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1.
Zhonghua Xin Xue Guan Bing Za Zhi ; 50(8): 761-766, 2022 Aug 24.
Article in Chinese | MEDLINE | ID: mdl-35982007

ABSTRACT

Objective: Near-infrared spectroscopy (NIRS) is widely used for intraoperative cerebral oxygen saturation monitoring in patients with acute type A aortic dissection. This study aimed to investigate the correlation between NIRS-derived oxygen saturation and risk of postoperative stroke. Methods: This study included 193 patients with acute type A aortic dissection undergoing emergency surgery and elective unilateral cerebral perfusion via the right axillary artery at the Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, Nanjing, China, from 2018 to 2020. NIRS was used for intraoperative cerebral oxygen saturation monitoring, and the basal values and the lowest values of cerebral oxygen saturation during deep hypothermic circulatory arrest (DHCA) were recorded. The patients were divided into no-stroke group (n=178, 92.2%) and stroke group (n=15, 7.8%) according to the absence or presence of postoperative stroke. The differences in preoperative, operative and postoperative clinical differences between the two groups were compared, and the relationship between the lowest cerebral oxygen saturation value and the change in cerebral oxygen saturation value ((base-lowest)/basal) and postoperative stroke were analyzed. Results: The proportion of preoperative atrial fibrillation (6.7% vs. 0.6%, P=0.026), and the proportion of preoperative hypotension (26.7% vs. 9.0%, P=0.031) were significantly higher in the stroke group than no-stroke group. There were no differences in the surgical approach between the two groups. Cardiopulmonary bypass (CPB) time ((256.1±84.8) h vs.(217.8±58.4) h, P=0.020), postoperative mechanical ventilation time ((139.3±172.8) h vs. (35.6±45.6) h, P<0.001) were significantly longer in stroke group as compared to no-stroke group. Incidence of postoperative tracheotomy (20.0% vs. 1.1%, P<0.001), acute kidney injury (73.3% vs. 30.3%, P=0.001) and continuous renal replacement therapy (46.7% vs. 11.8%, P<0.001) as well as mortality (20.0% vs. 5.1%, P=0.022) were significantly higher in the stroke group than in non-stroke group. There was no significant difference in the basal NIRS value and the lowest NIRS value during DHCA between the two groups. Patients in the stroke group had a significantly greater intraoperative change rate of right NIRS as compared to no-stroke group (15.2%±15.7% vs. 9.2%±7.0%, P=0.006). Conclusions: NIRS is valuable for monitoring cerebral oxygen saturation during acute type A aortic dissection surgery, and the rate change of NIRS during operation correlates significantly with postoperative stroke.


Subject(s)
Aortic Dissection , Stroke , Aortic Dissection/surgery , Humans , Monitoring, Intraoperative/methods , Oxygen , Oxygen Saturation , Spectroscopy, Near-Infrared/methods
2.
Mol Psychiatry ; 25(11): 3113, 2020 Nov.
Article in English | MEDLINE | ID: mdl-30867559

ABSTRACT

Following publication of this article, the authors noted that the bands of Na-K ATPase in Figure S1B were mislabelled when selecting representative blots, and were erroneously duplicated from GluA2. However, the data analysis was still made with the correct immunoblots. The Supplementary Information file has now been updated to include the corrected Figure S1 with the correct western blot bands of Na-K ATPase.The authors would like to apologise for this error and the inconvenience this may have caused. This has been corrected in both the PDF and HTML versions of the article.

