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Background: Radiation-induced cataracts in interventionalists and lens doses approaching the limit of 150 mSv per year during angiographic procedures have been reported. this study sought to determine radiation exposure across the Large flat-panel detectors (FPD) are currently applied to X-ray

The multidrug resistance protein 4 (MRP4) is a member of the ABCC subfamily of the adenosine triphosphate-binding cassette transporters that remove cyclic nucleotides from platelets and uptake ADP into dense granule in platelets. However, whether MRP4 directly involves platelet activation remains unclear. Thus, the aim of our study was to determine the detailed mechanisms underlying the regulation of MRP4 in platelet activation. Our results revealed that the MRP4 inhibitor MK571 inhibited collagen-induced platelet aggregation which was partially reversed by the PKA inhibitor H89, but not by the adenylyl cyclase (AC) inhibitor SQ22536 and the guanylyl cyclase (GC) inhibitor ODQ, suggesting that MK571 can prevent collagen-induced aggregation via a route independent of cyclic nucleotide production. In the present study, we found that MK571 inhibited collagen-induced ATP release and calcium mobilization. The phosphorylation of protein kinase C, JNK, and Akt was also inhibited by MK571, and electron spin resonance experiment showed that MK571 significantly reduced hydroxyl radical formation. Moreover, MK571 delayed platelet plug formation in vitro by a PFA-100 device, and delayed thrombus formation in mesenteric venules of mice irradiated by fluorescein sodium. However, previous studies have reported that MK571 also blocks MRP1 and leukotriene D4 (LTD4) receptor. Therefore, whether MK571 inhibits platelet activation through MRP1 or LTD4 receptor needs to be considered and further defined. In conclusion, in addition to blocking the transport of cyclic nucleotides, MRP4 inhibition may prevent thrombus formation in vitro and in vivo. Our findings also support the idea that MRP4 may represent a potential target for the development of novel therapeutic interventions for the treatment of thromboembolic disorders.

BACKGROUND AND AIMS: Agents having a positive inotropic effect on the heart are widely used for the treatment of heart failure. However, these agents have the side effect of altering heart rate. It has been established that peroxisome proliferator-activated receptor δ (PPARδ) is mediated in cardiac contraction, however the effect on heart rate is unknown. Thus, we used an agonist of PPARδ, GW0742, to investigate this issue in the present study. METHODS AND RESULTS: We used isolated hearts in Langendorff apparatus and hemodynamic analysis in catheterized rats to measure the actions of GW0742 extra-vivo and in vivo. In diabetic rats with heart failure, GW0742 at a dose sufficient to activate PPARδ reversed cardiac contraction without changes in heart rate. In normal rats, PPARδ enhanced cardiac contractility and hemodynamic dP/dtmax significantly more than dobutamine. Both actions were diminished by GSK0660 at a dose enough to block PPARδ. However, GW0742 at the same dose failed to modify heart rate, although it did produce a mild increase in blood pressure. Detection of intracellular calcium level and Western blotting analysis showed that the intracellular calcium concentration and troponin I phosphorylation were both enhanced by GW0742. CONCLUSION: Activation of PPARδ by GW0742 increases cardiac contractility but not heart rate. Thus, PPARδ may be a suitable target for the development of inotropic agents to treat heart failure without changing heart rate.

Background An impairment of cardiovascular function in streptozotocin (STZ)-diabetic rats has been mentioned within 5 days-to-3 months of induction. ATP-sensitive potassium (KATP) channels are expressed on cardiac sarcolemmal membranes. It is highly responsive to metabolic fluctuations and can have effects on cardiac contractility. The present study attempted to clarify the changes of cardiac KATP channels in diabetic disorders. Methods Streptozotocin-induced diabetic rats and neonatal rat cardiomyocytes treated with a high concentration of glucose (a D-glucose concentration of 30 mM was used and cells were cultured for 24 hr) were used to examine the effect of hyperglycemia on cardiac function and the expression of KATP channels. KATP channels expression was found to be linked to cardiac tonic dysfunction, and we evaluated the expression levels of KATP channels by Western blot and Northern blot analysis. Results The result shows diazoxide produced a marked reduction of heart rate in control group. Furthermore, the methods of Northern blotting and Western blotting were employed to identify the gene expression of KATP channel. Two subunits of cardiac KATP channel (SUR2A and kir 6.2) were purchased as indicators and showed significantly decreased in both diabetic rats and high glucose treated rat cardiac myocytes. Correction of hyperglycemia by insulin or phlorizin restored the gene expression of cardiac KATP in these diabetic rats. Conclusions Both mRNA and protein expression of cardiac KATP channels are decreased in diabetic rats induced by STZ for 8 weeks. This phenomenon leads to result in desensitization of some KATP channel drugs.

