Sevoflurane has postconditioning as well as preconditioning properties against hepatic warm ischemia-reperfusion injury in rats.

PURPOSE: Ischemia-reperfusion (IR) injury is inevitable after liver transplantation and liver resection with inflow occlusion. Sevoflurane has been widely used during hepatobiliary surgery and was reported to exhibit preconditioning (PreC) properties against hepatic IR injury; however, its postconditioning (PostC) properties remain unknown. This study examined whether a clinically applicable dose of sevoflurane has PostC and PreC properties against hepatic IR injury and roles of heme oxygenase-1 (HO-1). METHODS: Warm ischemia was induced in male Wistar rats, excluding the sham group, for 1 h, followed by 3 h of reperfusion. Group C received propofol from 60 min before ischemia until the end of the experimental procedure. In the SPreC and SPostC groups, propofol was replaced by 2.5% sevoflurane for 30 min from 35 min before ischemia in the SPreC group and for 30 min from 5 min before reperfusion in the SPostC group. The SPreC+Z and SPostC+Z groups received a HO-1 inhibitor, zinc protoporphyrin (Znpp), 60 min before ischemia, and sevoflurane PreC and PostC were induced. RESULTS: Serum aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase levels, and histological damage scores in the SPreC and SPostC groups were significantly lower than those in group C. Inhibiting HO-1 with Znpp partially blocked these protective effects of sevoflurane. Sevoflurane PreC and PostC significantly increased the number of HO-1-positive Kupffer cells in comparison with group C, and Znpp prevented sevoflurane-induced HO-1 expression. CONCLUSION: PostC and PreC by sevoflurane at a clinically applicable dose have equally protective effects against hepatic IR injury by increasing HO-1 expression.

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.

[The factors that require short acting beta-blockers during general anesthesia using remifentanil].

BACKGROUND: Short acting beta-blockers (SBB) have been utilized effectively to prevent adverse cardiac events perioperatively. After recent introduction of remifentanil in Japan, applications of SBB could have been changed because of its intense analgesic and negative chronotrophic effects. Thus, we evaluated the factors that require SBB during general anesthesia using remifentanil. MATERIALS AND METHODS: Total of 1,631 patients who had general anesthesia with remifentanil were enrolled. Groups were divided by the use of SBB. Using logistic multivariable analysis, the factors significantly increasing the chance of using SBB were evaluated including patients' characteristics, surgical procedures, and anesthetic methods. A P value < 0.05 was considered as statistical significance. RESULTS: One hundred thirty one patients received SBB perioperatively, 94 of them received only when awake and 34 of them received during remifentanil anesthesia. Emergency operation and preoperative ECG abnormalities were significant factors requiring SBB during anesthesia using remifentanil (OR; 3.0, 4.9 respectively). CONCLUSIONS: Even with use of remifentanil there are the patients, such as those under emergency operation or with ECG abnormalities who require SBB perioperatively.

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.

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

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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.

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.

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 microM 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.

Pharmacological preconditioning in type 2 diabetic rat hearts: the roles of mitochondrial ATP-sensitive potassium channels and the phosphatidylinositol 3-kinase-Akt pathway.

PURPOSE: The authors examined whether olprinone, a phosphodiesterase type 3 inhibitor, or isoflurane, a volatile anesthetic, could protect the heart against myocardial infarction in type 2 diabetic rats and whether the underlying mechanisms involve protein kinase C (PKC), mitochondrial ATP-sensitive potassium (m-K(ATP)) channels, or the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. METHODS: All rats underwent 30 min of coronary artery occlusion followed by 2 h of reperfusion. Wistar rats received isoflurane or olprinone before ischemia with or without the PKC inhibitor chelerythrine (CHE), the m-K(ATP) channel blocker 5-hydroxydecanoic acid (5HD), or the PI3K-Akt inhibitor LY294002 (LY). Goto-Kakizaki (GK) rats were randomly assigned to receive isoflurane or olprinone. In another group, GK rats received LY before the olprinone. RESULTS: In the Wistar rats, both isoflurane (38 +/- 11%) and olprinone (40 +/- 11%) reduced infarct size as compared to the control group (59 +/- 8%). In the GK rats, olprinone (41 +/- 9%) but not isoflurane (53 +/- 11%) reduced infarct size as compared to the GK control group (58 +/- 14%). The beneficial effects of olprinone were blocked by LY (58 +/- 14%). In the Wistar rats, CHE, 5HD, and LY prevented isoflurane-induced reductions of infarct size. On the other hand, LY but not CHE or 5HD prevented olprinone-induced reductions of infarct size. CONCLUSIONS: Olprinone but not isoflurane protects the heart against myocardial infarction in type 2 diabetic rats. The olprinone-induced cardioprotective effect is mediated by the PI3K-Akt pathway but not PKC or m-K(ATP) channels.

