Effects of volatile anesthetics on stiffness of mammalian ventricular muscle.

To assess the effects of halothane, isoflurane, and sevoflurane on cross bridges in intact cardiac muscle, electrically stimulated (0.25 Hz, 25 degrees C) right ventricular ferret papillary muscles (n = 14) were subjected to sinusoidal load oscillations (37-182 Hz, 0.2-0.5 mN peak to peak) at the instantaneous self-resonant frequency of the muscle-lever system. At resonance, stiffness is proportional to m * omega(2) (where m is equivalent moving mass and omega is angular frequency). Dynamic stiffness was derived by relating total stiffness to values of passive stiffness at each length during shortening and lengthening. Shortening amplitude and dynamic stiffness were decreased by halothane > isoflurane > or = sevoflurane. At equal peak shortening, dynamic stiffness was higher in halothane or isoflurane in high extracellular Ca(2+) concentration than in control. Halothane and isoflurane increased passive stiffness. The decrease in dynamic stiffness and shortening results in part from direct effects of volatile anesthetics at the level of cross bridges. The increase in passive stiffness caused by halothane and isoflurane may reflect an effect on weakly bound cross bridges and/or an effect on passive elastic elements.

Effects of volatile anesthetics on ryanodine-treated ferret cardiac muscle.

The volatile anesthetics halothane, isoflurane, and sevoflurane depress myocardial contractility by decreasing transsarcolemmal Ca2+ influx, Ca2+ release from the sarcoplasmic reticulum, Ca2+ sensitivity of the contractile proteins, and cross-bridge performance. The aim of this study is to assess and compare the effects of halothane, isoflurane, and sevoflurane on contractility in conditions in which sarcoplasmic reticulum Ca2+ release is abolished by pretreatment with ryanodine. Ferret right ventricular papillary muscles were exposed to ryanodine at 10(-6) M and then to incremental concentrations of halothane, isoflurane, or sevoflurane. In the presence of ryanodine, each anesthetic decreased isometric and isotonic contractility in a reversible, concentration-dependent manner with no differences between anesthetics and with little or no effect on time variables. It is likely that differences between anesthetic effects on contraction amplitude in isometric and isotonic twitches reside in their effects on the sarcoplasmic reticulum.

Load versus humoral activation in the genesis of early hypertensive heart disease.

BACKGROUND: The role of load versus angiotensin II (Ang II) and endothelin-1 (ET) in the pathogenesis of hypertensive heart disease is controversial. We sought to determine whether alterations in cardiac structure and function due to hypertension (HTN) were dependent on Ang II or ET activation. Methods and Results-- Bilateral renal wrapping to produce HTN (n=12) or sham surgery (n=6) was performed in adult dogs. Weekly blood pressure, plasma renin activity, Ang II, ET, and catecholamines were measured. Systolic (end-systolic elastance, Ees) and diastolic (tau) function were assessed in sham and HTN dogs at 5 (HTN-5wk) or 12 (HTN-12wk) weeks. Ang II and ET were assayed in the left ventricle (LV) and kidney. Mean arterial pressure was higher in renal wrap dogs at week 1 (*P<0.05 versus controls: 139+/-4* versus 123+/-4 mm Hg), week 5 (174+/-7* versus 124+/-4 mm Hg), and week 12 (181+/-12* versus 124+/-4 mm Hg). LV mass index was increased in HTN-5wk (22%*) and HTN-12wk (39%*). LV fibrosis was increased in HTN-12wk. Ees was preserved in HTN-5wk and HTN-12wk. tau was increased in HTN-5wk (50+/-3* ms) and HTN-12wk (62+/-10* ms) dogs compared with sham (41+/-2 ms). Plasma Ang II, ET, catecholamines, and plasma renin activity were unchanged during the progressive HTN. Ang II and ET in LV and kidney were not different from controls. CONCLUSIONS: Systemic HTN induces LV hypertrophy, myocardial fibrosis, and isolated diastolic dysfunction in the absence of local or systemic activation of Ang II or ET. These findings suggest that load is the prevailing stimulus for the structural and functional changes associated with early hypertensive heart disease.

Effects of isoflurane on intracellular calcium and myocardial crossbridge kinetics in tetanized papillary muscles.

