Lack of inhibition by inhalational anesthetics of myocardial contraction dependent on intracellular sodium activity.

BACKGROUND: When cardiac muscle is stimulated at a high frequency after rest, the peak force increases rapidly at first and then slowly. The slow phase reflects Ca2+ accumulation dependent on an increase in intracellular Na+ activity. The positive inotropic effect of high concentrations of cardiac glycosides also involves Ca2+ accumulation dependent on an increase in intracellular Na+ activity. The effect of isoflurane on the component of myocardial contraction dependent on an increase in intracellular Na+ activity is not well understood. METHODS: The isometric force of rabbit papillary muscle contractions was measured. The authors studied the effects of isoflurane on the force increase that occurs when the muscles are stimulated after a rest and on the force increase induced by ouabain. RESULTS: Isoflurane (1.5%, 2.4%) had no statistically significant effect on the magnitude of the slow phase of force increase when the muscles were stimulated at 2 Hz after a rest. Isoflurane (1.5%) did not decrease the magnitude of force increase induced by ouabain (1 microM). CONCLUSIONS: Isoflurane has little effect on myocardial contractions that depend on Ca2+ accumulation after an increase in intracellular Na+ activity. This may partly account for the smaller cardiac depressant effect of isoflurane observed at high frequencies rather than at low frequencies. The results of the present study and an earlier study with halothane suggest that the lack of inhibition of contractions dependent on Ca2+ accumulation after an increase in intracellular Na+ activity may be a common property of inhalational anesthetics.

Procaine enhancement of the rapid cooling contracture and inhibition of the decay of potentiated state in rabbit papillary muscle.

We tested the possibility that inhibition of Ca2+ release from the sarcoplasmic reticulum decreases the transsarcolemmal Ca2+ efflux and results in an increased sarcoplasmic reticulum Ca2+ content. We used procaine to inhibit sarcoplasmic reticulum Ca2+ release in rabbit papillary muscles. Rapid cooling-induced contractures were used as an index of sarcoplasmic reticulum Ca2+ content. Decay of potentiated state was measured to study whether the transsarcolemmal Ca2+ efflux is decreased in the presence of procaine. Procaine (0.5, 1.0 mM) inhibited contractions elicited by electrical stimulation and enhanced the rapid cooling-induced contracture. The initial decay of potentiated state that occurs when the muscle was stimulated at a low frequency was slowed in the presence of procaine. These results suggest that procaine inhibition of Ca(2+)-induced release of sarcoplasmic reticulum Ca2+ decreases the transsarcolemmal Ca2+ efflux relative to the influx, resulting in an increased sarcoplasmic reticulum Ca2+ content.

Effect of thiopental on Ca2+ release from sarcoplasmic reticulum in intact myocardium.

BACKGROUND: While thiopental is known to inhibit the myocardial transsarcolemmal influx of Ca2+, the effect of thiopental on sarcoplasmic reticular Ca2+ release has not been characterized. METHODS: Isolated papillary muscles of rabbits were used. We measured postrest contractions to assess the Ca2+ release by sarcoplasmic reticulum in response to electrical stimulation. Contractures induced by rapid cooling were used as an index of Ca2+ content of sarcoplasmic reticulum. The effect of thiopental on the availability of extracellularly derived Ca2+ was evaluated from measurements of contractions at 0.1 Hz in the presence of 1 microM ryanodine. RESULTS: Thiopental sodium (10, 20, and 30 mg/l; 38, 76, and 113 microM) inhibited the postrest contraction but not the contracture induced by rapid cooling. In the presence ryanodine, thiopental inhibited the postrest contraction elicited after 10 s of rest after 2-Hz stimulation much less than the steady-state contraction at 0.1 Hz (beat interval 10 s). Thiopental inhibited the postrest contraction (no ryanodine present) more strongly than did Ni2+ (an inhibitor of the transsarcolemmal Ca2+ influx) when the contraction at 0.1 Hz in the presence of ryanodine was inhibited to the same extent. CONCLUSIONS: These results suggest that thiopental decreases sarcoplasmic reticulum Ca2+ release induced by electrical stimulation and inhibits the ryanodine-induced efflux of sarcoplasmic reticulum Ca2+.

Potentiated state contractions in isolated hearts: effects of ischemia and reperfusion.

