix induced by isoproterenol.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blotting, Northern; Body Weight; Calcium Channel Blockers; Collagen; Dihydropyridines; Fibronectins; Heart Ventricles; Hypertrophy, Left Ventricular; Isoproterenol; Male; Myocardium; Nitrobenzenes; Organ Size; Piperazines; Pulse; Rats; Rats, Wistar; RNA, Messenger

We have evaluated the effects of a new calcium channel blocker, manidipine, given at both high, hypotensive and low, non-hypotensive doses, on vascular morphology, response to endothelin-1 and ICAM-1 production in mesenteric small resistance arteries of spontaneously hypertensive rats (SHR).. Ten SHR were treated with manidipine 3 mg/kg per day (high dose) and 10 with manidipine 0.3 mg/kg/per day (low dose). The drug was administered by gavage from the 4th to 12th weeks of age. Eighteen Wistar-Kyoto (WKY) rats and 18 SHR were kept untreated as controls. Rats were killed at 13 weeks. Mesenteric small arteries were dissected and mounted on a micromyograph for determination of indexes of vascular structure (media thickness, wall thickness, media/lumen ratio).. Systolic blood pressure was significantly reduced by the high dose of the drug, while no effect was observed with low-dose manidipine. A reduction in the media/lumen ratio was observed only in SHR treated with high-dose manidipine. The response to endothelin-1 in untreated SHR was significantly lower in comparison with WKY; a significant reduction was observed in SHR treated with high-dose manidipine. ICAM-1 vascular concentrations were higher in untreated SHR than in WKY controls. Both high- and low-dose manidipine reduced ICAM-1 concentrations toward normalization.. Manidipine at high, hypotensive, but not at low, non-hypotensive doses has been proven to reduce structural alterations in mesenteric small resistance arteries, and to normalize vascular responses to endothelin-1. In addition, manidipine, at both low and high doses, may reduce ICAM-1 vascular production, thus suggesting a possible anti-atherogenic effect.

Topics: Animals; Antihypertensive Agents; Arteries; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Endothelin-1; Intercellular Adhesion Molecule-1; Male; Muscle, Smooth, Vascular; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vascular Resistance

1. Long-term effects of manidipine hydrochloride (MAN), a calcium channel blocker, were examined in three groups of spontaneously hypertensive rats (SHR). Group 1 was given uninephrectomy (UNX) and MAN treatment, group 2 was given UNX and was not treated with MAN and group 3 was given neither UNX nor MAN treatment. 2. At week 15 after UNX, inulin clearance in group 1 rats decreased compared with rats in groups 2 and 3, but remained at the same level at week 40, when the level in group 2 rats declined below that in rats in groups 1 and 3. 3. Glomerular and tubulointerstitial lesions did not differ at week 15 after UNX among the three groups, whereas at week 40 both were advanced in the order of groups 2, 1 and 3. 4. Proteinuria did not differ between rats in groups 1 and 2 over the experimental period. 5. At week 15, the kidney weights of group 1 rats were greater than those of group 2 rats, indicating more prominent tubular hypertrophy in the former group. This was confirmed by morphometry of the proximal tubuli. In contrast, the glomerular volumes of rats in groups 1 and 2 were enlarged compared with that of rats in group 3, with no difference between the former two groups. 6. The findings suggest that MAN exerts renoprotective effects in SHR, both with regard to function and morphology. An effect on glomerular haemodynamics was considered to more likely be the mechanism underlying the renoprotective effect of MAN rather than that of a lowering of systemic blood pressure. 7. Augmented tubular hypertrophy after MAN treatment was an unexpected finding of the present study and the biological significance of this finding remains to be explored.

Topics: Animals; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Hypertension, Renal; Inulin; Kidney; Kidney Cortex; Kidney Glomerulus; Kidney Tubules, Proximal; Male; Nitrobenzenes; Piperazines; Proteinuria; Rats; Rats, Inbred SHR

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

The effect of regression of left ventricular hypertrophy was studied in deoxycorticosterone-acetate-salt hypertensive rats (DOCA-salt hypertensive rats) treated with tetrandrine. Treatment with tetrandrine (by gastric intubation, 50 mg/kg per day for 9 weeks) lowered systolic blood pressure, left ventricular weight, Ca2+ of mitochondria, and markedly decreased the density (Bmax) and total number of dihydropyridine binding sites in hypertrophic left ventricle (P < 0.001). There was no difference between groups in dissociation constant (Kd) values of dihydropyridine binding sites. These facts indicate that tetrandrine decreased cardiac mass in DOCA-salt hypertensive rats through mechanisms that may be associated with the density and the total number of dihydropyridine binding sites, Ca2+ and blood pressure control.

