lacidipine and Disease-Models--Animal

Lacidipine is an orally administered calcium channel blocker of the dihydropyridine class, which shows selectivity for vascular smooth muscle over cardiac tissue and has a long duration of action. In studies using ambulatory blood pressure monitoring, lacidipine 2 to 8mg administered once daily in the morning reduced blood pressure over 24 hours, with the reductions being greater during the day than at night in some studies. 77 to 87% of patients with mild to moderate hypertension had their blood pressure controlled by treatment with lacidipine 2 to 8 mg/day for 1 to 4 months in dose-finding studies. When administered once daily, lacidipine 4 to 6 mg was equivalent in antihypertensive efficacy to hydrochlorothiazide 25 to 50 mg/day, atenolol 50 to 100 mg/day, and the prototype calcium channel blocker nifedipine 20 to 40 mg twice daily (sustained-release formulation). The adverse effects of lacidipine are those common to other dihydropyridine calcium channel blockers, and include headache, flushing, ankle oedema, dizziness and palpitations. The long term effects of lacidipine on cardiovascular morbidity and mortality, and possible additional clinical benefits in terms of its antiatherosclerotic effects, are under investigation; the outcome of these studies will be important in defining the future role of this agent in the treatment of hypertension. Thus, available evidence suggests lacidipine provides a further alternative to the dihydropyridine calcium channel blockers currently available for the treatment of essential hypertension.

Topics: Adult; Aging; Animals; Antihypertensive Agents; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Hemodynamics; Humans; Hypertension; Middle Aged; Tissue Distribution

Lacidipine is an orally administered calcium channel blocker of the dihydropyridine class, which shows selectivity for vascular smooth muscle over cardiac tissue and has a long duration of action. In studies using ambulatory blood pressure monitoring, lacidipine 2 to 8mg administered once daily in the morning reduced blood pressure over 24 hours, with the reductions being greater during the day than at night in some studies. 77 to 87% of patients with mild to moderate hypertension had their blood pressure controlled by treatment with lacidipine 2 to 8 mg/day for 1 to 4 months in dose-finding studies. When administered once daily, lacidipine 4 to 6 mg was equivalent in antihypertensive efficacy to hydrochlorothiazide 25 to 50 mg/day, atenolol 50 to 100 mg/day, and the prototype calcium channel blocker nifedipine 20 to 40 mg twice daily (sustained-release formulation). The adverse effects of lacidipine are those common to other dihydropyridine calcium channel blockers, and include headache, flushing, ankle oedema, dizziness and palpitations. The long term effects of lacidipine on cardiovascular morbidity and mortality, and possible additional clinical benefits in terms of its antiatherosclerotic effects, are under investigation; the outcome of these studies will be important in defining the future role of this agent in the treatment of hypertension. Thus, available evidence suggests lacidipine provides a further alternative to the dihydropyridine calcium channel blockers currently available for the treatment of essential hypertension.

Topics: Adult; Aging; Animals; Antihypertensive Agents; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Hemodynamics; Humans; Hypertension; Middle Aged; Tissue Distribution

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Lacidipine is a potent dihydropyridine calcium channel blocker used for management of hypertension and atherosclerosis. The drug has low and fluctuating oral bioavailability owing to its extensive hepatic first-pass metabolism and reduced water solubility. Accordingly, this work aimed at overcoming the aforementioned challenges through the formulation of intranasal nano-sized lacidipine glycerosomes. Box-Behnken was successfully employed for the formulation and in vitro optimization of the glycerosomes. Statistical analysis revealed that cholesterol concentration exhibited a significant effect on the vesicle size, while Phospholipon® 90G and glycerol concentrations exhibited significant effects on both entrapment efficiency and deformability index. The optimized formulation showed spherical shape, good deformability, vesicular size of 220.25 nm, entrapment efficiency of 61.97%, and enhanced ex vivo permeation by 3.65 fold compared to lacidipine suspension. Confocal laser scattering microscope revealed higher penetration depth via nasal mucosa for rhodamine labelled glycerosomes (up to 60 µm) in comparison to rhoadamine dye solution (26 µm). In addition, the optimized lacidipine glycerosomes caused significant reduction in methylprednisolone acetate-induced hypertension in rats for up to 24 h in comparison to oral drug suspension. Histopathological assessment showed intact nasal mucosal epithelial lining with no signs of inflammation or necrosis confirming the safety and tolerability of the proposed glycerosomes. The declared results highlights the potential of utilizing the proposed glycerosomes as safe and effective platform for intranasal delivery of lacidipine.

