Amadou Camara - Academia.edu (original) (raw)

Papers by Amadou Camara

Journal of The Autonomic Nervous System, 1998

CNS angiotensin II (AII) hypertension is induced by chronic, low dose intracerebroventricular (IC... more CNS angiotensin II (AII) hypertension is induced by chronic, low dose intracerebroventricular (ICV) AII infusion only in rats raised on a relatively high sodium chloride diet (250 meq kg(-1)food) from weaning. This experimental model of hypertension is dependent upon renal sympathetic innervation and associated with neurogenic sodium retention. This study determined whether AT1 and/or AT2 receptor subtypes in the CNS mediate this neurogenic ICV AII hypertension. Rats were weaned at 21 days of age and fed a 1.5% sodium chloride diet for 10-12 weeks. At adulthood, animals were instrumented with CNS lateral ventricular cannulas, femoral arterial and vein catheters and housed in metabolic pens for chronic study. Low dose ICV AII infusion (20 ng min(-1) )increased mean arterial pressure by 12+/-2 mm Hg and decreased urinary sodium excretion for three consecutive days. Subsequent ICV AT1 blockade with losartan abolished both the pressor and antinatriuretic responses to low dose ICV AII. In contrast, ICV AT2 receptor blockade with PD 123319 did not affect either angiotensin induced pressor or antinatriuretic responses. Following cessation of ICV AII infusion, arterial pressure and sodium excretion returned to values not significantly different from control in both groups of rats. These data confirm that low dose ICV AII causes hypertension and sodium retention in rats raised from early age on moderately elevated sodium intakes. This AII mediated neurogenic hypertension and antinatriuresis is transduced by activation of CNS AT1 receptors and not by activation of central AT2 receptors.

Journal of Molecular and Cellular Cardiology, 2002

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Journal of Cardiovascular Pharmacology, 2003

The authors examined effects of positive (dopamine and digoxin) and negative (nifedipine and lido... more The authors examined effects of positive (dopamine and digoxin) and negative (nifedipine and lidocaine) inotropic interventions on the instantaneous cyclic relationship between myoplasmic [Ca2+] and simultaneously developed left ventricular pressure (LVP) in intact guinea pig hearts. Novel indices were developed to quantify this relationship based on (1) transient [Ca2+] and LVP signal morphology, ie, maxima and minima, peak derivatives, beat areas, durations, and ratios of indices of LVP to [Ca2+]; (2) temporal delay; and (3) LVP versus [Ca2+] loop morphology, ie, orientation, size, hysteresis, position, shape, and duration. These analyses were used to assess the cost of phasic [Ca2+] for contraction and relaxation over one beat after inotropic intervention. It was found that dopamine and digoxin increased contractile and relaxation responsiveness to phasic [Ca2+], cumulative Ca2+, and net Ca2+ flux. Unlike dopamine, digoxin did not decrease relaxation response time. Nifedipine and lidocaine decreased contractile and relaxation responsiveness to phasic [Ca2+], cumulative Ca2+, and net Ca2+ flux. Unlike lidocaine, nifedipine decreased net available Ca2+ and Ca2+ influx. Positive inotropic agents increased [Ca2+]-LVP loop area and hysteresis and resulted in a more vertically oriented loop. Nifedipine and lidocaine decreased these loop indices and lidocaine exhibited greater loop hysteresis than did nifedipine. These novel indices provide a quantitative assessment of myoplasmic [Ca2+] handling for cardiac contractile function.