Topics: Alkaloids; Animals; Antihypertensive Agents; Benzylisoquinolines; Binding, Competitive; Blood Pressure; Body Weight; Calcium; Desoxycorticosterone; Dihydropyridines; Disease Models, Animal; Heart Ventricles; Hypertension; Hypertrophy, Left Ventricular; Isradipine; Male; Mitochondria, Heart; Organ Size; Radioligand Assay; Random Allocation; Rats; Rats, Sprague-Dawley

The aim of this study was to compare the renal effects of angiotensin converting enzyme (ACE) inhibition with calcium channel blockade in a model combining genetic hypertension with diabetes. Streptozotocin diabetes was induced in spontaneously hypertensive rats (SHR). The animals were then randomized to receive no treatment, the ACE inhibitor, perindopril, or the dihydropyridine calcium antagonist lacidipine. Body weight, systolic blood pressure, glycemic control, renal function, and albumin excretion rate (AER) were assessed serially over the 32-week study period. At week 32 the animals were killed and glomerular volume was measured. Both antihypertensive regimens significantly reduced systolic blood pressure in diabetic SHR. There was no significant difference in glycemic control, serum creatinine, or glomerular filtration rate among the three groups at week 32. The ACE inhibitor perindopril significantly reduced AER and glomerular hypertrophy over the 32 weeks, whereas the calcium antagonist lacidipine failed to reduce AER or glomerular hypertrophy. Thus, in contrast to the effects of ACE inhibition, calcium channel blockade with lacidipine, despite significantly reducing blood pressure, failed to reduce renal injury in this model. These results support the hypothesis that antihypertensive regimens may differ in their capacity to protect the diabetic kidney, despite similar effects on systemic blood pressure.

Topics: Albuminuria; Animals; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Dihydropyridines; Disease Models, Animal; Hypertension; Indoles; Kidney Diseases; Male; Perindopril; Random Allocation; Rats; Rats, Inbred SHR; Renin

To assess the effects of chronic dietary sodium restriction and blood pressure reduction on glomerular function and structure during the pathogenesis of hypertensive renal disease, experiments were conducted in uninephrectomized (UNX) spontaneously hypertensive rats (SHR) using the dihydropyridine calcium antagonist manidipine. Male SHRs underwent UNX at age 10-11 weeks and subsequently were assigned to one of four groups: sodium-replete (0.4%); sodium-replete and a predetermined antihypertensive dose of manidipine (20 mg/kg body weight); sodium-deplete (0.09%); and sodium-deplete and manidipine (20 mg/kg body weight). Twelve weeks later, renal morphologic and functional studies were performed. Sodium restriction had no significant effect on systolic blood pressure, but creatinine clearance and urinary protein excretion were decreased. Importantly, mean glomerular volume and the prevalence of mesangial expansion were lower with sodium restriction. This occurred in the presence of high concentrations of plasma and renal tissue angiotensin II. Manidipine significantly reduced systolic blood pressure in the sodium-replete and sodium-deplete UNX-SHRs. This therapy was not associated with significant changes in creatinine clearance and urinary protein excretion in the sodium-deplete or sodium-replete UNX-SHRs. The prevalence of mesangial expansion in the sodium-replete UNX-SHR was approximately 50% lower with manidipine. Plasma and renal tissue angiotensin II concentrations were not affected by the drug. In the sodium-deplete UNX-SHR, the prevalence of mesangial expansion was not reduced further by manidipine. However, plasma and renal tissue angiotensin II concentrations were increased significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Diet, Sodium-Restricted; Dihydropyridines; Kidney Glomerulus; Male; Nephrectomy; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Sodium, Dietary

1. In order to evaluate the therapeutic effects of antihypertensive agents on malignant hypertension in M-SHRSP, EEG were performed as a non-invasive, therapeutic index. 2. Under pentobarbital anaesthesia, the EEG pattern of rats with severe hypertension and/or cerebrovascular lesions showed alternate short-active and long-depressive phases with spike and sharp waves. 3. When M-SHRSP were treated with an angiotensin converting enzyme inhibitor (SQ 29,852) or a calcium antagonist (manidipine), the depressive phases became shorter and active phases longer. These changes were more prominent in manidipine treated rats than in SQ 29,852 treated rats. 4. The EEG spike- and sharp-wave complex seems to be a convenient index for evaluating cerebrovascular lesions and cerebral activity in M-SHRSP.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Electroencephalography; Hypertension, Malignant; Longevity; Male; Nitrobenzenes; Organophosphorus Compounds; Piperazines; Proline; Rats; Rats, Inbred SHR