Topics: Administration, Intranasal; Administration, Oral; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cholesterol; Dihydropyridines; Disease Models, Animal; Drug Compounding; Drug Liberation; Glycerol; Hypertension; Liposomes; Male; Methylprednisolone Acetate; Nasal Absorption; Nasal Mucosa; Permeability; Phosphatidylcholines; Rats, Wistar; Solubility

Calcium channel blockers are increasingly used for the treatment of hypertension. Hypertension is an important risk factor for liver damage and several other circulatory abnormalities. The aim of this study was to determine the effects of lacidipine in a irradiation-induced hepatocellular damage model in Deoxyc Orticosterone Acetate (DOCA)-salt-induced hypertensive model in rats. In this study, animals were divided into five groups as follows: control (Group 1), hypertensive (Group 2), irradiated (Group 3), irradiated and hypertensive (Group 4) and irradiated, hypertensive and lacidipine-treated (Group 5). At the end of the experiment, the livers were removed and its homogenates were biochemically examined. Significant differences were found between values of all groups (p < 0.05). Group 3 and particularly Group 4 showed significant increase in lipid peroxidation and Nitric Oxide (NO) and serum tumor necrosis factor-alpha (TNF-alpha) with a significant reduction in serum level of alanine amine transferase (ALT) enzyme and in superoxide dismutase in red blood cells lysates. Lacidipine-treated group (5) showed a significant reduction in elevated systolic blood pressure together with a great protection of ALT and SOD enzymes from the destructive effects of irradiation and hypertension. Additionally, this CCB reduces hepatic NO and serum TNF-alpha levels that were increased in groups (2,3,4). The present study suggests that lacidipine has some important protective effects on liver of hypertensive irradiated albino rats.

Topics: Alanine Transaminase; Animals; Blood Pressure; Desoxycorticosterone Acetate; Dihydropyridines; Disease Models, Animal; Hypertension; Lipid Peroxidation; Liver; Liver Diseases; Nitric Oxide; Random Allocation; Rats; Salts; Superoxide Dismutase; Tumor Necrosis Factor-alpha

To investigate the effects of metyrosine, lacidipine, clonidine, and moxonidine on the renal damage in rats with unilateral ureteral ligation by examining the histological evidence of parenchymal damage and tubular dilatation, as well as biochemical changes indicating cell membrane damage and DNA oxidation.. Thirty-six albino Wistar rats were randomly divided into six equal groups: a healthy (intact) group, a unilateral ureteral ligation (control) group, and four drug treatment groups given metyrosine (50 mg/kg), lacidipine (2 mg/kg), clonidine (0.075 mg/kg), or moxonidine (0.2 mg/kg), respectively, for 10 days. The latter five groups underwent ligation of the left ureter. Ten days after the operation, we removed both kidneys from each rat in the control and drug treatment groups for renal pathological and biochemical [malondialdehyde (MDA), total glutathione, 8-hydroxy-2-deoxyguanine (8-OH-Gua)] examinations. Spectrophotometric assays were used to detect the malondialdehyde and total glutathione levels of the renal tissue. High-performance liquid chromatography was used to measure the 8-hydroxy-2-deoxyguanine levels.. When the drug treatment groups were compared with the control group, the drug treatment groups' total glutathione level was higher and their malondialdehyde level was lower than that of the control group (P < 0.05), especially in the clonidine group (P < 0.0001). The 8-hydroxy-2-deoxyguanine levels of the drug treatment groups, except the lacidipine group, were significantly lower than that of the control group (P < 0.0001). There was no significant difference between the contralateral kidneys of the treatment groups and control group, according to the biochemical results. As revealed via light microscopy, clonidine and moxonidine treatment significantly reduced the tubular and glomerular damage, as well as the tubular dilation. The interstitial inflammation of the kidneys in the lacidipine group was higher than that of the other treatment groups. However, the apoptotic cell count was at a high level in both the lacidipine and metyrosine groups. The increase in the collagen content was most pronounced in the lacidipine and metyrosine groups. An examination of the contralateral kidneys showed no marked pathological findings.. The use of a direct or indirect α2-adrenergic receptor agonist for the temporary treatment of unilateral ureteral obstruction-induced renal damage may be important for preventing renal structural injury. A more advanced study is necessary to determine the mechanisms underlying the protective effects of these drugs with regard to renal damage in ureteral obstruction.

