Ketamine Has Stereospecific Effects in the Isolated Perfused Guinea Pig Heart

Background: S(+)-Ketamine is judged to produce more potent anesthesia than either the racemate or the R(-) ketamine isomer because of differential activation of specific cerebral receptors. Other than central nervous system effects, the most important side effects of ketamine occur in the cardiovascular system. We examined the direct cardiac effects of the isomers and the racemate of ketamine in the isolated perfused guinea pig heart.

Methods: Twenty-three guinea pig hearts were perfused by the Langendorff technique with modified 37 degrees Celsius Krebs-Ringer's solution (97% oxygen and 3% carbon dioxide) at a constant perfusion pressure. Eight animals were pretreated with reserpine to deplete hearts of catecholamines. These pretreated hearts were also perfused with Krebs-Ringer's solution containing propranolol, phenoxybenzamine, and atropine to block any remaining effects of catecholamines and of acetylcholine. Five additional hearts were perfused with naloxone to block cardiac opioid receptors. Ten hearts were not treated. All 23 hearts were then exposed to four increasing equimolar concentrations of each isomer and the racemate of ketamine for 10 min. Heart rate, atrioventricular conduction time (AVCT), left ventricular pressure, coronary flow, and inflow and outflow oxygen tensions were measured. Percentage oxygen extraction, oxygen delivery, and oxygen consumption were calculated.

Results: Both isomers and the racemate caused a concentration-dependent depression of systolic left ventricular pressure and an increase in AVCT. in the untreated hearts, S(+)-ketamine decreased heart rate and left ventricular pressure and, at higher concentrations, oxygen consumption and percentage oxygen extraction significantly less than R(-)-ketamine independent of blocked or unblocked opioid receptors. Racemic ketamine depressed cardiac function to a degree intermediate to that produced by the isomers. Coronary flow and AVCT were equally affected by the isomers and by the racemic mixture. In the catecholamine-depleted hearts both isomers and the racemate caused equipotent depression of all variables. In these hearts cardiac depression was greater, and AVCT, coronary flow, and oxygen delivery were significantly greater than in untreated and opioid receptor-blocked hearts.     

Stereoselective Effects of Etomidate Optical Isomers on Gamma-aminobutyric Acid Type A Receptors and Animals

Background: The intravenous anesthetic etomidate is optically active and exists in two mirror-image enantiomeric forms. However, although the R(+) isomer is used as a clinical anesthetic, quantitative information on the relative potencies of the R(+) and S(-) isomers is lacking. These data could be used to test the relevance of putative molecular targets.

Methods: The anesthetic concentrations for a half-maximal effect (EC50) needed to induce a loss of righting reflex in tadpoles (Rana temporaria) were determined for both etomidate enantiomers. The effects of the isomers on gamma-aminobutyric acid (GABA)-induced currents in stably transfected mouse fibroblast cells was also investigated using the patch-clamp technique. In addition, the effects of the isomers on a lipid chain-melting phase transition were determined.

Results: The EC50 concentrations for general anesthesia for the R(+) and S(-) isomers were 3.4 +/- 0.1 micro Meter and 57 +/- 1 micro Meter, with slopes of n = 1.9 +/- 0.1 and n = 2.9 +/- 0.2, respectively. The R(+) isomer was also much more effective than the S(-) isomer at potentiating GABA-induced currents, although the degree of stereoselectivity varied with anesthetic concentration. R(+) etomidate potentiated the GABA-induced currents by increasing the apparent affinity of GABA for its receptor. Both isomers were equally effective at disrupting lipid bilayers.     

