[Effect and mechanism of Huangqi Shengmai Decoction in treatment of joint rat model of fatigue and myocardial injury].

This study aims to investigate the effects and the underlying mechanism of Huangqi Shengmai Decoction(HQSMD) in the treatment of fatigue and myocardial injury in a joint rat model. Wistar rats were assigned into 4 groups: sham, model, diltiazem hydrochloride(positive control), and HQSMD. The joint model of fatigue and myocardial injury was established by 14-day exhausted swimming followed by high ligation of the left anterior descending coronary artery. The rats in the sham group underwent a sham operation without coronary artery ligation or swimming. Since the fourth day after the ligation, swimming was continued in the model group and the drug-treated groups for the following 4 weeks. Meanwhile, the rats in the positive control group and the HQSMD group were respectively administrated intragastrically with diltiazem hydrochloride(20 mg·kg~(-1)·d~(-1)) and HQSMD(0.95 g·kg~(-1)·d~(-1)) for 4 weeks, while the shams and the models were given the same volume of normal saline. The left ventricular ejection fraction(LVEF), left ventricular fractional shortening(LVFS), grip strength, and myocardial pathophysiological changes were measured to evaluate the anti-fatigue and cardioprotective effects of HQSMD. The protein levels of PTEN-induced putative kinase 1(PINK1) and parkin in the myocardium were measured by Western blot to preliminarily elucidate the mechanism of HQSMD in ameliorating myocardial injury by suppressing mitochondrial autophagy. Compared with the shams, the models showed weakened heart function(LVEF and LVFS, P<0.01), decreased grasping ability(P<0.05), elevated blood urea nitrogen(BUN) and aldosterone(ALD) levels(P<0.01), aggravated myocardial fibrosis and connective tissue hyperplasia(P<0.01), and up-regulated protein levels of PINK1(P<0.01) and parkin(P<0.05). Four-week treatment with HQSMD increased the LVEF and LVFS levels(P<0.01), enhanced the grip strength(P<0.01), reduced the serum levels of BUN(P<0.01) and ALD(P<0.05), alleviated the pathological injury and fibrosis in the myocardium(P<0.01), and down-regulated the protein levels of PINK1(P<0.01) and parkin(P<0.05) in heart tissue. The results demonstrate that HQSMD may alleviate myocardial fibrosis and protect myocardium by suppressing the excessive mitochondrial auto-phagic activity and reducing the excessively elevated ALD level, thereby ameliorating fatigue and myocardial injury.

Effect of pectin and attapulgite filler on swelling, network parameters and controlled release of diltiazem hydrochloride from polyacrylic copolymer gel.

Pectin grafted polyacrylic copolymer hydrogels were made by free radical crosslink copolymerization of acrylic acid (AA) and acrylamide (AM) in an aqueous solution of pectin. N'N-methylene bis acrylamide (MBA) was used as a crosslinker. During the polymerization reaction the attapulgite (APG) filler was also incorporated in situ into the network of the copolymer gel. Several filled hydrogels were prepared by varying the amount of pectin and APG filler. These hydrogels were characterized by FTIR, 13C NMR, XRD, TGA, SEM, mechanical properties, DMA, swelling, diffusion characteristics and network parameters. The release kinetics of a model drug diltiazem hydrochloride (DT) was studied with these hydrogels. The wt% of pectin, APG and MBA was optimized with a central composite design (CCD) model of response surface methodology (RSM) with equilibrium swelling ratio (ESR), drug adsorption (mg/100 mg gel) and drug release% in 16 h as response. Accordingly, the hydrogel prepared with 5:1 AA:AM molar ratio, 25 wt% monomer concentration, 1% each of initiator and MBA concentration, 18 wt% pectin and 2 wt% APG showed an optimized ESR of 17.75, drug loading of 27.58 and a drug release % of 92.5 in 16 h at a solution pH of 7.4.

Diltiazem Inhibits Coronary Spasm via Inhibition of Cav1.2Phosphorylation and Protein Kinase C Activation in a Mouse Model of Coronary Spastic Angina.

