The neonatal but not the mature heart adapts to acute tachycardia by beneficial modification of the force-frequency relationship.

The force-frequency relationship (FFR) reflects alterations in intracellular calcium cycling during changing heart rate (HR). Tachycardia-induced heart failure is associated with depletion of intracellular calcium. We hypothesized (1) that the relative resistance to tachycardia-induced heart failure seen in neonatal pigs is related to differences in calcium cycling, resulting in different FFR responses and (2) that pretreatment with digoxin to increase intracellular calcium would modifies these changes. LV +dP/dt was measured during incremental right atrial pacing in 16 neonatal and 14 adult pigs. FFR was measured as the change in +dP/dt as HR was increased. Animals were randomized to control or intravenous bolus digoxin (n = 8 neonate pigs in the 0.05 mg/kg group and n = 7 adult pigs in the 0.025 mg/kg group) and paced for 90 min at 25 bpm greater than the rate of peak +dP/dt. Repeat FFR was then obtained. The postpacing FFR in neonatal control pigs shifted rightward, with peak force occurring 30 bpm greater than baseline (P < 0.03). There was no vertical shift; thus, force at 150 bpm decreased (P < 0.03) and force at 300 beats/min increased (P < 0.08). In adult control pigs, FFR shifted downward (P < 0.01), with decreased force generation at all HRs. In both neonates and adult pigs, digoxin increased +dP/dt at all HRs; however, in neonate pigs digoxin decreased the contractile reserve by abrogation of the rightward shift of FFR. An adaptive response to tachycardia in the neonate pig leads to improved force generation at greater HRs. Conversely, the response of the mature pig heart is maladaptive with decreased force generation. Pretreatment with digoxin modifies these responses.

Arrhythmia and sudden death associated with elevated cardiac chloride channel activity.

The identification and analysis of several cationic ion channels and their associated genes have greatly improved our understanding of the molecular and cellular mechanisms of cardiac arrhythmia. Our objective in this study was to examine the involvement of anionic ion channels in cardiac arrhythmia. We used a transgenic mouse model to overexpress the human cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a cAMP-regulated chloride channel. We used RNase protection and in situ hybridization assays to determine the level of CFTR expression, and radiotelemetry and in vivo electrophysiological study in combination with pharmacological intervention to analyse the cardiac function. Cardiac CFTR overexpression leads to stress-related sudden death in this model. In vivo intracardiac electrophysiological studies performed in anaesthetized mice showed no significant differences in baseline conduction parameters including atrial-His bundle (AH) or His bundle-ventricular (HV) conduction intervals, atrioventricular (AV) Wenckebach or 2:1 AV block cycle length and AV nodal functional refractory period. However, following isoproterenol administration, there was marked slowing of conduction parameters, including high-grade AV block in transgenic mice, with non-sustained ventricular tachycardia easily inducible using programmed stimulation or burst pacing. Our sudden death mouse model can be a valuable tool for investigation of the role of chloride channels in arrhythmogenesis and, potentially, for future evaluation of novel anti-arrhythmic therapeutic strategies and pharmacological agents.

The effect of weight training on bone mineral density and bone turnover in postmenopausal breast cancer survivors with bone loss: a 24-month randomized controlled trial.

SUMMARY: This study examined whether 24 months of weight training exercises enhanced the effectiveness of risedronate, calcium, and vitamin D in maintaining or improving bone mineral density (BMD) in 223 postmenopausal breast cancer survivors. Subjects who were > or =50% adherent to exercise had no improvement in BMD but were less likely to lose BMD. INTRODUCTION: This study examined whether (1) postmenopausal breast cancer survivors (BCS) with bone loss taking 24 months of risedronate, calcium, and vitamin D had increased bone mineral density (BMD) at the total hip, femoral neck, L1-L4 spine, total radius and 33% radius, and decreased bone turnover; (2) subjects who also participated in strength/weight training (ST) exercises had greater increases in BMD and greater decreases in bone turnover; and (3) subjects who also exercised were more likely to preserve (at least maintain) BMD. METHODS: Postmenopausal BCS (223) were randomly assigned to exercise plus medication or medication only groups. Both groups received 24 months of 1,200 mg of calcium and 400 IU of vitamin D daily and 35 mg of risedronate weekly, and the exercise group additionally had ST exercises twice weekly. RESULTS: After 24 months, women who took medications without exercising had significant improvements in BMD at the total hip (+1.81%) and spine (+2.85%) and significant decreases in Alkphase B (-8.7%) and serum NTx (-16.7%). Women who also exercised had additional increases in BMD at the femoral neck (+0.29%), total hip (+0.34%), spine (+0.23%), total radius (+0.30%), and additional decreases in Alkphase B (-2.4%) and Serum NTx (-6.5%). Additional changes in BMD and bone turnover with exercise were not significant. Subjects who were > or =50% adherent to exercise were less likely to lose BMD at the total hip (chi-square [1] = 4.66, p = 0.03) and femoral neck (chi-square [1] = 4.63, p = 0.03). CONCLUSION: Strength/weight training exercises may prevent loss of BMD in postmenopausal BCS at risk for bone loss.