Amrinone reverses cardiac depression and augments coronary vasodilation with isoflurane in the isolated heart

Amrinone is a positive inotropic and vasodilatory agent and may be administered during anesthesia with isoflurane. The authors' aims were 1) to examine if amrinone produces coronary artery vasodilation through an increase in metabolic demand or through a direct vasodilatory effect or through both and 2) to test if amrinone attenuates cardiac depression and enhances coronary artery vasodilation produced with exposure to isoflurane. The effects of these drugs were examined in 11 isolated perfused guinea pig hearts. Variables measured were: heart rate (HR), atrioventricular conduction time (AVCT), isovolumetric peak left ventricular pressure (LVP), coronary flow, percent O2 extraction, myocardial O2 consumption (MVO2), and the ratio of O2 delivery (DO2) to MVO2. Each heart was exposed for 10-min periods to 10, 50, 100, and 500 microM amrinone alone, and to 0.5 or 1% isoflurane before, during, and after amrinone. Initial control values were: heart rate 216 +/- 5 beats per min; AVCT 56 +/- 1 ms; peak LVP 86 +/- 3 mmHg; coronary flow 6.3 +/- 0.3 ml.min-1.g-1 (11.4 +/- 0.7 ml.min-1.g-1 with adenosine bolus), percent O2 extraction 52 +/- 3%; DO2 107 +/- 3 microliters.min-1.g-1; MVO2 56 +/- 4 microliters.min-1.g-1; and DO2/MVO2 1.75 +/- 0.08. Amrinone 500 microM alone increased (P less than 0.05) heart rate by 9%, LVP by 13%, coronary flow by 18%, and MVO2 by 23%; AVCT decreased by 3%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synergistic Inhibition of Muscarinic Signaling by Ketamine Stereoisomers and the Preservative Benzethonium Chloride

Background: Ketamine (Ketalar; Parke-Davis, Morris Plains, NJ) has been shown to inhibit muscarinic signaling with a median inhibitory concentration (IC50) of 5.7 micro Meter. Whereas Ketalar is a racemic mixture, recent interest has focused on clinical use of the S(+) ketamine isomer, which is three times as potent an analgesic as the R(-) isomer yet seems to be associated with fewer psychoactive side effects. Therefore, the authors studied the effects of S(+) and R(-) ketamine and the preservative benzethonium chloride on muscarinic signaling.

Methods: Rat m1 muscarinic acetylcholine receptors were expressed recombinantly in Xenopus laevis oocytes. Ca2+ -activated Cl sup - currents in response to 10 sup -7 M acetyl-beta-methylcholine were determined by two-electrode voltage clamping in the presence of various concentrations of ketamine and benzethonium. Concentration-inhibition curves were constructed and used for algebraic and isobolographic analysis.

Results: The IC50 was 125 +/- 33 micro Meter for S(+) ketamine, and 91 +/- 19 micro Meter for R(-) ketamine. This difference was not statistically significant, indicating that muscarinic inhibition by ketamine is not stereoselective. The R(-)/S(+) mixture had an IC50 of 48 +/- 1 micro Meter, and thus the stereoisomers interact synergistically. When appropriate concentrations of benzethonium were added, an IC50 of 15 +/- 2 micro Meter resulted.     

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 microm) 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 microm) 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 microm) but only at higher concentrations for ropivacaine (> 30 microm). 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.     

Proarrhythmic and Antiarrhythmic Effects of Bupivacaine in an In Vitro Model of Myocardial Ischemia and Reperfusion

Background: Bupivacaine may have toxic cardiovascular effects when accidentally administered by intravascular injection. However, its electrophysiologic effects in the presence of myocardial ischemia remain unknown. The authors evaluated the electrophysiologic and anti- and proarrhythmic effects of bupivacaine in an in vitro model of the ischemic and reperfused myocardium.

Methods: In a double-chamber bath, a guinea pig right ventricular muscle strip was subjected partly to normal conditions and partly to simulated ischemia followed by reperfusion. The electrophysiologic effects of bupivacaine were studied at 1, 5, and 10 micro Meter concentrations.

Results: Bupivacaine (5 and 10 micro Meter) decreased the maximal upstroke velocity of the action potential (Vmax) in normoxic conditions and further decreased (10 micro Meter) the Vmax decrease induced by ischemic conditions. Bupivacaine reduced the mean occurrence time to the onset of myocardial conduction blocks (9 +/- 3 min; mean +/- SD; P < 0.005 with 5 and 10 micro Meter, compared with 17 +/- 6 min during simulated ischemia with no drug or control), and it increased the number of preparations that became inexcitable to pacing (55% of preparations, with 1 micro Meter and 100% with 5 and 10 micro Meter, compared with 17% for the control group). The incidence of spontaneous arrhythmias was reduced by 5 and 10 micro Meter bupivacaine during ischemia and reperfusion and was enhanced by 1 micro Meter bupivacaine during the ischemic phase.     

