Takuji Maekawa

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

ABSTRACT Systemic administration of &agr;2-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. ABBREVIATIONS VT—ventricular tachycardia VF—ventricular fibrillation NE—norepinephrine DEX—dexmedetomidine PaCO2—arterial carbon dioxide tension PaO2—arterial oxygen tension LAD—left anterior descending coronary artery CBF—coronary blood flow LV—left ventricular LVP—left ventricular pressure LVdP/dtmax—peak rate of increase in left ventricular pressure %SS—percentage of segment shortening RMBF—regional myocardial blood flow endo/epi—subendocardial to subepicardial

Cardioprotection induced by olprinone, a phosphodiesterase III inhibitor, involves phosphatidylinositol-3-OH kinase-Akt and a mitochondrial permeability transition pore during early reperfusion

PurposeIschemic preconditioning is mediated by the activation of phosphatidylinositol-3-OH kinase-Akt (PI3K-Akt) and by the inhibition of the opening of a mitochondrial permeability transition pore (mPTP) during early reperfusion. Preischemic administration of the phosphodiesterase type III inhibitor olprinone protects the myocardium against infarction, but its mechanism has not been fully clarified. We hypothesized that this olprinone-induced cardioprotective effect was mediated by the activation of PI3K-Akt and by the inhibition of mPTP during early reperfusion.MethodsPentobarbital-anesthetized rats (n = 42) subjected to 30-min coronary occlusion followed by 2-h reperfusion, received olprinone (20 µg·kg−1) or saline (control) in the preischemic phase in the presence or absence of the PI3K-Akt inhibitor wortmannin (0.6 mg·kg−1) or the mPTP opener atractyloside (5 mg·kg−1) before 5 min of reperfusion. The myocardial infarct size was expressed as a percentage of the area at risk. All values were expressed as means ± SD. Statistical comparisons within groups were made using repeated-measures analysis of variance (ANOVA), followed by a paired t-test, and comparisons among groups were analyzed using a two-way ANOVA, followed by the Tukey-Kramer test.ResultsMean arterial pressure and heart rate showed no significant differences within or among groups. The preischemic administration of olprinone significantly reduced the infarct size (12 ± 4%) as compared with that in the control group (43 ± 4%). Wortmannin or atractyloside abolished the protective effect of olprinone (42 ± 11% or 41 ± 10%).ConclusionThe olprinone-induced cardioprotective effect could be exerted via the activation of PI3K-Akt and the inhibition of mPTP during early reperfusion.

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

BackgroundThe 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.MethodsMale 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).ResultsUnder 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%).ConclusionFasudil 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.

Roles of Cyclooxygenase 2 in Sevoflurane- and Olprinone-Induced Early Phase of Preconditioning and Postconditioning Against Myocardial Infarction in Rat Hearts

Purpose: 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. Methods: Male Sprague-Dawley rats were anesthetized with sodium pentobarbital. After opening the chest, all rats underwent 30-minute occlusion of left anterior descending coronary artery followed by 2-hour reperfusion, and the infarct size was measured after the reperfusion. The rats were randomly assigned to groups with pre- and postischemic exposure to sevoflurane and administration of olprinone with or without a selective COX-2 inhibitor, NS-398. Results: The infarct size in the control group was 42% ± 6% of the area at risk. Infarct size was significantly reduced by pre- and postischemic administration of sevoflurane (16% ± 7% and 17% ± 6%, respectively), as well as by olprinone (14% ± 4% and 15% ± 10%, respectively). NS-398 prevented the protective effects of both pre- and postischemic exposure to sevoflurane (35% ± 8% and 42% ± 10%, respectively), whereas the protective effect of both pre- and postischemic administration of olprinone was not influenced by NS-398 (12% ± 5% and 19% ± 7%, respectively). Conclusions: Cyclooxygenase 2 could be a critical mediator of sevoflurane-induced but not olprinone-induced E-PreC or PostC in rat hearts.

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

BackgroundThe 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).MethodsWistar 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.ResultsUnder 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.ConclusionMilrinone 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.

Catecholamine and renin-angiotensin response during controlled hypotension induced by prostaglandin E1 combined with hemodilution during isoflurane anesthesia

STUDY OBJECTIVE To evaluate the catecholamine and renin-angiotensin response during controlled hypotension combined with hemodilution in the clinical setting. DESIGN Randomized, prospective study. SETTING Inpatient surgery at Nagasaki Rosai Hospital. PATIENTS 30 ASA physical status I and II female patients scheduled for total hip arthroplasty. INTERVENTIONS Patients were randomly divided into three groups. Group A (N = 10) received hemodilution alone. Group B (N = 10) received controlled hypotension alone. Group C (N = 10) received hemodilution plus controlled hypotension. Hemodilution was carried out after induction of anesthesia, in which drawn blood was replaced with 6% hydroxyethyl starch, and the final hematocrit value was approximately 22%. Controlled hypotension was induced with prostaglandin E1 (PGE1) to maintain mean arterial blood pressure at 55 mmHg for 80 minutes. MEASUREMENTS AND MAIN RESULTS Measurements included plasma renin activity (RA) and plasma concentrations of angiotensin-II (AG-II), aldosterone (AS), norepinephrine (NE), and epinephrine (EP). These indices were measured before hemodilution, after hemodilution, 80 minutes after starting hypotension, and 60 minutes after recovery from hypotension. Hemodilution alone caused no significant change in the values throughout the time course. Controlled hypotension alone caused significant increases in plasma concentrations of NE (+295%) and EP (+203%) at 80 minutes after starting hypotension, whereas it caused no change in plasma RA and plasma concentrations of AG-II and AS. Hemodilution plus controlled hypotension caused significant increases in plasma RA (+271%) and plasma concentrations of AG-II (+188%), AS (+199%), NE (+279%), and EP (+184%) at 80 minutes after starting hypotension. CONCLUSION The combination of hemodilution and PGE1 induced controlled hypotension causes significant responses, especially in a renin-angiotensin-aldosterone system under isoflurane anesthesia.

