David F. Stowe

The pericardium substantially affects the left ventricular diastolic pressure-volume relationship in the dog.

We instrumented six dog hearts in vivo to study the relationship between left and right ventricular diastolic pressures with the pericardium closed and open. We measured left ventricular septum-to-free wall and anterior-posterior and right ventricular septum-to-free wall dimensions with implanted ultrasonic crystals, together with simultaneous high fidelity pressures. We varied diastolic pressure by infusing or withdrawing Mood or by increasing right ventricular afterload with transient pulmonary artery constriction. Although left and right ventricular diastolic pressures always correlated, this correlation was significantly higher with the pericardium closed than open. We fit left ventricular dfautolic pressure to an equation whkh included first order right ventricular pressure and fourth order left ventricular dimension terms. With the pericardium closed, the right ventricular pressure term dominated; with the pericardium open, left ventricular dimension terms dominated. Therefore, with the pericardium closed, right ventricular pressure was a more powerful predictor of left ventricular pressure than were left ventricular dimensions. In addition, the left ventricle appears much more compliant with the pericardium open. These results led us to modify the traditional view of the diastolic left ventricle as an unconstrained elastic shell of myocardium and replace it with a concept of the diastolic heart as a composite shell of stiff pericardium and compliant muscle, divided into subcompartments (ventricles) by the relatively compliant septum. The influence of the pericardium on the diastolic pressure-volume relationship should be considered in experiments on animals and patient management when the pericardium is open or closeab.

Cardioprotection with Volatile Anesthetics: Mechanisms and Clinical Implications

Cardiac surgery and some noncardiac procedures are associated with a significant risk of perioperative cardiac morbid events. Experimental data indicate that clinical concentrations of volatile general anesthetics protect the myocardium from ischemia and reperfusion injury, as shown by decreased infarct size and a more rapid recovery of contractile function on reperfusion. These anesthetics may also mediate protective effects in other organs, such as the brain and kidney. Recently, a number of reports have indicated that these experimentally observed protective effects may also have clinical implications in cardiac surgery. However, the impact of the use of volatile anesthetics on outcome measures, such as postoperative mortality and recovery in cardiac and noncardiac surgery, is yet to be determined.

Reactive oxygen species as mediators of cardiac injury and protection: the relevance to anesthesia practice.

Reactive oxygen species (ROS) are central to cardiac ischemic and reperfusion injury. They contribute to myocardial stunning, infarction and apoptosis, and possibly to the genesis of arrhythmias. Multiple laboratory studies and clinical trials have evaluated the use of scavengers of ROS to protect the heart from the effects of ischemia and reperfusion. Generally, studies in animal models have shown such effects. Clinical trials have also shown protective effects of scavengers, but whether this protection confers meaningful clinical benefits is uncertain. Several IV anesthetic drugs act as ROS scavengers. In contrast, volatile anesthetics have recently been demonstrated to generate ROS in the heart, most likely because of inhibitory effects on cardiac mitochondria. ROS are involved in the signaling cascade for cardioprotection induced by brief exposure to a volatile anesthetic (termed “anesthetic preconditioning”). ROS, therefore, although injurious in large quantities, can have a paradoxical protective effect within the heart. In this review we provide background information on ROS formation and elimination relevant to anesthetic and adjuvant drugs with particular reference to the heart. The sources of ROS, the means by which they induce cardiac injury or activate protective signaling pathways, the results of clinical studies evaluating ROS scavengers, and the effects of anesthetic drugs on ROS are each discussed.

sevoflurane Mimics Ischemic Preconditioning Effects on Coronary Flow and Nitric Oxide Release in Isolated Hearts