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 [mu]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 [mu]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 [mu]m) but only at higher concentrations for ropivacaine (> 30 [mu]m). The R (+)-isomer was more potent than the S (-)-isomer on increasing atrioventricular conduction time for both bupivacaine and ropivacaine.     

Regulation of intracellular calcium by bupivacaine isomers in cardiac myocytes from Wistar rats

In this study we investigated the effects of a racemic mixture of bupivacaine (RS(+/-)bupivacaine) and its isomers (S(-)bupivacaine and R(+)bupivacaine) on the Ca2+ handling by ventricular myocytes from Wistar rats. Single ventricular myocytes were enzymatically isolated and loaded with the fluorescent Ca2+ indicator fura 2-am to estimate intracellular Ca2+ concentration during contraction and relaxation cycles. S(-)bupivacaine (10 muM) significantly increased peak amplitude and the rate of increase of Ca2+ transients in 155% +/- 54% (P < 0.05) and 194% +/- 94% (P < 0.01) of control. However, exposure to R(+)bupivacaine had no effect on either peak amplitude or rate of increase at any concentration tested. Saponin-skinned ventricular fibers were used to investigate the effect of bupivacaine on the intracellular Ca2+ regulation by sarcoplasmic reticulum (SR) and on the Ca2+ sensitivity of contractile system. S(-), R(+), and RS(+/-)bupivacaine induced Ca2+ release from SR (P < 0.01). In SR-disrupted skinned ventricular cells, bupivacaine and its isomers (5 mM) increased the sensitivity of contractile system to Ca(2+). S(-), RS(+/-), and R(+)bupivacaine significantly increased pCa50 from 5.8 +/- 0.1, 5.8 +/- 0.1, and 5.8 +/- 0.1, to 6.1 +/- 0.1 (P < 0.05), 6.0 +/- 0.1 (P < 0.05), and 6.1 +/- 0.1 (P < 0.05). Ca2+ release from SR through RyR2 activation could explain the increase of Ca2+ transients in cardiac cells. Increased intracellular Ca2+ in cardiac myocytes display a stereoselectivity to S(-)bupivacaine.     

Is comparative cardiotoxicity of S(-) and R(+) bupivacaine related to enantiomer-selective inhibition of L-type Ca(2+) channels?

Cardiac toxicity can occur after accidental intravascular injection of bupivacaine. Racemic bupivacaine can inhibit both cardiac Na(+) and Ca(2+) channels, but the contribution of these actions to cardiac depression is not totally understood. We tested whether the effect of R(+) bupivacaine on cardiac electrical activity in isolated hearts and on L-type Ca(2+) channels (I(Ca-L)) in isolated cardiac myocytes could be responsible for its increased cardiotoxicity compared with S(-) bupivacaine. Cardiac electrical activity of spontaneously beating isolated hearts was recorded before and after exposure to increasing concentrations of R(+) and S(-) bupivacaine. An increase of the PR interval (80%) and the QRS duration (370%) by 10microM R(+) bupivacaine (80% and 370%) was significantly higher than for S(-) bupivacaine (25% and 200%, respectively). R(+) but not S(-) bupivacaine produced severe arrhythmias at concentrations larger than 2.5microM. The intensity of I(Ca-L) inhibition did not differ between bupivacaine isomers. At 0 mV, I(Ca-L) was irreversibly reduced by 40.2% +/- 8.8% and 51.4% +/- 3.8% in the presence of 10microM R(+) and S(-) bupivacaine, respectively. The arrhythmogenic effect of R(+) bupivacaine could not be explained by stereoselectivity on the I(Ca-L) inhibition. Thus, other mechanisms could contribute to the cardiac electrical and contractile dysfunction induced by R(+) bupivacaine.     

Absence of Stereospecific Effects of Bupivacaine Isomers on Heart Mitochondrial Bioenergetics

Background: Highly lipophilic local anesthetics interfere with mitochondrial energy metabolism. These metabolic effects could, in part, explain some toxic effects of local anesthetics, such as bupivacaine-induced myocardial depression. The purpose of this study was to compare the optically pure isomers of bupivacaine on heart mitochondrial bioenergetics.