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

Abstract Objectives. The present study was carried out to determine whether inhalation of hydrogen (H2) 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% H2 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% H2 plus 98% oxygen. Group E inhaled 4% H2 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% H2 gas improves myocardial stunning, and inhalation of 4% but not 2% H2 gas reduces myocardial infarct size in swine.

Effect of Controlled Hypotension Combined with Hemodilution on Gastric Intramural pH

STUDY OBJECTIVE To evaluate the effect of controlled hypotension combined with hemodilution on gastric intramural pH in the clinical setting. DESIGN Randomized, prospective study. SETTING Inpatient surgery at Nagasaki Rosai Hospital. PATIENTS 30 ASA physical status I and II patients scheduled for total hip arthroplasty. INTERVENTIONS Patients were randomly divided into two groups. Group A (n = 15) received controlled hypotension with mild hemodilution. Group B (n = 15) received controlled hypotension with moderate hemodilution. Hemodilution was carried out after induction of anesthesia. Drawn blood was replaced with 6% hydroxyethyl starch solution. Final hematocrit values were 32 +/- 2% (mean +/- SD) in Group A and 23 +/- 2% in Group B. Controlled hypotension was induced with prostaglandin E1 (PGE1) to maintain mean arterial blood pressure at 55 mmHg for 80 minutes. MEASUREMENTS AND MAIN RESULTS Measurements included gastric intramural pH (pHi), arterial blood pH (pHa), and plasma lactate. These indices were measured before hemodilution, after hemodilution, 80 minutes after starting hypotension, 60 minutes after recovery from hypotension, and on the first postoperative day. The value of pHi was measured by tonometry. The pHa and lactate values showed no change in either Group A or Group B throughout the time course. Gastric pHi values showed no change in Group A throughout the time course. The pHi value in Group B showed a significant decrease from 7.420 +/- 0.028 to 7.339 +/- 0.034 (p < 0.05) after hemodilution, while it showed no further decrease at 80 minutes after starting hypotension (7.331 +/- 0.039) and 60 minutes after recovery from hypotension (7.330 +/- 0.048). CONCLUSION The results suggest that moderate hemodilution, such as 23% of hematocrit value, might impair oxygenation in gastrointestinal mucosa, whereas controlled hypotension induced by PGE1 combined with the hemodilution would not increase this impairment.

Milrinone-induced postconditioning reduces hepatic ischemia-reperfusion injury in rats: the roles of phosphatidylinositol 3-kinase and nitric oxide.

BACKGROUND Ischemic postconditioning (PostC) protects the liver against ischemia-reperfusion (IR) injury. Milrinone, a phosphodiesterase 3 inhibitor, has been reported to exhibit preconditioning properties against hepatic IR injury; however, its PostC properties remain unknown. This study investigated whether milrinone has PostC properties against hepatic IR injury and the roles of phosphatidylinositol 3-kinase (PI3K) and nitric oxide synthase (NOS). MATERIALS AND METHODS Male Wistar rats were separated into six groups: (1) group S: animals that underwent sham operation without ischemia, (2) group C: ischemia followed by reperfusion with no other intervention, (3) group M: milrinone administered immediately after reperfusion, (4) group MW: wortmannin, a PI3K inhibitor, injected before milrinone administration, (5) group MN: l-NAME, a NOS inhibitor, injected before milrinone administration, and (6) group MD, milrinone administered 30 min after reperfusion. Except for group S, all groups underwent 1 h of warm ischemia of median and left lateral lobes, followed by 5 h of reperfusion. Biochemical liver function analysis and histologic examination were performed. RESULTS Serum aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase levels, histologic damage scores, and apoptotic rate in group M were significantly lower than those in group C. The inhibition of PI3K or NOS prevented this protective effect. Milrinone administered 30 min after reperfusion did not show obvious protective effects. CONCLUSIONS Milrinone-induced PostC protects against hepatic IR injury when it is administered immediately after reperfusion, and PI3K and NOS may play an important role in this protective effect.

Negative inotropic action of propofol is enhanced in the acute ischemic myocardium of dogs

PurposeWe investigated the effects of propofol on contractility and oxygen balance in acute ischemic myocardium and compared them with those of normal myocardium using a coronary microembolization model in dogs.MethodsIn open-chest dogs, the left anterior descending coronary artery (LAD) was perfused through an extracorporeal bypass from the carotid artery. Regional myocardial contractility and myocardial oxygen balance were evaluated along with segment shortening (%SS), regional myocardial oxygen consumption (MVO2), and lactate extraction ratio (LER) of the area perfused by the LAD. Acute ischemia was produced by repeated injection of microspheres into the LAD-perfused area until %SS decreased by 50% of baseline.ResultsIn normal myocardium, intracoronary infusion of propofol at doses of 1.2 and 2.4 mg·kg−1·h−1 caused slight decreases in %SS to 83% ± 8% and 80% ± 10%, respectively. In ischemic myocardium, propofol caused greater decreases in %SS (59% ± 18% and 35% ± 20%, respectively). The changes in MVO2 after propofol infusion generally paralleled the changes in %SS, but LER was not changed in either ischemic or normal myocardium.ConclusionPropofol causes a greater decrease in the contractility of acute ischemic myocardium as compared with normal myocardium in which myocardial oxygen imbalance is not involved as a mechanism.