To investigate mechanisms underlying the contractile dysfunction during myocardial "stunning," potentiated contractions were studied in Langendorff-perfused rabbit hearts paced at 2.5 Hz. Isovolumetric left ventricular pressure (LVP) and the first derivative of LVP (dP/dt) were measured via a balloon. Potentiated contractions, elicited after 3 s of rest (postrest potentiation, PRP) or with paired pulses (paired-pulse potentiation, PPP) were first characterized in nonischemic conditions. Exposure to 5 nM ryanodine changed PRP into postrest depression [control, 134 +/- 1.7% (SE); ryanodine, 65 +/- 3.4%; n = 5] but did not decrease PPP (control, 125 +/- 7.2%; ryanodine, 141 +/- 14.5%). When sarcolemmal Ca2+ influx was decreased by 0.2-2 microM verapamil, PRP increased (control, 136 +/- 3.7%; 1 microM verapamil, 214 +/- 23.8%; n = 5), whereas PPP was maintained (control, 134 +/- 8.0%; 1 microM verapamil, 154 +/- 11.5%). During ischemia, both PRP and PPP were increased above preischemic values (from 128 +/- 1.9 to 355 +/- 60.4% and from 122 +/- 5.4 to 313 +/- 37.4%, respectively, n = 5). Changes of potentiation of dP/dt were qualitatively similar to those of LVP. On reperfusion, rest potentiation transiently decreased (PRP of dP/dt: 127 +/- 6% preischemia vs. 112 +/- 3% at 2 min postischemia; n = 6). However, PPP increased during the first 20 min of reperfusion (PPP of dP/dt: 184 +/- 22% preischemia vs. 236 +/- 34% postischemia; n = 6). This transient depression of PRP during reperfusion suggests an impairment of sarcoplasmic reticulum function in stunned myocardium, at least during the early phase of reperfusion.

Effects of inhibition of transsarcolemmal calcium influx by nickel on force of postrest contraction and on contracture induced by rapid cooling.

OBJECTIVE: The aim was to characterise the influence of a decrease in transsarcolemmal calcium influx on the calcium content of the sarcoplasmic reticulum and on the force of postrest contraction, which is largely activated by calcium released from the sarcoplasmic reticulum. METHODS: Isometric force of postrest contractions in isolated rabbit papillary muscles was measured in the absence and in the presence of ryanodine (1 microM). The force measured in the presence of ryanodine was used as an index of transsarcolemmal calcium influx. The calcium content of the sarcoplasmic reticulum was estimated by rapid cooling induced contracture measurements. Nickel (Ni2+) was used to decrease the calcium influx, and the results were compared to those obtained by lowering the extracellular calcium concentration. RESULTS: The addition of Ni2+ or lowering extracellular Ca2+ markedly decreased the force of postrest contraction measured in the presence of ryanodine, and moderately decreased the force of postrest contraction measured in the absence of ryanodine. Neither the addition of Ni2+ nor lowering extracellular Ca2+ decreased maximum rapid cooling induced contracture; this was actually increased in the presence of Ni2+ even though a larger number of stimuli was required in the presence than in the absence of Ni2+ for the force of the subsequently elicited contracture to reach the maximum level. CONCLUSIONS: The results suggest: (1) that a decrease in the calcium influx reduces the force of the postrest contraction by decreasing the amount of calcium required to trigger the release of calcium from the sarcoplasmic reticulum, without decreasing its maximum calcium content; and (2) that Ni2+ decreases the rate of filling of sarcoplasmic reticular calcium stores even though the calcium content of the sarcoplasmic reticulum after a sufficiently large number of beats is higher in the presence of Ni2+ than in its absence.

Recovery of function and adenosine triphosphate metabolism following myocardial ischemia induced in the presence of volatile anesthetics.

