Activation Of Adenosine Triphosphate-sensitive Potassium Channels Research Articles

Reactive Oxygen Species Mediate Nicorandil-induced Metabolic Tolerance to Spinal Cord Injury

Spinal cord injury remains a devastating complication of thoracoabdominal aortic surgery. We previously demonstrated that pretreatment with nicorandil preserved motor function in a murine spinal cord injury model through mitochondrial adenosine triphosphate-sensitive potassium channel activation. We hypothesized that the neuroprotective effect of nicorandil is mediated by downstream generation of reactive oxygen species. Spinal cord injury was induced by 7 minutes of thoracic aortic cross-clamping in adult male C57BL/6 mice. Five groups were evaluated: ischemic control (n= 19); nicorandil 1.0 mg/kg (n= 17); nicorandil 1.0 mg/kg plus N acetyl L-cysteine (NAC [reactive oxygen species scavenger, n= 18)]) 150 mg/kg; NAC 150 mg/kg (n= 13); and sham (n= 10). Limb motor function and the number of viable neurons within the anterior horn of the spinal cord were evaluated. Mice in the sham group showed no functional deficits after surgery. Compared with ischemic control, motor function was significantly preserved in the nicorandil pretreatment group at every timepoint after ischemia. In the nicorandil plus NAC group, the motor-preserving effect of nicorandil was completely abolished (P < .001). Viable neuron quantification showed significant neuron preservation in the nicorandil group (29.± 2.6) compared with the ischemic control group (18.5 ± 2.1, P= .024) and nicorandil plus NAC group (14 ± 8.3, P= .001); no significant difference was observed between the ischemic control group and nicorandil plus NAC group (P= 0.768). Reactive oxygen species generation plays a key role in the nicorandil-induced metabolic tolerance to spinal cord injury. Manipulation of mitochondrial adenosine triphosphate-sensitive potassium channels may lead to improvement in preventing spinal cord injury after thoracoabdominal aortic interventions.

Nicorandil Protects Pial Arterioles From Endothelial Dysfunction Induced by Smoking in Rats

Our aims are to investigate the effect of nicorandil, which is used for angina prevention and treatment, on the endothelial dysfunction induced by acute smoking and to clarify the underlying mechanism. A closed cranial window preparation was used to measure changes in pial vessel diameters in Sprague-Dawley rats. The responses of arterioles were examined to an endothelium-dependent vasodilator acetylcholine (ACh) before smoking. After intravenous nicorandil (200 μg/kg bolus infusion and then 60 μg/kg/min continuous infusion; n=6) or saline (control; n=6) pretreatment, the pial vasodilator response to topical 10 M ACh infusion was reexamined both before and 1 hour after 1-minute cigarette smoking. Thereafter, either glibenclamide or N-ω-nitro-L-arginine methyl ester (L-NAME) was infused 20 minutes before nicorandil infusion. In the glibenclamide (n=6) or L-NAME; n=6 pretreatment group, the pial vasodilator response to topical ACh was examined before and after smoking. Percentage changes in pial vessel diameters were used for the statistical analysis. Cerebral arterioles were dilated during topical ACh infusion. After smoking, 10 M ACh constricted cerebral arterioles (-7.7±1.8%). After smoking, in the nicorandil-pretreatment group, 10 M ACh dilated cerebral pial arterioles by 10.5±3.0%. When given before nicorandil infusion, glibenclamide, but not L-NAME, abolished the preventive effects of nicorandil against smoking-induced endothelial dysfunction in pial vessels. Acute cigarette smoking causes dysfunction of endothelium-dependent pial vasodilatation, and nicorandil prevents this effect of smoking. The mechanism underlying this protective effect may depend mainly on adenosine triphosphate-sensitive potassium-channel activation.

Inhibition of vascular adenosine triphosphate-sensitive potassium channels by sympathetic tone during sepsis