3.
Mol Psychiatry ; 23(3): 597-608, 2018 03.
Article in English | MEDLINE | ID: mdl-28439098

ABSTRACT

Several preclinical studies have reported the rapid antidepressant effects of N-methyl-D-aspartate receptor (NMDAR) antagonists, although the underlying mechanisms are still unclear. Death-associated protein kinase 1 (DAPK1) couples GluN2B subunits at extrasynaptic sites to regulate NMDAR channel conductance. In the present study, we found that chronic unpredictable stress (CUS) induced extracellular glutamate accumulation, accompanied by an increase in the DAPK1-NMDAR interaction, the high expression of DAPK1 and phosphorylated GluN2B at Ser1303, a decrease in phosphorylated DAPK1 at Ser308 and synaptic protein deficits in the rat medial prefrontal cortex (mPFC). CUS also enhanced GluN2B-mediated NMDA currents and extrasynaptic responses that were induced by bursts of high-frequency stimulation, which may be associated with the loss of astrocytes and low expression of glutamate transporter-1 (GLT-1). The blockade of GLT-1 in the mPFC was sufficient to induce depressive-like behavior and cause similar molecular changes. Selective GluN2B antagonist, DAPK1 knockdown by adeno-associated virus-mediated short-hairpin RNA or a pharmacological inhibitor, and the uncoupling of DAPK1 from the NMDAR GluN2B subunit produced rapid antidepressant-like effects and reversed CUS-induced alterations in the mPFC. The inhibition of DAPK1 and its interaction with GluN2B subunit in the mPFC also rescued CUS-induced depressive-like behavior 7 days after treatment. A selective GluN2B antagonist did not have rewarding effects in the conditioned place preference paradigm. Altogether, our findings suggest that the DAPK1 interaction with the NMDAR GluN2B subunit acts as a critical component in the pathophysiology of depression and is a potential target for new antidepressant treatments.


Subject(s)
Death-Associated Protein Kinases/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Antidepressive Agents/pharmacology , Chronic Disease , Depression/physiopathology , Depressive Disorder/physiopathology , Disease Models, Animal , Excitatory Amino Acid Antagonists/therapeutic use , Glutamic Acid/metabolism , Male , Phosphorylation , Prefrontal Cortex/metabolism , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Signal Transduction/drug effects , Stress, Psychological/metabolism
4.
Mol Psychiatry ; 23(9): 1878-1891, 2018 09.
Article in English | MEDLINE | ID: mdl-29180675

ABSTRACT

Neuronal atrophy and alterations of synaptic structure and function in the medial prefrontal cortex (mPFC) have been implicated in the pathogenesis of depression, but the underlying molecular mechanisms are largely unknown. The protein kinase Mζ (PKMζ), a brain-specific atypical protein kinase C isoform, is important for maintaining long-term potentiation and storing memory. In the present study, we explored the role of PKMζ in mPFC in two rat models of depression, chronic unpredictable stress (CUS) and learned helplessness. The involvement of PKMζ in the antidepressant effects of conventional antidepressants and ketamine were also investigated. We found that chronic stress decreased the expression of PKMζ in the mPFC and hippocampus but not in the orbitofrontal cortex. Overexpression of PKMζ in mPFC prevented the depressive-like and anxiety-like behaviors induced by CUS, and reversed helplessness behaviors. Inhibition of PKMζ in mPFC by expressing a PKMζ dominant-negative mutant induced depressive-like behaviors after subthreshold unpredictable stress and increased learned helplessness behavior. Furthermore, stress-induced deficits in synaptic proteins and decreases in dendritic density and the frequency of miniature excitatory postsynaptic currents in the mPFC were prevented by PKMζ overexpression and potentiated by PKMζ inhibition in subthreshold stress rats. The antidepressants fluoxetine, desipramine and ketamine increased PKMζ expression in mPFC and PKMζ mediated the antidepressant effects of ketamine. These findings identify PKMζ in mPFC as a critical mediator of depressive-like behavior and antidepressant response, providing a potential therapeutic target in developing novel antidepressants.


Subject(s)
Depression/metabolism , Protein Kinase C/metabolism , Protein Kinase C/physiology , Animals , Antidepressive Agents/pharmacology , Depression/physiopathology , Depressive Disorder/physiopathology , Disease Models, Animal , Excitatory Postsynaptic Potentials/drug effects , Hippocampus/drug effects , Ketamine/pharmacology , Long-Term Potentiation/physiology , Male , Memory/physiology , Prefrontal Cortex/metabolism , Prefrontal Cortex/physiology , Protein Isoforms/metabolism , Rats , Rats, Sprague-Dawley , Stress, Psychological/metabolism
5.
Mol Psychiatry ; 22(9): 1274-1281, 2017 09.
Article in English | MEDLINE | ID: mdl-28831198

ABSTRACT

Exposure to addictive drugs triggers synaptic plasticity in reward-related brain regions, such as the midbrain, nucleus accumbens and the prefrontal cortex. Effects of chronic drug exposure on other brain areas have not been fully investigated. Here, we characterize synaptic plasticity in motor cortex after methamphetamine self-administration in rats. We show that this causes a loss of corticostriatal plasticity in rat brain slices and impaired motor learning in the rotarod task. These findings are paralleled by the observation of a lack of transcranial magnetic stimulation-induced potentiation or depression of motor evoked potentials in human patients with addiction, along with poor performance in rotary pursuit task. Taken together, our results suggest that chronic methamphetamine use can affect behavioral performance via drug-evoked synaptic plasticity occluding physiological motor learning.