Using a normothermic isolated working rabbit heart model, experiments were performed to determine whether exposure to halothane or isoflurane prior to ischemia improved postischemic recovery of myocardial function and the preservation of myocardial high energy phosphates. After 30 min of Langendorff perfusion, hearts were perfused for 30 min in the working mode. Three groups were studied: 1) the blank undergoing no pretreatment during an additional 15 min of working mode; 2) hearts exposed to 1.5% halothane; and 3) hearts exposed to 2.3% isoflurane during the additional 15 min of working mode. Subsequently, all hearts underwent 15 min of global normothermic ischemia, followed by 5 min of Langendorff reperfusion and 15 min of working heart mode using a perfusate devoid of volatile anesthetic. Adenosine triphosphate (ATP) and catabolites were determined after 15 min exposure to volatile anesthetics or blank, after 15 min global ischemia and at the end of the recovery phase. Myocardial function was determined after 30 min of working mode, after exposure to volatile anesthetics, and at the end of the recovery phase. In nonischemic hearts, 15-min treatment with 1.5% halothane or 2.3% isoflurane resulted in a significant decrease in positive LVdP/dt, from 1858 +/- 286 to 1316 +/- 180 mm Hg.s-1 and from 1888 +/- 304 to 1541 +/- 226 mm Hg.s-1, respectively. Coronary flow was increased significantly after isoflurane but not after halothane.(ABSTRACT TRUNCATED AT 250 WORDS)

Volatile anesthetics selectively alter [3H]ryanodine binding to skeletal and cardiac ryanodine receptors.

The effect of clinical concentrations of volatile anesthetics on ryanodine receptors of cardiac and skeletal muscle sarcoplasmic reticulum was evaluated using [3H]ryanodine binding. At 2 volume percent, halothane and enflurane stimulated binding to cardiac SR by 238% and 204%, respectively, while isoflurane had no effect. In contrast, halothane and enflurane had no effect on [3H]ryanodine binding to skeletal ryanodine receptors, while isoflurane produced a significant stimulation. These results suggest that volatile anesthetics interact in a site-specific manner with ryanodine receptors of cardiac or skeletal muscle to effect Ca2+ release-channel gating.

Comparison of logdose and bracket protocols for determination of epinephrine arrhythmia thresholds in dogs anesthetized with thiopental-halothane.

Previous studies in dogs of anesthetic-epinephrine arrhythmias have used logdose or bracketed epinephrine infusion protocols to determine the arrhythmic dose of epinephrine (ADE) or plasma level of epinephrine at arrhythmias (PCE). Reported logdose ADE values for halothane preceded by thiopental induction (thiopental-halothane) are twice those with the bracket protocol. There are no reported PCE data for the bracket protocol, and neither protocol has been directly compared in the same dogs. Therefore, direct comparisons were made of thiopental-halothane ADE and PCE in seven dogs (group 1). Dogs were induced with thiopental (20 mg/kg), followed by halothane inhalation at end-tidal concentrations equivalent to MAC 1.25. Epinephrine infusion protocols were compared on two weekly test occasions, with the sequence and order of protocol testing randomized. Logdose ADE for four or more ventricular beats within 15 s was 3.92 +/- 0.60 micrograms/kg (mean +/- standard error), higher than the bracket ADE (2.54 +/- 0.34 micrograms/ml) (P less than 0.05). PCE at ADE were similar for both protocols, but six separate infusions of epinephrine were required to establish ADE with the logdose compared to four with the bracket protocol (P less than 0.05). These findings suggested enhanced epinephrine clearance with the logdose protocol. Therefore, five additional but similarly anesthetized dogs (group 2) were tested to determine if physiologic or hemodynamic conditions prior to epinephrine infusions ("initial conditions") were equivalent for both protocols. Protocols were modified to avoid provocation of ventricular arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of thiopental and halothane on spontaneous contractile activity induced in isolated ventricular muscles of the rabbit.

To see if the known properties of thiopental of reducing Ca2+ and K+ fluxes across the myocardial sarcolemma account for its arrhythmogenic action, we have evaluated the effect of the anesthetic on spontaneous contractile activity induced in isolated rabbit papillary muscles. Thiopental (20 mg/l) prolonged the duration of sustained automaticity induced by stimulation at 1-2 Hz in the presence of 1 mumol/l isoproterenol. Thiopental (10, 20 mg/l) shortened the delay before the onset of Ba(2+)-induced automaticity, which involves a decrease in a K+ current. The minimum concentration of Ba2+ required to induce automaticity was lowered by thiopental. Whether spontaneous activities were induced by high frequency stimulation in the presence of isoproterenol or by Ba2+, thiopental lowered the frequency of spontaneous beats. Thus, thiopental appears to have both arrhythmogenic and antiarrhythmic actions, and the former may be unmasked when catecholamines counteract the latter by increasing Ca2+ influx. Like thiopental, halothane (1.0%) decreased the frequency and force of Ba(2+)-induced automatic beats but, unlike thiopental, prolonged the delay before the onset of Ba(2+)-induced automaticity, indicating that halothane acts as a purely antiarrhythmic agent in this type of automaticity.