Calcium antagonists are used for coronary spastic angina (CSA) treatment. We previously identified a phospholipase C (PLC) -δ1 gene variant that results in enhanced PLC activity in patients with CSA and developed a CSA animal model by generating vascular smooth muscle cell-specific human variant PLC-δ1 overexpression (PLC-TG) mice. In this study, we investigated the molecular mechanism of CSA using the PLC-TG mice and the inhibitory effect of a calcium antagonist, diltiazem hydrochloride (DL).We treated the PLC-TG and wild-type (WT) mice with oral DL or trichlormethiazide (TM) (control) for 2 weeks. Ergometrine injection-induced coronary spasm was observed on the electrocardiogram in all 5 PLC-TG mice treated with TM, but only in 1 of 5 PLC-TG mice treated with DL. Voltage-dependent calcium channel (Cav1.2) phosphorylation and protein kinase C (PKC) activity were enhanced in the aortas of PLC-TG mice treated with TM. DL treatment significantly inhibited Cav1.2 phosphorylation and PKC activity. Although total Cav1.2 expression was similar between WT and PLC-TG mice treated with TM, DL treatment significantly increased its expression in PLC-TG mice. Furthermore, its expression remained high after DL discontinuation. DL and PKC inhibitor suppressed intracellular calcium response to acetylcholine in cultured rat aortic smooth muscle cells transfected with variant PLC-δ1.These results indicate that enhanced PLC activity causes coronary spasm, presumably via enhanced Cav1.2 phosphorylation and PKC activity, both of which were inhibited by DL. Enhanced total Cav1.2 expression after DL discontinuation and high PKC activity may be an important mechanism underlying the calcium antagonist withdrawal syndrome.

Clinical Safety Outcomes in Patients With Nonvalvular Atrial Fibrillation on Rivaroxaban and Diltiazem.

BACKGROUND: It is unknown whether diltiazem, a moderate cytochrome P450 enzyme (CYP3A4) and P-glycoprotein (P-gp) inhibitor, increases the incidence of bleeding events in combination with rivaroxaban, a CYP3A4 and P-gp substrate. OBJECTIVE: To assess major and clinically relevant nonmajor (CRNM) bleeding outcomes in patients with nonvalvular atrial fibrillation (NVAF) on rivaroxaban with concomitant diltiazem in a real-world setting. METHODS: This retrospective case-cohort study included adult patients with NVAF prescribed both rivaroxaban and diltiazem for at least 30 days. Patients were matched 1:1 by age and baseline creatinine clearance (CrCl) to control patients taking rivaroxaban alone. The primary outcome was the composite of major and CRNM bleeding. Additional outcomes included bleeding events resulting in discontinuation of rivaroxaban, time to first bleeding event, and type of first bleed. RESULTS: A total of 143 cases and 143 controls were included. The mean age was 69 years and median baseline CrCl was 87 mL/min. Median follow-up time was 12.4 months for cases and 16.5 months for controls. There was no significant difference in proportion of patients experiencing a major and/or CRNM bleeding event between cases and controls: 23.1% versus 28.0%, respectively; 9 cases and 8 controls permanently discontinued rivaroxaban because of bleeding. Gastrointestinal/rectal bleeding and hematuria were the most frequently reported bleeding events in both groups. Conclusion and Relevance: This is the first study to assess major and CRNM bleeding outcomes in patients with NVAF on rivaroxaban and diltiazem. Diltiazem use was not associated with an increased rate of bleeding events.

Cardioprotective Effects of Combined Therapy with Hyperbaric Oxygen and Diltiazem Pretreatment on Myocardial Ischemia-Reperfusion Injury in Rats.

BACKGROUND/AIMS: In this study, we examined whether the combination of hyperbaric oxygen (HBO) and diltiazem therapy provided a cardioprotective effect on myocardial ischemia-reperfusion injury (MIRI) rat model. METHODS: Sixty healthy Sprague-Dawley rats were randomly divided into sham, IR, diltiazem (5 mg/kg), HBO (0.25 MPa, 60 min) and combination therapy (HBO plus diltiazem) groups. MIRI model was established by ligating the left anterior descending for 30 min, followed by 60 min of reperfusion. RESULTS: The results show that HBO and diltiazem preconditioning significantly improves cardiac function and myocardial infarction area, increases nitric oxide, endothelial nitric oxide synthase and ATPase (Na+-K+-ATPase and Ca2+-Mg2+-ATPase) activity and decreases levels of oxygen stress, myocardial enzymes and endothelin-1. Notably, HBO and diltiazem preconditioning significantly increased Bcl-2 protein expression and decreased Bax protein and caspase-3 mRNA expression. CONCLUSIONS: These data indicate that combination therapy protected against heart MIRI by reducing oxygen stress damage, correcting energy metabolism, improving endothelial function and inhibiting cell apoptosis.

Modulation of oxidative stress, apoptosis, and calcium entry in leukocytes of patients with multiple sclerosis by Hypericum perforatum.