Opioids and myocardial reperfusion injury.

It is well-established that reperfusion is the major method of salvaging ischemic myocardium following prolonged coronary artery occlusion, although the idea of reperfusion injury remains controversial. Moreover, more recent evidence strongly suggests that reperfusion per se is thought to result in further damage to the myocardium and blood vessel endothelium by various biochemical and physical factors including a burst of oxygen-derived free radicals (ROS), cellular or mitochondrial calcium overload and shear stress, to name a few. This has been termed lethal reperfusion injury. It has become increasingly evident that strategies in which interventions are administered during the early stages of reperfusion produce a reduction in reperfusion-mediated damage primarily by reducing massive calcium overload or by altering the intracellular milieu (pH, osmotic stress, etc.) and ROS release upon reperfusion. Furthermore, it is apparent that activation of blood borne elements such as neutrophils and macrophages and factors released by these cells such as cytokines may be responsible for a continuing expansion of infarction in the hours or even days following timely reflow and that inhibiting these factors may attenuate reperfusion injury. The present review will focus on the effect of endogenous and exogenous opioids on ischemic and reperfusion injury since these compounds are routinely used in the surgical arena and may have unappreciated cardioprotective effects in this subset of patients. Particular emphasis will be on the role of opioids in reperfusion injury and their relationship to the newly discovered phenomenon of postconditioning.

[Contribution of the endogenous opioid system to regulation of heart resistance to the arrhythmogenic effect of short-term ischemia and reperfusio].

Preliminary selective blockade of micro, delta1, delta2, kappa1, and kappa2 opioid receptors proved to have no effect on the incidence of ventricular arrhythmias during a 10-min coronary occlusion and subsequent reperfusion in ketamine-anesthetized rats. We propose that the endogenous opioid system has no considerable role in regulation of heart resistance to the arrhythmogenic effect of short-term local ischemia and subsequent reperfusion.

Role of endogenous opioid receptor agonists in regulation of heart resistance to the arrhythmogenic action of short-term ischemia and reperfusion.

Preliminary selective block of mu-, delta1-, delta2-, and kappa-opioid receptors had no effect on the incidence of ventricular arrhythmias during 10-min coronary occlusion-reperfusion in ketamine-narcotized rats. Repetitive short-term immobilization of rats for 2 weeks improved heart resistance to the arrhythmogenic action of coronary occlusion and reperfusion. Selective mu-opioid receptor antagonist CTAP completely abolished, while selective delta- and kappa-opioid receptor antagonists did not modulate the antiarrhythmic effect of adaptation. Probably, endogenous agonists of mu-opioid receptors play an important role in the adaptive improvement of heart resistance to arrhythmogenic factors, but are insignificant for the modulation of heart resistance to the arrhythmogenic action of short-term local ischemia-reperfusion in non-adapted animals.

Cardioprotection following adenosine kinase inhibition in rat hearts.