Background: Percutaneous coronary intervention (PCI) for a left main coronary artery (LMCA) with its distal bifurcation lesions remains a challenge. Acute sidebranch occlusion after main branch stenting can potentially lead to catastrophic events. Here we describe a novel balloon-cushion stenting technique to be incorporated into the culotte stenting technique for true LMCA bifurcation lesions to prevent acute sidebranch occlusion. Methods and Results: 1) Predilatation with 2 balloons with kissing for better sidebranch preparation. 2) Balloonstent simultaneous kissing inflation, with a stent in the dominant artery and a 1.5/20 mm balloon from LMCA to the sidebranch. 3) After the stent deployment, a Crusade microcatheter was introduced via wire in the dominant vessel for wire re-crossing of the stent strut. The standard culotte technique and final kissing balloon inflation were then performed. Twelve patients were treated with this balloon-cushion stenting technique (Group A) and 18 patients with the conventional double-stent techniques (Group B). One case of acute sidebranch occlusion occurred in Group B. The amount of contrast medium and procedural time did not differ statistically between the 2 groups. Conclusions: The present study suggests that incorporation of the balloon-cushion stenting technique into the culotte stenting technique for LMCA bifurcation intervention is feasible and effective in avoiding acute sidebranch occlusion.

Background/Aims: The role of opioid receptors in the regulation of vascular function remains unclear. In the current study, we evaluated the ability of loperamide, a peripheral opioid receptor agonist, to regulate blood pressure in spontaneously hypertensive rats (SHRs) and examined the mechanism(s) by which loperamide exerts its effects. Methods: In male SHRs, mean arterial pressure (MAP) was measured and hemodynamic analysis was recorded. Additionally, the isometric tension of aortic rings isolated from SHRs was determined. Results: Loperamide dose-dependently decreased MAP in SHRs but not in the normal group of Wistar-Kyoto rats. This reduction of MAP in conscious SHRs was abolished by the selective opioid µ-receptor antagonist cyprodime, but not by naloxonazine, the µ1-opioid receptor antagonist. However, cardiac output was not altered by loperamide in anesthetized SHRs. Moreover, loperamide-induced relaxation in isolated aortic rings precontracted with phenylephrine or vasopressin. This relaxation was abolished by cyprodime, but not by naloxonazine. Loperamide-induced relaxation was also attenuated by glibenclamide, an ATP-sensitive potassium (KATP) channel blocker. Additionally, vasodilatation by loperamide was reduced by an inhibitor of protein kinase A (PKA) and enhanced by an inhibitor of phosphodiesterases. Conclusion: We suggest that loperamide can lower MAP in SHRs via µ2-opioid receptor-dependent cAMP-PKA pathway that induces vascular relaxation by opening KATP channels.

The present study is designed to investigate the role of peroxisome proliferator-activated receptors delta (PPARdelta) in the action of digoxin in diabetic rats showing cardiac hypertrophy. We used Wistar rats to induce diabetes by injection of streptozotocin (STZ-rat) and examined the effect of digoxin on PPARdelta expression in these hyperglycemic rats (STZ-rat) at 10 weeks later. We measured the changes of body weight, water intake, and food intake in three groups of age-matched rats; the vehicle treated normal control (Wistar rats), the vehicle treated STZ-rats, and the digoxin-treated STZ-rats. Cardiac output, heart rate, and blood pressure in addition to plasma insulin or glucose level were also determined. The mRNA and protein levels of PPARdelta were measured using Northern and Western blotting, respectively. Cardiac output, heart rate, and blood pressure were markedly reduced while food intake, water intake, and blood glucose were raised in STZ-rats showing lower body weight and plasma insulin as compared with the vehicle-treated controls. After a 20-day of digoxin treatment, cardiac output was raised in STZ-rats but the diabetic parameters were not modified. The PPARdelta expressions, both mRNA and protein, were markedly elevated in the hearts of STZ-rats by digoxin treatment. The related signals with PPARdelta, such as carnitine palmitoyltransferase 1B (CPT1B), acetyl-coenzyme A, carboxylase alpha (ACC1), fatty acid synthase (FAS), and troponin I, were also raised. The increase of cardiac output by digoxin was reversed by the combined treatment with PPARdelta antagonist GSK0660. Thus, we suggest a new finding that PPARdelta is involved in digoxin induced cardiac inrotropic action.