Subject(s)
Methamphetamine/adverse effects , Motor Cortex/drug effects , Neuronal Plasticity/drug effects , Adult , Amphetamine-Related Disorders/physiopathology , Animals , Brain/cytology , Brain/pathology , Electric Stimulation , Evoked Potentials, Motor/drug effects , Evoked Potentials, Motor/physiology , Humans , Learning/physiology , Long-Term Potentiation/physiology , Male , Methamphetamine/pharmacology , Middle Aged , Neuronal Plasticity/physiology , Nucleus Accumbens/drug effects , Rats , Rats, Sprague-Dawley , Reward , Transcranial Magnetic Stimulation/methods
6.
Zhonghua Wai Ke Za Zhi ; 55(4): 260-265, 2017 Apr 01.
Article in Chinese | MEDLINE | ID: mdl-28355762

ABSTRACT

Objective: To discuss the perioperative and follow-up results of different surgical methods for acute Stanford type A aortic dissection patients and analyzed the results. Methods: The clinic data of 351 acute Stanford type A aortic dissection patients received surgical therapy at Department of Thoracic and Cardiovascular Surgery, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital from January 2008 to December 2015 were analyzed retrospectively. There were 272 male and 79 female patients, aging from 22 to 83 years with a mean age of (52±13) years. According to root size, aortic valve structure and the status of dissection involvement, these patients were devided into three major groups: 218 cases with root reconstruction using Dacron felts, 34 cases with root reconstruction concomitant with aortic valve resuspension repair and 99 cases in with Bentall procedure. Proper shape based on the status of dissection involvement of Dacron patch was cut and put between the middle and outerlayer of aorta, then inside the inner layerone band Dacron felt was sutured with the aorta and the new middle layer with Dacron patch as mentioned above. In some cases the prolapsed aortic valve was re-suspended to the aortic cusp. Clinical outcomes among the 3 procedures were compared by χ(2) test, Fisher's exact test, t test and analysis of variance. Results: Cardiopulmonary bypass, cross-clamp, and circulatory arrest times of all the patients were (250±78), (171±70) and (31±10) minutes, respectively. The 30-day mortality was 9.2%(33/351), while no difference among the 3 procedures (9.6%, 8.8% and 9.1%). In the average follow-up time of (26.0±23.0) months (range from 0.5 to 90.0 months), survival rates were similar among the 3 procedures (77.7%, 77.4% and 77.8%). Only one patient received redo Bentall procedure because of severe aortic regurgitation and dilated aortic root (diameter of 50 mm). Conclusions: The indication of root management of acute Stanford type A aortic dissection is based on the diameter of aortic root, structure of aortic leaflets, and the dissection involvement. For most acute Stanford type A aortic dissection patients, aortic root reconstruction is a feasible and safe method.


Subject(s)
Aortic Aneurysm, Thoracic/surgery , Aortic Dissection/surgery , Blood Vessel Prosthesis Implantation , Adult , Aged , Aged, 80 and over , Aorta , Aortic Aneurysm , Aortic Valve , Aortic Valve Insufficiency , Cardiac Surgical Procedures , Female , Humans , Male , Middle Aged , Retrospective Studies , Survival Rate , Young Adult
7.
Anal Bioanal Chem ; 382(4): 996-1000, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15895210

ABSTRACT

A novel nanoparticle-bioconjugate has been prepared by specific hybridization of the target with complementary thiol-labeled and nanoparticle-labeled probes. The rapid adsorption of the nanoparticle-bioconjugate onto a gold surface via a thiol-gold reaction was monitored in real-time using a quartz crystal microbalance, and used to perform microgravimetric flow analysis of nucleic acid for the first time. This innovative assay is highly reproducible and sensitive, and shows great promise for clinical applications.