Excessive opening of the adenosine triphosphate-sensitive potassium channel in vascular smooth muscle is implicated in the vasodilation and vascular hyporeactivity underlying septic shock. Therapeutic channel inhibition using sulfonylurea agents has proved disappointing, although agents acting on its pore appear more promising. We thus investigated the hemodynamic effects of adenosine triphosphate-sensitive potassium channel pore inhibition in awake, fluid-resuscitated septic rats, and the extent to which these responses are modulated by the high sympathetic tone present in sepsis. Temporal changes in ex-vivo channel activity and subunit gene expression were also investigated. In vivo and ex vivo animal study. University research laboratory. Male adult Wistar rats. Fecal peritonitis was induced in conscious, fluid-resuscitated rats. Pressor responses to norepinephrine and PNU-37883A (a vascular adenosine triphosphate-sensitive potassium channel inhibitor acting on the Kir6.1 pore-forming subunit) were measured at 6 or 24 hrs, in the absence or presence of the autonomic ganglion blocker, pentolinium. The aorta and mesenteric artery were examined ex vivo for rubidium efflux as a marker of adenosine triphosphate-sensitive potassium channel activity, and for adenosine triphosphate-sensitive potassium channel subunit gene expression using quantitative reverse transcription-polymerase chain reaction. A total of 120 rats (50 sham-operated controls, 70 septic) were included. Septic rats became hypotensive after 12 hrs, with a 24-hr mortality of 51.7% (0% in controls). At 6 hrs, there was an attenuated pressor response to norepinephrine (p < .01) despite blood pressure being elevated (p < .01). PNU-37883A had no pressor effect, except in the presence of pentolinium (p < .01). Kir6.1 subunit mRNA increased significantly in the mesenteric artery while rubidium efflux was increased in both the aorta and mesenteric artery at 24 hrs. Despite evidence of increased adenosine triphosphate-sensitive potassium channel activity in sepsis, it appears to be inhibited in vivo by high sympathetic tone. This may explain, at least in part, the reduced efficacy of adenosine triphosphate-sensitive potassium channel blockers in human septic shock.

Diazoxide maintenance of myocyte volume and contractility during stress: Evidence for a non-sarcolemmal K ATP channel location

Animal and human myocytes demonstrate significant swelling and reduced contractility during exposure to stress (metabolic inhibition, hyposmotic stress, or hyperkalemic cardioplegia), and these detrimental consequences may be inhibited by the addition of diazoxide (adenosine triphosphate-sensitive potassium channel opener) via an unknown mechanism. Both SUR1 and SUR2A subunits have been localized to the heart, and mouse sarcolemmal adenosine triphosphate-sensitive potassium channels are composed of SUR2A/Kir6.2 subunits in the ventricle and SUR1/Kir6.2 subunits in the atria. This study was performed to localize the mechanism of diazoxide by direct probing of sarcolemmal adenosine triphosphate-sensitive potassium channel current and by genetic deletion of channel subunits. Sarcolemmal adenosine triphosphate-sensitive potassium channel current was recorded in isolated wild-type ventricular mouse myocytes during exposure to Tyrode's solution, Tyrode's+ 100 μmol/L diazoxide, hyperkalemic cardioplegia, cardioplegia+ diazoxide, cardioplegia+ 100 μmol/L pinacidil, or metabolic inhibition using whole-cell voltage clamp (N=7-12 cells per group). Ventricular myocyte volume was measured from SUR1(-/-) and wild-type mice during exposure to control solution, hyperkalemic cardioplegia, or cardioplegia+ 100 μmol/L diazoxide (N=7-10 cells per group). Diazoxide did not increase sarcolemmal adenosine triphosphate-sensitive potassium current in wild-type myocytes, although they demonstrated significant swelling during exposure to cardioplegia that was prevented by diazoxide. SUR1(-/-) myocytes also demonstrated significant swelling during exposure to cardioplegia, but this was not altered by diazoxide. Diazoxide does not open the ventricular sarcolemmal adenosine triphosphate-sensitive potassium channel but provides volume homeostasis via an SUR1-dependent pathway in mouse ventricular myocytes, supporting a mechanism of action distinct from sarcolemmal adenosine triphosphate-sensitive potassium channel activation.

Mechanisms of Impaired Glucose Tolerance and Insulin Secretion during Isoflurane Anesthesia