1. We investigated the renal protective effect of efonidipine hydrochloride (NZ-105) in spontaneously hypertensive rats (SHR). SHR were given a diet containing 0.075% NZ-105 from 8 weeks old for 20 weeks. 2. 24-hr urinary protein excretion in the control SHR (drug-free diet) increased with age (from 77.3 mg/kg/day at 8 weeks old to 385.4 mg/kg/day at 28 weeks old), while that in NZ-105-treated SHR was maintained at almost the same level as that in Wistar-Kyoto rats (WKY), matched control animals throughout the experimental period. 3. The histological changes of the kidney were examined by light microscopy at the end of the treatment period. In control SHR, swelling and hyalinization of glomeruli, dilatation of renal tubules containing hyaline casts and arteriolosclerosis were revealed. The long-term administration of NZ-105 markedly suppressed these changes. 4. The kidney weights and plasma creatinine concentration in control SHR were higher than those in WKY, while they were significantly reduced in NZ-105-treated SHR. The long-term administration of NZ-105 also suppressed the elevation of systolic blood pressure and the increases of plasma renin activity and aldosterone concentration. 5. These findings suggest that NZ-105 inhibits the development of proteinuria and progressive kidney damage in SHR and may become a useful antihypertensive drug with the renal protective effect.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Hypertension; Kidney; Male; Nitrophenols; Organ Size; Organophosphorus Compounds; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Benidipine hydrochloride, a dihydropyridine calcium antagonist, decreases body weight and also has a hypotensive effect. The mechanism of its inhibitory effect on body weight is unclear, although this agent increases blood flow in brown adipose tissue, which functions as a main thermogenic organ. The hypothesis that benidipine hydrochloride activates brown adipose tissue to induce body weight loss was tested on mice made obese by pretreatment with monosodium-L-glutamate (MSG). When benidipine hydrochloride was incorporated in the diet (1.0 mg per gram of food) for 4 weeks, binding of guanosine-5'-diphosphate in brown adipose tissue mitochondria was significantly increased. Body weight and body fat decreased in both MSG obese mice and in lean controls. Results support the hypothesis and suggest the possibility that benidipine hydrochloride may be useful for treating obese hypertensive patients.

Topics: Adipose Tissue, Brown; Analysis of Variance; Animals; Body Weight; Calcium Channel Blockers; Dihydropyridines; Eating; Female; Mice; Mice, Inbred ICR; Obesity

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

Alterations in voltage-dependent Ca2+ channels in the arterial smooth muscle cells of spontaneously hypertensive rats (SHR) were investigated using the whole-cell voltage clamp and compared with Wistar-Kyoto (WKY) rats. Single cells were freshly isolated from resistance mesenteric arteries from 4- to 5-week-old (young) and 16- to 18-week-old (adult) SHR. Elevated blood pressure was only evident in adult SHR, not in young SHR. In young rats, the Ca2+ channel current density (current amplitude normalized by cell capacitance) was significantly higher (P < .01) in SHR than in WKY rats at the command potential of -10 mV or higher (with 50 mmol/L Ba2+): The current density at 20 mV was -16.8 +/- 1.1 pA/pF in SHR (n = 38 cells) and -11.0 +/- 0.8 pA/pF in WKY rats (n = 30 cells). In adult rats, the difference in current densities disappeared: -15.9 +/- 1.3 pA/pF in SHR (n = 25 cells) and -15.6 +/- 1.5 pA/pF in WKY rats (n = 29 cells). The ratio of maximal amplitude of T-type current to that of L-type current was low in young SHR (0.10 +/- 0.01) compared with the other three groups (0.16 to 0.20). Neither the activation curve nor the steady-state inactivation curve of SHR was different from that of age-matched WKY rats. However, the activation curves in adult rats were shifted to a hyperpolarized direction compared with those of young rats in both strains. These results suggest that the increased activity of voltage-dependent L-type Ca2+ channels of resistance arteries in young SHR may be related to the development of hypertension. The changes observed in adult rats may be due to a secondary modification of the channel during maturation and the presence of hypertension.

Topics: Animals; Arteries; Blood Pressure; Body Weight; Calcium Channels; Dihydropyridines; Electrophysiology; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vascular Resistance

Treatment of young rats with vitamin D3 and nicotine produced a 35-fold increase in the calcium content of the aorta and a 4-fold increase in the calcium content of the mesenteric arterial bed. Blood pressure was not modified. In vitro, aortic rings and mesenteric arterial bed preparations from such animals showed diminished vasoconstrictor responses to norepinephrine. After precontraction with norepinephrine, the endothelium-dependent vasodilator, carbachol, produced vasorelaxation. This latter effect was attenuated in aortic rings and mesenteric arterial bed preparations from animals previously treated with vitamin D3 and nicotine, but the vasodilator effect of sodium nitroprusside (which is independent of the endothelium) was unchanged. Prolonged treatment with the calcium entry blocker, isradipine, at a dose (1 mg/kg, i.p.) which had no effect on blood pressure, prevented calcium overload of the mesenteric arterial bed, but did not modify aortic calcium overload. Isradipine treatment had no effect on vasoconstrictor responses to norepinephrine in vitro. Such treatment did, however, restore the endothelium-dependent vasodilator effect of carbachol in the mesenteric arterial bed (but not in aortic rings). In conclusion, in a rat model of vascular calcium overload produced by administration of vitamin D3 plus nicotine, chronic treatment with a low dose of the calcium entry blocker, isradipine, restored the endothelium-dependent vasorelaxant effect of carbachol in the mesenteric arterial bed, but not in the aorta.