Subject(s)
DNA/analysis , Nanoparticles/chemistry , Spectrophotometry, Atomic/methods , Adsorption , Centrifugation/methods , Gold/chemistry , Microchemistry , Microwaves , Oligonucleotides/chemistry , Quartz , Reproducibility of Results , Sensitivity and Specificity , Sulfhydryl Compounds/chemistry , Surface Properties , Time Factors
8.
Am J Chin Med ; 28(3-4): 305-12, 2000.
Article in English | MEDLINE | ID: mdl-11154043

ABSTRACT

Qian-kun-nin is a Chinese herbal formulation considered to have anti-infection, anti-tumor and immuno-enhancing properties. Data from previous investigations showed that qian-kun-nin causes HIV growth inhibition and immunomodulation in vitro, suggesting that this formula has the ability to inhibit HIV and modulate impaired immune functions in humans. We conducted this pilot study to evaluate the anti-retroviral and immunological enhancing effects of this formula on HIV positive subjects. Eight subjects completed the study, receiving oral qian-kun-nin capsules for 24 consecutive weeks in a single blind design. Compared to baseline level, the plasma virus load decreased significantly at the end of week 12 (p < 0.01) and week 24 (p < 0.01), respectively. Four weeks after cessation of qian-kun-nin treatment, plasma virus load was still significantly lower compared to baseline (p < 0.01). Blood CD4 cell counts were increased significantly at the end of the 12th week compared to the baseline level (p < 0.01). No adverse effects were observed, and no significant side effects were recorded in any subjects. These data suggest that qian-kun-nin has therapeutic potential in the treatment of HIV positive patients.


Subject(s)
Drugs, Chinese Herbal/therapeutic use , HIV Infections/drug therapy , Adult , CD4 Lymphocyte Count , Consumer Product Safety , Drugs, Chinese Herbal/adverse effects , Female , HIV Infections/immunology , HIV Infections/virology , Humans , Male , Middle Aged , Personal Satisfaction , Pilot Projects , Single-Blind Method , Viral Load
9.
Naunyn Schmiedebergs Arch Pharmacol ; 358(6): 649-56, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9879724

ABSTRACT

We investigated effects of a new Na+ channel blocking antiarrhythmic drug, A-2545, N-3 (2,2,5,5-tetramethyl-3-pyrroline-3-carboxamido)-propyl-phthalimide-hydro chloride, on various canine ventricular automaticity arrhythmias induced by two-stage coronary ligation, digitalis and adrenaline, and compared them with those of mexiletine. A-2545 showed antiarrhythmic effects, significantly decreasing the arrhythmic ratio of 24-h and 48-h coronary ligation-, digitalis- and adrenaline-induced automaticity arrhythmias. The antiarrhythmic plasma concentrations (IC50) of A-2545, 2 mg kg(-1) 10 min(-1), i.v., for 24-h and 48-h coronary ligation-, digitalis- and adrenaline-induced arrhythmias were 1.8, 1.3, 5.8 and 3.7 microg ml(-1), respectively, and that calculated for oral A-2545 (25 mg kg(-1)) in 24-h coronary ligation-induced arrhythmia was 1.8 microg ml(-1). A-2545 is specifically potent in suppressing coronary ligation-induced arrhythmias, i.e., decreasing the arrhythmic ratio nearly to zero by oral administration, and among the intravenously given experiments A-2545 was effective at lower concentrations than other arrhythmia models; A-2545, 2 mg kg(-1) 10 min(-1), was equipotent to 5 mg kg(-1) 10 min(-1) mexiletine in suppressing 24-h coronary ligation-induced arrhythmia, indicating that A-2545 is more potent than mexiletine. In order to determine whether A-2545 has arrhythmogenic effects, we used programmed electrical stimulation (PES)-induced reentry arrhythmias in dogs with old myocardial infarction and compared effects of A-2545 and flecainide. A-2545, 2 and 5 mg kg(-1) 10 min(-1), significantly suppressed the PES-induced arrhythmias in all six dogs without aggravating them. These arrhythmias were not markedly suppressed by flecainide either with 1 or 3 mg kg(-1) 1O min(-1); moreover even in one out of six dogs aggravation of arrhythmia was noted after 1 mg kg(-1) 10 min(-1). In conclusion, A-2545 suppressed various canine ventricular arrhythmias, and the antiarrhythmic effect of A-2545 was more potent than that of mexiletine, and A-2545 did not show arrhythmogenic effects compared to flecainide.