OBJECTIVES: Hypericum perfortarum (HP, St John's wort) is a modulator of Ca(2+) entry in neutrophils and it may modulate intracellular free Ca(2+) ([Ca(2+)]i) entry in leukocytes of patients with multiple sclerosis (MS). We investigated effects of HP on oxidative stress, apoptosis, and [Ca(2+)]i concentrations in serum and leukocytes of patients with MS. METHODS: Neutrophils of nine newly diagnosed MS patients and nine healthy subjects within four subgroups were used in the study. The first group was a control; the second group was patients with MS. The neutrophils from patient group were incubated non-specific TRPM2 channel blocker (2-APB), voltage-gated calcium channel blockers, verapamil and diltiazem (V + D) with HP before N-formyl-L-methionyl-L-leucyl-L-phenylalanine stimulation, respectively. RESULTS: Neutrophil and serum lipid peroxidation, neutrophil apoptosis and [Ca(2+)]i levels in patients with MS were higher than in control although their levels were decreased by HP, 2-APB, and V + D incubations. The modulator role of V + D in MS and MS + HP groups was higher than in the 2-APB group. Neutrophilic glutathione peroxidase (GSH-Px) and serum vitamin A and E concentrations were lower in the MS group than in control. However, the neutrophil GSH-Px activity was increased by HP incubation. The neutrophil reduced glutathione, serum vitamin C and ß-carotene concentrations did not change in control and patients. DISCUSSION: We observed that HP-induced protective effects on oxidative stress and [Ca(2+)]i concentrations by modulating transient receptor potential and voltage gated calcium channel in the patients with MS. Thus, it may provide useful treatment of neutrophil activity in the patients.

Cardiotonic activity of methanolic extract of Saussurea lappa Linn roots.

The cardiac activity of Saussurea lappa roots was evaluated in isolated perfused rabbit heart by the Langendorff's technique. Heart rate, contractility and coronary flow were determined in the presence of different concentrations of methanolic extract of Saussurea lappa, digoxin and diltiazem. The extract exhibited significant (p<0.01) positive inotropic effect at the first three doses (0.5/µg, 2.5/µg and 5.0/µg) while a significant negative chronotropic effect and coronary flow rates were observed at all the doses tested. These effects were comparable to the effects of digoxin and diltiazem. The increase in force of contraction with decrease in heart rate and coronary flow rates were also observed to be dose dependent as increase in the dose of test extract further enhanced the effects except contractility that started decreasing at higher doses. It is conceivable therefore, that Saussurea lappa roots contain certain pharmacologically active compounds that could be involved in the cardiotonic activity of the extract.

Ferutinin induces in vitro eryptosis/erythroptosis in human erythrocytes through membrane permeabilization and calcium influx.

Ferutinin, isolated from the root of Ferula hermonis and proposed to be used as an antiosteoporosis phytoestrogen, has death promoting activities in a number of cancer cells. However, the effect of ferutinin on the induction of apoptosis in human red blood cells (RBCs), also known as eryptosis or erythroptosis, remains unclear. Given that ferutinin is a small molecule that can induce apoptosis in the cancer cells by opening the mitochondrial permeability transition pores, we therefore hypothesized that the effect of ferutinin to elicit apoptosis in human RBCs devoid of mitochondria would be minimal. This study tried to determine the in vitro effect of ferutinin on the induction of apoptosis in human RBCs. Eryptosis/erythroptosis after ferutinin treatment was examined for phosphatidylserine (PS) externalization, calcein leakage, and other apoptotic feature events by flow cytometry and confocal microscopy. Contrary to our prediction, ferutinin caused eryptosis/erythroptosis in human RBCs and simultaneously increased caspase-3 activity and the cytosolic free Ca(2+) ion level ([Ca(2+)]i). Yet, Ca(2+) seems not to be the sole mediator in ferutinin-mediated eryptosis/erythroptosis because depletion of the external Ca(2+) could not eliminate the apoptotic effect from ferutinin. Subsequent replenishment of the external Ca(2+) was able to promote PS externalization, caspase-3 activation, and rise of [Ca(2+)]i. Also, ferutinin at high dose (40 µM or above) was able to permeabilize the membrane of RBC ghosts in a way similar to that of digitonin. At low dose, ferutinin activated the P- and L-type Ca(2+) channels as the ferutinin-mediated [Ca(2+)]i rise was suppressed by the P-type (ω-agatoxin IVA) and L-type (verapamil and diltiazem) Ca(2+) channel blockers. Taken together, we report here for the first time that ferutinin induces in vitro apoptosis in human RBCs. Mechanistically, eryptosis/erythroptosis is mediated by membrane permeabilization and upregulation of [Ca(2+)]i with the activation of caspase-3.

Lipid peroxidation is another potential mechanism besides pore-formation underlying hemolysis of tentacle extract from the jellyfish Cyanea capillata.