Topics: Animals; Aorta, Thoracic; Blood Pressure; Body Weight; Calcium; Calcium Channel Blockers; Cholecalciferol; Dihydropyridines; Endothelium, Vascular; Heart Rate; Isradipine; Male; Mesenteric Arteries; Models, Biological; Muscle Relaxation; Muscle, Smooth, Vascular; Nicotine; Rats; Rats, Inbred Strains; Time Factors

1. The haemodynamic effects of S-12968-(-), a new dihydropyridine calcium entry blocker (enantiomer of S-11568), were compared with those of the stereoisomer, S-12967-(+), nifedipine, and sodium nitroprusside. 2. A first experiment was performed in conscious, young male rats chronically implanted with femoral artery and vein cannula and repeated in rats previously treated with vitamin D3 and nicotine. Such treatment produces marked vascular calcium overload, especially of the compliance arteries, with no overt sign of toxicity as far as can be judged from the plasma profile. 3. In conscious rats the hypotensive effects of S-12968-(-), nifedipine and sodium nitroprusside were of similar potency. The falls in blood pressure produced by nifedipine and sodium nitroprusside were accompanied by reflex tachycardia which was less marked in the vascular calcium overload model. S-12968-(-) did not induce reflex tachycardia. S-12967-(+) increased blood pressure in both models. 4. A second experiment was performed in open-chest pentobarbitone-anaesthetized rats with electromagnetic flowprobes on the ascending aorta. In controls the falls in blood pressure produced by low doses (0.1 and 0.3 mg kg-1, i.v.) of S-12968-(-) were accompanied by falls in total peripheral resistance. The higher dose (1 mg kg-1, i.v.) of S-12968-(-) produced no change in total peripheral resistance, and in rats pretreated with vitamin D3 and nicotine, cardiac output fell. 5. In conclusion, S-12968-(-) appears to have a dual action and to lower blood pressure at higher doses at least in part by a cardiac effect. This phenomenon is more pronounced in rats pretreated with vitamin D3 and nicotine.6. S-12967-(+) resembles a calcium channel activator in this model.

Topics: Animals; Blood Pressure; Body Weight; Calcium; Calcium Channel Blockers; Cardiac Output; Cholecalciferol; Dihydropyridines; Heart Rate; Hemodynamics; Magnesium; Male; Nicotine; Nifedipine; Nitroprusside; Rats; Stereoisomerism; Vascular Resistance

Regulation of the gene expression of type-1 angiotensin II receptor (AT1) by treatment with manidipine, a calcium channel blocker, or delapril, an angiotensin converting enzyme inhibitor, for one week was assessed in the adrenal gland, heart, kidney, and brain from spontaneously hypertensive rats (SHR). Tissue AT1 receptor messenger RNA (mRNA) content was measured by reverse transcriptase-polymerase chain reaction. Treatment with manidipine (3 mg/kg/day) or delapril (30 mg/kg/day) lowered systolic blood pressure (SBP) significantly (p < 0.01) (delta SBP; -73 mmHg or -67 mmHg, respectively). Although delapril markedly increased plasma renin activity (PRA), manidipine did not alter PRA. AT1 receptor mRNA content in the adrenal gland was significantly (p < 0.01) decreased by treatment with manidipine or delapril. In contrast, cardiac AT1 receptor mRNA content was significantly (p < 0.01) increased by treatment with either agent. There was no significant change in renal and brain AT1 receptor mRNA contents. These findings suggest that although the expression of AT1 receptor gene depends on the circulating renin-angiotensin system (RAS), it is regulated independently in a tissue-specific manner via the local RAS in each tissue of SHR.

Topics: Adrenal Glands; Angiotensin-Converting Enzyme Inhibitors; Animals; Autoradiography; Base Sequence; Blood Pressure; Body Weight; Brain; Calcium Channel Blockers; Dihydropyridines; Gene Expression Regulation; Heart Rate; Hypertension; Indans; Kidney; Male; Molecular Sequence Data; Myocardium; Nitrobenzenes; Piperazines; Polymerase Chain Reaction; Rats; Rats, Inbred SHR; Receptors, Angiotensin; Renin; RNA, Messenger

In the present study, arteriosclerotic change of the aorta was induced in rats. The effects of manidipine hydrochloride on the resulting hypertension and arteriosclerotic change were studied. In endothelium-injured cholesterol-fed Goldblatt 2K1C rats, moderate elevation of blood pressure was noted at 3, 4, and 5 weeks. Laboratory studies performed at the end of 6 weeks also showed hypercholesterolemia, accompanied by a reduction of triglycerides and HDL cholesterol. Regular doses of manidipine (200 or 500 mg/kg) resulted in a dose dependent inhibition of the blood pressure elevation and a reduction of HDL cholesterol, but had no effect on cholesterol or triglyceride levels. Morphological studies in endothelium-injured rats afflicted with hypercholesterolemia and hypertension, showed medial thickening and intimal hyperplasia. Hyperplasia of the intima was a result of excessive proliferation of the smooth muscle cells. These cells showed an unusually large number of fat droplets and were considered indicative of atheromatous plaque formation. In rats treated with manidipine, hyperplasia of the media was completely suppressed while hyperplasia of the intima was reduced by a minimum of 50%. This study demonstrated that hypercholesterolemia and hypertension produced arteriosclerotic change in endothelium-injured rats, which was inhibited by manidipine. It is not known whether antiarteriosclerotic action was involved in the antihypertensive effect of manidipine.