Anesthesiology, 2003

Ischemia causes an imbalance in mitochondrial metabolism and accumulation of nicotinamide adenine... more Ischemia causes an imbalance in mitochondrial metabolism and accumulation of nicotinamide adenine dinucleotide (NADH). We showed that anesthetic preconditioning (APC), like ischemic preconditioning, improved mitochondrial NADH energy balance during ischemia and improved function and reduced infarct size on reperfusion. Opening adenosine triphosphate-sensitive potassium (K(atp)) channels may be involved in triggering APC. The authors tested if effects of APC on NADH concentrations before, during, and after ischemia are reversible by 5-hydroxydecanoate (5-HD), a putative mitochondrial K channel blocker. Nicotinamide adenine dinucleotide fluorescence was measured in 60 guinea pig Langendorff-prepared hearts assigned into five groups: (1) no treatment before ischemia; (2) APC by exposure to 1.3 mm sevoflurane for 15 min; (3) 200 microm 5-HD from 5 min before to 15 min after sevoflurane exposure; (4) 35 min 5-HD alone; and (5) no treatment and no ischemia. Sevoflurane was washed out for 30 min, and 5-HD for 15 min, before 30-min ischemia and 120-min reperfusion. Nicotinamide adenine dinucleotide was reversibly increased during sevoflurane exposure before ischemia, and the increase and rate of decline in NADH during ischemia were reduced after APC. 5-HD abolished these changes in NADH. On reperfusion, function was improved and infarct size reduced after APC compared with other groups. Anesthetic preconditioning was evidenced by improved mitochondrial bioenergetics as assessed from NADH concentrations during ischemia and by attenuated reperfusion injury. Reversal of APC by bracketing sevoflurane exposure with 5-HD suggests that APC is triggered by mitochondrial K channel opening or, alternatively, by attenuated mitochondrial respiration without direct involvement of mitochondrial K channel opening.

Journal of Cardiovascular Pharmacology, 2008

Mitochondrial (m) K ATP channel opening has been implicated in triggering cardiac preconditioning... more Mitochondrial (m) K ATP channel opening has been implicated in triggering cardiac preconditioning. Its consequence on mitochondrial respiration, however, remains unclear. We investigated the effects of two different K ATP channel openers and antagonists on mitochondrial respiration under two different energetic conditions. Oxygen consumption was measured for complex I (pyruvate/malate) or complex II (succinate with rotenone) substrates in mitochondria from fresh guinea pig hearts. One of two mK ATP channel openers, pinacidil or diazoxide, was given before adenosine diphosphate in the absence or presence of an mK ATP channel antagonist, glibenclamide or 5-hydroxydecanoate. Without ATP synthase inhibition, both mK ATP channel openers differentially attenuated mitochondrial respiration. Neither mK ATP channel antagonist abolished these effects. When ATP synthase was inhibited by oligomycin to decrease [ATP], both mK ATP channel openers accelerated respiration for both substrate groups. This was abolished by mK ATP channel blockade. Thus, under energetically more physiological conditions, the main effect of mK ATP channel openers on mitochondrial respiration is differential inhibition independent of mK ATP channel opening. In contrast, under energetically less physiological conditions, mK ATP channel opening can be evidenced by accelerated respiration and blockade by antagonists. Therefore, the effects of mK ATP channel openers on mitochondrial function likely depend on the experimental conditions and the cell's underlying energetic state.

Anesthesia and Analgesia, 2003

Reactive oxygen species (ROS) are largely responsible for cardiac injury consequent to ischemia a... more Reactive oxygen species (ROS) are largely responsible for cardiac injury consequent to ischemia and reperfusion, but, paradoxically, there is evidence suggesting that anesthetics induce preconditioning (APC) by generating ROS. We hypothesized that sevoflurane generates the ROS superoxide (O(2)(.-)), that APC attenuates O(2)(.-) formation during ischemia, and that this attenuation is reversed by bracketing APC with the O(2)(.-) scavenger manganese (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) or the putative mitochondrial adenosine triphosphate-sensitive potassium (mK(ATP)) channel blocker 5-hydroxydecanoate (5-HD). O(2)(.-) was measured continuously in guinea pig hearts by using dihydroethidium. Sevoflurane was administered alone (APC), with MnTBAP, or with 5-HD before 30 min of ischemia and 120 min of reperfusion. Control hearts underwent no pretreatment. Sevoflurane directly increased O(2)(.-); this was blocked by MnTBAP but not by 5-HD. O(2)(.-) increased during ischemia and during reperfusion. These increases in O(2)(.-) were attenuated in the APC group, but this was prevented by MnTBAP or 5-HD. We conclude that sevoflurane directly induces O(2)(.-) formation but that O(2)(.-) formation is decreased during subsequent ischemia and reperfusion. The former effect appears independent of mK(ATP) channels, but not the latter. Our study indicates that APC is initiated by ROS that in turn cause mK(ATP) channel opening. Although there appears to be a paradoxical role for ROS in triggering and mediating APC, a possible mechanism is offered. Reactive oxygen species (ROS) are implicated in triggering anesthetic preconditioning (APC). The ROS superoxide (O(2)(.-)) was measured continuously in guinea pig isolated hearts. Sevoflurane directly increased O(2)(.-) but led to attenuated O(2)(.-) formation during ischemia. This demonstrates triggering of APC by ROS and clarifies the mechanism of cardioprotection during ischemia.