Methods: Both bupivacaine enantiomers were tested on rat heart isolated mitochondria. Oxygen consumption, adenosine triphosphate synthesis, and enzymatic activities of the four complexes of the respiratory chain were measured.

Results: No significant differences were found between R(+)- and S (-)-bupivacaine on mitochondrial oxidative phosphorylation with a similar dose-dependent decrease in adenosine triphosphate synthesis. Complex I (nicotinamide adenine dinucleotide ubiquinone reductase) was the enzymatic complex of the respiratory chain most sensitive to the bupivacaine isomers. Half-inhibitory concentrations for R (+)- and S (-)-bupivacaine were not statistically different (3.3 +/- 0.4 mm and 2.8 +/- 0.6 mm, respectively).     

Direct comparative effects of isoflurane and desflurane in isolated guinea pig hearts.

The aim of this study was to test if myocardial and coronary vascular effects of desflurane and isoflurane were similar in the isolated heart. The cardiac effects of these anesthetics were examined in 12 guinea pig hearts perfused in a retrograde manner. Spontaneous heart rate, atrioventricular (AV) conduction time, systolic left ventricular pressure and coronary flow were measured. To differentiate direct vasodilatory effects of these anesthetics from an indirect metabolic effect due to autoregulation of coronary flow, O2 delivery (DO2), myocardial O2 consumption (MVO2) and percent O2 extraction were also monitored. Isoflurane and desflurane were injected directly into sealed bottles containing oxygenated perfusate solution. Each heart was perfused randomly with these anesthetics. Anesthetic concentrations in the perfusate were 0.28 +/- 0.02 and 0.52 +/- 0.02 mM for isoflurane and 0.59 +/- 0.01 and 1.02 +/- 0.09 mM for desflurane (mean +/- standard error of the mean). Calculated vapor concentrations were 1.3 and 2.5 vol % for isoflurane and 6.8 and 11.8 vol % for desflurane which correspond to approximately 1 and 2 MAC in vivo. Each anesthetic similarly decreased heart rate and prolonged AV conduction time in a concentration-dependent manner. Left ventricular pressure (control 93 +/- 4 mmHg) decreased by 11 +/- 1% and 24 +/- 2% with isoflurane and by 15 +/- 1% and 30 +/- 2% with desflurane. The decreases in heart rate and pressure were accompanied by decreases in MVO2 of 12 +/- 2% and 30 +/- 3% with isoflurane and of 19 +/- 3% and 40 +/- 4% with desflurane from a control of 57 +/- 2 microliters.g-1.min-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial efficiency in stunned myocardium. Comparison of Ca(2+)-sensitization and PDE III-inhibition on energy consumption.

