Differential Effects of the Sedative Agents on the Heart Rate Response to Intravenous Isoproterenol Infusion.

Bradycardia is one of the adverse events associated with the sedatives, dexmedetomidine (DM) and propofol (PF). Because PF and DM attenuate the heart rate (HR) response to intravenous (IV) atropine, isoproterenol may be required for the treatment of bradycardia during DM or PF sedation. Therefore, we conducted the current study to evaluate the effect of DM or PF on the response of HR to IV isoproterenol. Male Sprague-Dawley rats were randomly allocated to one of three groups. Group C (n=7) received sodium pentobarbital intraperitonealy and IV saline. Group PF (n=7) received IV PF. Group DM (n=7) received IV DM. Then all groups received IV isoproterenol at incremental infusion rates (0.1, 0.3, 0.5, 1.0, and 3.0 ng/kg/min for 2 min each dose). Blood pressure decreased significantly in the groups C and DM, and HR decreased significantly in group DM after administration of each sedative. The increases in HR at 0.5, 1.0, and 3.0 ng/kg/min isoproterenol in group DM were 7 5ﾂｱ41, 86ﾂｱ36, and 110ﾂｱ39 beats/min, respectively, and were greater as compared with those in group C (35ﾂｱ29, 38ﾂｱ30, and 57ﾂｱ32 beats/min, respectively), but there were no significant differences between groups C and PF. In conclusion, DM but not PF enhances the HR response to the continuous IV infusion of isoproterenol, suggesting that isoproterenol may be useful when atropine is ineffective for the treatment of bradycardia during DM or PF sedation. (245 words

Hyperglycemia raises the threshold of levosimendan- but not milrinone-induced postconditioning in rat hearts

<p>Abstract</p> <p>Background</p> <p>The authors examined whether milrinone and levosimendan could exert cardiac postconditioning effects in rats under normoglycemia and hyperglycemia, and whether the effects could be mediated by mitochondrial permeability transition pore (mPTP).</p> <p>Methods</p> <p>Wistar rats underwent 30-min coronary artery occlusion followed by 2-h reperfusion. The rats received milrinone or levosimendan just before reperfusion under normoglycemic or hyperglycemic conditions with or without atractyloside, an mPTP opener.</p> <p>Results</p> <p>Under normoglycemia, both 30 μg/kg milrinone (29 ± 12%) and 10 μg/kg levosimendan (33 ± 13%) reduced infarct size compared with that in the control (58 ± 7%). Under hyperglycemia, milrinone (34 ± 13%) reduced infarct size at the same dose as under normoglycemia. In contrast, neither 10 nor 30 μg/kg levosimendan protected hyperglycemic hearts, and only 100 μg/kg levosimendan (32 ± 9%) reduced infarct size compared with that in the hyperglycemic control (58 ± 13%). All of these cardioprotective effects under normoglycemia and hyperglycemia are abolished by atractyloside.</p> <p>Conclusion</p> <p>Milrinone and levosimendan exert postconditioning effects via inhibition of mPTP opening. Hyperglycemia raises the threshold of levosimendan-induced postconditioning, while milrinone-induced postconditioning is not influenced by hyperglycemia.</p

Roles of cyclooxygenase 2 in sevoflurane- and olprinone-induced early phase of preconditioning and postconditioning against myocardial infarction in rat hearts.

It is known that selective cyclooxygenase 2(COX-2) inhibitors increase mortality in patients with previous myocardial infarction, and it has been suggested that COX-2 plays an important role in cardioprotection against ischemia. The current study was carried out to determine whether COX-2 is involved in the mechanisms of sevoflurane- and olprinone-induced early-phase preconditioning (E-PreC) and postconditioning (PostC) in rat hearts

Direct effect of mild hypothermia on the coronary vasodilation induced by an ATP-sensitive K channel opener, a nitric oxide donor and isoflurane in isolated rat hearts.

PURPOSE: Deliberate mild hypothermia (MHT) is applied for cerebroprotection after cardiopulmonary resuscitation and during cardiac surgery. MHT has been shown to alter both contractility and relaxation of blood vessels in the brain. However, the effects of MHT on drug-induced vasodilation are not fully understood. The aim of this study was to clarify the effects of MHT on the coronary vasodilation induced by cromakalim (an ATP-sensitive K channel opener), S-nitroso acetyl-penicillamine (SNAP; a nitric oxide donor), and isoflurane in isolated rat hearts. METHODS: Male SD rat hearts were isolated and perfused with Krebs-Henseleit buffer. Coronary flow was measured with the coronary perfusion pressure kept at 60 mmHg, and coronary vascular resistance (CVR) was calculated. After cardiac arrest was induced by tetrodotoxin, the hearts were allocated to one of three temperature groups: 37, 34, and 31 degrees C (n = 7 for each). All groups received 0.01, 0.1, and 1.0 muM of either cromakalim or SNAP or were exposed to isoflurane at 1MAC and 2MAC. Finally, 50 mM of adenosine was administered to obtain maximal coronary vasodilation. RESULTS: CVR significantly increased after cardiac arrest, but did not change after the application of each temperature. Cromakalim, SNAP and isoflurane significantly decreased CVR in each temperature group. There were no significant differences in CVR among the three temperature groups with any of the test drugs. CONCLUSION: These results indicate that cromakalim-, SNAP-, and isoflurane-induced coronary vasodilation are not affected by MHT