Topics: Acute Kidney Injury; alpha-Methyltyrosine; Animals; Biopsy, Needle; Clonidine; Dihydropyridines; Disease Models, Animal; Imidazoles; Immunohistochemistry; Kidney; Male; Random Allocation; Rats; Rats, Wistar; Reference Values; Sensitivity and Specificity; Ureteral Obstruction

Antihypertensive treatment may reduce prolonged QT duration in hypertension. Generally, the reductions of blood pressure and/or of cardiac mass are believed to be the responsible factors. However, drugs are not equivalent in QT modulation despite similar antihypertensive and antihypertrophic action. We investigated the effect of a calcium channel blocker, lacidipine and an angiotensin-converting enzyme inhibitor, enalapril on QT duration in rats. Normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were treated with lacidipine (at the dose of 1.5 mg/kg per day for WKY and 3 mg/kg per day for SHR) or enalapril (5 mg/kg per day for WKY and 10 mg/kg per day for SHR) during 8 weeks. Tail-cuff systolic blood pressure (sBP), left ventricular weight (LVW), vascular function of isolated aorta and mesenteric artery and duration of QT (and QTc) interval on Frank electrocardiograms were evaluated. As expected, untreated SHR showed elevated sBP, impaired vascular reactivity, increased LVW and prolonged QT when compared with WKY (p < 0.05). After treatment, both agents markedly improved vascular reactivity and reduced sBP in SHR (p < 0.05). Additionally, enalapril reduced LVW in both hypertensive (by 17%; p < 0.05) and normotensive rats (by 13%; p < 0.05) and, consequently, corrected QT duration in SHR. Interestingly, lacidipine also reduced LVW in SHR (by 9%; p < 0.05), but without influence on prolonged QT. Moreover, lacidipine had no effect on LVW in WKYs but prolonged their QT interval (by 10%; p < 0.05). In conclusion, lacidipine did not reverse a progressive prolongation of QT in SHR, despite sBP lowering and LVW reduction. Thus, the lowering of blood pressure and/or reduction of LVW are not sufficient per se to normalize ventricular repolarization in hypertensive cardiac disease. More likely, modulation of QT prolongation by antihypertensive drugs is a function of their complex action on blood pressure, vascular function, cardiac mass and on reflex neurohumoral activation.

Topics: Acetylcholine; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Disease Models, Animal; Enalapril; Heart Ventricles; Hypertension; Male; Mesenteric Arteries; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY

The cardiovascular drug lacidipine (Lc) is known to possess antibacterial activity. Further potentiation of action is possible by synergism between Lc and an antibiotic or a non-antibiotic. The minimum inhibitory concentration (MIC) of antibiotics, Lc and other non-antibiotics were detected by the agar dilution technique in different bacteria. Synergism was determined by disc diffusion assay, the fractional inhibitory concentration (FIC) index through checkerboard assessment and, also, the protective capacity of the combination by administering the drugs along with 50 x LD(50) challenge dose of virulent Salmonella typhimurium in animal experiments. Synergism between Lc and penicillin was found to be statistically significant (P

Topics: Animals; Anti-Bacterial Agents; Colony Count, Microbial; Dihydropyridines; Disease Models, Animal; Drug Synergism; Gram-Negative Bacteria; Gram-Positive Bacteria; Heart; Humans; Liver; Male; Mice; Microbial Sensitivity Tests; Salmonella Infections, Animal; Spleen; Treatment Outcome

Bone is a dynamic organ system that is directly related to calcium and phosphor metabolism. Imbalance in these two parameters upon aging or menopause leads to osteoporosis. Recently, it was also shown by researchers that high blood pressure in elderly women is statistically associated with decreased bone mineral content at the femoral neck, which may increase the susceptibility to fractures. The aim of our study was to investigate the effects of different doses of amlodipine and lacidipine on ovariectomized rat femurs' calcium and phosphor content. Bone calcium and phosphor concentration was measured by a Wavelength Dispersive Spectrometer. Calcium contents of the rat femurs were significantly lower in the ovariectomized group than in the sham group eight weeks after the operation. Amlodipine treatment at doses of 1 and 3 mg/kg significantly increased the calcium (P<0.01) and phosphor concentrations (P<0.01) in the femurs of ovariectomized rats, compared to those of control (ovariectomized) group. Both doses of lacidipine (1 and 3 mg/kg) also effectively increased calcium concentrations (P<0.01) significantly in ovariectomized rats. On the other hand amlodipine treatment at doses of 1 and 3 mg/kg significantly increased the calcium (P<0.01) and phosphor concentrations (P<0.01) in the femurs of ovariectomized rats compared with those of the sham group. In conclusion, amlodipine and lacidipine improved the bone loss in an ovariectomy induced osteopenic rat model. Our findings suggest that potent calcium channel blockers such as amlodipine and lacidipine have a beneficial effect on bone metabolism, and an antihypertensive effect.

