Effects of verapamil, diltiazem, nisoldipine and felodipine on sarcoplasmic reticulum

Verapamil, diltiazem, nisoldipine and felodipine, calcium antagonist drugs with different chemical structures, were studied for their effects on activities of sarcoplasmic reticulum (SR) isolated from dog cardiac and rabbit skeletal muscles. Nisoldipine and felodipine exerted biphasic actions on both cardiac and skeletal SR Ca²⁺-ATPase with maximum activation of 40–60% occurring at 20–40 μM for nisoldipine and 30–40% occurring at 15–30 μM for felodipine. At higher drug concentrations, Ca²⁺-ATPase was inhibited. In the presence of oxalate the maximum activation of the Ca²⁺ uptake rates at 5–20 μM nisoldipine were 30–50% for cardiac SR and 80–100 μM of the drug were 300–500% for skeletal SR. Felodipine inhibited the rate of Ca²⁺ uptake by dog cardiac SR, but activated Ca²⁺ uptake by rabbit skeletal SR with a maximum of 30–50% at 12–25 μM. At higher concentrations of the two drugs the rate of Ca²⁺ uptake was inhibited. In the absence of oxalate, i.e., limited tranport, nisoldipine shortened the duration of time that Ca²⁺ was bound to the cardiac and skeletal SR, while the rate of release of Ca²⁺ from skeletal SR was stimulated. Felodipine at low concentrations similarly caused a premature release of Ca²⁺ from skeletal SR at a rapid rate; at high concentrations both drugs did not alter Ca²⁺ binding but delayed Ca²⁺ release. Unlike nisoldipine and felodipine, verapamil and diltiazem inhibited the rates of Ca²⁺ transport both in cardiac and skeletal SR. The two drugs inhibited Ca²⁺-ATPase in cardiac SR but activated the enzyme in skeletal SR. Thus, these drugs caused complex and different effects on cardiac and skeletal SR, possibly resulting from perturbations of the lipid environment of the SR Ca²⁺-ATPase.     

Effects of intracoronary propranolol on coronary blood flow and regional myocardial function in dogs

The study was conducted to evaluate the effects of intracoronary administration of dl-propranolol on coronary blood flow and regional myocardial function in anesthetized open-chest dogs. The results were compared with those obtained with d-propranolol, atenolol and lidocaine. Bolus intracoronary injections of dl-propranolol (0.02-2 mg) dose dependently produced transient increases in coronary blood flow and subsequent depression in regional segment shortening which qualitatively resembled those produced by the dextro isomer (0.02-2 mg) and lidocaine (0.2-10 mg). Atenolol (up to 2 mg) was almost devoid of these effects. Isoproterenol-induced responses were abolished by dl-propranolol and atenolol but only incompletely blocked by d-propranolol. These results demonstrate that propranolol at high doses has direct coronary vasodilating and cardiodepressant effects in situ, and indicate that the major part of these effects can be attributed to the membrane-stabilizing action rather than beta-adrenoceptor blockade.     

地奥心血康对小鼠心肌营养性血流量的影响

采用放射性核素８６Ｒｂ测定小鼠心肌营养性血流量的方法。用地奥心血康８０ｍｇ／ｋｇ，ｉｇ或４０ｍｇ／ｋｇ，ｉｐ，均能增加心肌营养性血流量。＊Ｐ＜０．０１。讨论小鼠心肌对８６Ｒｂ摄取量的大小，在很大程度上取决于心肌内开放毛细血管的数量和面积，在一定条件下，心肌血流量愈大，对８６Ｒｂ的摄取量愈多，所以，心肌对８６Ｒｂ的摄取量可以代表心肌营养血流量。采用８６Ｒｂ测定心肌营养性血流量报道较多，但处理心脏的方法有组织研磨法［２］，组织消化法［３］和直接测定法［１，４］。本文采用直接测定法［１］，操作比较简便。关于注射８６ＲｂＣｌ后处死动物时间的选择，施新献认为心脏对８６Ｒｂ的摄取是一个动态过程，在注射后３０ｓ至１５ｍｉｎ的阶段内，心肌８６Ｒｂ含量高且平稳。因此，选择静注后３０ｓ作为观察心肌对８６Ｒｂ摄取能力的时间标准是比较合适的［５］。地奥心血康４０，８０ｍｇ／ｋｇ，ｉｐ和８０ｍｇ／ｋｇ，ｉｇ，均有不同程度地增加小鼠心肌营养性血流量作用，其中８０ｍｇ／ｋｇ，ｉｐ与双嘧达莫１００ｍｇ／ｋｇ，ｉｐ能显著增加小鼠心肌营养性血流量，其作用强度相似，与生理盐水组比较Ｐ＜０．０１。但地奥心血康２００ｍｇ／ｋｇ１次ｉｇ，反而减少心肌?     