BACKGROUND Like ischemic preconditioning, certain volatile anesthetics have been shown to reduce the magnitude of ischemia/ reperfusion injury via activation of K+ adenosine triphosphate (ATP)-sensitive (K(ATP)) channels. The purpose of this study was (1) to determine if ischemic preconditioning (IPC) and sevoflurane preconditioning (SPC) increase nitric oxide release and improve coronary vascular function, as well as mechanical and electrical function, if given for only brief intervals before global ischemia of isolated hearts; and (2) to determine if K(ATP) channel antagonism by glibenclamide (GLB) blunts the cardioprotective effects of IPC and SPC. METHODS Guinea pig hearts were isolated and perfused with Krebs-Ringers solution at 55 mm Hg and randomly assigned to one of seven groups: (1) two 2-min total coronary occlusions (preconditioning, IPC) interspersed with 5 min of normal perfusion; (2) two 2-min occlusions interspersed with 5 min of perfusion while perfusing with GLB (IPC+GLB); (3) SPC (3.5%) for two 2-min periods; (4) SPC+GLB for two 2-min periods; (5) no treatment before ischemia (control [CON]); (6) CON+GLB; and (7) no ischemia (time control). Six minutes after ending IPC or SPC, hearts of ischemic groups were subjected to 30 min of global ischemia and 75 min of reperfusion. Left-ventricular pressure, coronary flow, and effluent NO concentration ([NO]) were measured. Flow and NO responses to bradykinin, and nitroprusside were tested 20-30 min before ischemia or drug treatment and 30-40 min after reperfusion. RESULTS After ischemia, compared with before (percentage change), left-ventricular pressure and coronary flow, respectively, recovered to a greater extent (P<0.05) after IPC (42%, 77%), and treatment with SPC (45%, 76%) than after CON (30%, 65%), IPC+GLB (24%, 64%), SPC+GLB (20%, 65%), and CON+GLB (28%, 64%). Bradykinin and nitroprusside increased [NO] by 30+/-5 (means +/- SEM) and 29+/-4 nM, respectively, averaged for all groups before ischemia. [NO] increased by 26+/-6 and 27+/-7 nM, respectively, in SPC and IPC groups after ischemia, compared with an average [NO] increase of 8+/-5 nM (P<0.01) after ischemia in CON and each of the three GLB groups. Flow increases to bradykinin and nitroprusside were also greater after SPC and IPC. CONCLUSIONS Preconditioning with sevoflurane, like IPC, improves not only postischemic contractility, but also basal flow, bradykinin and nitroprusside-induced increases in flow, and effluent [NO] in isolated hearts. The protective effects of both SPC and IPC are reversed by K(ATP) channel antagonism.

Comparison of etomidate, ketamine, midazolam, propofol, and thiopental on function and metabolism of isolated hearts

The authors examined direct myocardial and coronary vascular responses to the anesthetic induction agents etomidate, ketamine, midazolam, propofol, and thiopental and compared their effects on attenuating autoregulation of coronary flow as assessed by changes in oxygen supply/demand relationships. Spontaneous heart rate, atrioventricular conduction time during a trial pacing, left ventricular pressure (LVP), coronary flow (CF), percent oxygen extraction, oxygen delivery, and myocardial oxygen consumption (MVo2) were examined in 55 isolated guinea pig hearts divided into five groups of 11 each. Hearts were perfused at constant pressure with one of the drugs administered at steady-state concentrations increasing from 0.5 μM to 1 mM. Adenosine was given to test maximal CF. At concentrations below 10 μM no significant changes were observed; beyond 50 μM for midazolam, etomidate, and propofol, and 100 μM for thiopental and ketamine, each agent caused progressive but differential decreases in heart rate, atrioventricular conduction time (leading to atrioventricular dissociation), LVP, +dLVP/dtrnax, percent oxygen extraction, and MVo2. The concentrations (μM) at which +dLVP/dtmax was reduced by 50% were as follows: etomidate, 82 ± 2 (mean ± SEM); propofol, 91 ± 4; midazolam, 105 ± 8; thiopental, 156 ± 11; and ketamine, 323 ± 7; the rank order of potency was etomidate = propofol = midazolam > thiopental > ketamine; results were similar for LVP. At the 100 μM concentration, CF was decreased 11% ± 2% by ketamine and 5% ± 3% by thiopental but was increased 17% ± 6% by etomidate, 21% ± 5% by midazolam, and near maximally to 57% ± 10% by propofol; MVo2 was decreased 8% ± 4% by thiopental, 10% ± 5% by ketamine, 19% ± 5% by midazolam, 29% ± 7% by etomidate, and 37% ± 5% by propofol; oxygen delivery/MVo2 was unchanged by thiopental and ketamine but was increased 62% ± 7% by midazolam, 71% ± 9% by etomidate, and 150% ± 15% by propofol. Between 100 μM and 1 mM, thiopental and ketamine did not increase CF but decreased MVo2 and percent oxygen extraction, whereas propofol maximally increased CF and decreased MVo2 and midazolam and etomidate had intermediate effects. These results indicate that on a molar basis, propofol, and less so midazolam and etomidate, depress cardiac function moderately more than thiopental and ketamine, and that propofol markedly attenuates autoregulation by causing coronary vasodilation. With doses used to induce anesthesia, propofol and thiopental appear to depress cardiac function more than ketamine or etomidate.

