Effect of nilvadipine on the voltage-dependent Ca channels in rat hippocampal CA1 pyramidal neurons

Effects of nilvadipine on the low- and high-voltage activated Ca²⁺ currents (LVA and HVA I_Ca, respectively) were compared with other organic Ca²⁺ antagonists in acutely dissociated rat hippocampal CA1 pyramidal neurons. The inhibitory effects of nilvadipine, amlodipine and flunarizine on LVA I_Ca were concentration- and use-dependent. The apparent half-maximum inhibitory concentrations (IC₅₀s) at every 1- and 30-s stimulation were 6.3×10⁻⁷ M and 1.8×10⁻⁶ M for flunarizine, 1.9×10⁻⁶ M and 7.6×10⁻⁶ M for nilvadipine, and 4.0×10⁻⁶ M and 8.0×10⁻⁶ M for amlodipine, respectively. Thus, the strength of the use-dependence was in the sequence of nilvadipine>flunarizine>amlodipine. Nilvadipine also inhibited the HVA I_Ca in a concentration-dependent manner with an IC₅₀ of 1.5×10⁻⁷ M. The hippocampal CA1 neurons were observed to have five pharmacologically distinct HVA Ca²⁺ channel subtypes consisting of L-, N-, P-, Q- and R-types. Nilvadipine selectively inhibited the L-type Ca²⁺ channel current which comprised 34% of the total HVA I_Ca. On the other hand, amlodipine non-selectively inhibited the HVA Ca²⁺ channel subtypes. These results suggest that the inhibitory effect of nilvadipine on the neuronal Ca²⁺ influx through both LVA and HVA L-type Ca²⁺ channels, in combination with the cerebral vasodilatory action, may prevent neuronal damage during ischemia.     

Long-term clinical effect of nilvadipine in patients with chronic heart failure: A double-blind placebo-controlled study

Summary The long-term effect of calcium channel blockers on chronic heart failure is disappointing, probably because of reflex sympathetic activation through arterial vasodilation. However, nilvadipine may be beneficial for treatment of chronic heart failure since this drug has minimal effects on sympathetic activation. In this study, the effects of 12-week administration of nilvadipine or placebo on symptoms of heart failure and cardiac function were investigated in 23 patients with mild-to-moderate chronic heart failure in a double-blind trial. The patients were randomly assigned to either a nilvadipine group (16 mg daily) or a placebo group. Intergroup comparisons did not show significant differences in any parameters. Serious adverse effects were not observed during the study. Thus, this study failed to show any beneficial effect of nilvadipine in the long-term treatment of patients with chronic heart failure. We conclude that the long-term administration of nilvadipine (16 mg daily) is neither effective nor harmful in the treatment of patients with chronic heart failure.Other members are listed in the appendix.     

Elevated plasma nilvadipine concentration after single and chronic oral administration to patients with chronic liver disease

Summary Fourteen normotensive patients with liver disease (6 with cirrhosis and 8 with chronic hepatitis) and 7 healthy volunteers were given a single oral dose of nilvadipine 2 mg. In addition, nilvadipine 4 mg was administered orally twice daily for several months to 6 hypertensive patients with mild liver dysfunction and 18 hypertensives with normal liver function.A significant increase in plasma nilvadipine was found in the patients with cirrhosis as compared both to the normal and chronic hepatitis subjects; the time to peak concentration was similar among the three groups.The peak plasma nilvadipine concentration was closely correlated both with the serum albumin level and the retention of indocyanine green. Changes in blood pressure, pulse rate and various vasoactive hormones following a single oral dose of nilvadipine did not differ between the groups.Thus, an increase in plasma nilvadipine relative to the level in normal subjects was demonstrated in patients with cirrhosis following a single oral dose, as well as in patients with slight liver dysfunction following long-term oral administration.     

Effects of Chronic Administration with Nilvadipine Against Immunohistochemical Changes Related to Aging in the Mouse Hippocampus

We investigated the effect of Ca²⁺ antagonist nilvadipine on age-related immunohistochemical alterations in ubiquitin and S100 protein of the hippocampal CA1 sector in mice using 8-, 18-, 40-, and 59-week-old mice. No significant changes in the number of neuronal cells were observed in the hippocampal CA1 sector up to 59 weeks after birth. The administration of nilvadipine did not affect the number of the hippocampal CA1 cells of 40-week-old mice. Age-dependent increases in ubiquitin immunoreactivity were observed in the hippocampal CA1 neurons up to 59 weeks after birth. The administration of nilvadipine prevented dose-dependently the increases in the number of ubiquitin-immunoreactive neurons in the hippocampal CA1 sector of 40-week-old mice. S100 immunoreactivity was unchanged in the hippocampal CA1 sector up to 40 weeks after birth. In 59-week-old mice, the level of staining of S100-immunoreactive cells increased significantly in the hippocampal CA1 sector. The administration of nilvadipine decreased dose-dependently the number of S100-immunoreactive cells in the hippocampal CA1 sector of 40-week-old mice. The present study demonstrates that age-related increases in ubiquitin system may play a pivotal role in protecting neuronal cell damage during aging. In contrast, our results suggest that expression of S100 protein in the hippocampal CA1 sector may play an exacerbating factor in some neuronal cells damaged by aging. Our results also demonstrate that nilvadipine, a dihydropyridine-type calcium channel blocker, can prevent dose-dependently the increases in the ubiquitin immunoreactive neurons and decrease the number of S100 immunoreactive cells in the hippocampal CA1 neurons of aged mice. These results suggest that nilvadipine may offer a new approach for the treatment of neuronal dysfunction in aged humans.     