MCI-154对大鼠皂苷蜕膜心肌收缩系统Ca~(2 )敏感性和肌浆网Ca~(2 )释放的作用(英文)

目的:探讨MCI-154的正变力机制.方法:用皂苷500或50 nag·L~(-1)破坏或保留肌浆网(SR)的蜕膜心肌标本.皂苷500 mg·L~(-1)蜕膜标本的张力-pCa关系曲线描述了心肌收缩蛋白Ca~(2 )敏感性,pCa_(50)是Ca~(2 )敏感性的指标;皂苷50 mg·L~(-1)蜕膜标本的咖啡因挛缩幅值是SR Ca~(2 )释放的指标.结果:1)在相同Ca~(2 )浓度下,MCI-154(0.1mmol·L~(-1))增强心肌Ca~(2 )激活张力,对收缩蛋白的Ca~(2 )敏感性具有明显的增敏效应,pCa_(50)由对照的5.54(5.30-5.79)升为5.84(5.54-6.14) (P<0.01,n=8);Hill系数n降低了0.29(P<0.01,n=8);2)在保留了SR的标本上,MCI-154不能引起SR内Ca~(2 )释放,并对咖啡因引起的挛缩幅值无显著影响(P>0.05).结论:MCI-154直接增强心肌收缩蛋白的Ca~(2 )敏感性,但对SR的Ca~(2 )释放无明显作用.     

Multiple effects of ryanodine on intracellular free Ca2+ in smooth muscle cells from bovine and porcine coronary artery: modulation of sarcoplasmic reticulum function.

1. The effects of ryanodine and caffeine on intracellular free Ca2+ concentration ([Ca2+]i) were studied by use of fura-2 microfluorometry in single smooth muscle cells freshly dispersed from bovine and porcine coronary artery. 2. Bovine and porcine cells demonstrated similar sensitivities to 10 min of exposure to ryanodine in physiological salt solution (PSS), as determined by comparable dose-dependent decreases in the subsequent [Ca2+]i transient induced by 5 mM caffeine. 3. Ryanodine (10 microM) caused a significant increase in [Ca2+]i to a plateau level 27 +/- 3% and 38 +/- 4% above baseline [Ca2+]i (baseline [Ca2+]i = [Ca2+]i at 0 min) in porcine and bovine cells, respectively, when bathed in PSS. In bovine cells the time required to reach 1/2 the plateau level was only 3 min versus 6 min for porcine cells. 4. The ryanodine-induced plateau increase in [Ca2+]i was 35 +/- 5% above baseline for bovine cells bathed in 0 Ca PSS (PSS including 10 microM EGTA with no added Ca2+), but only 7 +/- 3% above baseline in porcine cells during 10 min exposure to 10 microM ryanodine. In bovine cells [Ca2+]i showed proportional increases when extracellular Ca2+ was increased from the normal 2 mM Ca2+ PSS to 5 and 10 mM. 5. Cells pretreated with caffeine in 0 Ca PSS, which depleted the caffeine-sensitive sarcoplasmic reticulum Ca2+ store, showed no increase in [Ca2+]i when challenged with 10 microM ryanodine. The ryanodine-associated increase in [Ca2+]i, which was sustained in 0 Ca PSS during the 10 min ryanodine exposure in cells not pretreated with caffeine, suggests that ryanodine releases Ca2+ from the sarcoplasmic reticulum, but also inhibits Ca2+ efflux.(ABSTRACT TRUNCATED AT 250 WORDS)     