BACKGROUND: Isoflurane depresses the intracellular Ca2+ transient and force development during a twitch, but its effects on crossbridge cycling rates are difficult to predict because of the transient nature of the twitch. Measurements of the effects of isoflurane on crossbridge cycling kinetics during tetanic contractions, which provide a steady state level of activation in intact cardiac muscle, have not been previously reported. METHODS: Ferret right ventricular papillary muscles were isolated, and superficial cells were microinjected with the bioluminescent photoprotein aequorin to monitor the intracellular Ca2+ concentration. The rate of tension redevelopment (kTR) was measured during steady state isometric activation (tetanic stimulation, frequency 20 Hz, 1 microM ryanodine, temperature = 30 degrees C) in the absence of isoflurane (2, 6, and 12 mM extracellular [Ca2+]) and in the presence of 0.5, 1.0, and 1.5 minimum alveolar concentration isoflurane (12 mM extracellular [Ca2+]). RESULTS: Intracellular [Ca2+], isometric force, and kTR all increased when the extracellular [Ca2+] increased. Isoflurane (0.5, 1.0, and 1.5 minimum alveolar concentration) caused intracellular [Ca2+], isometric force, and kTR to decrease in a dose-dependent manner in the presence of 12 mM extracellular [Ca2+]. In the presence of increasing concentrations of isoflurane, the relation between intracellular [Ca2+] and force remained unchanged, whereas the relation between intracellular [Ca2+] and kTR was shifted toward higher [Ca2+]. CONCLUSIONS: These results indicate that isoflurane depresses myocardial crossbridge cycling rates. It appears that this effect is partially mediated by a decrease in the intracellular [Ca2+]. However, additional mechanisms must be considered to explain the shift of the relation between intracellular [Ca2+] and kTR toward higher [Ca2+].

Invited Review: pathophysiology of cardiac muscle contraction and relaxation as a result of alterations in thin filament regulation.

Cardiac muscle contraction depends on the tightly regulated interactions of thin and thick filament proteins of the contractile apparatus. Mutations of thin filament proteins (actin, tropomyosin, and troponin), causing familial hypertrophic cardiomyopathy (FHC), occur predominantly in evolutionarily conserved regions and induce various functional defects that impair the normal contractile mechanism. Dysfunctional properties observed with the FHC mutants include altered Ca(2+) sensitivity, changes in ATPase activity, changes in the force and velocity of contraction, and destabilization of the contractile complex. One apparent tendency observed in these thin filament mutations is an increase in the Ca(2+) sensitivity of force development. This trend in Ca(2+) sensitivity is probably induced by altering the cross-bridge kinetics and the Ca(2+) affinity of troponin C. These in vitro defects lead to a wide variety of in vivo cardiac abnormalities and phenotypes, some more severe than others and some resulting in sudden cardiac death.

Inotropic stimulation induces cardiac dysfunction in transgenic mice expressing a troponin T (I79N) mutation linked to familial hypertrophic cardiomyopathy.

The cardiac troponin T (TnT) I79N mutation has been linked to familial hypertrophic cardiomyopathy and a high incidence of sudden death, despite causing little or no cardiac hypertrophy. In skinned fibers, I79N increased myofilamental calcium sensitivity (Miller, T., Szczesna, D., Housmans, P. R., Zhao, J., deFreitas, F., Gomes, A. V., Culbreath, L., McCue, J., Wang, Y., Xu, Y., Kerrick, W. G., and Potter, J. D. (2001) J. Biol. Chem. 276, 3743-3755). To further study the functional consequences of this mutation, we compared the cardiac performance of transgenic mice expressing either human TnT-I79N or human wild-type TnT. In isolated hearts, cardiac function was different depending on the Ca(2+) concentration of the perfusate; systolic function was significantly increased in Tg-I79N hearts at 0.5 and 1 mmol/liter. At higher Ca(2+) concentrations, systolic function was not different, but diastolic dysfunction became manifest as increased end-diastolic pressure and time to 90% relaxation. In vivo measurements by echocardiography and Doppler confirmed that base-line systolic function was significantly higher in Tg-I79N mice without evidence for diastolic dysfunction. Inotropic stimulation with isoproterenol resulted only in a modest contractile response but caused significant mortality in Tg-I79N mice. Doppler studies ruled out aortic outflow obstruction and were consistent with increased chamber stiffness. We conclude that in vivo, the increased myofilament Ca(2+) sensitivity due to the I79N mutation enhances base-line contractility but leads to cardiac dysfunction during inotropic stimulation.