This study was performed to explore other potential mechanisms underlying hemolysis in addition to pore-formation of tentacle extract (TE) from the jellyfish Cyanea capillata. A dose-dependent increase of hemolysis was observed in rat erythrocyte suspensions and the hemolytic activity of TE was enhanced in the presence of Ca2+, which was attenuated by Ca2+ channel blockers (Diltiazem, Verapamil and Nifedipine). Direct intracellular Ca2+ increase was observed after TE treatment by confocal laser scanning microscopy, and the Ca2+ increase could be depressed by Diltiazem. The osmotic protectant polyethylenglycol (PEG) significantly blocked hemolysis with a molecular mass exceeding 4000 Da. These results support a pore-forming mechanism of TE in the erythrocyte membrane, which is consistent with previous studies by us and other groups. The concentration of malondialdehyde (MDA), an important marker of lipid peroxidation, increased dose-dependently in rat erythrocytes after TE treatment, while in vitro hemolysis of TE was inhibited by the antioxidants ascorbic acid-Vitamin C (Vc)-and reduced glutathione (GSH). Furthermore, in vivo hemolysis and electrolyte change after TE administration could be partly recovered by Vc. These results indicate that lipid peroxidation is another potential mechanism besides pore-formation underlying the hemolysis of TE, and both Ca2+ channel blockers and antioxidants could be useful candidates against the hemolytic activity of jellyfish venoms.

Diltiazem potentiates pentobarbital-induced hypnosis via 5-HT1A and 5-HT2A/2C receptors: role for dorsal raphe nucleus.

It has been reported that the sedative component of pentobarbital is mediated by GABA receptors in an endogenous sleep pathway and the ventrolateral preoptic area (VLPO)-tuberomammillary nucleus (TMN) or VLPO-dorsal raphe nucleus (DRN) neural circuit is important in the sedative response to pentobarbital. Our previous findings indicated that the VLPO-TMN neuronal circuit may play crucial part in the augmentative effect of diltiazem on pentobarbital sleep and the serotonergic system may be involved. This study was designed to investigate the role of DRN and the serotonergic receptors 5-HT(1A) and 5-HT(2A/2C) in the augmentative effect of diltiazem on pentobarbital-induced hypnosis in rats. The results showed that diltiazem (5mg/kg, i.g.) significantly reversed pentobarbital-induced (35 mg/kg, i.p.) reduction of c-Fos expression in 5-HT neurons of DRNV (at -7.5mm Bregma), DRND, DRNVL and MRN (at -8.0mm Bregma). However it did not influence this reducing effect of pentobarbital on non-5-HT neurons either in DRN or in MRN. Moreover, the effect of diltiazem (1 or 2mg/kg, i.g.) on pentobarbital-induced (35 mg/kg, i.p.) hypnosis was significantly inhibited by 5-HT(1A) agonist 8-OH-DPAT (0.5mg/kg, i.p.) and 5-HT(2A/2C) agonist DOI (0.5mg/kg, i.p.), and potentiated by 5-HT(1A) antagonist p-MPPI (2mg/kg, i.p.) and 5-HT(2A/2C) antagonist ritanserin (2mg/kg, i.p.), respectively. From these results, it should be presumed that the augmentative effect of diltiazem on pentobarbital-induced sleep may be related to 5-HT(1A) and 5-HT(2A/2C) receptors, and DRN may be involved. In addition, it also suggested that the DRN may play a multi-modulating role in sleep-wake regulation rather than being recognized simply as arousal nuclei.

[Effects of methyl protodioscin on [Ca2+]i and ATPase activity in cardiomyocytes and analysis of mechanisms].

OBJECTIVE: To study the effects of methyl protodioscin on the [Ca2+]i and the ATPase activity in cardiomyocytes, as well as their mechanisms. METHOD: The cardiomyocytes were randomly divided into three groups, the control group treated with no serumal DMEM, the MPD group treated with MPD and the dilthiazem group treated with dilthiazem. Fluorospectrophotometer was used to determined the level of myocardial cell intracellular Ca2+ [Ca2+]i. In the experiment of ATPase activity on cellular membrane, the cardiomyocytes were randomly divided into two groups, the control group treated with no serumal DMEM, the MPD group treated with MPD. The activity of Na+-K+-ATPase,Ca2+-Mg2+-ATPase and Mg2+-ATP ATPase were determined. The quantitative analysis of SERCA2a mRNA expression was studied by RT-PCR that the groups and treatments in cardiomyocytes same as the experiment for ATPase activity assay. RESULT: Under the quiescent condition, compared to the control group, the level of [Ca2+]i in cardiomyocytes of the MPD group and dilthiazem group was no different. After treatment with 40 mmol x L(-1) KCl, [Ca2+] was significantly lower in the MPD group and the dilthiazem group, and the intensity of peak value in time course of 60 s, the dilthiazem group and the MPD group also were lower than the control group (P < 0.001). Ca2+-Mg2+-ATPase and Na+-K+-ATPase in cultured rat were increased after treated with MPD compared to treatment with no serumal DMEM (P < 0.05, P < 0.01), but Mg2+-ATPase in these groups had no different. The expression of SERCA2a mRNA between the MPD group and the control group was no different. MPD could not up-regulated or down-regulated SERCA2a in endocytoplasmic reticulum. CONCLUSION: Methyl protodioscin could block the volt dependent form calcium channel in cellular membrane, and up-regulate the function of sodium pump and calcium pump, so that it could remain low calcium in the internal environment in cardiomyocytes.