C—硝基吡唑类和C—硝基吡咯类对局部缺血损伤后眼血流量和视网膜功能恢复的作用

AIM: Effects of C-nitropyrazoles and C-nitroazoles on ocular blood flow and retinal .function recovery after ischemia have been studied. METHODS: The compounds were tested on ocular blood flow of ocular hyperten-sive (40 mmHg) rabbit eyes with colored microsphere technique. They were also tested on the retinal function recovery after ischemia of rat eyes with electroretinography. RESULTS: All compounds (DC-1 through DC-17) showed significant increase in retinal function recovery after ischemia in the range of 26 % to 120 % (P<0.05). Among five compounds (DC-1 through DC-5) studied, four compounds (DC-2 through DC-5) in-creased the blood flow in choroid, iris, and ciliary body, but not in retina. DC-1 did not show significant increase of blood flow in any of these ocular tissues. CONCLUSION: C-Nitropyrazoles can facilitate significant retinal function recovery after ischemic insult through the increase of ocular blood flow. Since rabbit's retina is scarce in vasculature, it did not show significant chang     

Effect of bromocriptine on cardiac function and coronary blood flow

The present study was designed to investigate the effects of bromocriptine, a dopamine receptor agonist, on systemic and coronary hemodynamics and to determine the mechanisms involved in the action of this compound. Intravenous infusion of bromocriptine (1 microgram/kg/min for 20 min) to pentobarbital-anesthetized dogs produced significant decreases in blood pressure, heart rate, total peripheral resistance, peak dP/dt, left ventricular pressure, and coronary blood flow. There were significant increases in stroke volume and coronary vascular resistance, whereas the index of contractility was unaffected. Cardiac output was decreased 30 min after the termination of bromocriptine infusion. The cardiovascular actions of bromocriptine were significantly antagonized by the dopamine receptor antagonist, sulpiride. Bromocriptine also failed to exert these effects when administered to animals that were treated with ganglionic blocking agents. These results suggest that the hypotensive action of bromocriptine is mainly due to a decrease in total peripheral resistance. In addition, the actions of bromocriptine on cardiac function are the result of activation of presynaptic dopamine receptors and the drug does not have any direct action on the myocardium.     

Effects of propranolol on regional myocardial blood flow and function during severe coronary stenosis in dogs

The effects of propranolol alone or associated with atrial pacing were studied on regional myocardial blood flows (RMBF) and regional contractility (sonocardiometry) in non-ischemic, moderately and severely ischemic areas of the canine myocardium. In non-ischemic areas, propranolol reduced both epicardial and endocardial flows, increased the endo/epi ratio and decreased regional contractility. The reductions in subendocardial flow and function were correlated. In moderately and severely ischemic areas, propranolol increased subendocardial flow, reduced subepicardial flow, increased the endo/epi ratio and preserved or even slightly improved regional contractility. There was a good correlation between the propranolol-induced protective effects on regional contractility and the drug-induced increase in subendocardial flow since under atrial pacing subendocardial flow no longer increased and regional function dropped dramatically.     

Effects of MCI-154 on calcium sensitivity of contractile system and calcium release from sarcoplasmic reticulum in saponin-skinned rat myocardium.

AIM: To explore the possible mechanisms underlying the positive inotropic effect of MCI-154. METHODS: Skinned fibers with disrupted or preserved sarcoplasmic reticulum (SR) were prepared by saponin 500 or 50 mg.L-1. The tension-pCa relationship and pCa50 of saponin (500 mg.L-1)-skinned fibers were taken as the indices of Ca2+ sensitivity of contractile proteins. The amplitude of caffeine-induced contracture was an index of Ca2+ release from SR in saponin (50 mg.L-1)-skinned fibers. RESULTS: 1) MCI-154 (0.1 mmol.L-1) showed a Ca2+ sensitizing effect on contractile proteins. The pCa50 was increased to 5.84 (5.54-6.14) compared with control value 5.54 (5.30-5.79) (P < 0.01, n = 8). Hill coefficient n was decreased by 0.29 (P < 0.01, n = 8); 2) No contracture was produced by MCI-154 in preparations with preserved SR. Caffeine-induced contracture before and after MCI-154 treatment were not changed (P > 0.05, n = 4). CONCLUSION: MCI-154 directly enhances the Ca2+ sensitivity of contractile protein but has little effect on Ca2+ release from SR in rat skinned cardiac fibers.     