Abnormal contractile function in transgenic mice expressing a familial hypertrophic cardiomyopathy-linked troponin T (I79N) mutation.

This study characterizes a transgenic animal model for the troponin T (TnT) mutation (I79N) associated with familial hypertrophic cardiomyopathy. To study the functional consequences of this mutation, we examined a wild type and two I79N-transgenic mouse lines of human cardiac TnT driven by a murine alpha-myosin heavy chain promoter. Extensive characterization of the transgenic I79N lines compared with wild type and/or nontransgenic mice demonstrated: 1) normal survival and no cardiac hypertrophy even with chronic exercise; 2) large increases in Ca(2+) sensitivity of ATPase activity and force in skinned fibers; 3) a substantial increase in the rate of force activation and an increase in the rate of force relaxation; 4) lower maximal force/cross-sectional area and ATPase activity; 5) loss of sensitivity to pH-induced shifts in the Ca(2+) dependence of force; and 6) computer simulations that reproduced experimental observations and suggested that the I79N mutation decreases the apparent off rate of Ca(2+) from troponin C and increases cross-bridge detachment rate g. Simulations for intact living fibers predict a higher basal contractility, a faster rate of force development, slower relaxation, and increased resting tension in transgenic I79N myocardium compared with transgenic wild type. These mechanisms may contribute to mortality in humans, especially in stimulated contractile states.

Effects of sevoflurane on the contractility of ferret ventricular myocardium.

Isotonic and isometric variables of contractility and relaxation of isolated ferret right ventricular papillary muscles were measured before and during exposure to incremental concentrations of sevoflurane (0-4.9% vol/vol) (30 degrees C) (n = 9). In a second group of muscles (n = 8), effects of sevoflurane were compared with those of low [Ca(2+)](o) (0.45-2.25 mM in steps of 0.45 mM). Sevoflurane caused a reversible concentration-dependent decrease in contractility (ED(50) of developed force 4.6+/-0.9% vol/vol). When compared with twitches of equal amplitude in low extracellular Ca(2+) concentration, sevoflurane accelerated both isometric and isotonic relaxation. The myocardial depressant effect of sevoflurane is less than that of isoflurane and results mainly from a decrease of intracellular Ca(2+) availability. The abbreviated isometric relaxation likely reflects a decrease in Ca(2+) sensitivity and the faster isotonic relaxation may reflect a mild stimulation of Ca(2+) uptake by the sarcoplasmic reticulum.

Effects of halothane, enflurane, and isoflurane on measurements of Ca(2+) by calcium electrode and aequorin luminescence.

We assessed the possible effects of the volatile halogenated anesthetics halothane, enflurane, and isoflurane on Ca(2+) electrode measurements and on the Ca(2+) sensitivity of the bioluminescent protein aequorin. In Ca(2+)-EGTA buffers of different pCa values (7. 870, 6.726, 6.033, 4.974, 4.038, and 2.995) and in serial Ca(2+) dilutions (10(-4), 10(-3), and 10(-2) M), halothane, enflurane, and isoflurane each caused a concentration-dependent and reversible increase in the absolute value of the negative electrode potential. Isoflurane and enflurane had larger effects than halothane. Neither of these anesthetics changed aequorin luminescence at any pCa tested in the range 2-8. There was no potentiation or inactivation of aequorin luminescence over a period of up to 2 h. These results suggest that (1) halothane, enflurane, and isoflurane interfere with Ca(2+) electrode measurements, most likely by changing the physicochemical properties of the membrane; (2) these anesthetics do not inactivate or otherwise modify the characteristics of the reaction of Ca(2+) with aequorin; and (3) these anesthetics do not change the apparent affinity of EGTA for Ca(2+).

Effects of halothane and isoflurane on the intracellular Ca2+ transient in ferret cardiac muscle.