Contribution of the known subcellular effects of anesthetics to their negative inotropic effect in intact myocardium.

The results of these studies suggest that halothane, in addition to its effect of reducing the trans-sarcolemmal Ca2+ influx, has a direct effect on the function of the sarcoplasmic reticulum by making the organelle leaky to Ca2+ and reducing the amount of Ca2+ stored. Isoflurane, on the other hand, does not appear to make the sarcoplasmic reticulum leaky to Ca2+. In fact, our observations suggest that isoflurane makes the sarcoplasmic reticulum less leaky to Ca2+. Halothane may enhance the reduction in the myofibrillar response to activator Ca2+ when the muscle fiber length is shortened. Thiopental appears to reduce the trans-sarcolemmal Ca2+ influx without reducing the amount of Ca2+ stored in the sarcoplasmic reticulum.

Negative inotropic effect of ketamine in rabbit ventricular muscle.

The effect of ketamine on myocardial contractile force was examined in rabbit papillary muscles in order to determine the underlying mechanism of action of the anesthetic. Ketamine HCl (20 and 40 mg/L) inhibited rested-state contractions that are dependent on the transsarcolemmal influx of Ca2+ for activation and reduced the upstroke velocity of the slow action potential, which reflects Ca2+ influx through the slow Ca2+ channel. On the other hand, ketamine had a relatively small effect on potentiated-state contractions and no effect on rapid cooling induced contractures, both of which are activated by the release of Ca2+ stored in the sarcoplasmic reticulum. These results suggest that ketamine inhibition of transsarcolemmal Ca2+ influx plays a major role in the negative inotropic action of the anesthetic.

Direct effect of halothane and isoflurane on the function of the sarcoplasmic reticulum in intact rabbit atria.

The negative inotropic effect of halothane and isoflurane on potentiated-state contractions of isolated rabbit atria in a normal Ca2+ (2.5 mM) medium was compared with the force depression in low Ca2+ media without an anesthetic. When this comparison was made in the presence of 1 microM ryanodine so that the force of contraction was dependent only upon transsarcolemmal Ca2+ influx with no Ca2+ contribution from the sarcoplasmic reticulum (SR), the force of contraction was depressed equally by 0.6% halothane in a normal Ca2+ medium and by a 1.5 mM Ca2+ medium without the anesthetic. Similarly, 1.0% halothane or 1.5% isoflurane and a 1.0 mM Ca2+ medium were equally depressant as were 2.4% isoflurane and a 0.5 mM Ca2+ medium. In the absence of ryanodine, where the atrial contractile activity is largely dependent on Ca2+ released from the SR, 0.6% halothane in the normal Ca2+ medium depressed contractile force by 32%, whereas the force was depressed by only 16% in the 1.5 mM Ca2+ medium without the anesthetic. Similar results were obtained when the effects of 1.0% halothane and of 1.0 mM Ca2+ were compared. In contrast, the force of contraction measured in the absence of ryanodine was not at all inhibited by 1.5% isoflurane and minimally (11%) inhibited by 2.4% isoflurane. Consequently, the force depression by isoflurane was less than that found in the low Ca2+ media.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of isoflurane and halothane on rapid cooling contractures in myocardial tissue.

The effects of isoflurane and halothane on the availability of Ca2+ stored in and released from the sarcoplasmic reticulum (SR) were studied in isolated rabbit papillary muscles by measuring the effects of the anesthetics on rapid cooling contractures, which are known to be activated by Ca2+ released from the SR. Isoflurane (0.3%) reduced the force of the rapid cooling contracture to 57% of control with a marked slowing of the average rate of contracture development and increased the force of the first contraction after rewarming to 133% of control. In contrast, 1.7% halothane, which reduced the rapid cooling contracture to 51% of control (comparable to the value in the presence of 0.3% isoflurane), had little effect on the rate of contracture development and strongly inhibited the first contraction after rewarming to 5% of control. Halothane, but not isoflurane, strongly inhibited postrest potentiated-state contractions, which are also known to be activated by Ca2+ released from the SR. These results suggest that 1) isoflurane inhibits rapid cooling-induced Ca2+ release from the SR without inhibiting Ca2+ release triggered by rapid depolarization as occurs in the potentiated-state contraction, and 2) halothane inhibits contractile activity dependent on Ca2+ released from the SR regardless of mechanism involved.