Comparison of the organization of t-tubules, sarcoplasmic reticulum and ryanodine receptors in rat and human ventricular myocardium

1. It is apparent from the literature that there are significant differences in excitation–contraction coupling between species, particularly in the density of calcium transporting proteins in the t‐system and sarcoplasmic reticulum (SR) Ca²⁺ release channels. Unfortunately, there is a lack of information as to how the principal structures that link electrical excitation to the activation of calcium‐induced calcium release (CICR) are different between human and animal models (particularly rat). 2. Comparison of wheat germ agglutinin and caveolin‐3 labelling revealed a non‐uniform distribution of surface membrane glycosylation in the rat, rabbit and human, and that the rat t‐system appeared more complex in geometry than the latter species. Analysis of the t‐system skeleton showed that the t‐system was highly branched in the rat compared with that of the human (0.8 ± 0.08 and 0.2 ± 0.07 branch points per μm², respectively; P < 0.001). 3. We also compared the distribution of contractile machinery, sodium–calcium exchange, SR and ryanodine receptors (RyR) in rat and human. F‐Actin and RyR labelling was used to estimate the area of contractile apparatus supplied by each RyR cluster. In the rat, each RyR cluster supplied an average cross‐sectional area of contractile machinery of 0.36 ± 0.03μm² compared with 0.49 ± 0.04 μm² in human (P = 0.048). Sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a) labelling showed that the SR formed a tight network of loops surrounding contractile fibrils that were denser than the t‐tubule network, but otherwise appeared similar in both species. 4. In general, the results show a higher density in structures involved in CICR in the rat compared with human.     

Acute effects of ketanserin on left ventricular function, metabolism and coronary blood flow

An acute intravenous bolus of 10 mg ketanserin (a specific 5-HT antagonist) caused an abrupt fall in left ventricular systolic pressure of 17 +/- 9.2 mm Hg (P less than 0.025) in ten patients undergoing cardiac catheterisation for chest pains. A fall in pulmonary artery diastolic pressure of 2.1 +/- 0.74 mm Hg (P less than 0.02) was also observed. No changes in resting heart rate occurred and the response to pacing was largely unmodified by ketanserin, except for a reduction in pulmonary vascular resistance (3.70 +/- 1.27 units to 2.97 +/- 1.44 units, P less than 0.05), at the fastest rate (136 +/- 3 beats/min). At the highest pacing rate coronary sinus blood flow fell (83 +/- 12 ml 100 g-1 min-1 to 68 +/- 8 ml 100 g-1 min-1, P less than 0.05), as did myocardial oxygen consumption (18 +/- 2 ml-1 min to 14 +/- 1 ml min-1, P less than 0.05) after the drug. No changes in the parameters of left ventricular contractile function could be attributed to ketanserin, save for a modest increase in the ejection fraction (48 +/- 6% to 57 +/- 6%, P less than 0.05) in seven patients. There were no alterations in myocardial metabolism of lactate, pyruvate, hydroxybutyrate, glycerol nor free fatty acids after ketanserin. The findings are consistent with a peripheral site of action of this drug and its blood pressure lowering effect in the subjects suggest a non-specific hypotensive action rather than an anti-hypertensive effect.     

进食燕麦对控制糖尿病患者血生化数值的影响

目的 探讨进食燕麦控制对2型糖尿患者血糖、血脂等生化数值的影响,确定其饮食治疗的作用.方法 选择来保定市第一中心医院门诊就诊的糖尿病患者98例,按随机数字表法分为两组,燕麦组(49例)采取进食燕麦基础治疗方式,即每天早上食用燕麦50 ～ 100 g;对照组(49例)采取普通饮食控制方式.两组患者在无明显并发症发生的情况下,活动量不变.检测两组患者治疗前、治疗后第8周的空腹血糖(FBG)、餐后2h血糖(PBG),第8周时检测空腹胰岛素(F-INS)、餐后2h胰岛素(P-INS)、三酰甘油(TG)、血清总胆固醇(TC)等指标.结果 经进食燕麦和饮食控制后,两组较治疗前的FBG和PBG都有所下降,差异有统计学意义(P＜0.05).但是组间比较结果显示,进食燕麦第8周的FBG和PBG显著低于对照组,差异有统计学意义(P＜0.001).进食燕麦组8周后,血清胰岛素水平和血脂较治疗前都有所降低,P-INS和TC和治疗前相比,有显著下降,差异有统计意义(P＜0.05).对照组治疗8周后,血清胰岛素和血脂较治疗前相比,差异无统计学意义(P＞0.05).进食燕麦组8周后组间比较结果显示,P-INS和TC显著低于对照组,差异有统计意义(P＜0.05).结论 进食燕麦可明显降低2型糖尿病患者的FBG、P-INS和高胆固醇患者的血脂水平,燕麦可作为糖尿病患者的首选食物.     