Journal of Pharmacological and Toxicological Methods, 2009

Journal of Heart and Lung Transplantation, 2002

Objectives: Cardiac ischemia-reperfusion activates Na ϩ /H ϩ exchange; excess Na ϩ and the result... more Objectives: Cardiac ischemia-reperfusion activates Na ϩ /H ϩ exchange; excess Na ϩ and the resulting Ca 2ϩ overload, through reverse Na ϩ /Ca 2ϩ exchange, cause cellular injury and cardiac dysfunction. We postulated that inhibiting the Na ϩ /H ϩ isoform-1 exchanger would add to the protection of hearts after long-term cold storage in acidic cardioplegic solution.

Antioxidants & Redox Signaling, 2010

The mitochondrion is the most important organelle in determining continued cell survival and cell... more The mitochondrion is the most important organelle in determining continued cell survival and cell death. Mitochondrial dysfunction leads to many human maladies, including cardiovascular diseases, neurodegenerative disease, and cancer. These mitochondria-related pathologies range from early infancy to senescence. The central premise of this review is that if mitochondrial abnormalities contribute to the pathological state, alleviating the mitochondrial dysfunction would contribute to attenuating the severity or progression of the disease. Therefore, this review will examine the role of mitochondria in the etiology and progression of several diseases and explore potential therapeutic benefits of targeting mitochondria in mitigating the disease processes. Indeed, recent advances in mitochondrial biology have led to selective targeting of drugs designed to modulate and manipulate mitochondrial function and genomics for therapeutic benefit. These approaches to treat mitochondrial dysfunction rationally could lead to selective protection of cells in different tissues and various disease states. However, most of these approaches are in their infancy. Antioxid. Redox Signal. 13, 279-347.

Mitochondria generate reactive oxygen species (ROS) dependent on substrate conditions, O 2 concen... more Mitochondria generate reactive oxygen species (ROS) dependent on substrate conditions, O 2 concentration, redox state, and activity of the mitochondrial complexes. It is well known that the FADH 2 -linked substrate succinate induces reverse electron flow to complex I of the electron transport chain and that this process generates superoxide (O 2 ·-); these effects are blocked by the complex I blocker rotenone. We demonstrated recently that succinate + rotenone -dependent H 2 O 2 production in isolated mitochondria increased mildly on activation of the putative big mitochondrial Ca 2+ -sensitive K + channel (mtBK Ca ) by low concentrations of NS-1619. In the present study we examined effects of NS-1619 on mitochondrial O 2 consumption, membrane potential (ΔΨ m ), H 2 O 2 release rates, and redox state in guinea pig heart isolated mitochondria respiring on succinate but without rotenone. NS-1619 (30 µM) increased state 2 and state 4 respiration by 26±4% and 14±4%, respectively; this increase was abolished by the BK Ca channel blocker paxilline (5 µM). Paxilline alone had no effect on respiration. NS-1619 did not alter ΔΨ m or redox state but decreased H 2 O 2 production by 73% vs. control; this effect was incompletely inhibited by paxilline. We conclude that under substrate conditions that allow reverse electron flow, matrix K + influx through mtBK Ca channels reduces mitochondrial H 2 O 2 production by accelerating forward electron flow. Our prior study showed that NS-1619 induced an increase in H 2 O 2 production with blocked reverse electron flow. The present results suggest that NS-1619 -induced matrix K + influx increases forward electron flow despite the high reverse electron flow, and emphasize the importance of substrate conditions on interpretation of effects on mitochondrial bioenergetics. Page 3 of 30 Copyright Information 4 K + channels located in the IMM appear to play an important role in regulating mitochondrial function (15, 25), but the mechanism remains unclear. Xu et al. (41) found evidence for big Ca 2+ -sensitive K + (mtBK Ca ) channels in the IMM of guinea pig ventricular cells. Sato et al. (32) demonstrated that opening of mtBK Ca channels increases flavoprotein oxidation in ventricular myocytes placed in glucose-free Tyrode's solution, indicating an increase in electron transport in oxidized mitochondria. Recently, we investigated the effects of mtBK Ca channel opening and closing on function of mitochondria isolated from guinea pig hearts (16). We reported that putative mtBK Ca channel opening with low concentrations of NS-1619 accelerated states 2 and 4 respiration (electron flow) and H 2 O 2 generation at a stable ΔΨ m in the presence of succinate and rotenone (16). In the present study we investigated effects of NS-1619 on respiration, ΔΨ m , redox state (NADH and FAD), and H 2 O 2 generation using succinate alone, which can induce ROS generation via reverse electron flow. We proposed that under these conditions H 2 O 2 production would decrease because of a relative increase in forward electron flow, induced by matrix K + influx, thus countering the larger reverse electron flow caused by succinate with subsequent O 2