Topics: Amlodipine; Animals; Bone and Bones; Calcium; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Femur; Osteoporosis; Ovariectomy; Phosphorus; Rats; Rats, Wistar; Spectrometry, X-Ray Emission

Dihydropyridines can inhibit gene expression in-vitro and may have a protective vascular effect independent of blood pressure reduction. We tested the hypothesis that lacidipine prevents induction of inducible NO synthase (iNOS), influences leukocyte adhesion and infiltration, inhibits nuclear factor (NF)-kappaB transcription factor activity, and ameliorates end-organ damage in a transgenic rat model of angiotensin (Ang) II--dependent organ sclerosis. We treated rats transgenic for human renin and angiotensinogen (dTGR) from week 4 to 7 with lacidipine (0.3 or 3 mg/kg by gavage). Blood pressure was measured by tail cuff. Organ damage was assessed by histology and immunohistochemistry. Adhesion molecules and cytokines were analyzed by immunohistochemistry. Transcription factors were analyzed by mobility shift assays. Untreated dTGR developed moderate hypertension, cardiac hypertrophy, and severe renal damage with albuminuria. Lacidipine decreased blood pressure slightly at the low dose and substantially at the higher dose. However, both treatments reduced albuminuria and plasma creatinine to the same degree (P<0.05). Intercellular adhesion molecule-1 (ICAM-1) was markedly reduced by lacidipine as well as renal neutrophil and monocyte infiltration. Lacidipine reduced mitogen-activated protein (MAP) kinase phosphorylation and iNOS expression in both cortex and medulla. NF-kappaB and AP-1 were activated in dTGR but reduced by lacidipine. Lacidipine ameliorates Ang II-induced end-organ damage independent of blood pressure lowering, perhaps by inhibiting the MAP kinase pathway and NF-kappaB activation.

Topics: Angiotensins; Animals; Blood Pressure; Cell Adhesion Molecules; Dihydropyridines; Disease Models, Animal; Oxidoreductases; Rats; Rats, Sprague-Dawley; Vascular Diseases

We have investigated the activity of the calcium antagonist lacidipine in male hamsters fed an atherogenic diet containing 2% cholesterol and 5% butter. Animals were examined at 14, 20 and 24 weeks of treatment. At 14 weeks, in hamsters fed the atherogenic diet and without lacidipine treatment, there were significant increases in serum levels of total cholesterol, triglycerides and lipoproteins; these values were approximately similar at week 24. Lacidipine treatment at 0.3, 1.0 and 3.0 mg/kg/d did not affect levels of serum cholesterol, triglycerides and lipoproteins. At 24 weeks, in hyperlipidemic hamsters fed the atherogenic diet, the area of the fatty streak in the aortic arch covered a mean area of 375 +/- 145 micron2 x 100, which accounted for 2.7% of the total surface area of the aortic arch. In hamsters fed the atherogenic diet and treated with lacidipine at 0.3, 1.0 and 3.0 mg/kg, at 24 weeks, the surface area of the aortic arch lesion was significantly reduced by 41 to 71%. In the thoracic aorta at 24 weeks, in lacidipine-treated animals, both the incidence and degree of severity of the lesions was reduced, the area of the fatty streak being lowered by 78 to 97% in comparison with non-lacidipine-treated control animals. Ultrastructural examination demonstrated that the early changes in the aorta in hamsters fed the atherogenic diet involved the intima and smooth muscle cells; lacidipine treatment reduced the severity of the intimal lesions significantly. With SEM, lacidipine administration was seen to reduce endothelial irregularity and the presence of crater-like lesions. At TEM, treatment with lacidipine reduced the number of foam cells and the presence of liposomes in the subendothelium. This investigation demonstrates that in the hyperlipidemic hamster, lacidipine treatment decreases atheromatous lesions without lowering serum lipids. It is suggested that lacidipine influences the atherogenic process by an unusual mechanism which may be related to a combination of both the long-lasting calcium antagonism of the drug and significant antioxidant activity.