Inhibitory effects of nisoldipine on serotonin and potassium induced contractions of porcine coronary and femoral arteries

The inhibitory effect of nisoldipine (Baymycard, Syscor; CAS 63675-72-9) and nifedipine on the serotonin and potassium induced contractions of porcine coronary and femoral arteries in vitro has been investigated. Both nisoldipine and nifedipine inhibited preferentially the serotonin induced contraction in the coronary artery being less effective in the inhibition of the femoral artery. The coronary selectivity of nisoldipine is at least 10 times more pronounced than that of nifedipine. The serotonin antagonist ketanserin inhibited contractions on both vessels with the same potency. The potassium induced contraction was inhibited by the dihydropyridines in both coronary and femoral artery. Nisoldipine again, was more potent than nifedipine in the inhibition of coronary artery spasm but not in the contraction of femoral artery. Ketanserin did not inhibit contractions of any vessels.     

The effect of nisoldipine on apparent liver blood flow and effective renal plasma flow.

The effects of the acute and continued administration of the calcium antagonist nisoldipine on hepatic and renal blood flow and on renal function were studied in nine normotensive volunteers. There were no significant changes in supine blood pressure or heart rate but acute administration significantly increased both apparent liver blood flow and effective renal plasma flow. With continued administration these increases were attenuated and were not significantly different from placebo after 4 days treatment. Acute nisoldipine administration was also associated with significant increases in glomerular filtration rate and urinary sodium excretion.     

Effects of nisoldipine on coronary collateral perfusion and hemodynamics in chronically instrumented dogs

The effect of a new dihydropyridine slow-channel calcium blocking agent, nisoldipine, on hemodynamics and myocardial blood flow in normal and collateral-dependent areas distal to a chronic coronary artery occlusion were studied in chronically instrumented, conscious dogs. Nisoldipine produced significant and dose-related decreases in arterial blood pressure, an elevation of heart rate and large increases in coronary blood flow velocity. In dogs with an Ameroid constrictor previously implanted to enhance coronary collateral development, this agent produced large increases in perfusion distal to a chronic coronary artery occlusion. In addition, despite a reduction in arterial pressure, nisoldipine preserved renal cortical, intestinal and skeletal muscle blood flow while increasing tissue flow within liver and cerebral cortex. Thus, nisoldipine increases oxygen supply to collateral-dependent myocardium in the presence of reduced driving pressure for collateral perfusion.     

Effects of dihydroergotamine on psychomotor function, neuroendocrine parameters and blood pressure, in healthy volunteers

Following the infusion of 15 micrograms/kg of dihydroergotamine (DHE) a 50-fold rise in growth hormone plasma levels was observed in 9 healthy volunteers. Prolactin (PRL) secretion was depressed 240 minutes post infusion. For 170 min, diastolic blood pressure was increased reaching a peak of +19 mmHg at the end of the infusion. Mild sedation and nausea were induced by the treatment for a total duration of 60 min.     

血液细胞成分与男性冠状动脉慢血流的关系

目的：探讨血液细胞成分与男性冠状动脉慢血流（ SCF）的关系。方法2011年8月至2012年8月经造影证实冠状动脉狭窄＜40％的男性患者199例,根据校正的TIMI血流计帧法分为SCF组151例,正常对照组48例,比较2组临床变量。结果2组高血压病、2型糖尿病、吸烟史和冠脉轻度狭窄比例差异无统计学意义（P ＞0？．05）。 SCF组年龄较低,而高脂血症比例高于正常对照组（ P ＜0．05）。血液细胞成分比较发现SCF组白细胞计数[6．70（5．62,7．94）,6．12（5．38,6．65）]、血红蛋白[150（142,157）,145（137,151）]和红细胞压积[43．2（40．74,5．0）,42．2（40．4,44．2）]高于正常对照组（ P ＜0．05）,多因素分析提示高脂血症（ P ＝0．014,OR 2．385,95％CI 1．197～4．753）和血红蛋白（ P ＝0．030,OR 1．034,95％CI 1．003～1．066）是SCF的独立影响因素。结论高脂血症和血红蛋白是男性冠状动脉SCF的临床影响因素。     