Aqueous extract of Zanthoxylum schinifolium elicits contractile and secretory responses via beta1-adrenoceptor activation in beating rabbit atria.

AIM OF STUDY: Although Zanthoxylum schinifolium has long been used in the traditional oriental medicine, cardiac effects have not well been documented. The aim of the present study was to investigate the effects of aqueous extract of leaves and stems from Zanthoxylum schinifolium (AZS) on inotropic effect and atrial natriuretic peptide (ANP) secretion. MATERIALS AND METHODS: The AZS-induced changes in atrial dynamics, cAMP efflux and atrial ANP secretion were determined in isolated perfused beating rabbit atria. RESULTS: AZS increased atrial pulse pressure, stroke volume, and cAMP efflux concomitantly with inhibition of ANP secretion in a concentration-dependent manner. The AZS-induced increases in atrial dynamics and cAMP efflux, and decrease in ANP secretion were attenuated by pretreatment with propranolol and CGP 20712 but not ICI 118,551. Also, the AZS-induced changes in atrial dynamics and ANP secretion were attenuated by diltiazem and KT 5720. Diltiazem and KT 5720 had not significant effect on the AZS-induced increase in cAMP efflux. CONCLUSION: These results suggest that AZS elicits a positive inotropic effect and decrease in ANP secretion via beta(1)-adrenoceptor-cAMP-Ca(2+) signaling in beating rabbit atria.

Potentiating effect of diltiazem on pentobarbital-induced hypnosis is augmented by serotonergic system: the TMN and VLPO as key elements in the pathway.

To investigate the mechanism by which L-type Ca+ channel blockers exerted potentiating effects on pentobarbital-induced hypnosis, the present study was undertaken to determine if the interaction of diltiazem and serotonergic system influences the architecture of pentobarbital sleep in rats and examined c-Fos expression in the ventrolateral preoptic nucleus (VLPO) and the tuberomammillary nucleus (TMN). The polysomnogram consisting of EEG and EMG was recorded for analyzing sleep architecture. The results showed that diltiazem (2.0 and 5.0 mg/kg, p.o.) increased both total pentobarbital sleep and slow wave sleep (SWS), but decreased rapid eye movement (REM) sleep. These effects were potentiated by 5-hydroxytryptophan (5-HTP), a precursor of serotonin, but abolished by p-chlorophenylalanine (PCPA), an inhibitor of tryptophan hydroxylase. Diltiazem (1 mg/kg, p.o.) or 5-HTP (2 mg/kg, i.p.) alone did not change the architecture of pentobarbital sleep and pentobarbital-induced c-Fos expression in the VLPO and the TMN, but co-administration of them significantly increased both total pentobarbital sleep and SWS, whereas decreased REM sleep, with increasing c-Fos expression in the VLPO and concomitantly decreasing c-Fos expression in the TMN. These findings indicate that the serotonergic system may be involved in the augmentative effect of diltiazem on pentobarbital sleep and the VLPO-TMN neuronal circuit may play a key role.

Mechanistic basis of differential conduction in skeletal muscle arteries.

The goal of this investigation was to probe intercellular conduction in skeletal muscle feed arteries and to address why smooth muscle-initiated responses fail to robustly spread like their endothelial counterpart. Using computational and experimental approaches, two interrelated rationales were developed to explain this apparent discrepancy in cell-to-cell communication. The first rationale stressed that smooth muscle electrical responses, if initiated, will be actively dissipated as they spread from cell-to-cell along the arterial wall. Charge dissipation is promoted within arteries by the structural and connectivity properties of vascular cells. The second rationale centred on the idea that when agents other than KCl stimulate a limited number of smooth muscle cells, they fail to generate the currents required to elicit a localized membrane potential (V(M)) response. This insufficiency results in part from charge loss, via gap junctions, to neighbouring unstimulated cells. Experiments confirmed the latter rationale by showing that focal phenylephrine application: (1) elicited a localized constriction insensitive to L-type Ca(2+) channel blockade; and (2) failed to substantially depolarize vascular smooth muscle cells. Further investigation revealed that while focal phenylephrine-induced constriction was V(M) independent, it was reliant on internal Ca(2+) mobilization and the activation of inositol 1,4,5-trisphosphate (IP(3)) receptors. The preceding findings illustrate that by using computational modelling and experimentation in a complementary manner, one can isolate key cellular properties and rationally examine their role in limiting the conduction of smooth muscle-initiated responses. Functionally, these observations enable investigators to assign the concept of 'local and global' blood flow control to the electrical and/or non-electrical behaviour of specific cell types.

[Protective effect of Tongxinluo Ultramicro-pulverization on experimental myocardial infarction of rats].