Adenosine kinase phosphorylates adenosine to AMP, the primary pathway for adenosine metabolism under basal conditions. Inhibition of adenosine kinase results in a site-specific increase in interstitial adenosine. Using a rat model of myocardial infarction, we examined the protective effects of adenosine kinase inhibition. Male Sprague-Dawley rats underwent 30 min regional occlusion followed by 90 min reperfusion. Infarct size, expressed as a percent of the area-at-risk, IS/AAR(%), was 58.0 +/- 2.1 % in untreated rats. Pretreatment with the adenosine kinase inhibitor, 5-iodotubercidin (1 mg/kg), limited infarct development to 37.5+/-3.7% (P < 0.001). The A(1) adenosine receptor (A(1)AR) antagonist, DPCPX (100 microg/kg), abolished the infarct-sparing effect of 5-iodotubercidin (IS, 62.8 +/- 1.3%). Similarly, the A(3) adenosine receptor (A(3)AR) antagonist, MRS-1523 (2 mg/kg), and the delta-opioid receptor (DOR) antagonist, BNTX, (1 mg/kg) abolished the reduction of IS produced by iodotubercidin. Pretreatment with the ROS scavenger, 2-MPG (20 mg/kg), or the PKC-delta antagonist, rottlerin (0.3 mg/kg) also abolished iodotubercidin-mediated cardioprotection. Furthermore, pretreatment with 5-HD, a mitochondrial K(ATP) (mitoK(ATP)) channel inhibitor, but not the sarcolemmal K(ATP) channel blocker, HMR-1098, abrogated the beneficial effects of adenosine kinase inhibition (IS, 59.5 +/- 3.8%). These data suggest that inhibition of adenosine kinase is effective in reducing infarct development via A(1)AR, A(3)AR and DOR activation. Data also suggest that this protection is mediated via ROS, PKC-delta and mitoK(ATP) channels.

[Endogenic opioid peptides and antiarrhythmic effect of adaptation to stress]. / Endogennye opioidnye peptidy i antiaritmicheskii éffekt adaptatsii k stressu.

Adaptation of rats to repeated short-term immobilization increases cardiac resistance to an arrhythmogenic action of coronary artery occlusion (10 min) and reperfusion (10 min) in rats anesthetized with ketamine and artificially ventilated. We examined the role of opioid receptors and endogenous opioid peptides in the development of this antiarrhythmic effect produced in response to repeated periods of immobilization stress. We found that repeated daily stress during a 15-day period resulted in an increase of leu-enkephalin in blood plasma, in the suprarenal gland and myocardium. Adaptation to stress also resulted in an increase in beta-endorphinl-31 in blood plasma, the hypophysis, hypothalamus and midbrain. Pretreatment with selective mu, delta and cappa opioid receptor (OR) antagonists had no effect on the incidence of occlusion and reperfusion-induced arrhythmias in non-adapted control rats. However, pretreatment with the selective muOR antagonist CTAP (0.5 mg/kg) intravenously completely abrogated the antiarrhythmic effect of adaptation. Selective delta and cappa receptor antagonists did not affect the antiarrhythmic effect of adaptation. Prior administration of the selective muOR agonist DALDA (0.1 mg/kg) decreased the incidence of occlusion and reperfusion-evoked arrhythmias in non-adapted rats. This effect was abolished by pretreatment with the selective muOR antagonist CTAP (0.5 mg/kg). These data suggest that mu opioid receptors and endogenous opioid peptides play an important role in the antiarrhythmic effect of adaptation to stress in rats.

Anandamide content is increased and CB1 cannabinoid receptor blockade is protective during transient, focal cerebral ischemia.

The role of endocannabinoid signaling in the response of the brain to injury is tantalizing but not clear. In this study, transient middle cerebral artery occlusion (MCAo) was used to produce ischemia/reperfusion injury. Brain content of N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol were determined during MCAo. Whole brain AEA content was significantly increased after 30, 60 and 120 min MCAo compared with sham-operated brain. The increase in AEA was localized to the ischemic hemisphere after 30 min MCAo, but at 60 and 120 min, was also increased in the contralateral hemisphere. 2-Arachidonoylglycerol content was unaffected by MCAo. In a second set of studies, injury was assessed 24 h after 2 h MCAo. Rats administered a single dose (3 mg/kg) of the cannabinoid receptor type 1 (CB1) receptor antagonist SR141716 prior to MCAo exhibited a 50% reduction in infarct volume and a 40% improvement in neurological function compared with vehicle control. A second CB1 receptor antagonist, LY320135 (6 mg/kg), also significantly improved neurological function. The CB1 receptor agonist, WIN 55212-2 (0.1-1 mg/kg) did not affect either infarct volume or neurological score.

[Antiarrhythmic and cardioprotective effect of stimulation of delta1-opiate receptors in myocardial ischemia and reperfusion]. / Antiaritmicheskii i kardioprotektornyi éffekt stimuliatsii delta1-opiatnykh retseptorov v usloviiakh ishemii i reperfuzii miokarda.