Halothane, but not isoflurane or enflurane, protects against spontaneous and epinephrine-exacerbated acute thrombus formation in stenosed dog coronary arteries.

Occlusive platelet thrombi periodically form in mechanically stenosed dog coronary arteries producing cyclical blood flow reductions occurring over 4-7 min. Cyclical coronary flow reductions are exacerbated by IV epinephrine 0.4 microgram.kg-1.min-1 for 15 min. These flow reductions can be abolished by known inhibitors of platelet function. This study assesses the effect of halothane, isoflurane, and enflurane on spontaneous- and epinephrine-exacerbated cyclical coronary flow reductions. Twenty-three open-chest dogs [1% halothane (n = 5), 0.5% halothane (n = 5), 0.25% halothane (n = 3), 1.5% isoflurane (n = 5), and 2.0% enflurane (n = 5)] with a mechanically stenosed coronary artery showed cyclical blood flow reductions. With 1.0% halothane administration, spontaneous cyclical blood flow reductions were abolished (n = 5), whereas during administration of isoflurane 1.5% (n = 5) and enflurane 2.0% (n = 5) cyclical flow reductions and myocardial ischemia continued. Subsequent administration of halothane in the isoflurane and enflurane groups showed abolition of coronary flow reductions in all animals (n = 10). In eight animals a 15-min epinephrine infusion (0.4 microgram.kg-1.min-1) was given following a control period and again following abolition of coronary flow reductions by halothane 0.5% (n = 5) and halothane 0.25% (n = 3). The magnitude of cyclical blood flow reductions (difference between initial and final coronary flow level of each flow reduction) changed from 52 +/- 11 to 61 +/- 12 ml/min (NS), and frequency increased from 0.37 to 0.57/min (P less than 0.05, n = 8) during epinephrine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Isoflurane and halothane inhibit tetanic contractions in rabbit myocardium in vitro.

Rabbit right ventricular papillary muscles were tetanized by rapid stimulation in the presence of 1 microM ryanodine, an inhibitor of sarcoplasmic reticular function. Tetanic contractions elicited in this manner increased in strength as extracellular calcium concentration [Ca+2]ext was raised from 0.5 to 5 mM, exhibited saturation behavior above [Ca+2]ext = 5 mM, and were blocked by nifedipine. Accompanying membrane potentials depolarized to +10 mV and repolarized to -60 mV between stimuli. These data suggest that rabbit myocardial tetany is supported in large part by extracellular calcium influx via slow (L-type) calcium channels, consistent with similar recent findings in the ferret. At [Ca+2]ext = 2.5 mM, isoflurane (0.6-2.3%, gas phase) and halothane (0.4-1.5%) inhibited the strength of tetanic contractions in dose-dependent fashion. At [Ca+2]ext = 20 mM neither isoflurane (1.2%) nor halothane (0.8%) inhibited tetanic contraction strength. These data demonstrate that isoflurane and halothane inhibit contractile activity that is dependent on transsarcolemmal calcium influx via pathways independent of the ryanodine-sensitive sarcoplasmic reticulum. The exact sites of inhibition (e.g., slow channel vs. intracellular transit vs. myofibrillar binding) are not identified, but inhibition by either anesthetic may be competitively reversed by high extracellular calcium concentrations.

Differential effects of inhalation anesthetics on myocardial potentiated-state contractions in vitro.