Anesthesia and Analgesia, 2005

Negative inotropic agents may differentially modulate indices of cytosolic [Ca 2+ ]-left ventricu... more Negative inotropic agents may differentially modulate indices of cytosolic [Ca 2+ ]-left ventricular pressure (LVP) relationships when given before and after ischemia. We measured and calculated [Ca 2+ ], LVP, velocity ratios [d[Ca 2+ ]/dt max ]/[dLVP/dt max ] (VR max ), [d[Ca 2+ ]/dt min ]/[dLVP/dt min ] (VR min ), and area ratio (AR, area[Ca 2+ ]/area LVP per beat) before and after global ischemia in guinea pig isolated hearts. Ca 2+ transients were recorded by indo 1-AM fluorescence via a fiber optic probe placed at the LV free wall. [Ca 2+ ]-LVP loops were acquired by plotting LVP as a function of [Ca 2+ ] at multiple time points during the cardiac cycle. Hearts were perfused with bimakalim, 2,3-butanedione monoxime (BDM) nifedipine, or lidocaine before and after 30 min ischemia. Before ischemia each drug depressed LVP, but only nifedipine decreased both LVP and [Ca 2+ ] with a down-and leftward shift of the Ca 2+ -LVP loop. After ischemia each drug depressed LVP and [Ca 2+ ] with a down and leftward shift of the Ca 2+ -LVP loop. Each drug except BDM decreased dCa 2+ /dt max ; nifedipine

American Journal of Physiology-cell Physiology, 2006

Mitochondria are increasingly recognized as lynchpins in the evolution of cardiac injury during i... more Mitochondria are increasingly recognized as lynchpins in the evolution of cardiac injury during ischemia and reperfusion. This review addresses the emerging concept that modulation of mitochondrial respiration during and immediately following an episode of ischemia can attenuate the extent of myocardial injury. The blockade of electron transport and the partial uncoupling of respiration are two mechanisms whereby manipulation of mitochondrial metabolism during ischemia decreases cardiac injury. Although protection by inhibition of electron transport or uncoupling of respiration initially appears to be counterintuitive, the continuation of mitochondrial oxidative phosphorylation in the pathological milieu of ischemia generates reactive oxygen species, mitochondrial calcium overload, and the release of cytochrome c. The initial target of these deleterious mitochondrial-driven processes is the mitochondria themselves. Consequences to the cardiomyocyte, in turn, include oxidative damage, the onset of mitochondrial permeability transition, and activation of apoptotic cascades, all favoring cardiomyocyte death. Ischemia-induced mitochondrial damage carried forward into reperfusion further amplifies these mechanisms of mitochondrial-driven myocyte injury. Interruption of mitochondrial respiration during early reperfusion by pharmacologic blockade of electron transport or even recurrent hypoxia or brief ischemia paradoxically decreases cardiac injury. It increasingly appears that the cardioprotective paradigms of ischemic preconditioning and postconditioning utilize modulation of mitochondrial oxidative metabolism as a key effector mechanism. The initially counterintuitive approach to inhibit mitochondrial respiration provides a new cardioprotective paradigm to decrease cellular injury during both ischemia and reperfusion.

