Mitsuo Iwasaki

Identification of the central imidazoline receptor subtype involved in modulation of halothane-epinephrine arrhythmias in rats

We previously reported that imidazoline receptors in the central nervous system are involved in modulation of halothane-epinephrine arrhythmias. These receptors have been subclassified as I1 and I2 subtypes, but it is not known which receptor subtype is involved in halothane-epinephrine-induced arrhythmias. We designed the present study to clarify the involvement of central imidazoline receptor subtype in the modulation of halothane-epinephrine-induced arrhythmias. Rats were anesthetized with halothane and monitored continuously for systemic arterial blood pressure and premature ventricular contractions. The arrhythmogenic dose of epinephrine was defined as the smallest dose that produces three or more premature ventricular contractions within a 15-s period. Intracisternal moxonidine dose-dependently inhibited the epinephrine-induced arrhythmias during halothane anesthesia. Intracisternal efaroxan, a selective I1 antagonist with little affinity for I2 subtype, but not rauwolscine, an &agr;2 antagonist without affinity for imidazoline receptors, blocked the antiarrhythmic effect of moxonidine. Intracisternal BU 224 and 2-BFI, selective I2 ligands, also inhibited the epinephrine-induced arrhythmias dose-dependently; however, these effects were abolished by efaroxan. We conclude that central I1, but not I2, receptors play an important role in inhibition of halothane-epinephrine arrhythmia.

The antiarrhythmic effect of centrally administered rilmenidine involves muscarinic receptors, protein kinase C and mitochondrial signalling pathways

Background and purpose: We have previously demonstrated that stimulation of imidazoline receptors in the CNS prevented halothane–adrenaline arrhythmias during halothane anaesthesia and that stimulation of the vagus nerve may be critical to this effect. However, details of the mechanism(s) involved are not yet available. The present study was designed to examine the role of muscarinic receptors, protein kinase C (PKC), ATP‐sensitive potassium channels (KATP) and the mitochondrial permeability transition pore (MPTP) in the antiarrhythmic effect of rilmenidine, an imidazoline receptor agonist.

Diabetes mellitus reduces the antiarrhythmic effect of ion channel blockers.

We designed the present study to examine whether diabetes mellitus affects the antiarrhythmic effect of flecainide, a sodium channel blocker, E-4031, a potassium channel blocker, and verapamil, a calcium channel blocker, in diabetic rats. The experiments were performed in intact and diabetic rats 2, 4, and 6 wk after administration of streptozotocin. Rats were anesthetized with halothane and monitored continuously for arterial blood pressure and premature ventricular contractions. The arrhythmogenic dose of epinephrine was defined as the smallest dose producing 3 or more premature ventricular contractions within a 15-s period. The arrhythmogenic doses of epinephrine in the presence of flecainide were 8.2 ± 2.2 (mean ± sd), 7.4 ± 6.1, 5.5 ± 2.8, and 2.0 ± 0.5 &mgr;g/kg in intact and diabetic rats 2, 4, and 6 wk after streptozotocin administration, respectively. Similarly, the arrhythmogenic doses of epinephrine in the presence of E-4031 were 7.7 ± 2.6, 2.3 ± 0.7, 2.0 ± 0.7, and 1.2 ± 0.5 &mgr;g/kg, and those in the presence of verapamil were 8.2 ± 2.1, 3.1 ± 1.2, 2.3 ± 0.9, and 1.5 ± 0.5 &mgr;g/kg. Insulin partially recovered the antiarrhythmic effect of the blockers. We concluded that diabetes mellitus reduces the antiarrhythmic effects of flecainide, E-4031, and verapamil.

Nicorandil preserves myocardial function following brain death in rats by mitochondrial adenosine triphosphate-sensitive potassium channel-dependent mechanism.

OBJECTIVE Interventions to preserve myocardial function after brain death may increase the donor pool for heart transplantation. The present study using a brain death model of rats was designed to examine the protective potential of nicorandil, an adenosine triphosphate-sensitive potassium channel opener, on myocardial function after brain death. METHODS Rats were anesthetized with sevoflurane. A Fogarty catheter was placed intracranially for induction of brain death. The conductance catheter was inserted into the left ventricle for measurement of myocardial function. Rats were assigned randomly to two groups, one receiving nicorandil before brain death and the other receiving saline (control group). Mean blood pressure, heart rate, maximal rate of rise of left-ventricular pressure and ejection fraction were measured every 30 min for 6h after brain death. The same protocol was performed in the presence of nicorandil combined with 5-hydroxydecanoic acid, a mitochondrial adenosine triphosphate-sensitive potassium channel inhibitor. RESULTS Nicorandil temporally, but significantly, improved ejection fraction compared with the control group. Furthermore, 5-hydroxydecanoic acid inhibited the effects of nicorandil. CONCLUSIONS Nicorandil was effective to preserve ejection fraction after brain death, and myocardial mitochondrial adenosine triphosphate-sensitive potassium channels may be involved in this action.

