2,6-二甲基-4-(3-硝基苯基)-1,4-二氢-3,5-吡啶二羧酸-3-甲酯-5-正戊酯(MN9202)抗实验性血栓形成作用

 目的：探讨新的二氢吡啶钙通道阻滞剂MN9202对实验性血栓形成的影响及其作用机制。方法：采用iv胶原-肾上腺素或sc角叉菜胶，分别复制小鼠肺血栓和尾血栓模型。观察MN9202对实验性肺血栓小鼠死亡率，血栓黑尾形成率及微循环的影响。用凝血酶-ADP-肾上腺素复合诱导剂，复制大鼠脑血栓模型，观察MN9202对大鼠脑血栓损伤的预防作用。结果：MN9202 4mg·kg^-1ip，能明显降低胶原 肾上腺素引起的小鼠死亡率(30vs84P<0.01)；6mg·kg^-1ig，对凝血酶诱导的大鼠脑血栓损伤具有保护作用(0.069±0.068 vs 0.110±0.013,P<0.01);0.04,0.4mg·kg^-1能降低角叉菜胶诱导的血栓黑尾发生率(30,10 vs 90,P<0.05;P<0.01)，明显减轻微血管内皮的渗出，抑制血小板聚集和RBC聚集，改善微血管血流速度。结论：MN9202具有对抗血小板聚集诱导剂及角叉菜胶引起的血栓形成作用。其机制可能与其抑制RBC、血小板聚集，保护血管内皮，舒张痉挛血管有关。     

Internal male pseudohermaphroditism in a 6 week old child

Here we describe a 6-week-old infant with internal male pseudo-hermaphroditism, detected during the repair of a left inguinoscrotal hernia. We advocate early orchidopexy during a first laparatomy and call attention to the risk of adhesions and subsequent complications if the gonads are replaced into the peritoneal cavity in advance of a precise histological and cytogenetic diagnosis.     

Bay K 8644 stimulation of calcium entry and endogenous dopamine release in rat striatal synaptosomes antagonized by nimodipine

The calcium channel agonist Bay K 8644 (0.1 – 100 nM) significantly increased the fast-phase entry of calcium and release of endogenous dopamine from rat striatal synaptosomes partially depolarized with 15 mM KCl. This increase was completely blocked by 10 nM nimodipine which had no inhibitory effect on calcium influx and dopamine release in the absence of Bay K 8644. Bay K 8644's agonist effect was attenuated with higher KCl concentrations. These findings suggest that Bay K 8644, in combination with partial KCl depolarization, may expose brain synaptosomal calcium channels which are sensitive to nanomolar concentrations of dihydropyridine calcium channel blockers.     

丹参酮衍生物对K562细胞的生长抑制及诱导凋亡作用研究

目的研究丹参酮衍生物对人红白血病细胞株K562的生长抑制以及诱导凋亡作用。方法MTT比色法检测不同浓度丹参酮1、丹参酮2和丹参酮B对K562细胞的增殖抑制作用;PI单染法检测3者对K562细胞周期的影响;An-nexin V/PI双染法检测3者对K562细胞诱导凋亡的作用。结果丹参酮1和丹参酮B能够抑制K562细胞增殖,IC50分别为5.22和15.11μmol·L-1,且分别在2.5~10μmol·L-1和10~40μmol·L-1剂量范围内,G0/G1期细胞比例的增加及早期凋亡细胞百分率的提高均呈剂量相关性;丹参酮2在100μmol·L-1的剂量下,对K562细胞的抑制率仅为27.8%,无诱导其凋亡作用,但可以使G0/G1期细胞增多。结论丹参酮1和丹参酮B抑制K562细胞增殖,阻滞其于G0/G1期并诱导细胞凋亡;丹参酮2对K562细胞没有明显生长抑制及诱导凋亡作用,但可将其阻滞于G0/G1期。     

泥胡菜中新的酚酸类化合物的分离和鉴定

目的研究泥胡菜的化学成分。方法对泥胡菜全草的95%乙醇提取物的醋酸乙酯萃取部分进行色谱分离,根据光谱数据和理化性质确定各化合物的结构。结果分离并鉴定了2个化合物,分别为:8-羧甲基-对羟基肉桂酸乙酯(1)和8-羧甲基-对羟基肉桂酸甲酯(2)。结论化合物1和2均为新化合物。     

Effects of volatile anesthetics on cardiac calcium channels

In order to investigate how volatile anesthetics affect cardiac calcium channels, the effects of halothane, enflurane, and isoflurane on the specific binding of [3H]-nitrendipine to bovine heart sarcolemmal membranes were studied. All three anesthetics added in liquid form inhibited [3H]-nitrendipine binding in a dose-dependent manner, and more interestingly, the order of inhibition by these volatile anesthetics roughly followed that of their anesthetic potencies. The partial pressures, calculated using the gas/water partition coefficients of halothane, enflurane, and isoflurane which inhibited [3H]-nitrendipine binding by 30% at 37 degrees C were about 1.48 x 10(-2) atm. (1.48%), 4.89 x 10(-2) atm. (4.89%) and 2.76 x 10(-2) atm. (2.76%), respectively. One mmol/l halothane altered not only the maximal binding (Bmax) from 189 f mol/mg protein to 136 f mol/mg protein, but also the dissociation constant (Kd) from 0.074 nmol/l to 0.18 nmol/l. Halothane was also added to the reaction mixture in the gaseous form with air. The partial pressure of halothane needed to bring about 30% inhibition was 0.82 x 10(-2) (0.82%), a value almost similar to that for halothane added in the liquid form. These results indicate that all three volatile anesthetics have direct effects on cardiac calcium channels, and that the magnitude of the effects depends on their anesthetic potencies.     

