Direct Myocardial Depressant Effect of Desflurane: Mechanical and Electrophysiological Actions in Vitro / 대한마취과학회지

BACKGROUND: Desflurane actions on myocardial contractility and cellular electrophysiologic behavior were studied in isolated guinea pig and rat right ventricular papillary muscles. METHODS: The isometric force of isolated guinea pig ventricular papillary muscles was studied in normal and 26 mM K+ Tyrode's solution at various stimulation rates. Experiments using rat papillary muscles under normal Tyrode's solution at the rested-state (RS) and using guinea pig papillary muscles under low Na+ Tyrode's solution (25 mM) were performed to evaluate the effect of Ca2+ release from the sarcoplasmic reticulum (SR). Effects of desflurane on SR function in situ were examined by its effect on rapid cooling contractures (RCCs). Normal and slow action potentials (APs) were evaluated by using a conventional microelectrode technique. Finally, Ca2+ currents of isolated guinea pig ventricular myocytes were examined using the whole cell patch clamp technique. RESULTS: 1 MAC (minimum alveolar concentration: 6%) and 2 MAC desflurane were applied. 1 MAC and 2 MAC desflurane depressed guinea pig myocardial contractions by ~30% and ~60%, respectively, from RS to 3 Hz stimulation rates. 1 MAC (1.15%) and 2 MAC isoflurane depressed peak force by ~25% and ~45%, respectively. Contractile force after rest in rat and guinea pig myocardium under low Na+ Tyrode's solution showed modest depression. In the partially depolarized, adrenergically stimulated myocardium, 1 MAC and 2 MAC desflurane caused a marked depression of the late peak force (1 MAC:~60%, 2 MAC:~80%) with moderate changes of the early peak force (1 MAC: ~20%, 2 MAC: ~40%). RCCs were abolished at 1 MAC desflurane. Desflurane did not alter the peak amplitude or maximum depolarization rate of normal and slow APs, however, AP duration was significantly prolonged. In isolated guinea pig myocytes at room temperature, 1 MAC and 2 MAC desflurane caused a ~28% and ~55% decrease in Ca2+ currents, respectively. CONCLUSIONS: These results indicate that desflurane causes a dose-dependent depression of contractile force in isolated myocardium, which is comparable to that of isoflurane. The depression seems to be related, at least in part, to its ability to reduce inward Ca2+ currents through the cardiac membrane. Therefore, it is likely that various methods employed to enhance inward Ca2+ current may improve the hemodynamic depression induced by desflurane.

The Local Anesthetic Effect of Meperidine on the Direct Myocardial Depression in Isolated Ventricular Myocardium / 대한마취과학회지

BACKGROUND: The effects of various concentration (20, 50, 100 micrometer) of meperidine were studied in isolated guinea pig and rat ventricular papillary muscles. METHODS: Isometric force of guinea pig ventricular papillary muscle was examined in normal and 26 mM K+ Tyrode's solution. Experiments using rat and guinea pig papillary muscle under normal and low Na+ (40 mM), respectively, were performed to evaluate the effect on Ca2+ release from the sarcoplasmic reticulum (SR). Normal and slow action potentials (APs) were evaluated by using conventional microelectrode technique. Rapid cooling contractures were performed. RESULTS: Meperidine caused dose-dependent depression of peak force from rested-state (RS) to 3 Hz stimulation rates in guinea pig papillary muscles. Conduction block was frequently noted at high stimulation rates (2 and 3 Hz) at 150 micrometer meperidine. ~40% depression of peak force was shown at RS contraction under low Na+ Tyrode's solution, although contractile depression was not shown at RS and low stimulation rates in rat papillary muscles. 100 micrometer naloxone did not reverse the contractile depression caused by 100 micrometer meperidine. Either depression of dV/dt-max from 0.1 to 3 Hz stimulation rates or rate-dependent depression among 1, 2 and 3 Hz could be observed at 150 micrometer meperidine. In 26 mM K+ Tyrode's solution, 50 and 100 micrometer meperidine caused dose-dependent depression of early and late force development. In slow APs, changes of dV/dt-max were not shown at 100 micrometer meperidine. ~40% depression of contracture induced by rapid cooling following 2 Hz stimulation rates was shown at 100 micrometer meperidine. CONCLUSION: The direct myocardial depressant effect of meperidine seems likely to be caused by local anesthetic properties of meperidine, not by the opioid action. Inhibition of SR Ca2+ release, and decreased intracellular Ca2+ secondary to Na+ channel blocking action of meperidine may at least in part be related to direct myocardial depression.