Xenon Does Not Alter Cardiac Function or Major Cation Currents in Isolated Guinea Pig Hearts or Myocytes

Background The noble gas xenon (Xe) has been used as an inhalational anesthetic agent in clinical trials with little or no physiologic side effects. Like nitrous oxide, Xe is believed to exert minimal unwanted cardiovascular effects, and like nitrous oxide, the vapor concentration to achieve 1 minimum alveolar concentration (MAC) for Xe in humans is high, i.e., 70–80%. In the current study, concentrations of up to 80% Xe were examined for possible myocardial effects in isolated, erythrocyte-perfused guinea pig hearts and for possible effects on altering major cation currents in isolated guinea pig cardiomyocytes. Methods Isolated guinea pigs hearts were perfused at 70 mmHg via the Langendorff technique initially with a salt solution at 37°C. Hearts were then perfused with fresh filtered (40-&mgr;m pore) and washed canine erythrocytes diluted in the salt solution equilibrated with 20% O2 in nitrogen (control), with 20% O2, 40% Xe, and 40% N2, (0.5 MAC), or with 20% O2 and 80% Xe (1 MAC), respectively. Hearts were perfused with 80% Xe for 15 min, and bradykinin was injected into the blood perfusate to test endothelium-dependent vasodilatory responses. Using the whole-cell patch-clamp technique, 80% Xe was tested for effects on the cardiac ion currents, the Na+, the L-type Ca2+, and the inward-rectifier K+ channel, in guinea pig myocytes suffused with a salt solution equilibrated with the same combinations of Xe, oxygen, and nitrogen as above. Results In isolated hearts, heart rate, atrioventricular conduction time, left ventricular pressure, coronary flow, oxygen extraction, oxygen consumption, cardiac efficiency, and flow responses to bradykinin were not significantly (repeated measures analysis of variance, P > 0.05) altered by 40% or 80% Xe compared with controls. In isolated cardiomyocytes, the amplitudes of the Na+, the L-type Ca2+, and the inward-rectifier K+ channel over a range of voltages also were not altered by 80% Xe compared with controls. Conclusions Unlike hydrocarbon-based gaseous anesthetics, Xe does not significantly alter any measured electrical, mechanical, or metabolic factors, or the nitric oxide–dependent flow response in isolated hearts, at least partly because Xe does not alter the major cation currents as shown here for cardiac myocytes. The authors’ results indicate that Xe, at approximately 1 MAC for humans, has no physiologically important effects on the guinea pig heart.

Sevoflurane exposure generates superoxide but leads to decreased superoxide during ischemia and reperfusion in isolated hearts.

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 (O2·−), that APC attenuates O2·− formation during ischemia, and that this attenuation is reversed by bracketing APC with the O2·− scavenger manganese (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) or the putative mitochondrial adenosine triphosphate-sensitive potassium (mKATP) channel blocker 5-hydroxydecanoate (5-HD). O2·− 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 O2·−; this was blocked by MnTBAP but not by 5-HD. O2·− increased during ischemia and during reperfusion. These increases in O2·− were attenuated in the APC group, but this was prevented by MnTBAP or 5-HD. We conclude that sevoflurane directly induces O2·− formation but that O2·− formation is decreased during subsequent ischemia and reperfusion. The former effect appears independent of mKATP channels, but not the latter. Our study indicates that APC is initiated by ROS that in turn cause mKATP 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 Precede the ε Isoform of Protein Kinase C in the Anesthetic Preconditioning Signaling Cascade