Subject(s)
Anti-Arrhythmia Agents/pharmacology , Flecainide/pharmacology , Mexiletine/pharmacology , Pyrroles/pharmacology , Animals , Arrhythmias, Cardiac/chemically induced , Blood Pressure/drug effects , Coronary Vessels/surgery , Dogs , Dose-Response Relationship, Drug , Electric Stimulation , Electrocardiography , Heart Rate/drug effects , Models, Biological , Molecular Structure , Pyrroles/blood
10.
Eur J Pharmacol ; 339(2-3): 121-7, 1997 Nov 27.
Article in English | MEDLINE | ID: mdl-9473125

ABSTRACT

Cariporide (4-isopropyl-3-methylsulphonylbenzoyl-guanidine methanesulphonate: HOE642) is a novel Na+-H+ exchange subtype 1 inhibitor and has antiarrhythmic effects on ischemia/reperfusion arrhythmias without apparent cardiovascular effects in dogs and rats when given before coronary occlusion. The aim of this study was to determine the minimum effective dose and to examine the dose related effects of cariporide when it was administered before and during coronary occlusion as well as simultaneously with reperfusion. In the pre-treatment group, cariporide dose-dependently reduced the ventricular tachycardia duration from 140 to 36 (P < 0.01), 59 (P < 0.05) and 23 s (P < 0.01) with 0.03, 0.1 and 1 mg/kg, respectively, and reduced the incidence of reperfusion-induced ventricular tachycardia from 100 to 50 and 58% (P < 0.01), ventricular fibrillation from 83 to 8 and 0% (P < 0.01), and mortality from 75 to 8 and 8% (P < 0.01) with 0.1 and 1 mg/kg, respectively. In the post-treatment group, cariporide dose-dependently reduced the ventricular tachycardia duration from 92 to 37, 40, 42 (P < 0.05) and 24 s (P < 0.01) with 0.03, 0.1, 0.3 and 1 mg/kg, respectively, and the incidence of ventricular tachycardia from 100 to 53% (P < 0.01) by 1 mg/kg, and ventricular fibrillation from 87 to 33, 7 and 7% (P < 0.01), and the mortality from 73 to 27 (P < 0.05), 0 and 7% (P < 0.01) with 0.1, 0.3 and 1 mg/kg, respectively. In the group with simultaneous injection, both doses of cariporide (1 and 3 mg/kg) reduced the incidence of ventricular fibrillation from 83 to 42% (P < 0.05). The heart rate, blood pressure and QT interval did not change after drug treatment.


Subject(s)
Anti-Arrhythmia Agents/pharmacology , Arrhythmias, Cardiac/drug therapy , Guanidines/pharmacology , Heart/drug effects , Myocardial Reperfusion Injury/complications , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Sulfones/pharmacology , Animals , Anti-Arrhythmia Agents/chemistry , Guanidines/chemistry , Hemodynamics/drug effects , Male , Myocardial Reperfusion Injury/drug therapy , Rats , Rats, Sprague-Dawley , Sulfones/chemistry , Ventricular Function/drug effects
11.
Eur J Pharmacol ; 317(2-3): 309-16, 1996 Dec 19.
Article in English | MEDLINE | ID: mdl-8997615

ABSTRACT

HOE642 (4-isopropyl-3-methylsulphonylbenzoyl-guanidine methanesulphonate), a novel Na(+)-H+ exchange subtype 1 inhibitor, was investigated for its possible antiarrhythmic effects on coronary artery ligation/reperfusion and ouabain-induced arrhythmias in the canine heart which may occur after intracellular Ca2+ overload. Also, the effects of HOE642 on coronary artery ligation/reperfusion of the left coronary artery were tested in rat hearts. HOE642 (1 mg/kg) significantly suppressed the occurrence of fatal ventricular fibrillation during coronary artery ligation and after reperfusion in dogs (2 out of 8 dogs in the treated group compared to 7 out of 8 dogs in the control group, P < 0.05), but did not suppress ventricular premature contractions and ventricular tachycardia during ischemia in the canine hearts. HOE642 at the same dose markedly reduced the total duration and the incidence of reperfusion-induced ventricular tachycardia, and the incidence and mortality of reperfusion-induced ventricular fibrillation in rats (ventricular tachycardia duration, 159 +/- 12 s to 21 +/- 8 s, P < 0.01; ventricular tachycardia, 100% to 69%; ventricular fibrillation, 89% to 0%, P < 0.01; mortality, 89% to 11%, P < 0.01). The heart rate, blood pressure, QT interval and ST segment did not change in the canine and rat hearts. HOE642 slightly decreased the arrhythmic ratio of the ouabain-induced arrhythmia only at two time points (28 and 35 min after injection) in the canine hearts. In conclusion, HOE642 has obvious antifibrillatory effects on ischemia/reperfusion arrhythmias and, in addition, has a weak suppressing effect on the ouabain-induced arrhythmia.