Myocardial Depressant Effects of Sevoflurane: A comparative Study with Isoflurane on Mechanical and Electrophysiologic Effects In Vitro / 대한마취과학회지

Dose-related depression of left ventricular function or cardiac output has been reported in humans and in vivo animal studies with sevoflurane (SEVO) anesthesia and myocardial depressant effect of SEVO appeared to be comparable to that produced by isoflurane (ISO). This study was designed to determine the mechanical and electrophysiologic mechanism of the direct negative inotropic effects of SEVO. The effects of SEVO were comprared to those produced by equipotent concentration of ISO in the same isolated myocardial preparations. Isometric force of isolated guinea pig ventricular papillary muscle was studied in normal and 26 mM K+ Tyrode's solution. Rat papillary muscle was also used to evaluate the effect on Ca2+ release from the sarcoplasmic reticulum (SR) at low stimulation rates. Muscles were bathed at 36-37 degrees C in normal K Tyrode's solution bubbled with 95% O2/ 5% CO2 (pH 7.4) and were electrically stimulated following rest and at rates up to 3 Hz. Normal and slow action potentials were evaluated by using conventional microelectrodes. Muscles were also subjected to rapid cooling (from 37 degrees C to 2 degrees C) in order to elicit a transient rapid cooling contracture (RCC) known to be activatel by Ca2+ content released from the SR. RCCs were elicited after 2 Hz stimulation, which produced an RCC tension similar to that of the preceding contraction in control. SEVO and ISO were administered by dial setting in each vaporizer at 1.7 (1 MAC) and 3.4% (2 MAC), and 1.15 (1 MAC) and 2.3% (2 MAC), respectively. 20% and 40% depression of contractility was shown at 1.7 and 3.4% concentration of SEVO and the extent of depression was similar to equipotent concentration of ISO from rested state up to 3Hz stimulation rates. 1 and 2 MAC concentrations of SEVO (1.7 and 3.4%) or ISO (1.15% and 2.3%) in normal K+ Tyrode's solution caused dose-related depression of peak force at low stimulation rates (RS, 0.1, and 0.5 Hz). Although the normal action potential (AP) amplitude or Vmax were not changed, APD50 and APD90 were prolonged characteristically at 2 MAC of both anesthetics. Whereas no contractile depression was shown at RS and 0.1 Hz stimulation rates in rat papillary muscles, significant depression was noted from 0.5 to 3 Hz in 3.4% SEVO or 2.3% ISO. In the partially depolarized (26 mM K+ Tyrode's solution) beta-adrenergically stimulated myocardium, 2 MAC concentration of both anesthetics caused selective depression of late peak in the biphasic contraction without changing early peak. In slow AP, 3.4% SEVO or 2.3% ISO did not cause any change in AP amplitude and Vmax whereas APD50 and APD90 were prolonged as in Normal APs. Rapid cooling preceded by 15 min rest showed little contractile force and marked prolongation of the time to peak contracture with almost complete absence of contracture after 2Hz stimulation rates following 3.4% SEVO or 2.3% ISO. Although complete recovery of peak force could be observed, little restoration of RCC was shown after washout for 15 minutes at 2 MAC concentration of both anesthetics characteristically. The effect of SEVO on isolated myocardial contraction was similar to that of ISO. While neither anesthetic depressed the rapid initial Ca+ release from the SR, the depression of RCC and late tension suggest an alteration in some SR pathway. The direct myocardial depressant effects of SEVO and ISO are likely to be related to depressed Ca2+ influx through the cardiac memebrane, while AP prolongation may be due to actions on K+ currents.

Cardiotoxic Depressant Effects of Protamine / 대한마취과학회지

The cellular cardiac effects of protamine, the cationic polypeptide employed to reverse heparin anticoagulation, were examined in vitro to define its mechanisms of action. Isometric contractile force and action potential (AP) characteristics after rest (RS) and at frequencies up to 3 Hz were recorded in guinea pig ventricular papillary muscle. The actions of protamine (10-300 ug/ ml) were compared to those of heparin (10, 30 units/ml), and to heparin (10 units/ml) neutralized with equivalent (100 ug/ml) or excess (200 ug/ml) protamine. The effects of protamine were also examined using muscle rapid cooling contractures (RCCs to assess intracellular Ca(z+) stores). Protamine (100-300 ug/ml) depressed contractions by 35-65% at 3 Hz, whereas contractions were enhanced 150-500% at lower rates (RS-0.5 Hz), with a concommitant rise in resting force. Protamine caused a resting depolarization from -84 to -72 mV and depressed AP amplitude. In contrast, heparin minimally altered contractile or AP characteristics. In 26 mM K(+)-solution with 0.1 uM isoproterenol, 30-300 ug/ml protamine caused dose-dependent depression of late peaking force development and slow AP prolongation. After 15 minutes rest, when RCCs were not normally elicited, rest RCCs became prominent in 100-300 ug/ml protamine. Effects of heparin with 100 ug/ml excess protamine were similar to those of 100 ug/ml protamine alone. In conclusion the loss of normal force-frequency relation, partial depolarization, rise in resting tension, and appearance of rested state RCCs suggest that unbound protamine can lead to excess intracellular Ca(2+), mediated by an alteration in memebrane ionic conductances.