Volatile anesthetics impair insulin secretion and glucose utilization; however, the precise mechanism of action that underlies these effects is unknown. The authors hypothesized that isoflurane inhibits glucose-induced inhibition of adenosine triphosphate-sensitive potassium channel activity in pancreatic beta cells, which could result in impaired insulin secretion and glucose tolerance. Intravenous glucose tolerance tests were performed on 28 male Japanese White rabbits anesthetized with sodium pentobarbital. Glibenclamide (50 microg/kg + 33.5 microg x kg x h) or vehicle was administered 75 min before intravenous administration of 0.6 g/kg glucose. Half of the animals (n = 7) in the vehicle and glibenclamide groups received isoflurane at 1.0 minimum alveolar concentration 30 min before administration of glucose, and the other half received a vehicle control. Hemodynamics, blood glucose, and plasma insulin were measured. A cell-attached patch clamp configuration was used to record single channel currents in the pancreas from male Swiss-Webster mice. Isoflurane alone or a combination of isoflurane and glibenclamide inhibited the insulinogenic index to a greater extent than in the vehicle and glibenclamide groups. In the patch clamp experiments, channel activity was significantly decreased as the glucose concentration was increased from 0 to 10 mm. The subsequent application of 0.5 mm isoflurane reversed the effects of glucose on channel activity. These results show that isoflurane impairs insulin secretion and glucose utilization. The mechanism of action responsible for these effects may involve a decrease in glucose-induced inhibition of adenosine triphosphate-sensitive potassium channel activity in pancreatic beta cells.

Analysis of Vasodilator Responses to Peroxynitrite in the Hindlimb Vascular Bed of the Cat

The free radical peroxynitrite (ONOO-) is formed in biological systems from the reaction of nitric oxide (NO) with superoxide (O2-) and can react with protein and nonprotein thiol groups to produce tissue injury. However, these pathologic actions of (ONOO-) may have been overemphasized, in that (ONOO-) has vasorelaxant properties through activation of soluble guanylate cyclase; inhibits leukocyte-endothelial cell interactions; and reduces ischemia-reperfusion injury in the heart, lung, and liver. It has been reported that tolerance develops to the vasodilator actions of (ONOO-) and that (ONOO-) impairs vascular function. However, little, if anything, is known about responses to (ONOO-) in the hindlimb circulation of the cat. To better understand the effects of (ONOO-) on responses to vasoactive agonists and the mechanism by which (ONOO-) induces vasodilation, the effects of short-term exposure to (ONOO-) were investigated under constant-flow conditions in the hindlimb vascular bed of the cat. In these studies, direct intraarterial injections of (ONOO-) produced dose-dependent decreases in hindquarters perfusion pressure. The vasodilator responses to (ONOO-) were rapid in onset, were short in duration, and could be repeated without exhibiting tachyphylaxis. Vasodilator responses to (ONOO-) were not changed in the presence of inhibitors of nitric-oxide synthase, cyclooxygenase, or K+-ATP (adenosine triphosphate-sensitive potassium) channels. Furthermore, responses to (ONOO-) were enhanced in duration by the type 5-cGMP (cyclic guanosine monophosphate) phosphodiesterase inhibitor zaprinast, whereas rolipram, a type 4-cGMP phosphodiesterase inhibitor, was without effect. Repeated administration of (ONOO-) had no significant effect on responses to vasoconstrictor or to vasodilator agents including acetylcholine. These results show that (ONOO-) has significant vasodilator activity in the hindlimb vascular bed of the cat and suggest that the response is mediated by a cGMP- dependent mechanism. The results of experiments with repeated injections of (ONOO-) indicate that (ONOO-) does not impair vasoconstrictor and endothelium-dependent or endothelium-independent vasodilator responses. Furthermore, tolerance did not develop with repeated short-term exposure to (ONOO-). Moreover, the results of experiments with inhibitors suggest that responses to (ONOO-) are not dependent on K-ATP (adenosine triphosphate-sensitive potassium) channel activation, increased NOS activity, or the formation of products in the cyclooxygenase pathway. The results of these studies are consistent with the hypothesis that (ONOO-) is rapidly converted in the hindlimb circulation to a substance that has the properties of an NO donor. These studies suggest that under physiologic conditions, the cytotoxic effects of (ONOO-) on a short-term basis may have been overemphasized.

Mechanism of Cardiac Sarcolemmal Adenosine Triphosphate–sensitive Potassium Channel Activation by Isoflurane in a Heterologous Expression System