Milrinone and levosimendan administered after reperfusion improve myocardial stunning in swine.

OBJECTIVES: We assessed the effect of milrinone application timing after reperfusion against myocardial stunning as compared with levosimendan in swine. Furthermore, we examined the role of p38 mitogen-activated protein kinase (p38 MAPK) in the milrinone-induced cardioprotection. DESIGN: All swine were subjected to 12-minutes ischemia followed by 90-minutes reperfusion to generate stunned myocardium. Milrinone or levosimendan was administered intravenously either for 20 minutes starting just after reperfusion or for 70 minutes starting 20 minutes after reperfusion. In another group, SB203580, a selective p38 MAPK inhibitor, was administered with and without milrinone. Regional myocardial contractility was assessed by percent segment shortening (%SS). RESULTS: Milrinone starting just after reperfusion, but not starting 20 minutes after reperfusion, improved %SS at 30, 60, and 90 minutes after reperfusion compared with that in the control group. SB203580 abolished the beneficial effect of milrinone. On the other hand, levosimendan starting 20 minutes after reperfusion, but not for 20 minutes starting just after reperfusion, improved %SS at 60 and 90 minutes after reperfusion. CONCLUSIONS: Milrinone should be administered just after reperfusion to protect myocardial stunning through p38 MAPK, whereas levosimendan improvement of contractile function could be mainly dependent on its positive inotropic effect.

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.

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.

Administration of the Rho-kinase inhibitor fasudil before ischemia or just after reperfusion, but not 30 min after reperfusion, protects the stunned myocardium in swine.

OBJECTIVES: We assessed the effect of administration time for fasudil treatment of the stunned myocardium in 40 anesthetized open chest swine. MATERIALS AND METHODS: All swine were subjected to 12 min ischemia followed by reperfusion to generate stunned myocardium. Group A (n = 11) received saline in place of fasudil both before ischemia and after reperfusion. Group B (n = 10) received 30 min intravenous fasudil at a rate of 13 mug/kg/min starting 45 min before ischemia and received saline after reperfusion. Groups C (n = 10) and D (n = 9) received saline before ischemia, and received fasudil at a rate of 13 microg kg(-1) min(-1) starting just before reperfusion in group C and 30 min after reperfusion in group D. In both groups, treatment lasted 30 min. Myocardial contractility was assessed by percent segment shortening (%SS). RESULTS AND DISCUSSION: Three swine in group A, 2 swine in each of groups B and C, and one swine in group D had ventricular fibrillation or tachycardia after reperfusion and were excluded from further analysis. The changes of %SS from baseline at 90 min after reperfusion in groups B and C were 68 +/- 8% and 75 +/- 8%, respectively, which were significantly higher than in group A or D (47 +/- 10% or 43 +/- 8%). CONCLUSION: We conclude that fasudil administered before ischemia or just after reperfusion, but not 30 min after reperfusion, protects the stunned myocardium.

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

PURPOSE: Ischemic 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. METHODS: Pentobarbital-anesthetized rats (n = 42) subjected to 30-min coronary occlusion followed by 2-h reperfusion, received olprinone (20 microg.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. RESULTS: Mean 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%). CONCLUSION: The olprinone-induced cardioprotective effect could be exerted via the activation of PI3K-Akt and the inhibition of mPTP during early reperfusion.

Milrinone administered before ischemia or just after reperfusion, attenuates myocardial stunning in anesthetized swine.

PURPOSE: We assessed the dose or timing effect of milrinone administered against myocardial stunning in 37 anesthetized open-chest swine. METHODS: All swine were subjected to 12-min ischemia followed by reperfusion to produce myocardial stunning. Group A (n = 12) received saline in place of milrinone both before and after ischemia. Group B (n = 9) and C (n = 9) received intravenous milrinone at a rate of 5 microg/kg/min for 10 min followed by 0.5 microg/kg/min for 10 min and 10 microg/kg/min for 10 min followed by 1 microg/kg/min for 10 min, respectively, until 30 min before coronary occlusion. Group D (n = 7) received the same dose of milrinone as group B starting 1 min after reperfusion. Myocardial contractility was assessed by percentage segment shortening (%SS). RESULTS: Five swine in group A and two swine in groups B and C each had ventricular fibrillation or tachycardia after reperfusion, and were thus excluded from further analysis. The percentage changes of %SS from the baseline 90 min after reperfusion in groups B, C, and D were 78 +/- 9%, 82 +/- 13%, and 79 +/- 7%, respectively, which were significantly higher than those in group A (43 +/- 13%). CONCLUSION: We conclude that milrinone administered before ischemia or just after reperfusion attenuates myocardial stunning.