Risk of Hematoma in Patients With a Bleeding Risk Undergoing Cardiovascular Surgery with a Paravertebral Catheter.

OBJECTIVE This study aimed to determine the risk of hematoma associated with thoracic paravertebral block (TPVB) in patients undergoing cardiovascular surgery. DESIGN Retrospective analysis. SETTING Single university hospital. PARTICIPANTS The study comprised 141 patients who underwent cardiovascular surgery with TPVB to relieve postoperative pain. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Three patients were excluded and of the remaining 138, TPVB was performed in 135, ages 11 to 96 years, who either had a clotting abnormality or were on anticoagulant or antiplatelet therapy. No paravertebral, epidural, or spinal hematoma was detected, and only 1 case of superficial bleeding was observed. The frequency of hematoma associated with TPVB in patients with a risk of bleeding undergoing cardiovascular surgery was calculated as 0% (95% confidence interval 0-2.7). CONCLUSION Hematoma did not occur in patients at risk of bleeding who underwent cardiovascular surgery with TPVB for postoperative pain management. However, the risk and benefit in each case still must be considered carefully to determine whether TPVB is indicated.

Activation of phosphatidylinositol 3-kinase/Akt signaling pathway and endogenous nitric oxide are needed for the antiarrhythmic effect of centrally administered rilmenidine

Activation of imidazoline receptors in the central nervous system has protective effect on several types of arrhythmias. We demonstrated that centrally administered rilmenidine, a selective imidazoline receptor agonist, prevented adrenaline-induced arrhythmias during halothane anaesthesia. However, detailed myocardial signaling of the antiarrhythmic effect remains to be unexplored. The present study was designed to examine a role of pertussis toxin-sensitive G protein, phosphatidylinositol 3-kinase/Akt signaling pathway and endogenous nitric oxide in the antiarrhythmic effect of rilmenidine. Male Sprague-Dawley rats were anaesthetized with halothane and monitored continuously for arterial blood pressure and premature ventricular contractions. The arrhythmogenic dose of adrenaline was defined as the smallest dose producing 3 or more premature ventricular contractions within 15-s period. Firstly, we confirmed that centrally administered rilmenidine prevented adrenaline-induced arrhythmias during halothane anaesthesia and examined the effect of pertussis toxin, wortmannin (a phosphatidylinositol 3-kinase inhibitor), and nitro-L-arginine methyl ester (L-NAME) (a specific nitric oxide synthesis inhibitors), on the antiarrhythmic effect of rilmenidine. We also performed Western blot analysis to determine phosphorylation of Akt and glycogen synthase kinase 3β, a direct Akt downstream target, following the central administration of rilmenidine. The antiarrhythmic effect of rilmenidine was significantly inhibited by pertussis toxin, wortmannin and L-NAME. Rilmenidine increased Akt and glycogen synthase kinase 3β phosphorylation (28±13% and 32±13%, respectively), and this action was abolished by wortmannin. The present results demonstrated that pertussis toxin-sensitive G protein, phosphatidylinositol 3-kinase-Akt-GSK3β signaling pathway and endogenous nitric oxide may play a key role in antiarrhythmic effect of centrally administered rilmenidine.

Prophylactic Antiarrhythmic Effect of Anesthetics at Subanesthetic Concentration on Epinephrine-Induced Arrhythmias in Rats after Brain Death

The present study using brain death model of rats was designed to examine whether prophylactic administration of volatile anesthetics and propofol prevent the epinephrine-induced arrhythmias. A Fogarty catheter was placed intracranially for induction of brain death. After brain death, the rats were randomly assigned to five groups: the control group (no anesthetics), the sevoflurane group (0.8%), the isoflurane group (0.5%), the halothane group (0.3%), and the propofol group (195 μg·kg−1 ·min−1). These anesthetics were about 30% of ED50 of each anesthetic. The arrhythmogenic dose of epinephrine was determined in each anesthetic group. In addition, we examined left ventricular levels of connexin 43 phosphorylation 30 min after administration of each anesthetic with Western blot analysis. The arrhythmogenic dose of epinephrine in the sevoflurane group was significantly higher than that in the control group, while the arrhythmogenic dose of epinephrine in any other anesthetic group was not different. On the other hand, the ratio of phosphorylated-connexin 43/total connexin 43 was also similar among the study groups. Thus, prophylactic administration of subanesthetic dose of sevoflurane is effective in preventing epinephrine-induced arrhythmias after brain death, but phosphorylation of connexin is not involved in the antiarrhythmic property of sevoflurane.