Direct protective effects of dexmedetomidine against myocardial ischemia-reperfusion injury in anesthetized pigs

Systemic administration of α2-adrenergic agonists has been shown to protect ischemic myocardium, but the direct effects on ischemia-reperfused myocardium have not yet been clarified. This study was carried out to determine the effects of intracoronary dexmedetomidine (DEX) on the myocardial ischemia-reperfusion injury in anesthetized pigs. In open-chest pigs, the left anterior descending coronary artery was perfused through an extracorporeal circuit from the carotid artery. They received intracoronary infusion of DEX at a rate of 1 ng • mL -1 (group LD, n = 9), 10 ng • mL -1 (group MD, n = 9), or 100 ng • mL -1 (group HD, n = 9) of coronary blood flow or vehicle (group C, n = 12) for 30 min before ischemia. Myocardial stunning was produced by 12-min ischemia of the perfused area of left anterior descending coronary artery and 90-min reperfusion. The effect on reperfusion-induced arrhythmias was evaluated using the incidence of ventricular tachycardia or fibrillation after reperfusion. Regional myocardial contractility was evaluated with segment shortening (%SS). Dexmedetomidine significantly reduced the incidence of reperfusion-induced ventricular arrhythmias. Dexmedetomidine significantly improved the recovery of percentage segment shortening at 90 min after reperfusion (32.6% ± 3.1% in group C, 58.2% ± 2.1% in group LD, 61.1% ± 1.8% in group MD, and 72.0% ± 2.0% in group HD). Dexmedetomidine suppressed the increase in plasma norepinephrine concentration after reperfusion. The results indicate that DEX would exert the protective effect against ischemia-reperfusion injury by the direct action on the myocardium, which is not mediated through the central nervous system

High-dose fasudil preserves postconditioning against myocardial infarction under hyperglycemia in rats: Role of mitochondrial KATP channels

Background: The current study was carried out to determine whether fasudil hydrochloride (fasudil), a Rho-kinase inhibitor, has myocardial postconditioning (PostC) activity under hyperglycemia as well as normoglycemia, and if so, whether the effects could be mediated by mitochondrial ATP-sensitive potassium (m-KATP) channels.Methods: Male Sprague-Dawley rats were anesthetized with sodium pentobarbital. After opening the chest, all rats underwent 30-min coronary artery occlusion followed by 2-h reperfusion. The rats received low-dose (0.15 mg/kg) or high-dose (0.5 mg/kg) fasudil or diazoxide, an m-KATP channel opener, at 10 mg/kg, just before reperfusion under normoglycemic or hyperglycemic conditions. In another group, rats received 5-hydroxydecanoic acid (5HD), an m-KATP channel blocker, at 10 mg/kg, before high-dose fasudil. Myocardial infarct size was expressed as a percentage of area at risk (AAR).Results: Under normoglycemia, low-dose and high-dose fasudil and diazoxide reduced myocardial infarct size (23 ± 8%, 21 ± 9% and 21 ± 10% of AAR, respectively) compared with that in the control (42 ± 7%). Under hyperglycemia, low-dose fasudil (40 ± 11%) and diazoxide (44 ± 14%) could not exert this beneficial effect, but high-dose fasudil reduced myocardial infarct size in the same manner as under normoglycemia (21 ± 13%). 5HD prevented fasudil-induced reduction of myocardial infarct size (42 ± 13%).Conclusion: Fasudil induces PostC against myocardial infarction via activation of m-KATP channels in the rat. Although hyperglycemia attenuates the PostC, high-dose fasudil can restore cardioprotection

Direct effect of mild hypothermia on the coronary vasodilation induced by an ATP-sensitive K channel opener, a nitric oxide donor and isoflurane in isolated rat hearts.

PURPOSE: Deliberate mild hypothermia (MHT) is applied for cerebroprotection after cardiopulmonary resuscitation and during cardiac surgery. MHT has been shown to alter both contractility and relaxation of blood vessels in the brain. However, the effects of MHT on drug-induced vasodilation are not fully understood. The aim of this study was to clarify the effects of MHT on the coronary vasodilation induced by cromakalim (an ATP-sensitive K channel opener), S-nitroso acetyl-penicillamine (SNAP; a nitric oxide donor), and isoflurane in isolated rat hearts. METHODS: Male SD rat hearts were isolated and perfused with Krebs-Henseleit buffer. Coronary flow was measured with the coronary perfusion pressure kept at 60 mmHg, and coronary vascular resistance (CVR) was calculated. After cardiac arrest was induced by tetrodotoxin, the hearts were allocated to one of three temperature groups: 37, 34, and 31 degrees C (n = 7 for each). All groups received 0.01, 0.1, and 1.0 muM of either cromakalim or SNAP or were exposed to isoflurane at 1MAC and 2MAC. Finally, 50 mM of adenosine was administered to obtain maximal coronary vasodilation. RESULTS: CVR significantly increased after cardiac arrest, but did not change after the application of each temperature. Cromakalim, SNAP and isoflurane significantly decreased CVR in each temperature group. There were no significant differences in CVR among the three temperature groups with any of the test drugs. CONCLUSION: These results indicate that cromakalim-, SNAP-, and isoflurane-induced coronary vasodilation are not affected by MHT