Background Human recombinant activated protein C (APC) has been found to be beneficial in treating heatstroke in both humans and rats. Here, we further investigated the possible mechanism underlying the therapeutic action exerted by APC in experimental heatstroke. Methods Unanesthetized and unrestrained mice were exposed to an ambient temperature of 42.4°C for 1 hour to induce heatstroke. They were given normal saline or APC (5 mg/kg of body weight, intravenously) 1 hour after the termination of heat stress. Their physiologic and biochemical parameters were continuously monitored for 4 hours after cessation of heat stress. Mice that survived on day 4 of heat treatment were considered survivors. Results When the vehicle-treated mice underwent heat treatment, the fraction survival and core temperature at 4 hours of body heating were found to be 0 of 12 and 33.8 ± 0.6°C, respectively. Administration of APC 1 hour after the cessation of heat stress rescued the mice from heat-induced death (fraction survival, 12 of 12) and reduced hypothermia (core temperature, 37.4 ± 0.2°C). Heat-induced apoptosis in the hypothalamus was significantly reduced by APC. The increased levels of cellular ischemia (eg, glutamate, lactate-to-pyruvate ratio, nitrite, and dihydroxybenzoic acid) and damage (eg, glycerol) markers in the hypothalamus during heatstroke were also decreased significantly by APC therapy. The hypothalamic levels of tumor necrosis factor- α (a proinflammatory cytokine) that are upregulated in heat-stressed mice were significantly lower in APC-administered mice. Conclusions Our results show that human recombinant APC improves heatstroke through restoration of normal hypothalamic and thermoregulatory function.

Background Transgenic mice have been used to examine the role of heat shock protein (HSP)72 in experimental heatstroke. Transgenic mice that were heterozygous for a porcine HSP70β gene ([+] HSP72) and transgene-negative littermate controls ([-] HSP72), under pentobarbital sodium anesthesia, were subjected to heat stress to induce heatstroke. It was found that the overexpression of HSP72 in multiple organs improved survival during heatstroke by reducing hypotension and cerebral ischemia and damage in mice. Herein we attempted to further assess the effect of heat exposure on thermoregulatory function, hypothalamic integration, and survival in unrestrained, unanesthetized [+]HSP72 and compare with those of [-]HSP72. In this research with the transgenic mice, we first conducted several biochemical, physiologic and histological determinations and then investigated the beneficial effects of HSP72 overexpression on the identified hypothalamic deficits, thermoregulatory dysfunction, and mortality during heatstroke. Results We report here that when [-]HSP72 mice underwent heat stress (ambient temperature 42.4°C for 1 h), the fraction survival and core temperature at 4 h after heat stress were found to be 0 of 12 and 34.2°C ± 0.4°C, respectively. Mice that survived to day 4 after heat stress were considered as survivors. In [+]HSP72 mice, when exposed to the same heat treatment, both fraction survival and core temperature values were significantly increased to new values of 12/12 and 37.4°C ± 0.3°C, respectively. Compared to [-]HSP mice, [+]HSP72 mice displayed lower hypothalamic values of cellular ischemia (e.g., glutamate and lactate-to-pyruvate ratio) and damage (e.g., glycerol) markers, pro-oxidant enzymes (e.g., lipid peroxidation and glutathione oxidation), pro-inflammatory cytokines (e.g., interleukin-1beta and tumor necrosis factor-alpha), and neuronal damage score evaluated 4 h after heat stress. In contrast, [+]HSP72 mice had higher hypothalamic values of antioxidant defences (e.g., glutathione peroxidase and glutathione reductase), ATP, and HSP72 expression. Conclusion This study indicates that HSP72 overexpression appears to be critical to the development of thermotolerance and protection from heat-induced hypothalamic ischemic and oxidative damage.