OBJECTIVE: To study the effects of Tongxinluo ultramicro-pulverization (TXLU) on experimental myocardial infarction and platelet aggregation of rats, investigate its mechanisms on ischemia heart disease and offer a reference to clinical usage. METHOD: Rats were separated randomly into 7 groups: sham, model, diltiazem (0.15 mg x kg(-1)), TXL(1.2 g x kg(-1)), TXLU (1.2, 0.6, 0.3 g x kg(-1)). The experimental myocardial infarction was induced with ligating the left anterior descending branch of the coronary of rats. The infarction size was determined after myocardium tissue was stained with 2,3,5-triphenyltetrazolium chloride (TTC). And the serum of rats was separated to analyze CK, LDH, SOD, MDA. Another 60 rats were separated randomly into 6 groups: control, aspirin (0.15 mg x kg(-1)), TXL (1.2 g x kg(-1)), TXLU (1.2 ,0.6,0.3 g x kg(-1)). The rat platelet aggregation was induced with adenosine diphosphate (ADP) and collagen to observe the inhibitory effects of TXLU. RESULT: TXLU could relieve the myocardial infarction size and weight stained with TTC significantly, the myocardial infarction size of the three groups of TXLU were (2.7 +/- 2.1)%, (3.4 +/- 1.2)%, (2.8 +/- 1.8)%, compared with model group (8.9 +/- 5.9)%, P < 0.05 or P < 0.01. The myocardial infarction weight of the three groups of TXLU were (8.4 +/- 3.5)%, (8.7 +/- 4.1)%, (9.7 +/- 4.1)%, compared with model group (l2.2 +/- 3.6)% P < 0.05 or P < 0. 01. And the content of MDA and the activities of CK and LDH in rats subjected with ligation of coronary artery were inhibited obviously too, compared with model group P < 0.05 or P < 0.01, then the activity of SOD increased. TXLU could inhibit the maximum percentage of rats platelet aggregation induced with ADP and collagen, the maximum percentage of platelet aggregation induced with ADP were (26.9 +/- 9.2)%, (24.4 +/- 13.4)%, (30.6 +/- 12.2)%, compared with control group (44.3 +/- 15. 7)% P < 0.05 or P < 0.01; The maximum percentage of platelet aggregation induced with collagen were (33.8 +/- 6.9)%, (32.1 +/- 8.3)%, (41.5 +/- 7.8)%, compared with control group (49.2 +/- 15.9)%, P < 0.05 or P < 0.01. CONCLUSION: The experiment results indicated that TXLU could protect myocardial tissue of rats from ischemic injury and the mechanism may be related with antioxidation and inhibiting platelet aggregation, and the results also suggested TXLU could lower clinical dosage.

Effect of aqueous-ethanol extract from Crocus sativus (saffron) on guinea-pig isolated heart.

In this study, the effects of an aqueous-ethanol extract from Crocus sativus on heart rate and contractility were examined. Isolated guinea-pig hearts were perfused through the aorta in a Langendorff mode. Heart rate and contractility were determined in the presence of four concentrations of the extract (0.1, 0.5, 1.0 and 5.0 mg%) and diltiazem (0.1, 1, 10 and 100 microm) in perfused heart with: (1) ordinary Krebs solution (group 1, n = 9), (2) calcium-free Krebs solution (group 2, n = 7). In group 1, three higher concentrations of diltiazem (1, 10 and 100 microm), but only the highest (5.0 mg%) and two higher concentrations (1.0 and 5.0 mg%) of the extract caused significant reduction in heart rate and contractility, respectively (p < 0.05 to p < 0.001). In group 2, the highest (100 microm) and two higher concentrations (10 and 100 microm) of diltiazem (p < 0.05 to p < 0.01), but only the highest concentration of the extract showed significant reductions in the heart rate and contractility (p < 0.05 to p < 0.01). There were significant negative correlations between concentrations of the extract and diltiazem and their effects in both groups (p < 0.01 to p < 0.001). These results suggested a potent inhibitory effect of aqueous-ethanol extract from C. sativus on the calcium channel of guinea-pig heart.

Effects of anethole and structural analogues on the contractility of rat isolated aorta: Involvement of voltage-dependent Ca2+-channels.