MECHANISMS UNDERLYING THE CARDIOVASCULAR ACTION OF A NEW DIHYDROPYRIDINE VASODILATOR, YC-93

1.The mechanisms underlying the cardiovascular action of YC-93, a new dihydropyridine vasodilator with cyclic AMP phosphodiesterase inhibitory activity, was investigated by comparing its effects wth those of papaverine in various isolated, blood-perfused heart preparations of the dog. 2. In all preparations YC-93 injected into the nutrient arteries produced a dose-dependent increase in blood flow, and in this respect YC-93 was about twenty times more potent than papaverine on a weight basis. 3. In sinoatrial node preparations YC-93 injected into the sinus node artery decreased sinus rate in a dose-dependent manner, and in large doses produced atrial standstill. 4. In atrioventricular (a.v.) node preparations YC-93 injected into the a.v. node artery increased a.v. conduction time in a dose-dependent manner, and in large doses produced a second or third degree block of a.v. conduction. However YC-93 injected into the anterior septal artery scarcely affected a.v. conduction. 5. In spontaneously contracting papillary muscle preparations YC-93 injected into the anterior septal artery failed to affect ventricular automaticity in doses which markedly decreased developed tension of papillary muscles. 6. In papillary muscle preparations driven at a fixed rate YC-93 injected into the anterior septal artery produced a dose-dependent decrease in developed tension of papillary muscles. 7. Unlike YC-93, papaverine decreased a.v. conduction time in a.v. node preparations and increased developed tension of papillary muscle preparations. 8. The cardiac effects of YC-93 elucidated in the present experiments are characteristic of calcium-antagonistic vasodilators. The action of YC-93 as an inhibitor of cyclic AMP phosphodiesterase does not appear to play a role in its cardiac action.     

Regulated sarcolemmal localization of the muscle-specific ClC-1 chloride channel

The skeletal muscle-specific ClC-1 is a voltage-gated chloride channel protein. Specific antibodies against ClC-1 revealed in muscle sections a sarcolemmal staining that was absent in the myotonic arrested development of righting response (ADR) mouse muscle. The intensity of the sarcolemmal staining varied from one type of muscle to another and in lateral sections showed a typical mosaic pattern that colocalized with beta-dystroglycan and left the transverse tubule openings clear. Surprisingly, in isolated myofibers, the ClC-1 protein was absent from the sarcolemma. Instead, it localized to intracellular I band areas as soon as the myofibers were isolated. When the isolated myofibers were incubated with the kinase inhibitor staurosporine, the ClC-1 protein shifted back to the sarcolemma. Electric stimulation of the cultivated fibers had a similar effect. Also, myofibers infected with a recombinant Semliki Forest virus (SFV) expressing myc-tagged ClC-1 showed intracellular localization of the protein. The virally expressed mycClC-1 reached the Golgi apparatus but sarcolemmal staining remained nondetectable, and addition of staurosporine into the growth medium recruited the mycClC-1 to the sarcolemma. These data indicate that sarcolemmal targeting of the ClC-1 requires specific signals that are provided by the physiological environment.     

Pharmacokinetics and bioavailability of a newly synthesized dihydropyridine compound with multidrug resistance reversal activity

(+/-)3-(3-(4,4-diphenylpiperidin-1-yl)propyl) 5-methyl 4-(3,4-dimethoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate ((+/-)-DHP-014), is a new 4-aryl-1,4-dihydropyridine that can reverse multidrug resistance mediated by the ATP-binding cassette (ABC) transport proteins, P-glycoprotein, multidrug resistance-associated protein 1 and breast cancer resistance protein; it exhibits negligible calcium channel blocking activity. The objective of this work was to investigate the pharmacokinetics of this new compound in rats. Three intravenous (1, 2 and 5 mg/kg) and two oral (25 and 50 mg/kg) doses were administered to female Sprague-Dawley rats. A two-compartment model with nonlinear elimination best characterized the pharmacokinetic profiles after intravenous and oral administration in rats. The terminal half-life of (+/-)-DHP-014 increased and the systemic clearance significantly decreased at higher doses, indicating nonlinear elimination. The dose-dependent clearance is likely due to saturation of metabolism. The apparent volume of distribution of (+/-)-DHP-014 was 2.0 L/kg in rats and was unchanged with increasing intravenous doses of (+/-)-DHP-014. The estimated oral bioavailability of (+/-)-DHP-014 was 8.2%. The poor bioavailability is likely due to the poor solubility of the compound, as well as to substantial first-pass elimination.     

Malignant hyperthermia and excitation–contraction coupling

Malignant hyperthermia (MH) is a state of elevated skeletal muscle metabolism that may occur during general anaesthesia in genetically pre‐disposed individuals. Malignant hyperthermia results from altered control of sarcoplasmic reticulum (SR) Ca²⁺ release. Mutations have been identified in MH‐susceptible (MHS) individuals in two key proteins of excitation–contraction (EC) coupling, the Ca²⁺ release channel of the SR, ryanodine receptor type 1 (RyR1) and the α1‐subunit of the dihydropyridine receptor (DHPR, L‐type Ca²⁺ channel). During EC coupling, the DHPR senses the plasma membrane depolarization and transmits the information to the ryanodine receptor (RyR). As a consequence, Ca²⁺ is released from the terminal cisternae of the SR. One of the human MH‐mutations of RyR1 (Arg614Cys) is also found at the homologous location in the RyR of swine (Arg615Cys). This animal model permits the investigation of physiological consequences of the homozygously expressed mutant release channel. Of particular interest is the question of whether voltage‐controlled release of Ca²⁺ is altered by MH‐mutations in the absence of MH‐triggering substances. This question has recently been addressed in this laboratory by studying Ca²⁺ release under voltage clamp conditions in both isolated human skeletal muscle fibres and porcine myotubes.