Adherence with prescription medications among elderly patients with cardiac conditions is poor. Mechanisms underlying adherence behavior have not been fully investigated. The purpose of this study was to develop a substantive model that describes medication-taking behavior in elderly individuals with chronic diseases. The study was exploratory using grounded theory. Purposive sampling was used to recruit 19 elderly cardiac patients. Four major themes were delineated from the data to describe readiness to adhere: perceived effectiveness, perceived partnership, perceived reality, and interpersonal influences. To convert perceptions into actions, 2 influencing factors, facilitating and inhibiting factors, played pivotal roles. This model could provide a useful framework for health professionals to design valid interventions for elderly patients to increase medication adherence.

Naltrexone, a nonselective antagonist of opioid receptors, is found to be beneficial in protecting against heatstroke. Further investigation using selective mu, delta, and kappa opioid receptor antagonists are needed to prove the involvement of specific receptors in heatstroke. Rats under sodium pentobarbital anesthesia were exposed to high ambient temperature of 43 degrees C to induce heatstroke. Control rats were exposed to 24 degrees C. In rats treated with normal saline 20 minutes before heat stress, the values for survival time were found to be 89-101 minutes. Intravenous administration of CTAP (a selective mu-opioid receptor antagonist; 50-200 microg/kg), but not nor-binaltorphimine (20-200 microg/kg; a kappa-opioid receptor antagonist) or ICI-174864 (50-500 microg/kg; a delta-opioid receptor antagonist), significantly increased the survival time to new values of 180-212 minutes. In vehicle-treated rats after heatstroke onset, the values for core temperature, intracranial pressure, and the extracellular markers for ischemia (eg, glutamate and lactate/pyruvate ratio) or damage (eg, glycerol) and neuronal damage scores in striatum were significantly higher than those of normothermic controls. In contrast, the values for mean arterial pressure, cerebral perfusion pressure, cerebral blood flow, and brain partial pressure of O2 were significantly lower than those of normothermic controls. The heatstroke-induced hyperthermia, arterial hypotension, intracranial hypertension, cerebral hypoperfusion and hypoxia, and increased levels of cellular ischemia and damage markers in striatum were all significantly attenuated by prior administration of CTAP. The data indicate that prior antagonism of mu-opioid receptors protects against circulatory shock and cerebral ischemia during heatstroke.

We hypothesized that hydroxyethyl starch (HES), which maintains colloid osmotic pressure and potentially "seals" capillary leaks, would ameliorate circulatory shock and cerebral ischemia during heatstroke in a rat model. Animals under urethane anesthesia were exposed to high ambient temperature (Ta) of 42 degrees C until mean arterial pressure and local cerebral blood flow in the striatum began to decrease from peak level, which was arbitrarily defined as the onset of heatstroke. Control rats were exposed to 24 degrees C. In rats treated with 1 mL/kg, 11 mL/kg, or 22 mL/kg of normal saline (NS) immediately after the onset of heatstroke, the values for survival time (interval between the initiation of heatstroke and animal death) were found to be 21 +/- 2, 36 +/- 9, or 92 +/- 7 min, respectively. Intravenous administration of 11 mL/kg of HES (about 5 times the volume-expanding effect of 11 mL/kg of NS), but not 2 mL/kg of HES (about the same volume-expanding effect as 11 mL/kg NS), significantly increased the survival time from the control values of 36 +/- 9 min to new values of 181 +/- 13 min. In NS (11 mL/kg)-treated or HES (2 mL/kg)-treated rats after heatstroke onset, the values for mean arterial pressure, stroke volume, total peripheral resistance, cerebral blood flow, blood pH, Paco2, Pao2, and brain Po2 were significantly lower than those of rats kept at Ta 24 degrees C. In contrast, the values for colonic temperature and the extracellular concentrations of glutamate, glycerol, and lactate/pyruvate ratio obtained in striatum were significantly higher than those of controls. The heatstroke-induced arterial hypotension, decreased stroke volume and total peripheral resistance, decreased blood pH and Pao2, decreased brain Po2, and increased levels of striatal glutamate, glycerol, and lactate/pyruvate ratio in NS-treated rats were all attenuated significantly by increasing the volume expansion with 11 mL/kg of HES administered immediately at the onset of heatstroke. Our data suggest that HES therapy seems superior to NS treatment during heatstroke. The benefit of HES therapy during heatstroke might have something to do with volume expansion rather than capillary permeability.