Anethole is a naturally occurring aromatic oxidant, present in a variety of medicinal plant extracts, which is commonly used by the food and beverage industry. Despite its widespread occurrence and commercial use, there is currently little information regarding effects of this compound on the vasculature. Therefore the actions of anethole on the contractility of rat isolated aorta were compared with those of eugenol, and their respective isomeric forms, estragole and isoeugenol. In aortic rings precontracted with phenylephrine (PE; 1 microM), anethole (10(-6) M-10(-4) M) induced contraction in preparations possessing an intact endothelium, but not in endothelium-denuded tissues. At higher concentrations (10(-3) M-10(-2) M), anethole-induced concentration-dependent and complete relaxation of all precontracted preparations, irrespective of whether the endothelium was intact or not, an action shared by eugenol, estragole and isoeugenol. The contractile and relaxant effects of anethole in PE-precontracted preparations were not altered by L-NAME (10 microM) or indomethacin (10 microM), indicating that neither nitric oxide nor prostaglandins were involved in these actions. The mixed profile of effects was not confined to PE-mediated contraction, since similar responses were obtained to anethole when tissues were precontracted with 25 mM KCl. Anethole and estragole (10(-6)-10(-4) M), but not eugenol or isoeugenol, increased the basal tonus of endothelium-denuded aortic rings, an action that was abolished by VDCC blockers nifedipine (1 microM) and diltiazem (1 microM), or by withdrawal of extracellular Ca(2+). Our data suggest complex effects of anethole on isolated blood vessels, inducing contraction at lower doses, mediated via opening of voltage-dependent Ca(2+)-channels, and relaxant effects at higher concentrations that are shared by structural analogues.

Comparative interaction of few antihypertensive drugs with cyclosporine-A in rats.

The maximal endothelial dependent relaxation of isolated aortic rings to cumulative doses of acetylcholine was significantly decreased in the Cyclosporine-A (CSA, 20 mg kg(-1) day(-1)) treated animals compared to olive oil (CSA vehicle) treated control. Administration of antihypertensive drugs like diltiazem, enalapril or propranolol to CSA treated animals augmented the endothelial damage induced by CSA. These drugs also increased the bioavailability of CSA. However, administration of losartan to CSA treated animals produced a significant increase in endothelial dependent relaxation as compared to CSA treated control but did not affect the bioavailability of CSA significantly. The results suggest that losartan is safer compared to other antihypertensives for the treatment of CSA induced hypertension.

La respuesta inicial al diltiazem tópico puede predecir la evolución de la fisura anal crónica / Initial response to topical diltiazem can predict outcome of chronic anal fissure

Introducción. Durante los últimos años, el tratamiento médico de la fisura anal crónica (esfinterotomía química) se ha ido implantando en la práctica como consecuencia de la morbilidad atribuida a la esfinterotomía quirúrgica. Sin embargo, el tratamiento médico presenta dos inconvenientes: la moderada eficacia, entre el 30 y el 80% y la necesidad de prolongarlo más de 8 semanas. Objetivo. Valorar la respuesta inicial a diltiazem al 2% tópico como factor de predicción de la curabilidad de la fisura anal crónica. Pacientes y método. Durante el período de febrero de 2004 a diciembre de 2005, todas las fisuras anales de más de 6 semanas de evolución fueron incluidas. Se excluyó a los pacientes con cirugía anal previa, embarazo, enfermedad inflamatoria intestinal, intolerancia al diltiazem y problemas de contacto para el seguimiento. Se empleó una fórmula magistral de gel de diltiazem al 2%, en 3 aplicaciones diarias durante 8 semanas. Se realizaron controles clínicos y medida del dolor mediante escala analógica visual (EAV) al final de la primera, la tercera, sexta y octava semanas. Se compararon los grupos con y sin respuesta al diltiazem mediante las pruebas de la χ2, exacta de Fisher y t de Student. Se realizó una curva ROC (Receiver Operating Characteristic) para valorar la eficacia diagnóstica de la respuesta inicial del dolor al diltiazem, así como la sensibilidad, la especificidad y los valores predictivos. Resultados. Se analizaron 100 pacientes (70 varones), con una media de edad de 43 (22-76) años. Localización posterior en el 87%, anterior en el 11% y lateral en el 2%. Todos tenían dolor; 65, sangrado y 13, prurito. Al final de las 8 semanas de tratamiento se curó el 62%, con una morbilidad del 5% (cefalea leve en el 2% y prurito en el 3%). No hubo diferencias significativas entre los grupos con y sin respuesta al diltiazem al 2% en relación con la edad, el sexo, la localización, el sangrado o el prurito. Hubo diferencias notables en la EAV del dolor al final de la primera, la tercera, la sexta y la octava semanas entre los grupos con y sin respuesta al tratamiento médico (p = 0,00). Con curvas ROC se estableció un punto de corte de 4 en la EAV al final de la primera semana, con un área bajo la curva de 0,925 (intervalo de confianza [IC] del 95%, 0,858-0,989). La capacidad predictora de curabilidad de la respuesta precoz al diltiazem mostró una sensibilidad del 85,5% (IC del 95%, 74,7-92,2%), una especificidad del 92,1% (IC del 95%, 79,2-97,3%), un valor predictivo positivo del 94,6% (IC del 95%, 85,4-98,2%) y un valor predictivo negativo del 79,5% (IC del 95%, 65,5-88,8%). Al final de la primera semana, tan sólo un 9% de los pacientes que no mejoraron con el diltiazem se curaron a las 8 semanas. Y por el contrario, de los que respondieron bien la primera semana, se curó el 94,6%. Conclusiones. La ausencia de respuesta al diltiazem al 2% tópico al final de la primera semana predice con buena fiabilidad el fracaso del tratamiento médico de la fisura anal crónica, y no es necesario prolongarlo hasta las 8 semanas (AU)