Journal of Heart and Lung Transplantation, 2008

Background-Donor human hearts cannot be preserved for >5 hours between explantation and recipient... more Background-Donor human hearts cannot be preserved for >5 hours between explantation and recipient implantation. A better approach is needed to preserve transplantable hearts for longer periods, ideally at ambient conditions for transport. We tested whether Lifor solution could satisfactorily preserve guinea pig isolated hearts perfused at low flow with no added oxygen at room temperature for 20 hours.

Journal of Cardiovascular Pharmacology, 2005

We examined if sevoflurane given before cold ischemia of intact hearts (anesthetic preconditionin... more We examined if sevoflurane given before cold ischemia of intact hearts (anesthetic preconditioning, APC) affords additional protection by further improving mitochondrial energy balance and if this is abolished by a mitochondrial KATP blocker. NADH and FAD fluorescence was measured within the left ventricular wall of 5 groups of isolated guinea pig hearts: (1) hypothermia alone; (2) hypothermia+ischemia; (3) APC (4.1% sevoflurane)+cold ischemia; (4) 5-HD+cold ischemia, and (5) APC+5-HD+cold ischemia. Hearts were exposed to sevoflurane for 15 minutes followed by 15 minutes of washout at 37 degrees C before cooling, 2 hours of 27 degrees C ischemia, and 2 hours of 37 degrees C reperfusion. The KATP channel inhibitor 5-HD was perfused before and after sevoflurane. Ischemia caused a rapid increase in NADH and a decrease in FAD that waned over 2 hours. Warm reperfusion led to a decrease in NADH and an increase in FAD. APC attenuated the changes in NADH and FAD and further improved postischemic function and reduced infarct size. 5-HD blocked the cardioprotective effects of APC but not APC-induced alterations of NADH and FAD. Thus, APC improves redox balance and has additive cardioprotective effects with mild hypothermic ischemia. 5-HD blocks APC-induced cardioprotective effects but not improvements in mitochondrial bioenergetics. This suggests that mediation of protection by KATP channel opening during cold ischemia and reperfusion is downstream from the APC-induced improvement in redox state or that these changes in redox state are not attenuated by KATP channel antagonism.

Anesthesiology, 2004

Anesthetic preconditioning protects against cardiac ischemia/reperfusion injury. Increases in red... more Anesthetic preconditioning protects against cardiac ischemia/reperfusion injury. Increases in reduced nicotinamide adenine dinucleotide and reactive oxygen species during sevoflurane exposure suggest attenuated mitochondrial electron transport as a trigger of anesthetic preconditioning. The authors investigated the effects of sevoflurane on respiration in isolated cardiac mitochondria. Mitochondria were isolated from fresh guinea pig hearts, and mitochondrial oxygen consumption was measured in the presence of complex I (pyruvate) or complex II (succinate) substrates. The mitochondria were exposed to 0, 0.13, 0.39, 1.3, or 3.9 mM sevoflurane. State 3 respiration was determined after adenosine diphosphate addition. The reactive oxygen species scavengers manganese(III) tetrakis (4-benzoic acid) porphyrin chloride and N-tert-Butyl-a-(2-sulfophenyl)nitrone sodium (10 microM each), or the K(ATP) channel blockers glibenclamide (2 microM) or 5-hydroxydecanoate (300 microM), were given alone or before 1.3 mM sevoflurane. Sevoflurane attenuated respiration for both complex I and complex II substrates, depending on the dose. Glibenclamide and 5-hydroxydecanoate had no effect on this attenuation. Both scavengers, however, abolished the sevoflurane-induced attenuation for complex I substrates, but not for complex II substrates. The findings suggest that sevoflurane-induced attenuation of complex I is mediated by reactive oxygen species, whereas attenuation of other respiratory complexes is mediated by a different mechanism. The opening of mitochondrial K(ATP) channels by sevoflurane does not seem to be involved in this effect. Thus, reactive oxygen species formation may not only result from attenuated electron transport by sevoflurane, but it may also contribute to complex I attenuation, possibly leading to a positive feedback and amplification of sevoflurane-induced reactive oxygen species formation in triggering anesthetic preconditioning.