Thrombomodulin is an endothelial glycoprotein that decreases thrombin activity and activates protein C. A recent study has shown that G-33A promoter mutation of the thrombomodulin gene occurs particularly in Asians. In this study, we analyzed the distribution of G-33A mutation in the promoter region of the thrombomodulin gene in the Chinese population and determined whether the mutation might be a risk for coronary artery disease (CAD). In addition, the influence of this mutation on plasma soluble thrombomodulin levels in patients with CAD was also examined. We studied 320 consecutive patients (mean age 63 years; 73% men) with CAD and 200 age- and sex-matched control subjects. Screening for thrombomodulin G-33A promoter mutation was conducted using polymerase chain reaction, single-strand conformation polymorphism, and direct deoxyribonucleic acid sequencing. The frequency of the G-33A mutation (GA+AA genotypes) was significantly higher in the CAD group (23.8% vs 15.5%, odds ratio [OR] 1.70, p = 0.031). Multiple logistic regression analysis showed that the mutation was an independent risk factor (OR 1.81, p = 0.016) for CAD, as was hypertension (OR 1.44, p = 0.040), diabetes mellitus (OR 2.50, p0.001), and smoking (OR 2.15, p0.001). In CAD patients with GG genotype, the soluble thrombomodulin level increased with the extent of CAD (36 +/- 15 vs 47 +/- 18 vs 55 +/- 36 ng/ml in 1-, 2-, or 3-vessel CAD, p0.001). However, in CAD patients with G-33A mutation, there was no difference between the levels of soluble thrombomodulin (39 +/- 17 vs 37 +/- 15 vs 42 +/- 18 ng/ml, p = NS) in 1-, 2-, or 3-vessel CAD. Our observations suggest that there is a significant association of the G-33A mutation in thrombomodulin gene with CAD, and this mutation may influence the soluble thrombomodulin levels in patients with CAD.

Acute ingestion of more than 200 mg dipyridamole may result in minor symptoms. The reported highest dosage of acute ingestion was 1250 mg. Most experiences of acute ingestion come from dipyridamole thallium image, oral application of 300–400 mg or intravenous 0.56 mg/kg. The systemic or cardiovascular complication could be rapidly reversed by intravenous use of aminophylline, 50–240 mg. We report an experience in dealing with the highest ever dose, 1750 mg, of dipyridamole overdose by usual dose of aminophylline.

Background Despite the known risk of diabetes-induced cardiac fibrosis, less is known about whether diabetes causes an altered cardiac phenotype independent of coronary atherosclerosis. Peroxisome proliferator-activated receptor δ (PPARδ), a versatile regulator of metabolic homeostasis, may be a potential therapeutic target. Herein we investigated the effectiveness of telmisartan, a unique angiotensin receptor blocker that increases PPARδ expression, in improving left ventricular remodeling in diabetic humans and rats. Methods In this longitudinal, prospective study, we enrolled 15 diabetic patients receiving telmisartan (20 mg/day) for 12 weeks. After treatment, strain was measured and compared with the baseline value. Using streptozotocin to induce type 1 diabetes rat model, we measured PPARδ expression and downstream targets. Results After treatment with telmisartan, both longitudinal and circumferential strains improved in diabetic patients. Compared with that of controls, the diabetic rat heart developed significant fibrosis, which markedly decreased after treatment with telmisartan (30 mg/kg/day, orally) for 7 days. After incubation with 30 mM glucose, rat cardiomyocytes showed a significant down-regulation of PPARδ. Interestingly, the increased expression of fibrosis-associated proteins, including signal transducer and activator of transcription 3 (STAT3) was attenuated by the co-incubation of GW0742, a PPARδ agonist. By knockdown or inhibition of STAT3, the hyperglycemia related high expression of fibrosis associated targets was reversed. Independent from the hyperglycemic incubation, STAT3 over-expression led to similar results. Conversely, in the presence of GSK0660, a PPARδ inhibitor, the protective effects of telmisartan were diminished. Conclusion Telmisartan improved the hyperglycemia-induced cardiac fibrosis through the PPARδ/STAT3 pathway.Graphical abstractSummary of the mechanism of telmisartan’s effect on the suppression of hyperglycemia-induced cardiac fibrosis through PPARδ instead of the AMPK pathway. PPARδ peroxisome proliferator-activated receptor δ, STAT3 signal transducer and activator of transcription 3, CTGF connective tissue growth factor, MMP9 matrix metallopeptidase 9