Introduction. In the last few years, the medical treatment of chronic anal fissure (chemical sphincterotomy) has been introduced as a consequence of the morbidity attributed to surgical sphincterotomy. However, medical treatment has two disadvantages: moderate effectiveness (between 30% and 80%) and the need for treatment to be prolonged for more than 8 weeks. Objective. To evaluate initial response to topical diltiazem 2% topical gel as a predictive factor in the curability of chronic anal fissure. Patients and method. From February 2004 to December 200, all patients with a history of anal fissure of more than 6 weeks were included in this study. Pregnant patients and those with prior anal surgery, inflammatory bowel disease, diltiazem intolerance and problems for maintaining contact during follow-up were excluded. A magistral formula of diltiazem 2% gel was used in three applications daily for 8 weeks. Patients were followed-up clinically and pain was measured through a visual analog scale (VAS) at the end of weeks 1, 3, 6, and 8. Groups with and without response to diliazem were compared through the χ2 test, Fisher's exact test and Student's t-test. A Receiver Operating Characteristic (ROC) curve was used to evaluate the diagnostic efficacy of initial pain response to diliazem, as well as sensitivity, specificity and predictive values. Results. One hundred patients (70 men), with a mean age of 43 years (22-76) were analyzed. Localization was posterior in 87%, anterior in 11% and lateral in 2%. All patients had pain, 65 had bleeding, and 13 had pruritus. At the end of the 8-week treatment, cure was achieved in 62%, with morbidity of 5% (mild headache in 2%, and pruritus in 3%). No significant differences were found between the groups with and without response to diltiazem 2% in terms of age, sex, localization, bleeding, or pruritus. Notable differences were found in the VAS for pain at the end of weeks 1, 3, 6, and 8 between the two groups (p = 0.00). ROC curves established a cut-off point of 4 in the VAS at the end of week 1, with an area below the curve of 0.925 (95% CI, 0.858-0.989). The capacity of early response to diliazem to predict curability showed a sensitivity of 85.5% (95% CI, 74.7%-92.2%), a specificity of 92.1% (95% CI, 79.2%-97.3%), a positive predictive value of 94.6% (95% CI, 85.4%-98.2%), and a negative predictive value of 79.5% (95% CI, 65.5%-88.8%). Among patients who showed no response to diltiazem by the end of week 1, cure was achieved in only 9% at 8 weeks. In contrast, among those with a favorable response in the first week, cure was achieved in 94.6%. Conclusions. Lack of response to topical diltiazem 2% gel at the end of the first week reliably predicts failure of medical treatment for chronic anal fissure, obviating the need to prolong treatment for 8 weeks (AU)

Atrial, SA nodal, and AV nodal electrophysiology in standing horses: normal findings and electrophysiologic effects of quinidine and diltiazem.

BACKGROUND: Although atrial arrhythmias are clinically important in horses, atrial electrophysiology has been incompletely studied. HYPOTHESES: Standard electrophysiologic methods can be used to study drug effects in horses. Specifically, the effects of diltiazem on atrioventricular (AV) nodal conduction are rate-dependent and allow control of ventricular response rate during rapid atrial pacing in horses undergoing quinidine treatment. ANIMALS: Fourteen healthy horses. METHODS: Arterial blood pressure, surface electrocardiogram, and right atrial electrogram were recorded during sinus rhythm and during programmed electrical stimulation at baseline, after administration of quinidine gluconate (10 mg/kg IV over 30 minutes, n = 7; and 12 mg/kg IV over 5 minutes followed by 5 mg/kg/h constant rate infusion for the remaining duration of the study, n = 7), and after coadministration of diltiazem (0.125 mg/kg IV over 2 minutes repeated every 12 minutes to effect). RESULTS: Quinidine significantly prolonged the atrial effective refractory period, shortened the functional refractory period (FRP) of the AV node, and increased the ventricular response rate during atrial pacing. Diltiazem increased the FRP, controlled ventricular rate in a rate-dependent manner, caused dose-dependent suppression of the sinoatrial node and produced a significant, but well tolerated decrease in blood pressure. Effective doses of diltiazem ranged from 0.125 to 1.125 mg/kg. CONCLUSIONS AND CLINICAL IMPORTANCE: Standard electrophysiologic techniques allow characterization of drug effects in standing horses. Diltiazem is effective for ventricular rate control in this pacing model of supraventricular tachycardia. The use of diltiazem for rate control in horses with atrial fibrillation merits further investigation.