Subject(s)
Anti-Arrhythmia Agents/pharmacology , Guanidines/pharmacology , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Sulfones/pharmacology , Ventricular Fibrillation/prevention & control , Animals , Anti-Arrhythmia Agents/blood , Cardiotonic Agents , Coronary Vessels/physiology , Digitalis Glycosides , Dogs , Dose-Response Relationship, Drug , Female , Guanidines/blood , Injections, Intravenous , Male , Myocardial Ischemia/physiopathology , Myocardial Reperfusion Injury/physiopathology , Rats , Rats, Sprague-Dawley , Sulfones/blood , Ventricular Fibrillation/etiology , Ventricular Fibrillation/physiopathology
12.
Eur J Pharmacol ; 318(2-3): 333-40, 1996 Dec 30.
Article in English | MEDLINE | ID: mdl-9016923

ABSTRACT

We examined the effects of an aconitine-like compound, TJN-505 (1alpha-16beta-dimethoxy-20-ethyl-14alpha-(4-methox ybenzoyloxy)-aconitan-8,13-diol hydrochloride), on canine arrhythmias provoked by digitalis, two-stage coronary ligation, adrenaline, programmed electrical stimulation, or aconitine. TJN-505 (2-2.5 mg/kg i.v.) suppressed digitalis-, two-stage coronary ligation- and adrenaline-induced ventricular arrhythmias. The antiarrhythmic plasma concentrations (IC50) of TJN-505 for these arrhythmia models were 1.26, 0.94 and 1.31 microg/ml, respectively. TJN-505 (2 mg/kg i.v. followed by the infusion of 0.1 mg/kg per min) prolonged PR, QRS, QTc and JTc intervals and the ventricular effective refractory period and reduced the incidence of programmed electrical stimulation-induced arrhythmias in dogs with 7-day-old myocardial infarction (P < 0.05). TJN-505 (2 mg/kg i.v.) also suppressed the aconitine-induced atrial arrhythmias. In conclusion, TJN-505 suppressed various canine ventricular and atrial arrhythmias and seems to act as a blocker of multiple channels.


Subject(s)
Aconitine/analogs & derivatives , Anti-Arrhythmia Agents/therapeutic use , Arrhythmias, Cardiac/drug therapy , Aconitine/therapeutic use , Animals , Calcium Channels/drug effects , Digitalis , Dogs , Electrocardiography , Epinephrine , Female , Male , Plants, Medicinal , Plants, Toxic , Potassium Channels/drug effects , Sodium Channels/drug effects
13.
Toxicol Appl Pharmacol ; 139(1): 109-14, 1996 Jul.
Article in English | MEDLINE | ID: mdl-8685892

ABSTRACT

The cardiovascular effects of the antihypoxic and neuroprotective drug, lubeluzole, were investigated using beagle dogs anesthetized with halothane. Endocardial-contact electrode catheter was used for continuous monitoring of monophasic action potential (MAP), which could provide a precise information of repolarization phase. Intravenous administration of an efficacious dose of lubeluzole (0.63 mg/kg, n = 6) slightly decreased both the heart rate and the blood pressure. It did not change PQ interval and QRS width, while it significantly prolonged QT interval, corrected QT (QTc) and the duration of the MAP during the observation period over 60 min. The effects of drug on repolarization phase were late-onset and long-lasting compared with the time course of plasma drug concentrations, which changed as predicted by the two-compartment theory of pharmacokinetics. Additional injection of lubeluzole (2.5 mg/kg, n = 6) showed qualitatively similar changes to those of lower dose, and did not induce the cardiovascular collapse in any dog. Neither afterdepolarization nor ventricular escaped beat was detected during the observation period. The drug concentration in cardiac tissue was correlated linearly with the plasma drug concentration at 60 min after the second drug administration. These results indicate that lubeluzole exerts only minor cardiovascular effects except the prolongation of the repolarization period. The monitoring of plasma drug concentration may be helpful to estimate the steady-state distribution of drug to the heart, but less helpful to predict the QT prolongation. In future clinical trials, care must be taken with patients, especially those at risk to have prolonged repolarization.