Activation of the cardiac sarcolemmal adenosine triphosphate-sensitive potassium (KATP) channel during metabolic stress initiates cellular events that preserve cardiac performance. Previous studies showed that halogenated anesthetics prime KATP channels under whole cell voltage clamp and act in intracellular pH (pHi)-dependent manner on KATP channels in excised membrane patches. However, it is not known how halogenated anesthetics interact with these channels. The authors evaluated the effect of pHi and isoflurane on the KATP channel subunits, the pore-forming inward rectifier Kir6.2, and the regulatory sulfonylurea receptor SUR2A, using HEK293 cells as a heterologous expression system. Single channel activity was recorded in the inside-out patch configuration. At pHi 7.4, isoflurane had negligible effect on activity of wild-type Kir6.2/SUR2A, but at pHi 6.8, the channel open probability was increased by isoflurane (0.177 +/- 0.077 to 0.364 +/- 0.164). By contrast, the open probability of truncated Kir6.2DeltaC26, which forms a functional channel without SUR2A, was attenuated by isoflurane at both pHi 7.4 and pHi 6.8. Coexpression of Kir6.2DeltaC26 with SUR2A restored pHi sensitivity of channel activation by isoflurane. Site-directed mutagenesis within the Walker motifs of SUR2A abolished isoflurane activation of KATP channel at pHi 6.8. In addition, the pancreatic-type channels expressing sulfonylurea receptor SUR1 could not be activated by isoflurane. The nucleotide binding domains of SUR2A play a crucial role in isoflurane facilitation of the KATP channel activity at moderately acidic pHi as would occur during early ischemia. These findings support direct and differential interaction of isoflurane with the subunits of the cardiac sarcolemmal KATP channel.

Inhibiting Effect of Amiodarone to Protective Action against Ischemia/Reperfusion Injury Induced by Ischemic Preconditioning

Background: Ischemic preconditioning (IPC) has protective effects on myocardial ischemia. These effects may be caused by ATP (adenosine triphosphate) sensitive potassium () channel activation. Amiodarone also has pharmacologic preconditioning effects, especially suppression of reperfusion arrhythmia. The mechanisms of amiodarone effects are different from that of IPC. The aim of this study using the isolated rat working heart was 1) to confirm whether IPC and amiodarone protected against reperfusion injury; and, if so, 2) to example whether combination of IPC and amiodarone demonstrated additive effect or not. Methods: Isolated rat hearts were stabilized for 30 minutes and were subdivided into four groups. Control group was subjected low-flow ischemia of 5% dextrose water for 30 minutes. IPC group was pretreated with IPC. In Amiodarone group, whole process was same as control group except amiodarone administration during low-flow ischemia. Amiodarone-IPC group, IPC was applied and also administrated amiodarone. Isovolumetric left ventricular end systolic pressure (LVESP), left ventricular end diastolic pressure (LVEDP), dP/ and heart rate were measured. Results: Group II showed more recovered LVESP, less developed ventricular stiffness, more preserved coronary effluent flow, earlier termination of arrhythmia and smaller infarct size than Group I. Group III showed preserved LVESP and dP/, less developed ventricular stiffness, shortest arrhythmia sustaining time, smallest infarct size among all groups. These myocardial protective effects were abolished in Group IV. Conclusions: We observed that IPC and amiodarone administration, each has myocardial protective effects against myocardial ischemia, but when they are dealt at the same time, their beneficial effects diminished.

Morphine preconditions Purkinje cells against cell death under in vitro simulated ischemia-reperfusion conditions.

Morphine pretreatment via activation of delta1-opioid receptors induces cardioprotection. In this study, the authors determined whether morphine preconditioning induces ischemic tolerance in neurons. Cerebellar brain slices from adult Sprague-Dawley rats were incubated with morphine at 0.1-10 microM in the presence or absence of various antagonists for 30 min. They were then kept in morphine- and antagonist-free buffer for 30 min before they were subjected to simulated ischemia (oxygen-glucose deprivation) for 20 min. After being recovered in oxygenated artificial cerebrospinal fluid for 5 h, they were fixed for morphologic examination to determine the percentage of undamaged Purkinje cells. The survival rate of Purkinje cells was significantly higher in slices preconditioned with morphine (> or = 0.3 microM) before the oxygen-glucose deprivation (57 +/- 4% at 0.3 microM morphine) than that of the oxygen-glucose deprivation alone (39 +/- 3%, P < 0.05). This morphine preconditioning-induced neuroprotection was abolished by naloxone, a non-type-selective opioid receptor antagonist, by naltrindole, a selective delta-opioid receptor antagonist, or by 7-benzylidenenaltrexone, a selective delta1-opioid receptor antagonist. However, the effects were not blocked by the mu-, kappa-, or delta2-opioid receptor antagonists, beta-funaltrexamine, nor-binaltorphimine, or naltriben, respectively. Morphine preconditioning-induced neuroprotection was partially blocked by the selective mitochondrial adenosine triphosphate-sensitive potassium channel antagonist, 5-hydroxydecanoate, or the mitochondrial electron transport inhibitor, myxothiazol. None of the inhibitors used in this study alone affected the simulated ischemia-induced neuronal death. These data suggest that morphine preconditioning is neuroprotective. This neuroprotection may be delta1-opioid receptor dependent and may involve mitochondrial adenosine triphosphate-sensitive potassium channel activation and free radical production. Because morphine is a commonly used analgesic, morphine preconditioning may be explored further for potential clinical use to reduce ischemic brain injury.