BACKGROUND: Halothane and isoflurane depress myocardial contractility by decreasing transsarcolemmal Ca2+ influx and Ca2+ release from the sarcoplasmic reticulum. Decreases in Ca2+ sensitivity of the contractile proteins have been shown in skinned cardiac fibers, but the relative importance of this effect in intact living myocardium is unknown. The aims of this study were to assess whether halothane and isoflurane decrease myofibrillar Ca2+ sensitivity in intact, living cardiac fibers and to quantify the relative importance of changes in myofibrillar Ca2+ sensitivity versus changes in myoplasmic Ca2+ availability caused by these anesthetics. METHODS: The effects of halothane and isoflurane (0-1.5 times the minimum alveolar concentration (MAC) in three equal increments) on isometric and isotonic variables of contractility and on the intracellular calcium transient were assessed in isolated ferret right ventricular papillary muscle microinjected with the Ca2+-regulated photoprotein aequorin. The intracellular calcium transient was analyzed in the context of a multicompartment model of intracellular Ca2+ buffers in mammalian ventricular myocardium. RESULTS: Halothane and isoflurane decreased contractility, time-to-peak force, time to half-isometric relaxation, and intracellular Ca2+ transient in a reversible, concentration-dependent manner. Halothane, but not isoflurane, slowed the increase and the decrease of the intracellular Ca2+ transient. Increasing extracellular Ca2+ in the presence of anesthetic to produce peak force equal to control values increased intracellular Ca2+ to values higher than control values. CONCLUSIONS: Halothane decreases myoplasmic Ca2+ availability more than isoflurane; halothane and isoflurane decrease myofibrillar Ca2+ sensitivity to the same extent; in halothane at 0.5 MAC and isoflurane at 1.0 MAC, the decrease in Ca2+ sensitivity is already fully apparent; halothane decreases intracellular Ca2+ availability more than myofibrillar Ca2+ sensitivity; and isoflurane decreases myoplasmic Ca2+ availability and Ca2+ sensitivity to the same extent, except at 1.5 times the MAC, which decreases Ca2+ availability more.

Effects of sevoflurane on the intracellular Ca2+ transient in ferret cardiac muscle.

BACKGROUND: Sevoflurane depresses myocardial contractility by decreasing transsarcolemmal Ca2+ influx. In skinned muscle fibers, sevoflurane affects actin-myosin cross-bridge cycling, which might contribute to the negative inotropic effect. It is uncertain to what extent decreases in Ca2+ sensitivity of the contractile proteins play a role in the negative inotropic effect of sevoflurane in intact cardiac muscle tissue. The aim of this study was to assess whether sevoflurane decreases myofibrillar Ca2+ sensitivity in intact living cardiac fibers and to quantify the relative importance of changes in myofibrillar Ca2+ sensitivity versus changes in myoplasmic Ca2+ availability by sevoflurane. METHODS: The effects of sevoflurane 0-4.05% vol/vol (0-1.5 minimum alveolar concentration [MAC]) on isometric and isotonic variables of contractility and on the intracellular calcium transient were assessed in isolated ferret right ventricular papillary muscles microinjected with the Ca2+-regulated photoprotein aequorin. The intracellular calcium transient was analyzed in the context of a multicompartment model of intracellular Ca2+ buffers in mammalian ventricular myocardium. RESULTS: Sevoflurane decreased contractility, time to peak force, time to half isometric relaxation, and the [Ca2+]i transient in a reversible, concentration-dependent manner. Increasing [Ca2+]o in the presence of sevoflurane to produce peak force equal to control increased intracellular Ca2+ transient higher than control. CONCLUSIONS: Sevoflurane decreases myoplasmic Ca2+ availability and myofibrillar Ca2+ sensitivity in equal proportions except at 4.05% vol/vol (1.5 MAC), where Ca2+ availability is decreased more. These changes are at the basis of the negative inotropic effect of sevoflurane in mammalian ventricular myocardium.

Comparison of volatile anesthetic effects on actin-myosin cross-bridge cycling in neonatal versus adult cardiac muscle.