Aim Damage to the mitochondrial electron transport chain (ETC) occurs during ischaemia. Blockade ... more Aim Damage to the mitochondrial electron transport chain (ETC) occurs during ischaemia. Blockade of electron flow in the ETC just before ischaemia with the reversible complex I inhibitor amobarbital protects isolated mitochondria against ischaemic damage and preserves oxidative phosphorylation and cytochrome c content. We hypothesized that brief amobarbital perfusion just before ischaemia would improve cardiac recovery and decrease infarct size after ischaemia and reperfusion (IR) by preserving the mitochondrial redox state and reducing mitochondrial superoxide (O 2 2 † ) generation, in turn would decrease mitochondrial Ca 2þ accumulation (mt[Ca 2þ ]). Methods Guinea pig Langendorff-perfused hearts were treated with Krebs Ringer solution (KR; untreated) or amobarbital (2.5 mM) in KR for 1 min immediately before 30 min of no flow, global ischaemia, followed by reperfusion without additional treatment. Cardiac function, mitochondrial NADH, FAD, mt[Ca 2þ ], and O 2 2 † levels were assessed during the 1 min perfusion period and throughout IR. Results Amobarbital perfusion alone before ischaemia significantly increased O 2 2 † levels and NADH, without altering FAD, and decreased mt[Ca 2þ ]. During ischaemia, mitochondrial NADH was higher, O 2 2 † levels were lower, and mt[Ca 2þ ] was less elevated in the amobarbital group. On reperfusion O 2 2 † levels and mt[Ca 2þ ] were significantly reduced, NADH-FAD redox state was preserved and cardiac function was markedly improved in the amobarbital group; infarct size was smaller in the amobarbital group compared to the untreated group.

Anesthesiology, 2001

Volatile anesthetics exert their negative chronotropic and inotropic effects, in part by depressi... more Volatile anesthetics exert their negative chronotropic and inotropic effects, in part by depressing the L- and T-type calcium channels. This study examines and compares the dose-dependent effects of isoflurane on atrial L- and T-type calcium currents (I(Ca,L) and I(Ca,T)) and ventricular I(Ca,L). Whole cell I(Ca) was recorded from enzymatically isolated guinea pig cardiomyocytes. Current-voltage relations for atrial and ventricular I(Ca,L) was obtained from holding potentials of -90 and -50 mV to test a potential of +60 mV in 10-mV increments. Atrial I(Ca,T) was determined by subtraction of currents obtained from holding potentials of -50 and -90 mV. Steady state inactivation was determined using standard two-pulse protocols, and data were fitted with the Boltzmann equation. Isoflurane depressed I(Ca) in a dose-dependent manner, with Kd values of 0.23+/-0.03, 0.34+/-0.03, and 0.71+/-0.02 mM of anesthetic for atrial I(Ca,T) and I(Ca,L) and ventricular (ICa,L), respectively, and caused a significant (P < 0.05) hyperpolarizing shift in steady state inactivation. At 1.2 and 1.6 mm, isoflurane caused a significant (P < 0.05) depolarizing shift in the steady state activation in ventricular I(Ca,L) but not in atrial I(Ca,L) or I(Ca,T). In addition to the depression of I(Ca,L), isoflurane also induced a hyperpolarizing shift in the reversal potential of I(Ca) for both atrial and ventricular L-type calcium channels. The results show that atrial I(Ca,T) is more sensitive to isoflurane than atrial I(Ca,L), and ventricular I(Ca,L) was the least responsive to the anesthetic. These differential sensitivities of the calcium channels in the atrial and ventricular chambers might reflect phenotypic differences in the calcium channels or differences in modulation by the anesthetic.