Intracellular mechanism of mitochondrial adenosine triphosphate-sensitive potassium channel activation with isoflurane.

The precise mechanism of isoflurane and mitochondrial adenosine triphosphate-sensitive potassium channel (mitoK(ATP)) interaction is still unclear, although the mitoK(ATP) is involved in isoflurane-induced preconditioning. We examined the role of various intracellular signaling systems in mitoK(ATP) activation with isoflurane. Mitochondrial flavoprotein fluorescence (MFF) was measured to quantify mitoK(ATP) activity in guinea pig cardiomyocytes. To confirm isoflurane-induced MFF, cells were exposed to Tyrode's solution containing either isoflurane (1.0 +/- 0.1 mM) or diazoxide and then both drugs together (n = 10 each). In other studies, the following drugs were each added during isoflurane administration: adenosine or the adenosine receptor antagonist 8-(p-sulfophenyl)-theophylline (SPT); the protein kinase C (PKC) activators phorbol-12-myristate-13-acetate (PMA) and phorbol-12,13-dibutyrate (PDBu); the PKC inhibitors polymyxin B and staurosporine; the tyrosine kinase inhibitor lavendustin A; or the mitogen-activated protein kinase inhibitor SB203580 (n = 10 each). Isoflurane potentiated MFF induced by diazoxide (100 micro M), and diazoxide also increased isoflurane-induced MFF. PMA (0.2 micro M), PDBu (1 micro M), and adenosine (100 micro M) induced MFF. However, SPT (100 micro M), polymyxin B (50 micro M), staurosporine (200 nM), lavendustin A (0.5 micro M), and SB203580 (10 micro M) all failed to inhibit the effect of isoflurane. Our results show that isoflurane, adenosine, and PKC activate mitoK(ATP). However, our data do not support an action of isoflurane through pathways involving adenosine, PKC, tyrosine kinase, or mitogen-activated protein kinase. These results suggest that isoflurane may directly activate mitoK(ATP). Our results show that isoflurane activates mitochondrial adenosine triphosphate-sensitive potassium (mitoK(ATP)) channels, but not through pathways involving adenosine, protein kinase C, tyrosine kinase, or p38 mitogen-activated protein kinase. Isoflurane may directly activate mitoK(ATP) channels.

Effects of Ketamine and Its Isomers on Ischemic Preconditioning.