Topics: Animals; Aorta; Arteriosclerosis; Blood Pressure; Body Weight; Calcium Channel Blockers; Cholesterol; Dihydropyridines; Endothelium, Vascular; Heart Rate; Hypertension, Renovascular; Male; Nitrobenzenes; Piperazines; Rats; Rats, Wistar

To study the effect of antihypertensive therapy on the regulation of renin gene expression, the levels of tissue renin messenger RNA (mRNA) were measured after treatment with a calcium channel blocker (manidipine hydrochloride 3 mg/kg/day) or an angiotensin-converting enzyme inhibitor (delapril hydrochloride 30 mg/kg/day), administered orally for 1 week, in spontaneously hypertensive rats (SHR). Male SHR, aged 15 weeks old, were used in this study (n = 5 per group). Control rats were administered the vehicle alone. Tissue total RNA was isolated from kidney, adrenal gland, heart, and brain tissue, and tissue RNA was reverse-transcribed to complementary DNA (cDNA), which was specifically amplified by polymerase chain reaction with labeled-primers for the rat renin gene. The radioactivity of the cDNA products was measured directly. Although delapril increased plasma renin activity (PRA) about 5-fold compared with the control group, manidipine did not change PRA. The kidney renin mRNA content was increased about 6-fold by treatment with delapril. Manidipine and delapril significantly decreased the renin mRNA content in the heart (p < 0.01 and p < 0.05, respectively). The level of renin mRNA in the adrenal gland and brain tissues was not significantly changed by treatment with either drug. These results suggest that tissue renin gene expression in SHR is regulated by a tissue-specific process independent of the circulating renin-angiotensin system.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Autoradiography; Base Sequence; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Gene Expression; Gene Expression Regulation; Heart Rate; Hypertension; Indans; Kidney; Male; Molecular Sequence Data; Nitrobenzenes; Piperazines; Polymerase Chain Reaction; Rats; Rats, Inbred SHR; Renin; RNA, Messenger

An enhanced renal vasoconstrictive response to emotional stress may be related to the pathogenesis of essential hypertension. We examined the effects of chronic manidipine treatment on renal blood flow (RBF) responses to air jet stress, angiotensin II (ANG II), and endothelin-3 (ET-3) in the conscious unrestrained spontaneously hypertensive rat (SHR). Male SHRs were placed on a control diet or one containing 0.05% of manidipine for 4 weeks. Age-matched Wistar-Kyoto (WKY) rats placed on a control diet served as normotensive controls. In comparison with control SHRs, manidipine reduced blood pressure (p < 0.01), increased urinary sodium excretion (p < 0.01), and reduced body weight (p < 0.01). Air jet stress elevated arterial pressure and increased RBF. The pressor response was enhanced more in the control SHRs than in the WKY rats (p < 0.01) and was not altered by manidipine. The percent fall in RBF in the manidipine-treated SHRs (-16%) was less than that in the control SHRs (-30%, p < 0.05) and similar to that in the WKY rats (-18%). In contrast, the pressor effect and the percent fall in RBF caused by ANG II (0.1 nmol/kg/min) were similar in the three groups. Intravenous ET-3 (1 nmol/kg) caused a transient fall, followed by a sustained increase in systemic blood pressure, both of which were associated with a decrease in RBF. The RBF response to ET-3 was blunted in SHRs compared to WKYs and was not altered by manidipine treatment. These results suggest that antihypertensive therapy with manidipine may be beneficial in maintaining RBF during emotional stress.