OBJECTIVE: In stunned myocardium oxygen consumption is relatively high compared with the reduced ventricular function. On the other hand, inotropic stimulation is frequently required to improve postischemic ventricular dysfunction. However, inotropic agents which act via intracellular increased calcium result in a higher oxygen demand. Therefore Ca(2+)-sensitization might be a favorable alternative. METHODS: The effects of a novel Ca(2+)-sensitizer (EMD 60263, 10 microM, group 1) were compared with a phosphodiesterase (PDE) III-inhibitor (enoximon, 20 microM, group 2) on 14 isolated, blood-perfused rabbit hearts during reperfusion after a global ischemia of 20 min. Ventricular function, the pressure-volume area (PVA, a measure of total mechanical work), and total myocardial oxygen consumption (MVO(2)) were assessed. Contractile efficiency (EF(cont)), derived from the reciprocal of the slope of the MVO(2)-PVA relation, and external efficiency (EF(ex), stroke work/MVO(2)), were calculated. RESULTS: At matched heart rate (group 1: 141+/-10 min(-1) group 2: 151+/-28 min(-1)) and end-diastolic volume (1.3+/-0.2 ml) systolic variables were significantly decreased in stunned myocardium: LVP(max) to 57+/-13% of control value in group 1 and to 76+/-7% in group 2, aortic flow to 20+/-4 vs. 25+/-8%. PVA was decreased to 57+/-13 and 67+/-11%, MVO(2) was non-significantly decreased to 73+/-22 and 88+/-14%. After administration of either inotropic agent LVP(max) was significantly improved to 96+/-12 vs. 90+/-8% compared with preischemic levels, aortic flow to 103+/-24 vs. 88+/-9%, and PVA 99+/-11 vs. 89+/-16%, respectively. EMD 60263 increased MVO(2) to control levels (107+/-9%), and enoximon raised MVO(2) even more significantly above control (139+/-13%). Both myocardial efficiency indices were significantly diminished during reperfusion: EF(ex) to 14+/-9 vs. 23+/-7% and EF(cont) to 71+/-7 vs. 65+/-9% compared with preischemic levels. EF(ex) (109+/-21%) was significantly, but EF(cont) only slightly (84+/-11%) increased after administration of EMD 60263, whereas EF(ex) (57+/-13%) and EF(cont) (71+/-12%) remained depressed after enoximon. CONCLUSIONS: In stunned myocardium, the decreased efficiency indices show that energy utilization is disturbed. Both agents recruited an inotropic reserve, whereas Ca(2+)-sensitization seemed to be more favorable in terms of myocardial efficiency indices. These results indicate that alteration of myocardial calcium sensitivity contributes a major part to postischemic dysfunction. Therefore, Ca(2+)-sensitization may potentially be a superior method for inotropic support in the postischemic heart.     

Comparison of halothane, enflurane, and isoflurane with nitrous oxide on contractility and oxygen supply and demand in isolated hearts.

The authors' aim was to examine direct cardiac responses to isoflurane, enflurane and halothane, as altered during mild hypoxia by the substitution of nitrogen (N2) for oxygen (O2), and additionally by the substitution of nitrous oxide (N2O) for N2. Heart rate, atrioventricular conduction time, left ventricular pressure (LVP), peak positive and negative derivatives of LVP (dLVP/dtmax), coronary flow, O2 delivery (DO2), percent O2 extraction, and myocardial O2 consumption (MVo2) were examined in 47 isolated guinea pig hearts. Changes in the ratio of DO2 to MVO2 indicated the relationship of autoregulation of coronary flow to myocardial O2 utilization. Each heart was first exposed to 96% O2 and then randomly exposed to 48% N2 and 48% N2O alone and with three equivalent concentrations of one of three volatile anesthetics: isoflurane (n = 15), halothane (n = 16), or enflurane (n = 16). Results were as follows: 1) N2 alone significantly decreased LVP, +dLVP/dtmax and -dLVP/dtmax, DO2 and MVO2; increased coronary flow; and produced no change in heart rate, atrioventricular conduction time, percent O2 extraction, or the DO2/MVO2 ratio. 2) Compared to N2, N2O alone only produced additional significant decreases in LVP and +dLVP/dtmax. 3) In the presence of N2 or N2O, each volatile anesthetic caused significant stepwise decreases in heart rate, LVP, +dLVP/dtmax and -dLVP/dtmax, MVO2, and percent O2 extraction; no additional change in coronary flow or DO2; and a stepwise increase in the DO2/MVO2 ratio. The effects of halothane and enflurane were generally greater than those of isoflurane. 4) Each volatile anesthetic caused an additive, parallel depression of LVP and percent O2 extraction as a function of MAC with N2O compared to N2. This study demonstrates that the direct negative inotropic effects of halothane and enflurane are more pronounced than those of isoflurane and are accompanied by a greater reduction in O2 utilization by halothane and enflurane than by isoflurane in the presence of mild hypoxia alone or with the addition of N2O. The study also demonstrates that N2O accentuates the negative inotropic effects of volatile anesthetics during reduced O2.     

Effects of Ropivacaine on a Potassium Channel (hKv1.5) Cloned from Human Ventricle

Background: Ropivacaine, a new amide local anesthetic agent chemically related to bupivacaine, is able to induce early after depolarizations in isolated cardiac preparations. The underlying mechanism by which ropivacaine induces this effect has not been explored, but it is likely to involve K sup + channel block.