Postischemic infusion of sivelestat sodium hydrate, a selective neutrophil elastase inhibitor, protects against myocardial stunning in swine.

PURPOSE: It seems controversial whether or not neutrophil elastase inhibitors are effective in attenuating myocardial ischemia/reperfusion injury. We thus investigated possible protective effects of sivelestat, a neutrophil elastase inhibitor, against myocardial stunning i.e., prolonged myocardial dysfunction following a brief episode of ischemia. METHODS: Swine were divided into control group (group C), low-dose sivelestat group (group L), and high-dose sivelestat group (group H) (n = 7 for each group). All the swine were subjected to myocardial ischemia through ligation of the left anterior descending (LAD) coronary artery for 12-min, followed by 90-min reperfusion. Sivelestat was infused intracoronally at concentrations of 6 and 60 mg/ml throughout the reperfusion period in groups L and H, respectively, while saline was infused in the group C. Heart rate (HR), left ventricular developed pressure (LVdP), maximum rate of LVdP (LVdP/dt (max)), LV end-diastolic pressure (LVEDP), percentage of segment shortening (%SS, an index of regional myocardial contractility), and coronary venous interleukin-6 concentration in the LAD perfusion area were measured before ischemic induction and during reperfusion. RESULTS: The ischemia/reperfusion insult did not cause any significant changes in HR, LVdP, LVdP/dt (max), and LVEDP in all groups. However, it significantly reduced %SS in the LAD perfusion area and increased the interleukin-6 concentration in group C. Those changes in %SS and the interleukin-6 concentration were both greatly attenuated, but not prevented, in groups L and H. CONCLUSION: Sivelestat presumably attenuates myocardial contractile dysfunction due to myocardial stunning by inhibiting neutrophil-derived elastase, thereby suppressing the production of interleukin-6 in activated neutrophils

SNP@Domain: a web resource of single nucleotide polymorphisms (SNPs) within protein domain structures and sequences.

The single nucleotide polymorphisms (SNPs) in conserved protein regions have been thought to be strong candidates that alter protein functions. Thus, we have developed SNP@Domain, a web resource, to identify SNPs within human protein domains. We annotated SNPs from dbSNP with protein structure-based as well as sequence-based domains: (i) structure-based using SCOP and (ii) sequence-based using Pfam to avoid conflicts from two domain assignment methodologies. Users can investigate SNPs within protein domains with 2D and 3D maps. We expect this visual annotation of SNPs within protein domains will help scientists select and interpret SNPs associated with diseases. A web interface for the SNP@Domain is freely available at http://snpnavigator.net/ and from http://bioportal.net/.This project was supported by the Korean Ministry of Science and Technology (MOST) under grant number M10508040002-05N0804-00210 and M10407010001-05N0701-00100. Y.B.C. is supported by Biogreen21 program (20050401-034-791-006-03-00 and 20050301-034-481-006-02-00). Funding to pay the Open Access publication charges for this article was provided by M10407010001-05N0701-00100 grant of MOST

Inhalation of hydrogen gas protects against myocardial stunning and infarction in swine

Objectives. The present study was carried out to determine whether inhalation of hydrogen (H 2) gas protects myocardium against ischemia-reperfusion (I/R) injury in swine. Design. In anesthetized open-chest swine, myocardial stunning was produced by 12-minute occlusion of left anterior descending coronary artery (LAD) followed by 90-minute reperfusion in the first study. Group A inhaled 100% oxygen, and group B inhaled 2% H 2 plus 98% oxygen during ischemia and reperfusion. In the second study, myocardial infarction was produced by 40-minute occlusion of LAD followed by 120-minute reperfusion. Group C inhaled 100% oxygen during ischemia and reperfusion. Group D inhaled 2% H 2 plus 98% oxygen. Group E inhaled 4% H 2 plus 96% oxygen. Results. The change of segment shortening (%SS) from baseline at 90 minutes after reperfusion in group B was 74±13 (mean ± SD) %, which was significantly higher than that in group A (48±15%). Myocardial infarct size in group E (32±10%), but not in group D (40±9%) was smaller than that in group C (46±6%). Conclusions. Inhalation of 2% H 2 gas improves myocardial stunning, and inhalation of 4% but not 2% H 2 gas reduces myocardial infarct size in swine