Topics: Air Pressure; Angiotensin II; Animals; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Endothelins; Heart Rate; Hypertension; Infusions, Intravenous; Injections, Intraventricular; Kidney; Male; Natriuresis; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Sodium; Stress, Physiological; Stress, Psychological; Time Factors

The purpose of this study was to investigate the effects of 4-week oral administration of manidipine (40 mg daily), a newly developed calcium channel blocker, on blood pressure and renal function in salt-loaded (8% NaCl) spontaneously hypertensive rats. Systolic blood pressure of spontaneously hypertensive rats increased from 167 +/- 4 to 221 +/- 7 mmHg with salt loading for 4 weeks; manidipine completely prevented this elevation in blood pressure. Urinary excretion of sodium in salt-loaded spontaneously hypertensive rats was twelve-fold compared with those receiving a normal diet (0.38% NaCl). The pressure-natriuresis relationship was obtained during week 4 of the metabolic study. At similar renal perfusion pressures, sodium excretion was significantly higher in salt-loaded rats than in rats fed a normal diet. Glomerular filtration rate and renal plasma flow were similar between the two groups. In salt-loaded spontaneously hypertensive rats, treatment with manidipine improved the pressure-natriuresis relationship toward lower pressures. Further, manidipine attenuated the autoregulation of glomerular filtration rate and renal plasma flow. These results indicate that manidipine normalizes the relation between sodium excretion and renal perfusion pressure in salt-loaded spontaneously hypertensive rats by resetting pressure natriuresis.

Topics: Animals; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Glomerular Filtration Rate; Hypertension; Kidney; Natriuresis; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Renal Circulation; Sodium; Sodium Chloride

The antihypertensive effect of calcium antagonists is altered little by high salt intake or concomitant diuretic treatment. We therefore investigated whether modest changes in the salt balance might alter the acute response of the renin-angiotensin system to the calcium antagonist isradipine in conscious rabbits. Mongrel rabbits with indwelling arterial and venous catheters were pretreated with either a single subcutaneous injection of 20 mg/kg furosemide 24 h before the experiment [sodium depletion (SD)] or the addition of 0.45% NaCl to the drinking water, which was available ad libitum for 24 h [sodium loading (SL)]. Compared with SL, SD pretreatment modestly increased plasma renin activity and lowered body weight; mean arterial pressure and heart rate were unchanged. Isradipine (10, 30, and 100 micrograms/kg) infused into the femoral vein catheter decreased blood pressure and increased heart rate similarly in both groups. Increases in plasma renin activity plotted as a function of the decreases in blood pressure showed a significantly steeper slope in SD than in SL animals. When blood pressure started to recover 15 min after the end of drug infusion, plasma renin activity decreased in SL animals only. Therefore, SL or SD strongly influences the responsiveness of the renin-angiotensin system to calcium antagonists, and this may be one reason why high salt intake does not diminish the antihypertensive effect of calcium antagonists and a calcium antagonist/diuretic combination may not yield optimal therapeutic results.

Topics: Analysis of Variance; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Furosemide; Heart Rate; Isradipine; Rabbits; Renin; Sodium; Sodium, Dietary

An experimental focal segmental glomerular sclerosis (FSGS) was induced by the combined administration of puromycin aminonucleoside (PAN) and protamine sulfate (PS). Blood collections were made on days 0, 37, 70 and 94. Urine collections were made on days 0, 24, 80 and 94. Vehicle-treated rats showed severe proteinuria and an increase in serum total cholesterol (sTC). Benidipine (1 or 3 mg/kg, p.o.)-treated rats exhibited less proteinuria and lower sTC than the vehicle-treated rats. On days 70 and 94, both blood urea nitrogen (BUN) and serum creatinine (sCR) values in the vehicle-treated rats were significantly higher than those in normal rats (without treatment with PAN and PS). On the other hand, the treatment with benidipine (1 or 3 mg/kg, p.o.) attenuated the increases in BUN and sCR. On day 94, vehicle-treated rats showed a significant decrease in creatinine clearance as compared with normal rats, but benidipine (1 or 3 mg/kg, p.o.)-treated rats did not. The histology was examined on day 94. Vehicle-treated rats demonstrated a significantly greater percentage of glomeruli with segmental areas of glomerulosclerosis/hyalinosis, mesangial cell proliferation, and mesangial foam cell. Benidipine (3 mg/kg, p.o.) ameliorated the development of renal regeneration as estimated by histological examination. These results suggest that the Ca-channel blocker benidipine is a favorable drug for preventing the progression of glomerular sclerosis.

Topics: Animals; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Glomerulosclerosis, Focal Segmental; Kidney; Male; Nephrotic Syndrome; Protamines; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley; Urine

To examine the status of ATP-sensitive K+ (K+ATP) channels and 1,4-dihydropyridine-sensitive Ca2+ (Ca2+DHP) channels during experimental cardiac failure, we have measured the radioligand binding properties of [3H]glyburide and [3H]PN 200 110, respectively, in tissue homogenates from the rat cardiac left ventricle, right ventricle, and brain 4 wk after myocardial infarction induced by left coronary artery ligation. The maximal values (Bmax) for [3H]glyburide and [3H]PN 200 110 binding were reduced by 39 and 40%, respectively, in the left ventricle, and these reductions showed a good correlation with the right ventricle-to-body weight ratio in heart-failure rats. The ligand binding affinities were not altered. In the hypertrophied right ventricle, Bmax values for both the ligands were not significantly different when data were normalized to DNA content or right ventricle weights but showed an apparent reduction when normalized to unit protein or tissue weight. Moderate reductions in channel densities were observed also in whole brain homogenates from heart failure rats. Assessment of muscarinic receptors, beta-adrenoceptors and alpha 1-adrenoceptors by [3H]quinuclidinyl benzilate, [3H]dihydroalprenolol, and [3H]prazosin showed reductions in left ventricular muscarinic and beta-adrenoceptor densities but not in alpha 1-adrenoceptor densities, consistent with earlier observations. It is suggested that these changes may in part contribute to the pathology of cardiac failure.