Methods: Cloned human cardiac K sup + channels (hKv1.5) were stably transfected in Ltk cells, and the effects of ropivacaine on the expressed hKv1.5 currents were assessed using the whole-cell configuration of the patch-clamp technique.

Results: Ropivacaine (100 micro Meter) did not modify the initial activation time course of the current, but induced a fast subsequent decline to a lower steady-state current level with a time constant of 12.2 +/- 0.6 ms. Ropivacaine inhibited hKv1.5 with an apparent KD of 80 +/- 4 micro Meter. Block displayed an intrinsic voltage-dependence, consistent with an electrical distance for the binding site of 0.153 +/- 0.007 (n = 6) (from the cytoplasmic side). Ropivacaine reduced the tail current amplitude recorded at -40 mV, and slowed the deactivation time course, resulting in a "crossover" phenomenon when control and ropivacaine tail currents were superimposed.     

The action of S-(+)-ketamine on serum catecholamine and cortisol. A comparison with ketamine racemate]

The S(+)-isomer of ketamine has about twice the anaesthetic potency of the commercially available racemic mixture of ketamine. It is assumed that the known side-effects of ketamine are significantly reduced when administering half the usual dose with the same pharmacodynamic effect [17, 25]. The aim of the present study was to determine the haemodynamic effects, the catecholamine and cortisol plasma levels after administration of equally potent doses of S-(+)-Ketamine and racemic mixture of ketamine. In addition, the effect of premedication with i.v. midazolam was assessed. METHOD. After approval by the ethics committee and written informed consent, 30 healthy male volunteers were randomly allocated to three groups (n = 10). Group 1 received 2 mg/kg ketamine racemate, group 2 1 mg/kg S-(+)-Ketamine, and group 3 1 mg/kg S-(+)-Ketamine 5 min after i.v.-premedication with 0.1 mg/kg midazolam. Non-invasive blood pressure (BP) and heart rate (HR) were continuously recorded. Blood samples were drawn 7 min before, and 2, 4, 8, 16, 32, 64 and 128 min after drug administration. Plasma epinephrine and norepinephrine (NE) levels were determined by HPLC and cortisol plasma levels by RIA. Data were analysed with the Kruskal-Wallis test (P < or = 0.05) for differences between groups. RESULTS. HR and BP showed a significant rise after injection of racemate and isomer, without any significant differences between groups. This was also seen for norepinephrine and cortical plasma levels. Epinephrine levels, however, differed between groups, showing a significant rise after racemate compared to isomer. Premedication with midazolam, in contrast, blunted major haemodynamic and hormonal changes. DISCUSSION. The haemodynamic changes did not differ between the racemate and isomer group despite a reduced isomer dose. HR and BP rise were similar, although epinephrine levels were significantly lower after isomer than racemate. Hence we assume that the increase in the haemodynamic parameters were mainly caused by NE. Midazolam apparently prevented the centrally mediated sympathetic stimulation caused by ketamine and its isomers. Therefore, i.v. premedication with midazolam should be applied when racemate or isomer is used, especially in high-risk cardiac patients.     

Absence of stereospecific effects of bupivacaine isomers on heart mitochondrial bioenergetics

BACKGROUND: Highly lipophilic local anesthetics interfere with mitochondrial energy metabolism. These metabolic effects could, in part, explain some toxic effects of local anesthetics, such as bupivacaine-induced myocardial depression. The purpose of this study was to compare the optically pure isomers of bupivacaine on heart mitochondrial bioenergetics. METHODS: Both bupivacaine enantiomers were tested on rat heart isolated mitochondria. Oxygen consumption, adenosine triphosphate synthesis, and enzymatic activities of the four complexes of the respiratory chain were measured. RESULTS: No significant differences were found between R(+)- and S(-)-bupivacaine on mitochondrial oxidative phosphorylation with a similar dose-dependent decrease in adenosine triphosphate synthesis. Complex I (nicotinamide adenine dinucleotide ubiquinone reductase) was the enzymatic complex of the respiratory chain most sensitive to the bupivacaine isomers. Half-inhibitory concentrations for R(+)- and S(-)-bupivacaine were not statistically different (3.3 +/- 0.4 mm and 2.8 +/- 0.6 mm, respectively). CONCLUSIONS: No stereospecific effects of bupivacaine enantiomers were shown in the inhibition of complex I activity and uncoupling of oxidative phosphorylation. This can be correlated with the lack of stereospecific effects of bupivacaine on myocardial depression. The lipid solubility of local anesthetics appears to be the principal physicochemical factor affecting the potency of these tertiary amines on mitochondrial bioenergetics.     