The effects of enflurane, halothane, and isoflurane on myocardial potentiated-state contractions were examined in a study in which each of the anesthetics was presented, in random order, to each of eight isolated rabbit papillary muscles. Post-rest potentiated-state contractions were elicited by imposing a stimulus at precisely timed intervals following a 2-Hz steady-state stimulus train. The strength of these contractions is known to be highly dependent on sarcoplasmic reticulum (SR) Ca2+ release. The increment in tension developed in potentiated state, as compared to the steady state, is directly attributed to the potentiation process, and is defined here as potentiated-state strength (PSS). Effects of enflurane, halothane, and isoflurane on the time course of development of the potentiated state were characterized, as were the effects of incremental doses of these anesthetics on PSS. Anesthetic gas phase concentrations that produced 50% depression of contractile tension at 0.05 Hz steady-state stimulation were 0.6% halothane, 1.4% isoflurane, and 1.6% enflurane. Muscles exhibited maximal PSS of 0.91 +/- 0.01 g/mm2 in the absence of anesthetics. Halothane (0.6%) and enflurane (1.6%) caused significant depression of PSS to 0.45 +/- 0.06 and 0.61 +/- 0.06 g/mm2, respectively, while isoflurane (1.4%) preserved PSS at 0.95 +/- 0.09 g/mm2. Concentration profiles showed that the depression of PSS by halothane and enflurane was dose dependent. Isoflurane, up to 2.3%, failed to depress PSS. The time interval for development of optimum PSS, 1.5 to 2.0 s, was unaffected by any of the anesthetics.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetic depression of myocardial contractility: a review of possible mechanisms.

The bulk of experimental evidence indicates that anesthetics do not produce their negative inotropic effect via an inhibitory action on mitochondrial electron transport. Anesthetics decrease energy need, rather than energy production. Anesthetics also decrease the rate of sequestration of Ca2+ by mitochondria, but, again, this appears not to be an important cause of reduced myocardial contractility. The role played by direct anesthetic depression of the myofibrils in reducing contractility is uncertain. Most experimental evidence now available suggests that significant myofibrillar depression, measured in terms of inhibition of actomyosin ATPase activity or inhibition of force production, occurs only at anesthetic concentrations which are high compared to concentrations employed clinically. This would seem to indicate that the myofibrils are not an important target for anesthetics in regard to the production of depressed myocardial contractility. However, the experimental act of removing myofibrils from their intracellular environment, or of removing the sarcolemma or making it hyperpermeable, appears to prevent some regulatory myofibrillar phosphorylation reactions from taking place. As stated by Winegrad, "certain forms of regulation of the cardiac myofibril are fragile and can be seen only when cellular constituents and structure are maintained." It is possible that this type of regulation is susceptible to inhibition by anesthetics. Methods for preserving this regulation are available, and will need to be employed before a depressant action of anesthetics on the myofibril can be definitely dismissed as a significant cause of the inhibition of cardiac contractility. A single study, of intracellular Ca2+ levels in the intact cell (where myofibrillar regulation was presumably preserved), has indicated that halothane may decrease myofilament Ca2+ sensitivity. However, for reasons stated above, this study cannot be taken as unequivocal proof of such an action. Despite the fact that the normal action potential is little affected by anesthetics, the sarcolemma appears to play a pivotal role in the production of anesthetic-induced contractile depression. Significant depression of the rate of upstroke of the slow (Ca2+-mediated) action potential by clinical concentrations of both inhalation and intravenous anesthetics has been demonstrated by several workers. This has been interpreted to mean that anesthetics inhibit the influx of Ca2+ through the slow channel, and such has been confirmed (to date, for halothane and thiamylal) by direct measurement of the slow inward Ca2+ current using a voltage clamp technique.(ABSTRACT TRUNCATED AT 400 WORDS)

Negative inotropic effects of isoflurane and halothane in rabbit papillary muscles.

The possibility that the negative inotropic effect of isoflurane is primarily due to a competitive inhibition of the influx of extracellular Ca2+ with little effect on the availability of Ca2+ stored intracellularly in the sarcoplasmic reticulum was examined in rabbit papillary muscle. The negative inotropic effect of isoflurane (1.4%) on steady state contractions (primarily dependent on the influx of extracellular Ca2+) was significantly greater than that on potentiated-state contractions (primarily dependent on Ca2+ released from the sarcoplasmic reticulum). In previous work from this laboratory we found that halothane has an opposite effect in this regard. Increasing stimulation frequency in the presence of isoproterenol (0.1, 1 microM) completely reversed the negative inotropic effect of isoflurane (1.4%) but not that of halothane (0.6%). These results suggest that isoflurane inhibits Ca2+ influx with little effect on the availability of activator Ca2+ stored in and released from the sarcoplasmic reticulum, and that the effect of isoflurane but not that of halothane can be effectively counteracted by conditions that are known to increase Ca2+ influx in the absence of an anesthetic. These properties of isoflurane may in part account for the minimal myocardial depressant effect of the anesthetic on the intact heart in the presence of a functional autonomic system.