Effects of Ketamine and Its Isomers on Ischemic Preconditioning.Molojavyi et al. and Mullenheim et al.(page 623) and (page 630)Ischemic preconditioning, in which brief periods of myocardial ischemia followed by reperfusion provide protection from subsequent ischemic injury, has been shown to occur in animals as well as humans. Current evidence suggests that opening of the adenosine triphosphate–sensitive potassium channel is a key mechanism. Based on this evidence and the finding of a concentration-dependent inhibitory effect of ketamine on adenosine triphosphate–sensitive potassium channel activity, two research teams from the same institution investigated the effects of ketamine and its stereoisomers on preconditioning in animal models.In the first study, Molojavyi et al. subjected 80 isolated rat hearts to 30 min of no-flow ischemia followed by 60 min of reperfusion. The hearts were assigned randomly to one of 10 groups: two groups of eight hearts received no preconditioning stimulus before undergoing the study protocol; in another group of eight hearts, preconditioning was elicited by two 5-min periods of ischemia before the 30-min ischemic period. In six treatment groups, ketamine, R (−)-ketamine, or S (+)-ketamine were administered at concentrations of 2 or 20 μg/ml before the preconditioning stimulus. A final group of eight hearts received 20 μg/ml R (−)-ketamine before ischemia. Left ventricular (LV) end-diastole pressure, LV developed pressure, and maximum and minimum dP/dt were obtained from digitized signals and later processed on a personal computer. LV end-diastole was determined as the point at which dP/dt started its rapid upstroke after crossing the zero line.Baseline LV developed pressure was similar in all groups of hearts. Those hearts in the control groups showed the poorest recovery of LV developed pressure, as well as a high creatine kinase release (evidence of cellular injury) after ischemia. Preconditioning improved recovery of LV developed pressure and reduced creatine kinase release. Administration of 2 μg/ml ketamine or 2 or 20 μg/ml S (+)-ketamine did not influence recovery of LV developed pressure. After 20 μg/ml ketamine or 2 or 20 μg/ml R (−) ketamine, the protective effects of preconditioning were abolished.In vivo , the pathophysiology of preconditioning and ischemia–reperfusion injury is more complex. Accordingly, Mullenheim et al. investigated the effects of ketamine and S (+)-ketamine on preconditioning in rabbit hearts in vivo . Forty-eight male New Zealand white rabbits were anesthetized with α-chloralose and instrumented for measurement of left ventricular pressure, cardiac output, and myocardial infarct size. Rabbits were assigned to one of five groups: a control group of 10 rabbits that received no pretreatment or conditioning before ischemia; a preconditioning group (n = 10) that underwent 30 min of coronary artery occlusion followed by 60 min of reperfusion; a group to which either 10 mg/kg ketamine (n = 9) or 10 mg/kg S (+)-ketamine (n = 8) was administered before preconditioning; and a final group of nine rabbits to which only 10 mg/kg−2ketamine was administered before ischemia. Two rabbits died during coronary artery occlusion, so the researchers were able to evaluate a total of 46 rabbits for analysis.All rabbits underwent 30 min of coronary occlusion, during which left ventricular pressure was reduced to 83 ± 14% of baseline values, and cardiac output was reduced to 84 ± 19% of baseline values. Functional recovery after 2 h of reperfusion did not differ significantly among groups. Infarct size (assessed by triphenyltetrazolium staining) was reduced from 45 ± 16% of the area at risk in controls to 24 ± 17% in the preconditioning group. Administration of ketamine had no effect on infarct size in animals without preconditioning but abolished the cardioprotective effects of preconditioning. S (+)-ketamine, however, had no effect, so the researchers conclude that the influence of ketamine on ischemic preconditioning is most likely enantiomer specific.

Selective mitochondrial adenosine triphosphate–sensitive potassium channel activation is sufficient to precondition human myocardium

Objectives: Recently, the mitochondrial adenosine triphosphate–sensitive potassium channel has been suggested to be the final common effector of myocardial preconditioning. The purpose of this study is to determine whether selective mitochondrial adenosine triphosphate–sensitive potassium channel activation alone can precondition human myocardium from an ischemia/reperfusion insult. Methods: Isolated human right atrial trabeculae were placed in tissue baths, paced, and subjected to 30 minutes of normothermic hypoxia (ischemia) followed by 45 minutes of reoxygenation (reperfusion). Trabeculae were preconditioned with a selective mitochondrial adenosine triphosphate–sensitive potassium channel opener (diazoxide 30 μmol/L) or a nonselective purinergic agonist, adenosine (125 μmol/L), for 5 minutes (adenosine) followed by a 10-minute washout period. Developed force at end reperfusion (mean ± standard error) was compared with baseline, and tissue creatine kinase and adenosine triphosphate levels were measured after ischemia/reperfusion. Results: Trabeculae subjected to ischemia/reperfusion exhibited 30% ± 2% of baseline developed force, whereas trabeculae subjected to selective adenosine triphosphate–sensitive potassium channel opening (diazoxide) and nonselective purinergic agonist (adenosine) recovered to 55% ± 7% and 46% ± 3% of baseline developed force, respectively. Tissue creatine kinase activity was preserved in both the diazoxide- and adenosine-treated trabeculae (5.4 ± 12 and 5.4 ± 14 μmol/L per gram wet tissue) compared with ischemia/reperfusion (1.8 ± 0.2 U/mg wet tissue). Adenosine triphosphate levels at end reperfusion were also increased in the trabeculae treated with selective (diazoxide) and nonselective (adenosine) adenosine triphosphate–sensitive potassium channel opener (4.1 ± 0.01 and 4.4 ± 0.2 μmol/L per gram wet tissue) compared with trabeculae subjected to ischemia/reperfusion (1.5 ± 0.1 μmol/L per gram wet tissue). Conclusions: These results suggest that selective mitochondrial adenosine triphosphate–sensitive potassium channel activation preconditions human myocardium and the protection conferred is equal to that of adenosine preconditioning. Targeted openers of mitochondrial adenosine triphosphate– sensitive potassium channels promote constructive protection of myocellular energy levels, contractile function, and cellular viability in human myocardium after ischemia/reperfusion. (J Thorac Cardiovasc Surg 2000;120:387-92)