Subject(s)
Action Potentials/drug effects , Cardiovascular Agents/pharmacology , Heart/drug effects , Neuroprotective Agents/pharmacology , Piperidines/pharmacology , Thiazoles/pharmacology , Animals , Blood Pressure/drug effects , Cardiac Catheterization , Cardiovascular Agents/administration & dosage , Cardiovascular Agents/blood , Disease Models, Animal , Dogs , Electrocardiography/drug effects , Heart Rate/drug effects , Injections, Intravenous , Microelectrodes , Myocardium/metabolism , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/blood , Piperidines/administration & dosage , Piperidines/blood , Rats , Thiazoles/administration & dosage , Thiazoles/blood
14.
Eur J Pharmacol ; 300(3): 203-10, 1996 Apr 11.
Article in English | MEDLINE | ID: mdl-8739209

ABSTRACT

To determine whether a hyperpolarization-activated current (If) participates in ventricular tachyarrhythmias, we investigated the effects of zatebradine, an I(f) inhibitor, on the ventricular tachyarrhythmias induced by ouabain, two-stage coronary ligation and epinephrine infusion in the dog heart. We determined atrial rate, ectopic ventricular rate, total heart rate and arrhythmic ratio (the number of ectopic ventricular beats divided by total heart beats). Zatebradine (0.15, 0.5 and 1.5 mg/kg, i.v.) dose dependently decreased the arrhythmic ratio, ectopic ventricular rate and atrial rate of the ouabain-induced ventricular tachyarrhythmias in pentobarbital-anesthetized dogs. The inhibition by zatebradine of the ventricular arrhythmias needed larger doses than the inhibition of the atrial rate. Zatebradine weakly depressed the ectopic ventricular rate but not the arrhythmic ratio of the ventricular arrhythmias induced by two-stage coronary ligation 24 h after the ligation in conscious dogs. Although neither the ectopic ventricular rate nor the arrhythmic ratio of the epinephrine-induced ventricular arrhythmias was affected by zatebradine, after treatment with zatebradine, the arrhythmias elicited by epinephrine developed more slowly. Together with the previously reported spectra of the effects of the antiarrhythmic agents in three ventricular tachyarrhythmia models, our results suggest that zatebradine may improve automaticity-related ventricular tachyarrhythmias due to I(f) inhibition or to other undetermined mechanisms in the heart.


Subject(s)
Benzazepines/pharmacology , Cardiotonic Agents/pharmacology , Heart Rate/drug effects , Tachycardia, Ventricular/prevention & control , Animals , Benzazepines/blood , Cardiotonic Agents/blood , Dogs , Dose-Response Relationship, Drug , Epinephrine , Female , Ligation , Male , Ouabain , Tachycardia, Ventricular/etiology , Vasoconstrictor Agents
15.
Eur J Pharmacol ; 298(3): 247-56, 1996 Mar 18.
Article in English | MEDLINE | ID: mdl-8846823

ABSTRACT

We examined whether a new positive inotropic agent with Ca(2+)-sensitizing activity, MCI-154, 6-[4-(4-pyridylamino)phenyl]-4, 5-dihydro-3-(2H)-pyridazinone hydrochloride trihydrate, had deleterious effects on ventricular arrhythmias, since several phosphodiesterase III inhibitors have been shown to aggravate arrhythmias in our earlier studies. Continuous infusion of MCI-154 (1 microgram/kg/min for 15 min) did not suppress or aggravate the arrhythmias generated in the two-stage coronary ligation-, digitalis- and adrenaline-induced canine arrhythmia models studied. Also in the case of a bolus injection of 30 micrograms/kg, MCI-154 did not aggravate the adrenaline-induced arrhythmias. To explain these results in vivo, a whole-cell voltage-clamp experiment on guinea-pig ventricular cells was performed. MCI-154 (10-100 microM) did not increase the inward Ca2+ current under the condition where these currents were increased by isoprenaline. These results indicate that MCI-154 does not aggravate ventricular arrhythmias and does not act on membrane currents associated with arrhythmogenesis. Thus, MCI-154 may become a useful positive inotropic agent with little arrhythmogenic effect.