Ca sensitizer superior to catecholamine during myocardial stunning?

BACKGROUND: After open-chest cardiac surgery, ventricular function remains depressed (myocardial stunning). Catecholamines (epinephrine) improve ventricular function by increasing the intracellular Ca(2+) concentration. In parallel, the oxygen consumption is increased, so that the hitherto intact myocardium can be jeopardized. In the very insufficient ventricle, epinephrine can even become ineffective. Since Ca(2+) sensitizers provide another therapeutic avenue, the effects of epinephrine and levosimendan on postischemic hemodynamics were investigated. METHODS: After hemodynamic steady state, isolated, blood (erythrocyte-enriched Krebs-Henseleit solution)-perfused rabbit hearts were subjected to 25 min normothermic, no-flow ischemia and 20 min reperfusion. Heart rate (HR), cardiac output (CO), left ventricular pressure (LVP), coronary blood flow (CBF), and arterio-venous oxygen difference (AVDO(2)) were recorded during reperfusion and after administration of either epinephrine (n=16; 0.03 micromol), or levosimendan (n=11; 0.75 micromol) or epinephrine plus levosimendan (n=5). RESULTS: Epinephrine increased HR (19%, p=0.01) and improved hemodynamics in terms of CO (62%, p=0.0006), stroke volume SV (46%, p=0.02), stroke work W (158%, p=0.01), LVP(max) (58%, p=0.0001), maximal pressure increase dP/dt(max)(140%, p=0.0004), minimal pressure increase dP/dt(min) (104%, p=0.0002), LVP(ed) (-26%, p=0.02), and increased coronary resistance CR (31%, p=0.05). Epinephrine impaired hemodynamics in terms of AVDO(2) (+63%, p=0.003), myocardial oxygen consumption MVO(2) (+67%, p=0.0003) and MVO(2)/beat (+36%, p=0.01). External efficiency eta was increased by 92% (p=0.02). Levosimendan in postischemic hearts increased HR (32%, p=0.009) and improved hemodynamics in terms of CO (85%, p=0.01), SV (44%, p=0.03), W (115%, p=0.04), LVP(max) (95%, p=0.04), dP/dt(max) (133%, p=0.009), dP/dt(min) (121%, p=0.007), LVP(ed) (-63%, p=0.0006), and CR (-17%; n.s., p=0.1). It altered hemodynamics in terms of AVDO(2) (+7.0%; n.s., p=0.3) and MVO(2) (+32%, p=0.007) and MVO(2)/beat (+2.3%; n.s., p=0.4). External efficiency was increased by 307% (p=0.04). In five additional extremely dysfunctional rabbit hearts, epinephrine was ineffective. Additional levosimendan increased hemodynamics in terms of HR (56%; n.s., p=0.1), CO (159%, p=0.04), SV (89%, p=0.03), W (588%, p=0.02), LVP(max) (168%, p=0.03), dP/dt(max) (102%, p=0.005), dP/dt(min) (78%, p=0.006), LVP(ed) (-98%, p=0.0006), and CR (-50%, p=0.02). It altered hemodynamics in terms of AVDO(2) (-11%; n.s., p=0.05), MVO(2) (+131%, p=0.04) and MVO(2)/beat (+171%, p=0.03). External efficiency was increased by 212% (p=0.04). CONCLUSION: In contrast to epinephrine, levosimendan improves ventricular function without increasing oxygen demand, thereby considerably improving external efficiency. Even during epinephrine resistance in extremely dysfunctional hearts, levosimendan successfully improves ventricular function.     