Cardioprotective Effects of Sevoflurane during Ischemia and Reperfusion in Dogs.Toller et al. (page 1437)

To determine whether sevoflurane, like isoflurane, protects against consequences of prolonged coronary artery occlusion, Toller et al. assigned 75 dogs to one of seven experimental groups. All dogs were anesthetized with barbiturates, intubated, ventilated, and instrumented for measurement of aortic and left ventricular pressures and maximum rate of increase of left ventricular pressure (+dP/dtmax). They first underwent a 60-min left anterior descending coronary artery occlusion, followed by 3 h of reperfusion. In four experiments designed to test whether sevoflurane reduces myocardial infarct size by adenosine triphosphate–sensitive potassium channel activation, dogs received either intravenous drug vehicle (50% polyethylene glycol and 50% ethyl alcohol) or adenosine triphosphate–sensitive potassium channel antagonist glyburide in the presence or absence of a 30-min administration of 1 minimum alveolar concentration end-tidal concentration of sevoflurane.Another set of experiments was designed to determine whether sevoflurane is associated with an acute memory phase and whether it reduces the time threshold to ischemic preconditioning. For these additional studies, sevoflurane was either discontinued 30 min (memory) before the 60-min left anterior descending occlusion, or a 2-min left anterior descending occlusion as an ischemic preconditioning stimulus was used with or without subsequent sevoflurane (with memory) pretreatment.At the end of each experiment, regional myocardial perfusion was measured with radioactive microspheres, and infarct size was measured with triphenyltetrazolium staining. Vehicle and glyburide had equivalent effects on myocardial infarct size. Sevoflurane significantly decreased infarct size, an effect that was abolished by glyburide. Discontinuing sevoflurane 30 min before the prolonged left anterior descending occlusion did not afford myocardial protection, but sevoflurane enhanced the effects of the brief ischemic stimulus and reduced infarct size.

Myocardial protection in the acutely injured heart: Hyperpolarizing versus depolarizing hypothermic cardioplegia

Objectives: The superiority of hyperpolarized arrest with adenosine triphosphate–sensitive potassium channel openers over standard hyperkalemic depolarizing cardioplegia during normothermic ischemia has been documented. This study examined the hypothesis that pinacidil would provide superior protection in a more clinically relevant model of an acutely injured heart and hypothermic cardioplegic arrest. Methods: In a blood-perfused, parabiotic, rabbit heart Langendorff model, hearts underwent 15 minutes of unprotected global normothermic ischemia before the administration of 50 ml of cardioplegic solution at 4° C, followed by 50 minutes of hypothermic (15° C) ischemia and 30 minutes of reperfusion. The cardioplegic solutions administered consisted of Krebs-Henseleit solution alone ( N = 6), Krebs-Henseleit solution with pinacidil (50 μmol/L; N = 10), Krebs-Henseleit solution with pinacidil (50 μmol/L) and glibenclamide (a potassium channel blocker, 10 μmol/L; N = 8), or St. Thomas' Hospital solution ( N = 8). The percent recovery of developed pressure, linear diastolic pressure-volume relationships, and coronary blood flow were compared. Results: The percent recovery of developed pressure was 32.8% ± 2.8%, 43.0% ± 4.3%, 46.5% ± 2.2%, and 49.3% ± 2.7% for the Krebs-Henseleit, the Krebs-Henseleit with pinacidil and glibenclamide, the St. Thomas' Hospital, and the Krebs-Henseleit with pinacidil groups, respectively. No hearts had ventricular fibrillation on reperfusion. Conclusions: During hypothermic hyperpolarized arrest, as opposed to normothermic ischemia as in our previous studies, there was neither an increased incidence of ventricular fibrillation nor prolonged electrical activity when compared with results during traditional hyperkalemic arrest. Myocardial protection by St. Thomas' Hospital solution and pinacidil was superior ( p = 0.009) to that with Krebs-Henseleit solution alone. The protection provided by pinacidil was lost with the addition of glibenclamide, indicating that the drug has adenosine triphosphate–sensitive potassium channel activity during hypothermia. (J Thorac Cardiovasc Surg 1997;113:567-75)