Journal of Applied Physiology, 2005

Ischemia-reperfusion injury changes the dynamics of Ca 2ϩcontraction coupling due to inotropic dr... more Ischemia-reperfusion injury changes the dynamics of Ca 2ϩcontraction coupling due to inotropic drugs in isolated hearts. Positive inotropic drugs may attenuate or exacerbate the deleterious effects of ischemia and reperfusion (IR) injury on excitation-contraction coupling in hearts. We 1) quantified the phase-space relationship between simultaneously measured myoplasmic Ca 2ϩ concentration ([Ca 2ϩ ]) and isovolumetric left ventricular pressure (LVP) using indexes of loop area, orientation, and position; and 2) quantified cooperativity by linearly modeling the phase-space relationship between [Ca 2ϩ ] and rate of LVP development in intact hearts during administration of positive inotropic drugs before and after global IR injury. Unpaced, isolated guinea pig hearts were perfused at a constant pressure with Krebs-Ringer solution (37°C, 1.25 mM CaCl 2). [Ca 2ϩ ] was measured ratiometrically by indo 1 fluorescence by using a fiber-optic probe placed at the left ventricular free wall. LVP was measured by using a saline-filled latex balloon and transducer. Drugs were infused for 2 min, 30 min before, and for 2 min, 30 min after 30-min global ischemia. IR injury worsened Ca 2ϩ -contraction coupling, as seen from decreased orientation and repositioning of the loop rightward and downward and reduced cooperativity of contraction and relaxation with or without drugs. Dobutamine (4 M) worsened, whereas dopamine (8 M) improved Ca 2ϩ -contraction coupling before and after IR injury. Dobutamine and dopamine improved cooperativity of contraction and relaxation after IR injury, whereas only dopamine increased cooperativity of relaxation before IR injury. Digoxin (1 M) improved Ca 2ϩ -contraction coupling and cooperativity of contraction after but not before ischemia. Levosimendan (1 M) did not alter Ca 2ϩcontraction coupling or cooperativity, despite producing concomitant increases in contractility, relaxation, and Ca 2ϩ flux before and after ischemia. Dynamic indexes based on LVP-[Ca 2ϩ ] diagrams (area, shape, position) can be used to identify and measure alterations in Ca 2ϩ -contraction coupling during administration of positive inotropic drugs in isolated hearts before and after IR injury.

Anesthesia and Analgesia, 2002

Cardiac ischemia/reperfusion (IR) injury is associated with mitochondrial (m)Ca(2+) overload. Ane... more Cardiac ischemia/reperfusion (IR) injury is associated with mitochondrial (m)Ca(2+) overload. Anesthetic preconditioning (APC) attenuates IR injury. We hypothesized that mCa(2+) overload is decreased by APC in association with mitochondrial adenosine triphosphate-sensitive K(+) (mK(ATP)) channel opening. By use of indo-1 fluorescence, m[Ca(2+)] was measured in 40 guinea pig Langendorff-prepared hearts. Control (CON) hearts received no treatment for 50 min before IR; APC hearts were exposed to 1.2 mM (8.8 vol%) sevoflurane for 15 min; APC + 5-hydroxydecanoate (5-HD) hearts received 200 micro M 5-HD from 5 min before to 15 min after sevoflurane exposure; and 5-HD hearts received 5-HD for 35 min. Sevoflurane was washed out for 30 min and 5-HD for 15 min before 30 min of global ischemia and 120 min of reperfusion. During ischemia, the peak m[Ca(2+)] accumulation was decreased by APC from 489 +/- 37 nM (CON) to 355 +/- 28 nM (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05); this was abolished by 5-HD (475 +/- 38 nM m[Ca(2+)]). APC resulted in improved function and reduced infarct size on reperfusion, which also was blocked by 5-HD. 5-HD pretreatment alone did not affect m[Ca(2+)] (470 +/- 34 nM) or IR injury. Thus, preservation of function and morphology on reperfusion is associated with attenuated mCa(2+) accumulation during ischemia. Reversal by 5-HD suggests that APC may be triggered by opening mK(ATP) channels. Myocardial ischemia/reperfusion injury is associated with mitochondrial Ca(2+) overload. Mitochondrial [Ca(2+)] and function were measured in guinea pig isolated hearts. Anesthetic preconditioning attenuated mitochondrial Ca(2+) overload during ischemia, improved function, and reduced infarct size. Reversal by 5-hydroxydecanoate suggests that anesthetic preconditioning may be triggered by mitochondrial adenosine triphosphate-sensitive K channel opening.