Topics: Animals; Aorta, Thoracic; Arteriosclerosis; Calcium Channel Blockers; Cholesterol; Cholesterol, Dietary; Cricetinae; Dihydropyridines; Disease Models, Animal; Lipids; Lipoproteins; Male; Mesocricetus

Carvedilol and lacidipine have been shown to exert cardioprotective effects in rat models of chronic hypertension. We investigated their effects in an acute model of pressure overload produced by suprarenal aortic constriction, in which enhanced myocardial production of endothelin-1 could play a crucial role. In the absence of drug treatment, after 1 week, aortic banding provoked an increase in carotid pressure associated with left ventricular hypertrophy (29%; P<0.01). These changes were accompanied by increased myocardial expression of preproendothelin-1 (2.5 times; P<0.05) and skeletal alpha-actin (3.6 times; P<0.05), but the expression of cardiac alpha-actin was not modified. Oral administration of carvedilol at a dose of 30 mg. kg(-1). d(-1) to rats with aortic banding normalized carotid pressure and left ventricular weight as well as preproendothelin-1 and skeletal alpha-actin gene expression. Carvedilol at a lower dose (7.5 mg x kg(-1) x d(-1)) and lacidipine 1 mg x kg(-1) x d(-1) had only moderate and nonsignificant effects on carotid pressure but largely prevented left ventricular hypertrophy (P<0.01) and preproendothelin-1 overexpression (P<0.05). Labetalol (60 mg x kg(-1) x d(-1)) tended to exert similar effects but insignificantly. These results show that the antihypertrophic properties of carvedilol and lacidipine are partly independent of their antihypertensive effects and may be related to their ability to blunt myocardial preproendothelin-1 overexpression. Moreover, carvedilol at a dose of 7.5 mg x kg(-1) x d(-1) did not prevent myocardial overexpression of skeletal alpha-actin, which suggests that, in this model, reexpression of a fetal gene can be activated by pressure overload independently of cardiac hypertrophy.

Topics: Actins; Animals; Antihypertensive Agents; Aortic Diseases; Blood Pressure; Carbazoles; Carotid Arteries; Carvedilol; Constriction, Pathologic; Dihydropyridines; Disease Models, Animal; Endothelin-1; Endothelins; Gene Expression; Heart Rate; Heart Ventricles; Hypertrophy, Left Ventricular; Labetalol; Ligation; Male; Myocardium; Organ Size; Propanolamines; Protein Precursors; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger

Functional and structural changes of chronic renal allograft failure share similarities with other chronic nephropathies with low nephron number. In models of reduced nephron number, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers prevented proteinuria and retarded renal lesions. This study investigates whether blockade of angiotensin II activity prevented chronic allograft injury in the Fisher 344 --> Lewis rat kidney transplant model, and compares its effect with that of calcium channel blockers, the main antihypertensive agents used in transplant patients to control BP. Transplanted rats received either no treatment (control), the type 1 angiotensin II receptor antagonist losartan, or the calcium channel blocker lacidipine. Rats received cyclosporine for the first 10 d posttransplant to prevent acute rejection. Doses of antihypertensive drugs were adjusted to achieve a comparable level of BP control throughout the study. Awake systolic BP was comparable in animals given losartan or lacidipine during the 6-mo observation period. Daily treatment with losartan but not lacidipine resulted in a significant decrease in the amount of proteinuria, preserved glomerular and tubulointerstitial structure, and improved graft survival compared with corresponding parameters in control untreated rats. GFR, measured as inulin and p-aminohippurate clearances, respectively, in rats surviving the 6-mo follow-up, was numerically but not significantly higher in losartan-treated animals than in all other groups. Thus, at comparable levels of BP control, losartan but not lacidipine effectively protects animals from chronic allograft injury and allows long-term survival.

Topics: Analysis of Variance; Animals; Calcium Channel Blockers; Chronic Disease; Dihydropyridines; Disease Models, Animal; Graft Rejection; Kidney; Kidney Function Tests; Kidney Transplantation; Losartan; Male; Nephrotic Syndrome; Rats; Rats, Inbred F344; Rats, Inbred Lew; Reference Values; Survival Rate; Transplantation, Homologous