Pretreatment with intravenous peptide delta1-opioid receptor (OR) agonist DPDPE (0.5 mg/kg) decreases the incidence of occlusion (10 min) and reperfusion (10 min) arrhythmias in rats. The agonist of delta2-OR DSLET has no effect on arrhythmias in coronary artery occlusion and reperfusion. Pretreatment with selective delta-antagonists ICI 174,864 (2.5 mg/kg) eliminates an antiarrhythmic effect of DPDPE. The addition of DPDPE to the perfusion solution in a final concentration of 0.1 mg/l and/or 0.5 mg/l fifteen min before ischemia also decreases the incidence of reperfusion arrhythmias in a concentration-dependent manner. The addition of DPDPE to the perfusion solution in a final concentration of 0.1 mg/l decreases creatine kinase levels in the coronary sinus effluent. However, DPDPE has no cardioprotective effect in a concentration of 0.5 mg/l or after intravenous administration. It is suggested that antiarrhythmic and cardioprotective effects of DPDPE during reperfusion may be due to stimulation of cardiac delta1-receptors.

[The effect of K(ATP)-channel activation on the electrical stability of myocardium in rats with postinfarction cardiosclerosis]. / Vliianie aktivatsii K(ATP)-kanalov na élektricheskuiu stabil'nost' miokarda pri postinfarktnom kardioskleroze.

Opening of the ATP-dependent K-channels (K(ATP) channels) upon intravenous administration of the cardioselective activator BMS 180448 (3 mg/kg) decreased the ventricular fibrillation threshold (VFT) in rats with postinfarction cardiosclerosis (PIC). Preliminary injection of the selective K(ATP) channel blocker glibenclamide (0.3 mg/kg, i.v.) completely abolished the profibrillatory effect of BMS 180448. At the same time, the mitochondrial K(ATP) channel blocker 5-hydroxydecanoic acid (5 mg/kg) did not influence the proarrhythmogen activity of BMS 180448. Simultaneous administration of the sarcoK(ATP) channel inhibitor HMR 1098 (3 mg/kg) and BMS 180448 increased the VFT up to a level in intact animals. Administration of the mitoK(ATP) channel activator diazoxide (5 mg/kg) after preliminary treatment with guanethidine (50 mg/kg) increased the VFT in rats with PIC. It is concluded that opening of the mitoK(ATP) channels increases the cardiac electrical stability in rats with PIC.

[The role of delta-1 opiate receptors in regulation of contractility in isolated rat heart during normal oxygenation and ischemia-reperfusion]. / Rol' delta1-opiatnykh retseptorov v reguliatsii sokratimosti izolirovannogo serdtsa krys v usloviiakh normal'noi oksigenatsii i ishemii-reperfuzii.

The experiments on isolated rat heart demonstrated significant decrease in reperfusion-induced damage of cardiomyocytes by addition of selective delta 1 receptor agonist DPDPE (0.1 mg/l) to the perfusion solution. On the contrary, no cardioprotective effect was observed for 0.5 mg/l concentration of the peptide or after its intravenous injection. Stimulation of the cardiac delta 1 opioid receptors by intravenous injection of 0.5 mg/kg DPDPE or its addition to the perfusion solution decreased myocardial contractility both in conditions of normal oxygenation and during reperfusion. Thus, the cardioprotective and negative inotropic effect of DPDPE is mediated by activation of the cardiac delta 1 opioid receptors.

Activation of peripheral delta opioid receptors eliminates cardiac electrical instability in a rat model of post-infarction cardiosclerosis via mitochondrial ATP-dependent K+ channels.