Effects of tetrandrine on calcium transport, protein fluorescences and membrane fluidity of sarcoplasmic reticulum

To understand whether the molecular mechanism of Tetrandrine (Tet)'s pharmacological effects is concerned with sarcoplasmic reticulum calcium transport so as to be involved in myocardial contractility, we observed the effects of Tet on calcium transport and membrane structure of rabbit skeletal muscle sarcoplasmic reticulum vesicles (SR) and rat cardiac sarcoplasmic reticulum vesicles (CSR). Calcium uptake was monitored with a dual-wavelength spectrophotometer. Protein conformation and fluorescence polarization were measured by fluospectrophotometric method and membrane lipids labelled with fluorescence probes for SR, respectively. 128 micromol l(-1) Tet reduced the initial rate of calcium uptake to 59% of control 6 min after reaction. Tet un-competitively inhibited SR Ca(2+), Mg(2+)-ATPase activity, causing the stoichiometric ratio of SR Ca(2+)/ATP to decrease to 1.43 from 2.0 of control. Inhibitory rates on SR Ca(2+),Mg(2+)-ATPase by Tet were reduced from 60% in the absence of phosphate to 50% in the presence of phosphate and reduced from 92% in 1 mmol l(-1) ATP to 60% in 5 mmol l(-1) ATP. Tet markedly reduced SR intrinsic protein fluorescence, while it slightly decreased the thiol(SH)-modified protein fluorescence of SR labelled with N-(3-pyrene)-maleimide. Tet slightly increased fluorescence polarization in the middle and deep layers of SR membrane lipids labelled with 7- or 12-(9-anthroyloxy) stearic acid (AS) probes, whereas it did not change that of SR labelled with 1, 6-diphenyl-1,3,5-hexatrine (DPH). These results revealed that prevention of SR calcium uptake by Tet was due to inhibition of the SR calcium pump Ca(2+),Mg(2+)-ATPase, changes in spatial conformation of the pumps protein molecules and a decrease in the extent of motion of membrane lipid molecules, thus altering the regulation of [Ca(2+)](i) and myocardial contractility.     

Effect of dopamine and blockade of dopaminergic and adrenergic receptors on coronary blood flow in ischemic rabbit myocardium

The effect of a broad dose range of dopamine on coronary blood flow was studied in rabbits with coronary artery occlusion. Dopaminergic and adrenergic receptor blockade was established to distinguish the mechanism of the dopamine-induced increase in coronary blood flow. Dopamine, 10, 100, or 1,000 micrograms/kg/min, was infused in the presence of dopaminergic, beta-, or alpha-adrenergic receptor blockade. Coronary blood flow, as measured by radiolabeled microspheres, and hemodynamic parameters were monitored in 60 anesthetized open-chest rabbits. Dopamine, 1,000 micrograms/kg/min, significantly increased coronary blood flow 157% in normal and 118% in occluded rabbit myocardium. Propranolol (2 mg/kg) prevented the dopamine-induced increases in coronary blood flow within occluded and nonoccluded myocardium. Practolol (2 mg/kg) blunted the coronary blood flow increases within occluded myocardium, but flow within normal myocardium remained significantly elevated. In animals given phenoxybenzamine (2 mg/kg), dopamine infusion produced significant blood pressure reductions along with no change in either occluded or nonoccluded coronary blood flow. Bulbocapnine (8 mg/kg), a dopamine receptor antagonist, did not block blood flow increases in normal myocardium, but prevented significant increases in blood flow within occluded myocardium. It can be concluded that direct or indirect vasodilator receptors (dopaminergic, beta 1-, and beta 2-adrenoceptors) must be stimulated and perfusion pressure must not fall in order for dopamine to produce increases of coronary blood flow within occluded myocardium.