Background Protein kinase C (PKC) and reactive oxygen species (ROS) are known to have a role in anesthetic preconditioning (APC). Cardiac preconditioning by triggers other than volatile anesthetics, such as opioids or brief ischemia, is known to be isoform selective, but the isoform required for APC is not known. The authors aimed to identify the PKC isoform that is involved in APC and to elucidate the relative positions of PKC activation and ROS formation in the APC signaling cascade. Methods Isolated guinea pig hearts were subjected to 30 min of ischemia and 120 min of reperfusion. Before ischemia, hearts were either untreated or treated with sevoflurane (APC) in the absence or presence of the nonspecific PKC inhibitor chelerythrine, the PKC-&dgr; inhibitor PP101, or the PKC-&egr; inhibitor PP149. Spectrofluorometry and the fluorescent probes dihydroethidium were used to measure intracellular ROS, and effluent dityrosine as used to measure extracellular ROS release. Results Previous sevoflurane exposure protected the heart against ischemia–reperfusion injury, as previously described. Chelerythrine or PP149 abolished protection, but PP101 did not. ROS formation was observed during sevoflurane exposure and was not altered by any of the PKC inhibitors. Conclusions APC is mediated by PKC-&egr; but not by PKC-&dgr;. Furthermore, PKC activation probably occurs downstream of ROS generation in the APC signaling cascade.

Potential Therapeutic Benefits of Strategies Directed to Mitochondria

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.

Differences in Cardiotoxicity of Bupivacaine and Ropivacaine Are the Result of Physicochemical and Stereoselective Properties

Background Ropivacaine is believed to have a lower incidence of clinical cardiac side effects than bupivacaine. The aim of this study was to compare the direct cardiac effects of the optically pure S (−)-ropivacaine isomer and its nonclinically used R (+)-isomer with both optically pure bupivacaine isomers in isolated hearts. The hypothesis was that differences in direct cardiac effects are distinguished not only by stereoselective actions of local anesthetic molecules to specific receptors, but also by physicochemical differences triggered by replacing the butyl- by a propyl-residual on pipecoloxylide. Methods Guinea pig hearts (n = 31) were excised and perfused by the Langendorff method. Atrial and ventricular bipolar electrodes were placed to measure heart rate and atrioventricular conduction time. Left ventricular pressure, coronary flow, and oxygen tensions were measured. Twelve hearts were perfused with increasing concentrations (0.5, 1.0, 5.0, and 10 &mgr;m) of both isomers of bupivacaine, and 13 hearts were perfused with the same concentrations of ropivacaine isomers. Six hearts were perfused with higher concentrations (20, 30, 40, and 50 &mgr;m) of both isomers of ropivacaine. The order of isomers and anesthetic chosen were randomized. Results Both anesthetics had negative inotropic and chronotropic effects without evidence of stereoselectivity. Equal concentrations of both isomers of bupivacaine had negative inotropic effects greater than that of ropivacaine isomers. Atrioventricular conduction time was prolonged by both anesthetics in a concentration-dependent manner, but bupivacaine isomers increased atrioventricular conduction time more than ropivacaine isomers. In contrast to other variables, atrioventricular conduction time showed evident stereoselectivity for bupivacaine at the lowest concentration (0.5 &mgr;m) but only at higher concentrations for ropivacaine (> 30 &mgr;m). The R (+)-isomer was more potent than the S (−)-isomer on increasing atrioventricular conduction time for both bupivacaine and ropivacaine. Conclusions The results confirm that stereoselectivity can be demonstrated by a lengthening of atrioventricular conduction time for the more fat-soluble bupivacaine. However, for the less fat-soluble ropivacaine, the S (−)-isomer has no advantage over the R (+)-isomer for preventing slowing of atrioventricular conduction in clinical concentrations. Neither anesthetic showed stereoselective inotropic effects, but ropicavaine isomers had lesser cardiodepressant effects than bupivacaine isomers because of the replacement of the butyl- by a propyl-terminal group.