The effects of the selective delta-1 (delta(1)) opioid receptor agonist, DPDPE, and the selective delta(2) opioid receptor agonist, DSLET, have been studied on the ventricular fibrillation threshold (VFT) in rats with an experimental post-infarction cardiosclerosis (CS). It has been found that CS induced a significant decrease in VFT. This CS-induced decrease in VFT was significantly reversed by intravenous administration of DPDPE (0.1 mg/kg) 10 min before VFT measurement. On the contrary, intravenous injection of DSLET (0.5 mg/kg) exacerbated the CS-induced cardiac electrical instability. Pretreatment with the selective delta opioid receptor antagonist, ICI 174,864 (0.5 mg/kg), completely abolished the changes in VFT produced by both DPDPE and DSLET. Previous administration of a nonselective peripherally acting opioid receptor antagonist, naloxone methiodide (5 mg/kg) also completely reversed the antifibrillatory action of DPDPE. Naloxone methiodide and ICI 174,864 alone had no effect on VFT. Pretreatment with the nonselective K(ATP) channel blocker, glibenclamide (0.3 mg/kg), or with the mitochondrial selective K(ATP) channel blocker, 5-hydroxydecanoic acid (5-HD, 5 mg/kg), completely abolished the DPDPE-induced increase in cardiac electrical stability. Glibenclamide and 5-HD alone had no effect on VFT. These results demonstrate that the delta opioid receptor plays an important role in the regulation of electrical stability in rats with post-infarction cardiosclerosis. We propose that peripheral delta(1) opioid receptor stimulation reverses CS-induced electrical instability via mitochondrial K(ATP) channels. On the contrary, delta(2) opioid receptor stimulation may exacerbate the CS-induced decrease in VFT. Further studies are necessary to determine the delta opioid receptor subtype which mediates the antifibrillatory effect of DPDPE and pro-fibrillatory effect of DSLET.

[The opiatergic link between the antiarrhythmic effect of adaptation and hypoxia in the model of ischemia and reperfusion in vivo]. / Opiatergicheskoe zveno antiaritmicheskogo éffekta adaptatsii k gipoksii na modeli ishemii i reperfuzii in vitro.

Rat adaptation to repeated periods of hypobaric hypoxia has been found to prevent the occurrence of ischemic and reperfusion ventricular arrhythmias on a 10-minte coronary artery occlusion model. Inhibition of delta-opioid receptors by intravenous administration of the selective delta-opioid antagonist TIPP (psi) in a dose of 0.5 mg/kg, intravenously (i.v.), completely abolished the antiarrhythmic effect of adaptation to hypoxia. Inhibition of mu-opioid receptors by CTAP (0.5 mg/kg, i.v.) or kappa-receptors by nor-binaltorphimine (9 mg/kg i.v.) had no effect on the incidence cardiac rhythm disturbances in adapted rats during coronary artery occlusion and reperfusion. Therefore, these findings suggest that delta-opioid receptors play an important role in inhibiting arrhythmia formation in this model.

[The role of opiate receptors and ATP-dependent potassium channels of mitochondria in the formation of myocardial adaptive resistance to the arrhythmogenic effect of ischemia and reperfusion]. / Rol' opiatnykh retseptorov i ATF-zavisimykh kalievykh kanalov mitokhondrii v formirovanii adaptatsionnoi ustoichivosti miokarda k aritmogennomu deistviiu ishemii i reperfuzii.

Preliminary stimulation of opiate receptors (ORs) by intravenous administration of mu agonist DALDA (0.5 mg/kg), delta 1 agonist DPDPE (0.5 mg/kg), and kappa agonist (-)-U-50.488 (1 mg/kg) increases rat myocardial resistance to arrhythmogenic effect of coronary occlusion (10 min) and reperfusion (10 min). Activation of delta 2 ORs (DSLET, 0.5 mg/kg) has no effect on the incidence rate of ischemic and reperfusion arrhythmias. Preliminary administration of glibenclamide (0.3 mg/kg), an inhibitor of KATP channels, blocks the antiarrhythmic effect of DALDA and DPDPE. Repeated short-term exposures of rats to immobilization within two weeks increases the heart tolerance to the arrhythmogenic effect of coronary occlusion and reperfusion. This effect disappears after administration of CTAP (0.5 mg/kg), a mu antagonist, or injection of 5-hydroxydecanoate (5 mg/kg), an inhibitor of mitochondrial KATP channels. The selective antagonists of delta and kappa ORs have no effect on cardiac adaptation-induced resistance to the arrhythmogenic effect of ischemia and reperfusion. We believe that stimulation of mu, delta, and kappa ORs increases myocardial tolerance to the arrhythmogenic effect of ischemia and reperfusion through activation of KATP channels. The antiarrhythmic effect of the adaptation is mediated by stimulation of mu ORs and mitochondrial KATP channels.

[Interactions of peripheral mu-opioid receptors and K(ATP)-channels in regulation of cardiac electrical stability in ischemia, reperfusion, and postinfarction cardiosclerosis]. / Vzaimodeistvie perifericheskikh mu-opiatnykh retseptorov i K(ATF)-kanalov v reguliatsii élektricheskoi stabil'nosti serdtsa pri ishemii, reperfuzii i postinfarktnom kardioskleroze.