Subject(s)
Arrhythmias, Cardiac/prevention & control , Calcium/physiology , Cardiotonic Agents/pharmacology , Ion Channels/metabolism , Pyridazines/pharmacology , Animals , Arrhythmias, Cardiac/chemically induced , Cardiotonic Agents/blood , Cell Membrane/drug effects , Cell Membrane/metabolism , Coronary Vessels/physiology , Dogs , Electrophysiology , Epinephrine , Female , Guinea Pigs , Heart Ventricles/drug effects , Heart Ventricles/metabolism , Heart Ventricles/physiopathology , In Vitro Techniques , Ion Channels/drug effects , Male , Myocardium/metabolism , Ouabain , Patch-Clamp Techniques , Pyridazines/blood
16.
Jpn J Pharmacol ; 70(2): 129-38, 1996 Feb.
Article in English | MEDLINE | ID: mdl-8866750

ABSTRACT

Using canine ventricular arrhythmia models induced by two-stage coronary ligation, digitalis, adrenaline, coronary ligation and reperfusion, and programmed electrical stimulation (PES), we examined the antiarrhythmic or proarrhythmic effects of sematilide, N-[2(diethylamino)ethyl]-4-[(methylsulfonyl)amino]-benzamide hydrochloride. Sematilide in an intravenous (i.v.) dose range of 0.3 to 6.0 mg/kg prolonged the QTc interval, but had an antiarrhythmic effect only on the arrhythmias induced by PES (7 out of 10 dogs with old myocardial infarction). Sematilide was not effective on coronary ligation and reperfusion arrhythmia or the spontaneously occurring automaticity arrhythmias induced by two-stage coronary ligation, digitalis and adrenaline, respectively, and even aggravated digitalis- and adrenaline-induced arrhythmias. These results indicate that the class III agent sematilide is similar to other new class III agents, such as d-sotalol, E-4031 and MS-551, in that it was not effective on the automaticity arrhythmias, but different from these new class III agents, in that sematilide prevented only the induction of ventricular arrhythmias induced by PES and did not suppress the coronary ligation-reperfusion arrhythmias. The PES induced arrhythmias are thought to be induced exclusively by a reentrant mechanism, but the reperfusion arrhythmias may involve not only re-entry, but also automaticity, and we reported the effectiveness of MS-551, E-4031 and d-sotalol on the latter arrhythmia. Sematilide is different in that it even aggravated some automaticity arrhythmias.


Subject(s)
Anti-Arrhythmia Agents/pharmacology , Procainamide/analogs & derivatives , Animals , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Electric Stimulation , Female , Injections, Intravenous , Male , Procainamide/pharmacology , Time Factors
17.
Jpn J Physiol ; 45(2): 337-45, 1995.
Article in English | MEDLINE | ID: mdl-7563968

ABSTRACT

To clarify the effects of manual acupuncture on the autonomic nervous system, we measured efferent muscle sympathetic nerve activity (MSNA) from the right peroneal nerve while simultaneously recording blood pressure and heart rate both during the resting period and after manual acupuncture applied to the Tsusanli acupoint of the same limb. The needle was rotated intermittently for 30 s at 5-min intervals. MSNA increased transiently with the suppression of heart rate during rotation of the acupuncture needle. No consistent change in blood pressure was found throughout the acupuncture session. After removal of the needle, both the MSNA and heart rate returned to the initial control values, and the mean blood pressure showed an increase over the resting value. MSNA showed a negative correlation with heart rate in four out of five subjects who received acupuncture. These results suggest that the coactivation of cardiac vagal and muscle sympathetic nerves is evoked by the acupuncture maneuver.


Subject(s)
Acupuncture Therapy , Muscles/physiology , Sympathetic Nervous System/physiology , Adult , Blood Pressure , Case-Control Studies , Efferent Pathways/physiology , Electrophysiology , Female , Heart Rate , Humans , Male , Muscles/innervation , Peroneal Nerve/physiology
18.
Environ Med ; 37(1): 91-4, 1993.
Article in English | MEDLINE | ID: mdl-12269351

ABSTRACT

In attempting to clarify the effects of aging on the regulatory functions of the cardiovascular system, we measured blood pressure, heart rate and stroke volume during thermoneutral head-out water immersion in seven healthy elderly and eight healthy young subjects. In the young subjects water immersion resulted in a marked increase in stroke volume, a deceleration of the heart rate and stable blood pressure values. In the elderly group the blood pressure increased significantly during shoulder-level water immersion. Compared to the young subjects, the elderly presented a less pronounced elevation of the stroke volume, and no change in the heart rate. These results indicate that the vasodepressive mechanisms regulated by baroreflexes diminish with aging, resulting in an elevation of blood pressure.


Subject(s)
Aging/physiology , Baroreflex/physiology , Fluid Shifts/physiology , Immersion/physiopathology , Stroke Volume/physiology , Adult , Aged , Blood Pressure/physiology , Heart Rate/physiology , Humans , Male , Water , Weightlessness Simulation
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