Effects of Nilvadipine on Cytokine-Levels and Soluble Factors in Collagen Disease Complicated with Essential Hypertension

We examined some immunological parameters, particularly cytokines and soluble factors in collagen diseases complicated with essential hypertension. We also investigated the effects of Nilvadipine on immunological parameters after treatment with this drug for six months. The frequency of helper/inducer T cells (CD4+ CD8- cells, CD4+ CD45RA- cells) decreased in the peripheral blood on a 6 month treatment with nilvadipine. There was a significant decrease of suppressor/inducer T cells (CD4+ 45RA+cells), and an insignificant decrease of activated T cells (CD3+ HLA-DR+ cells) and memory T cells (CD45RA- CD45RO+ cells) after treatment. Before treatment with Nilvadipine, interleukin-1 β, tumor necrosis factor-α, and interleukin-6 levels increased higher in the patients than in healthy volunteers. However, interleukin-1 β and interleukin-6 concentrations tended to decrease after treatment with Nilvadipine. Besides, tumor necrosis factor-α decreased significantly after treatment. The soluble interleukin-2 receptor concentrations also showed a decreased tendency after treatment, although high concentrations were found in the patients before treatment.     

Ambulatory blood pressure monitoring in elderly hypertensives treated with the new calcium antagonist,nilvadipine

Summary. A newly developed calcium antagonist, nilvadipine, was administered to 7 hypertensive patients aged 75.6 y.Nilvadipine 4 mg b.d. decreased the average 24-h blood pressure significantly from 169/89 mm Hg to 152/81 mm Hg after 7 to 14 days without any change in the pulse rate. The circadian patterns of blood pressure and pulse rate were not affected by nilvadipine.Although the present study was a preliminary one done over a short period in a small number of patients, the results suggest that nilvadipine exerts an antihypertensive effect without altering the circadian pattern or the variability of blood pressure in elderly hypertensive patients.     

尼维地平对大鼠局灶脑缺血的治疗作用

本实验探讨了尼维地平（Ｎｉｌｖａｄｉｐｉｎｅ）对大鼠局灶脑缺血的治疗作用。在氟烷麻醉下，由颈内动脉插入单尼龙线阻断大脑中动脉。阻断后１、２、３和４ｈ，皮下注射Ｎｉｌｖａｄｉｐｉｎｅ或其溶剂聚乙二醇。局灶脑缺血后１ｈ，Ｎｉｌｖａｄｉｐｉｎｅ投与组，神经缺损体征评分和脑水肿体积明显减少。局灶脑缺血３ｈ以内，Ｎｉｌｖａｄｉｐｉｎｅ投与组，皮层梗塞灶、总梗塞灶体积均较对照组明显减少。定性分析后显示：额顶皮层梗塞灶边缘部即缺血性半暗区的缩小为主。Ｎｉｌｖａｄｉｐｉｎｅ于大鼠大脑中动脉阻断３ｈ以内应用能缩小梗塞灶，可用于临床治疗急性脑梗塞。     

Photochemical stabilities of some dihydropyridine calcium-channel blockers in powdered pharmaceutical tablets

Photostabilities of some dihydropyridine calcium-channel blockers in pulverized pharmaceutical tablets were studied. Powdered tablets including amlodipine, nifedipine, or nilvadipine were exposed to D65 daylight lamp radiation according to an ICH guideline (ICH Q1B). The photodegradation of pharmaceutical components and their degradation products were monitored by HPLC using a reversed phase column with UV detection; their peak components were identified using MS analysis. Photochemical reactions involved in the photodegradation of these pharmaceuticals include aromatization of the dihydropyridine moiety and conversion to nitroso group from the nitro group in benzene rings. Chemical stability studies of these drugs indicate that nifedipine is the most photosensitive. The rate constant of nifedipine is indicated as seven times higher than those of the other two drugs.     

Therapeutic effects of nilvadipine on rat focal cerebral ischemia

The present study was conducted to invetigate the therapeutic effects of nilvadipine, a Ca²⁺ entry blocker, on rat focal cerebral ischemia. Under halothane anesthesia, a 3-0 nylon thread was introduced into the neck internal carotid artery to occlude the left middle cerebral artery. Either nilvadipine (3.2 mg/kg) or vehicle was administered subcutaneously 1, 2, 3, 4, 5 and 6 h following the occlusion (groups 1–6, respectively). Twenty-four hours after the occlusion, the percentage infarct volumes in nilvadipine-treated animals in groups 1–3 (21±11%, 24±11%, and 26±7%, respectively) were smaller than those in the respective control groups (36±5%, 35±3%, and 35+3%; P<0.05). Compared with controls, the infarct size of the periphery of the fronto-parietal cortex decreased in nilvadipine-treated animals. The results indicate that nilvadipine decreases the size of infarction when administered up to 3 h after an ischemic insult. Thus, nilvadipine can be considered a potential therapeutic agent for acute focal cerebral ischemia, and may be clinically useful in stroke patients.