It has been shown that mu-opioid receptor stimulation by intravenous administration of the selective mu receptor agonist DALDA in a dose of 0.1 mg/kg prevented ischemic and reperfusion arrhythmias in rats subjected to coronary artery occlusion (10 min) and reperfusion (10 min), and also increased the ventricular fibrillation threshold in rats with postinfarction cardiac fibrosis. These effects were abolished by pre-treatment with the selective mu receptor antagonist CTAP in a dose of 0.5 mg/kg or by prior injection of the opioid receptor antagonist naloxone methiodide (2 mg/kg) which does not penetrate the blood-braib barrier. Both antagonists by themselves had no effect on the incidence of occlusion or reperfusion-induced arrhythmias or on the ventricular fibrillation threshold. Pre-treatment with ATP-sensitive K+ channel (KATP channel) blocker glibenclamide in a dose of 0.3 mg/kg completely abolished the antiarrhythmic effect of DALDA. We believe that DALDA prevents occurrence of electrical instability during ischemia and reperfusion and increases the ventricular fibrillation threshold in rats with postinfarction cardiac fibrosis via stimulation of peripheral mu-opioid receptor which appear to be coupled to the KATP channel.

Predictors of refractory tachycardia in infants with supraventricular tachycardia.

Reentrant supraventricular tachycardia (SVT) is the most common arrhythmia in infants. There are few predictors as to which patients will have recurrent or refractory SVT. We retrospectively reviewed records of all infants with SVT evaluated at The Hospital for Sick Children, Toronto, between January 1, 1995, and December 31, 1999. Patients with reentrant SVT documented in infancy and structurally normal hearts were included. Patients were placed in two groups: the "simple" group consisted of patients with SVT completely controlled by not more than one medication, and the "complex" group consisted of patients with recurrent episodes requiring at least one medication change for control. Forty-two cases were analyzed-23 in the simple group and 19 in the complex group. One patient in each group died. Age at presentation was 50.4 +/- 13.2 days for the simple group versus 10.2 +/- 2.5 days for the complex group (p <0.01). Complex patients were treated with a median of three medications and were more likely to have echocardiographically reduced ventricular function. The surface electrocardiogram RP interval during SVT was significantly longer in complex patients (p <0.001). There were no differences between the groups in gender, cycle length in SVT or sinus rhythm, the presence of pre-excitation, initial medication choice, or duration of therapy. Recurrent SVT in infancy is associated with younger age and/or ventricular dysfunction at presentation and also with slower ventriculoatrial conduction. The similar duration of therapy for simple and complex patients suggests that the early clinical course of SVT in infancy is not predictive of long-term outcome.

Receptor specificity of the antiarrhythmic effect produced by opioid peptides Dalargin and DADLE during myocardial reperfusion.

Nonselective agonists of mu- and delta-opioid receptors dalargin (D-Ala2,Leu5,Arg6-enkephalin) and DADLE (D-Ala2,D-Leu5-enkephalin) administered immediately before coronary reperfusion in a dose of 0.1 mg/kg prevented the development of ventricular arrhythmias. Blockade of mu-opioid receptors abolished the antiarrhythmic effect of these peptides. Hence, antiarrhythmic activity of dalargin and DADLE is primarily associated with activation of mu-opioid receptors.

Sarcolemmal and mitochondrial K(ATP) channels and myocardial ischemic preconditioning.

Ischemic preconditioning (IPC) is the phenomenon whereby brief periods of ischemia have been shown to protect the myocardium against a sustained ischemic insult. The result of IPC may be manifest as a marked reduction in infarct size, myocardial stunning, or incidence of arrhythmias. While many substances and pathways have been proposed to play a role in the signal transduction mediating the cardioprotective effect of IPC, overwhelming evidence indicates an intimate involvement of the ATP-sensitive potassium channel (K(ATP) channel) in this process. Initial hypotheses suggested that the surface or sarcolemmal K(ATP) (sarcK(ATP)) channel mediated the cardioprotective effects of IPC. However, much research has subsequently supported a major role for the mitochondrial K(ATP) channel (mitoK(ATP)) as the one involved in IPC-mediated cardioprotection. This review presents evidence to support a role for the sarcK(ATP) or the mitoK(ATP) channel as either triggers and/or downstream mediators in the phenomenon of IPC.