Effects of arteriovenous fistulas on cardiac oxygen supply and demand

BACKGROUND: Arteriovenous (AV) fistulas used for hemodialysis access may affect cardiac load by increasing the preload while decreasing the afterload. In dogs, AV fistulas have also been shown to affect coronary perfusion negatively. We investigated the net effect of AV fistulas on cardiac oxygen supply and demand. METHODS: Aortic pressure waves were reconstructed from finger pressure recordings obtained on the nonfistula arm using a wave-form filter. Changes in systolic, mean, and diastolic aortic pressure were calculated, together with changes in heart rate (HR), stroke volume (SV), cardiac output (CO), and systemic vascular resistance (SVR) during a 60-second compression of AV fistulas in 10 patients. Changes in cardiac supply and demand were estimated by calculating the area under the aortic pressure curve during diastole [diastolic pressure time index (DPTI)] and systole [systolic pressure time index (SPTI)], respectively. RESULTS: During fistula compression, systolic, mean and diastolic pressure increased by 4.2 +/- 4.3, 2.6 +/- 3.0, and 2.8 +/- 2.9 mm Hg (mean +/- SD, all P < 0.05). The HR decreased by 3.8 +/- 2.5 beats per minute (P < 0.01), and SV decreased 3.7 +/- 6.1% (NS). CO decreased 9.4 +/- 8.6%, and SVR increased 14.3 +/- 11.7% (both P < 0.05). The SPTI increased by 1.5 +/- 1.5 mm Hg.sec (P < 0.01), and the DPTI increased by 7.6 +/- 8.1 mm Hg.sec (14.8% increase, P < 0.05) during compression. The ratio of supply and demand (DPTI/SPTI) improved by 13.5 +/- 13.0% (P < 0.01) when the fistula was compressed. CONCLUSION: AV fistulas have a small effect on left ventricular oxygen demand, but decrease cardiac oxygen supply considerably.     

Motor nerve blockade potency and toxicity of non-racemic bupivacaine in rats

BACKGROUND: Racemic [RS(+/-)] bupivacaine can be associated with severe cardiotoxicity. The S(-) isomer is known to be less neuro- and cardiotoxic, but demonstrates a lower potency to block motor activity than RS(+/-) bupivacaine. Thus, the potency and toxicity of a non-racemic bupivacaine mixture were studied. METHODS: Gastrocnemic muscle twitches induced by electrical stimulation of sciatic nerves in rats were used to compare the impact by bupivacaine solutions on motor activity. Field stimulation at 1 Hz eliciting ventricular muscle twitches was used to investigate the effects on cardiac contractility. The lethal dose of each local anesthetic agent was determined following drug infusions during general anesthesia in mechanically ventilated rats. RESULTS: Non-racemic (75S:25R) bupivacaine was more potent (P<0.05) than S(-) or R(+) enantiomers to block motor nerve activity. The concentrations of RS(+/-), 75S:25R, R(+) and S(-) bupivacaine to inhibit nerve conduction by 50% were 0.84 (0.37- 2.20), 0.84 (0.47-2.48), 2.68 (0.98-3.42) and 2.11 mM (1.5-4.03), respectively. Pronounced reductions in ventricular muscle twitches were observed with RS(+/-) and R(+) bupivacaine at low concentrations (0.5-4 microM). Lethal doses for 75S:25R (39.9 mg kg(-1)), and S(-) (34.7 mg kg(-1)) were higher (P<0.05) than for R(+) (16.2 mg kg(-1)) and RS(+/-) bupivacaine (18.4 mg kg(-1)), respectively. DISCUSSION: The potency of S(-) bupivacaine to block the motor activity in the sciatic nerve was enhanced when 25% of the S(-) isomer was replaced by the antipode R(+) bupivacaine. This effect was not associated with increased toxicity.     

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 atrial 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 microM to 1 mM. Adenosine was given to test maximal CF. At concentrations below 10 microM no significant changes were observed; beyond 50 microM for midazolam, etomidate, and propofol, and 100 microM for thiopental and ketamine, each agent caused progressive but differential decreases in heart rate, atrioventricular conduction time (leading to atrioventricular dissociation), LVP, +dLVP/dtmax, percent oxygen extraction, and MVo2. The concentrations (microM) 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 greater than thiopental greater than ketamine; results were similar for LVP. At the 100 microM 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 microM 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.