Topics: Animals; Body Weight; Brain; Calcium Channel Blockers; Calcium Channels; Coronary Vessels; Dihydropyridines; Glyburide; Heart Failure; Heart Ventricles; Isradipine; Ligation; Male; Organ Size; Potassium Channels; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Receptors, Muscarinic

Lacidipine is a long-lasting 1,4-dihydropyridine calcium antagonist that has been reported to protect salt-loaded Dahl-S rats from vascular damage and accelerated mortality when it is administered prophylactically at 0.1 and 0.3 mg/kg p.o. once a day (equivalent to the recommended dose in humans). The aim of this study was to investigate the vasoprotective properties of lacidipine in Dahl-S rats that had already developed sustained hypertension after 4 weeks of a salt-rich diet. Although none of the dosages of lacidipine (0.3, 1, and 3 mg/kg) reduced the elevated values of blood pressure, an almost complete protection from mortality was obtained. Moreover, lacidipine dose-dependently inhibited the development of macroscopic and microscopic alterations in the distal branches of mesenteric arteries and in the brain. A clear regression of vascular damage and cardiac hypertrophy was observed at the highest dose tested (3 mg/kg). These findings further support the assumption that the protective properties of lacidipine are not restricted to a reduction in blood pressure.

Topics: Animals; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Heart; Heart Rate; Hypertension; Male; Organ Size; Rats; Rats, Inbred Strains; Retinal Diseases; Vascular Diseases

ICI 153,110 and ICI 170,777, two pyridyl diazinone cardiotonic agents, produced a different profile of effects on hepatic microsomal mixed function oxidase enzymes following multiple oral dosing to rats and dogs; these differences may be related to the molecular dimensions of the two molecules. ICI 153,110 significantly increased levels of total P450, ethoxycoumarin O-deethylase and ethoxyresorufin O-deethylase in rat microsomes, indicating an induction profile (P448) similar to that of beta-naphthoflavone. This was supported by gel electrophoresis (SDS-PAGE) of microsomal proteins; a similar type of induction was observed in dog microsomes. In contrast, ICI 170,777 produced no changes indicating enzyme induction in either rat or dog. Instead, ICI 170,777 appeared to inhibit specifically the activity of aldrin epoxidase in the rat. Inhibitory activity was also indicated in the rat by prolongation of pentobarbitone sleeping time following single oral doses of either ICI 153,110 or ICI 170,777. The time-course of this effect appeared to correlate more closely with the profile of circulating metabolites, although both parent compounds were found to produce type II spectral changes on interaction with control rat microsomes. The molecular dimensions (area/depth2) of the compounds supported the finding that only ICI 153,110 should interact with or induce P448 isozymes.

Topics: Animals; Body Weight; Cardiotonic Agents; Dihydropyridines; Dogs; Drug Evaluation, Preclinical; Enzyme Induction; Half-Life; Male; Microsomes, Liver; Mixed Function Oxygenases; Pyridazines; Pyridines; Rats; Thiadiazines; Vasodilator Agents

We explored the effect of age and of hypertrophy on Ca2+ antagonist binding site density (Bmax), affinity (Kd), and selectivity in cardiac membranes harvested from the hearts of young adult (9-week-old) and older (25-week-old) Sprague Dawley (SD) rats, Wistar Kyoto rats (WKY), and spontaneously hypertensive rats (SHR). Radioligand binding studies with (+)[3H]PN200-110 failed to show a significant difference between the Bmax obtained for the cardiac membranes of 9-week-old SD, WKY, or SHR. Similarly, at 25 weeks, the Bmax values were the same for each group, but in each group the Bmax tended to increase with age. The Kd and selectivity were unchanged. For (-)[3H]D888 binding, the Kd values changed with age, but there was no hypertension or hypertrophy-linked increase in Bmax. In the SD and SHR series, but not in the WKY, there was a tendency for the Bmax to increase with age. We interpreted these results to mean that age may contribute to the different Kd and Bmax values described for cardiac membranes from 25-week-old WKY and SHR.