The effects of dexmedetomidine on left ventricular function during hypoxia and reoxygenation in isolated rat hearts.

Hypoxia resulting from apnea in patients with sleep apnea is an important factor in heart disease. We designed the present study to determine whether dexmedetomidine (DEX) has a direct protective effect against hypoxia-reoxygenation-induced left ventricular dysfunction without systemic hemodynamic and humoral effects. Isolated rat hearts were exposed to 60-min hypoxia followed by 30-min reoxygenation with 0, 10, or 100 nM DEX prehypoxia administration (n = 7 each group). In a second experiment (n = 7), 100 nM DEX was administered posthypoxia. In a third experiment (n = 7 each group), an alpha 2 antagonist, yohimbine was given with and without 100 nM DEX prehypoxia administration. DEX prehypoxia, but not posthypoxia, administration significantly improved the recovery of left ventricular developed pressure after reoxygenation (0, 10, 100 nM DEX prehypoxia or 100 nM DEX posthypoxia values were 53 +/- 6, 64 +/- 9, 78 +/- 13, or 62 +/- 12 mm Hg [mean +/- sd]) and reversed by yohimbine, 58 +/- 8 mm Hg, respectively. We conclude that DEX exerts the direct protective effect on the left ventricular dysfunction caused by hypoxia-reoxygenation through mainly alpha 2-adrenergic stimulation before and during the hypoxic period.

Cardioprotective effects of KB-R7943, a novel inhibitor of Na+/Ca2+ exchanger, on stunned myocardium in anesthetized dogs.

PURPOSE: The present study was carried out to determine the cardioprotective effects of KB-R7943 (KBR), a selective inhibitor of the reverse mode of Na+/Ca2+ exchanger (NCX), on stunned myocardium in anesthetized dogs. METHODS: The dogs were allocated to one of three groups (n = 7 for each group), and received drug vehicle (group C), low-dose KBR (5 mg x kg(-1) i.v.) (group L) or high-dose KBR (10 mg x kg(-1) i.v.) (group H) at 15 min before left anterior descending coronary artery (LAD) occlusion. Stunned myocardium was produced by 15-min occlusion of LAD and 90-min reperfusion in all dogs. Regional myocardial contractility was evaluated with segment shortening (%SS). RESULTS: Recovery of %SS at 90 min after reperfusion was significantly improved in group H (70.8% +/- 3.9% of baseline), whereas the recovery was poor in groups C and L (34.3% +/- 2.8% and 36.4% +/- 5.4% of baseline, respectively). Regional myocardial blood flow showed no significant difference among groups. KBR had no effect on coronary or systemic hemodynamics. CONCLUSION: The results show that preischemic administration of high-dose KBR markedly improves myocardial contractile dysfunction after ischemia-reperfusion in anesthetized dogs, indicating that KBR protects myocardium against the ischemia-reperfusion injury in vivo.

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

PURPOSE: We 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. METHODS: In 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. RESULTS: In normal myocardium, intracoronary infusion of propofol at doses of 1.2 and 2.4 mg x kg(-1) x 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. CONCLUSION: Propofol 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.

Hemodynamic interactions of propofol and dantrolene in chronically instrumented dogs.

UNLABELLED: The hemodynamic interaction of dantrolene, a specific drug for malignant hyperthermia, and propofol which appears to be safe in malignant hyperthermia-susceptible patients, has not been investigated. We performed this study to examine the hemodynamic actions of dantrolene at a therapeutic dose during propofol anesthesia. Ten dogs were chronically instrumented for the measurements of systemic and coronary hemodynamics. The dogs were assigned to receive propofol with vehicle or dantrolene in a random manner on separate experimental days. Propofol significantly decreased mean arterial blood pressure, left ventricular systolic and end-diastolic pressure, the maximal rate of increase in left ventricular pressure, and left ventricular regional segment shortening. Coronary blood flow (CBF) was unchanged but coronary vascular resistance (CVR) decreased. Dantrolene reversed the decrease in mean arterial blood pressure and left ventricular systolic pressure caused by propofol, and significantly increased heart rate. However, left ventricular end-diastolic pressure, cardiac output, maximal rate of increase in left ventricular pressure, and segment shortening were unchanged. CBF was significantly increased with a decrease in CVR. These results suggest that dantrolene reverses the hypotensive action produced by propofol and causes an increase in CBF with a decrease in CVR, but does not significantly change the negative inotropic effects. Thus, dantrolene exerts favorable hemodynamic effects during propofol anesthesia. IMPLICATIONS: Our study suggests that dantrolene reverses the hypotensive action produced by propofol and causes an increase in coronary blood flow with a decrease in coronary vascular resistance, but does not significantly change the negative inotropic effects.