We investigated the effects of lacidipine on focal cerebral ischemia in rats, and these effects were compared with those of nicardipine. Drugs were administered orally 5 min after middle cerebral artery occlusion (MCAO). Neurological scores as described by Bederson et al. (Stroke 17, 472-476, 1986) and cerebral infarct size (CIS) determined by the 2,3,5-triphenyltetrazolium chloride staining method were measured 24 hr after MCAO. Cerebral blood flow (CBF) and energy metabolites were determined by the hydrogen clearance method and an enzymatic method, respectively. In the drug-untreated group, we observed low-CBF of approximate 13 ml/100 g/min during 0.5-6 hr of occlusion and extensive cerebral infarction associated with severe neurologic deficits (ND). Lacidipine at 1 and 3 mg/kg, although it lowered blood pressure, improved low-CBF to approximate 20 ml/100 g/min during 1.5-6 hr of occlusion and increased tissue levels of ATP 6 hr after MCAO in a dose-dependent manner. Nicardipine at 30 mg/kg also improved low-CBF and increased tissue levels of ATP significantly. However, the improvement of low-CBF by nicardipine was transient. Lacidipine at 3 mg/kg reduced CIS and ameliorated ND significantly. In contrast, nicardipine at 30 mg/kg could not ameliorate ND in spite of a significant reduction of CIS similar to that of lacidipine (3 mg/kg). These results suggest that the improvement of focal cerebral ischemia by lacidipine may be partly due to long-lasting improvement of collateral blood supply to the ischemic area.

Topics: Adenosine Triphosphate; Animals; Brain; Calcium Channel Blockers; Cerebral Arterial Diseases; Cerebral Infarction; Cerebrovascular Circulation; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Energy Metabolism; Ischemic Attack, Transient; Male; Neurologic Examination; Nicardipine; Rats; Rats, Sprague-Dawley

We examined the cerebral protective effects of lacidipine (L) using three different types of cerebral ischemia models, and the effects were compared with those of nicardipine (N). (1) In the transient forebrain ischemia model of the rat, oral administration of L (0.3 and 1 mg/kg) before ischemia significantly decreased the number of acidophilic neurons in CA1 regions of the hippocampus 7 days after ischemia. N (3 mg/kg, p.o.) before ischemia also produced a significant reduction in the number of acidophilic neurons, and it's effectiveness was almost the same as that of L (1 mg/kg). (2) In the focal cerebral ischemia model of the rat, oral administration of L (1 and 3 mg/kg) before of after left middle cerebral artery occlusion (MCAO) significantly reduced infarct size at 24 hr after MCAO. Such an ameliorative effect was also observed when N was administered orally. However, the effect of N at 30 mg/kg was less than that of L at 1 mg/kg. (3) In the delayed cerebral vasospasm model of the dog after subarachnoid hemorrhage (SAH), intravertebral artery injection of L (10 micrograms/kg) or N (10 micrograms/kg) dilated the contracted basilar artery 3 days after SAH to the level before SAH. Finally, while both L and N increased cerebral blood flow (CBF) in a dose-dependent manner in conscious normal rat, the increment of CBF induced by L at a given level of reduced-blood pressure was greater than that induced by N. These results indicate that lacidipine may be a potential therapeutic agent that exerts a protective effect against brain damage after cerebral ischemia.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Circulation; Dihydropyridines; Disease Models, Animal; Dogs; Ischemic Attack, Transient; Male; Nicardipine; 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

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

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

The aim of this study was to characterize the antihypertensive and vasoprotective properties of lacidipine in salt-loaded Dahl-S rats, a suitable animal model of malignant hypertension. After 9 weeks of a high (8%) sodium chloride (NaCl) diet, 80% of the untreated Dahl-S rats died (20% survival rate) whereas a 100% survival rate was observed with chronic treatment with lacidipine at doses of 0.1 (equivalent to the recommended dose in humans), 0.3, 1, and 10 mg/kg once daily by gastric gavage. The most interesting results included the following: (a) Only the highest dose tested (10 mg/kg once daily) was able to control the increase in blood pressure, which was measured 24 h after the preceding administration of drug, yet a 100% survival rate was maintained. (b) There appeared to be prevention of brain lesions, which is very likely the cause of the survival of all of the lacidipine-treated rats in this study. (c) A clear dose-related vascular protection was observed in other tissues. In conclusion, lacidipine protects against the vascular damage and concomitant increase in mortality of salt-loaded Dahl-S rats even at doses that do not adequately control the development of hypertension.

Topics: Administration, Oral; Animals; Blood Pressure; Brain; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Fundus Oculi; Hypertension, Malignant; Male; Myocardium; Organ Size; Rats; Rats, Inbred SHR; Sodium, Dietary