Topics: Aging; Animals; Blood Pressure; Body Weight; Calcium Channels; Cardiomegaly; Cell Membrane; Dihydropyridines; Indicators and Reagents; Isradipine; Male; Myocardium; Oxadiazoles; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Receptors, Nicotinic; Time Factors; Verapamil

To determine whether pharmacological control of blood pressure could affect the renal function and levels of atrial natriuretic polypeptide (ANP) in spontaneously hypertensive rats (SHR) with renal ablation, and to ascertain the benefits of antihypertensive drugs, we studied effects of oral administration of captopril (50 mg/kg/day), an inhibitor of angiotensin converting enzyme, benidipine (3 mg/kg/day) and nilvadipine (10 mg/kg/day), newly developed blockers of calcium channel, and indapamide (10 mg/kg/day) for 14 days on systolic blood pressure, serum creatinine, blood urea nitrogen, and plasma ANP concentration in SHR subjected to surgical removal of the left kidney and infarction of two-thirds of the right kidney (5/6 nephrectomy) a week before. Three weeks after the surgery, systolic blood pressure (mmHg) in the untreated group was 253 +/- 9 (n = 10), in the captopril group 156 +/- 9 (n = 7, p less than 0.05), in the benidipine group 197 +/- 9 (n = 7, p less than 0.05), in the nilvadipine group 146 +/- 9 (n = 7, p less than 0.05) and in the indapamide group 206 +/- 5 (n = 7, p less than 0.05). Serum creatinine (mg/100 ml) was lower in the captopril group (0.58 +/- 0.02, n = 7, p less than 0.05) and in the benidipine group (0.50 +/- 0.03, n = 7, p less than 0.05) but not in the nilvadipine group and in the indapamide group 3 weeks after 5/6 nephrectomy compared to the untreated group. Blood urea nitrogen was also lower in the captopril group and in the benidipine group but not in the nilvadipine group and in the indapamide group. Plasma ANP concentration was significantly reduced by the treatment with captopril and benidipine but not with nilvadipine and indapamide. These results suggest that the reduction of blood pressure by the inhibition of angiotensin converting enzyme with captopril has the potential to ameliorate renal function of the SHR with remnant kidney, a model of chronic renal failure with hypertension, associated with the decreased concentration of plasma ANP. However, it remains to be determined whether the reduction of blood pressure by calcium channel blockers may be involved in the delayed progression of renal failure in this model since there were disparate effects on renal function and plasma ANP concentration with these two calcium channel blockers.

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Calcium Channel Blockers; Captopril; Dihydropyridines; Indapamide; Kidney; Male; Nephrectomy; Nifedipine; Rats; Rats, Inbred SHR; Reference Values

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

We have developed a redox-chemical delivery system for brain-enhanced drug delivery of estradiol based on an interconvertible dihydropyridine in equilibrium pyridinium salt carrier. Estradiol, when combined with the carrier, readily crosses the blood-brain barrier and upon oxidation of the carrier is "locked" in the brain. The aim of this study was to evaluate the effects of the estradiol-chemical delivery system (E2-CDS) on body weight change and associated alterations in the secretion of anterior pituitary hormones in middle-aged, male rats. The data revealed that rats receiving E2-CDS exhibited a significant weight loss by 2 days which continued to day 14, the last observation day. A significant weight difference was observed between E2-CDS and DMSO-treated animals. Serum estradiol levels of rats treated with E2-CDS were elevated 100-fold by day 1 and decreased thereafter and serum prolactin concentrations were doubled by 24 hours and continued to increase to the completion of the experiment. Testosterone levels were markedly suppressed by 24 hours while serum levels of LH, TSH, T3, T4 and GH were not significantly altered. These data indicate that the E2-CDS causes a long-term reduction in body weight and testosterone secretion and that these changes are not mediated by alterations in the secretion of anterior pituitary hormones.

Topics: Age Factors; Animals; Blood-Brain Barrier; Body Weight; Dihydropyridines; Estradiol; Luteinizing Hormone; Male; Pituitary Hormones, Anterior; Prolactin; Rats; Testosterone; Thyroid Hormones

Administration of 3,5,5-trimethylhexanoyl ferrocene in the diet of male Wistar rats results in a substantial increase in hepatic ferritin protein (greater than 2-fold) and of ferritin iron (4-8-fold). The iron-loading in liver, under the conditions used, appears to be essentially in parenchymal cells rather than in reticulo-endothelial cells. It is suggested that the model represents a useful system for the study of the potential efficacy of new iron chelators for the mobilization of hepatic storage iron. The ability of desferal (DFO) and of a new siderophore, desferrithiocin (DFT), to mobilize hepatic ferritin iron is observed in this model of iron overload. Desferrithiocin stimulates ferritin iron mobilization, when administered either by gavage or by intraperitoneal injection, whereas desferal is active intraperitoneally but inactive orally. Our studies lead to the conclusion that DFT merits further examinations, for its activity as an orally active iron chelator.

Topics: Administration, Oral; Animals; Body Weight; Chelating Agents; Deferoxamine; Dihydropyridines; Ferritins; Ferrous Compounds; Injections, Intraperitoneal; Liver; Male; Metallocenes; Organ Size; Organometallic Compounds; Pyridines; Rats; Rats, Inbred Strains; Thiazoles