BACKGROUND: The neonatal myocardium is more sensitive to volatile anesthetics compared with adults. The greater myocardial sensitivity of neonates may be attributable to greater anesthetic effect on force regulation at the level of the cross-bridge. In the current study, the authors compared the effects of 1 and 2 minimum alveolar concentration (MAC) halothane and sevoflurane on cardiac muscle from 0- to 3-day-old (neonate) and 84-day-old (adult) rats. METHODS: Triton X-100-skinned muscle strips were maximally activated at pCa (negative logarithm of the Ca2+ concentration) of 4.0, and the following were measured in the presence or absence of anesthetic: Rate of force redevelopment after rapid shortening and restretching (ktr) and isometric stiffness at maximal activation and in rigor. The fraction of attached cross-bridges (alphafs) and apparent rate constants for cross-bridge attachment (fapp) and detachment (gapp) were calculated assuming a two-state model for cross-bridge cycling. Anesthetic-induced changes in the mean stiffness per cross-bridge were also estimated from values in rigor versus maximum activation in the presence or absence of anesthetic. RESULTS: Neonatal cardiac muscle displayed significantly smaller alphafs slower ktr and slower fapp compared with adult cardiac muscle; however, gapp was not significantly different. Halothane, and sevoflurane to a significantly lesser extent, decreased alphafs, fapp, and the mean force per cross-bridge and increased gapp to a greater extent in neonates. CONCLUSIONS: These data indicate that weaker force production in neonatal cardiac muscle involves, at least in part, less efficient cross-bridge cycling kinetics. The authors conclude that the greater myocardial sensitivity of neonates to volatile anesthetics reflects, at least in part, a direct inhibition of cross-bridge cycling, especially the rates of cross-bridge attachment and detachment.

Effects of isoproterenol on twitch contraction of wild type and phospholamban-deficient murine ventricular myocardium.

Ablation of the gene for phospholamban (PLB), a transmembrane peptide regulator for the cardiac sarcoplasmic reticulum Ca2+ pump, in mice brings about a complete loss of the myocardial responses to beta-adrenergic agonists (e.g., Luo et al., Circ. Res. 1994; 75: 401). We have evaluated the functional significance of PLB-independent mechanisms in the myocardial responses to beta-adrenergic stimulation in isolated intact ventricular myocardium. We compared the effects of (-)-isoproterenol (ISO) on isometric twitch contraction of paced right ventricular muscle strips of wild type (WT) and PLB-deficient (PLBKO) mice. At 37 degrees C, frequent spontaneous contractions in both types of muscles required the inclusion of lidocaine, an antiarrhythmic, in the bathing medium. Thus the experiments were also performed at two lower temperatures, 30 degrees C and 25 degrees C, at which lidocaine was not needed. Under three conditions, in the absence of ISO, PLBKO ventricular muscles exhibited substantially shortened time to peak tension (TPT) and half relaxation time (TR1/2), compared with the WT muscles. In both WT and PLBKO muscles ISO increased the peak developed tension and decreased TPT and TR1/2 in a dose-dependent manner although the effects were generally smaller in PLBKO than in WT muscles. One micromolar ISO caused TPT and TR1/2 to decrease by 7.3+/-1.2% (mean+/-SEM) and 7.5+/-1.2% in PLBKO vs. 22.8+/-0.7% and 29.1+/-1.7% in WT at 37 degrees C; by 13.5+/-0.4% and 14.1+/-1.2% in PLBKO vs. 31.3+/-0.8%, and 44.8+/-1.3% in WT at 30 degrees C; by 15.0+/-2.3% and 21.1+/-4.9% in PLBKO vs. 25.8+/-1.9% and 54.0+/-1.9% in WT at 25 degrees C. These findings strongly suggest that PLB-independent mechanisms play a significant role in mediating the positive inotropic and lusitropic effects of beta-adrenergic agonists on ventricular myocardium.

Comparison of cross-bridge cycling kinetics in neonatal vs. adult rat ventricular muscle.

The developmental shift in contractile protein isoform expression in the rodent heart likely affects actin-myosin cross-bridge interactions. We compared the Ca2+ sensitivity for force generation and cross-bridge cycling kinetics in neonatal (postnatal days 0-3) and adult (day 84) rats. The force-pCa relationship was determined in Triton-X skinned muscle bundles activated at pCa 9.0 to 4.0. In strips maximally activated at pCa 4.0, the following parameters of cross-bridge cycling were measured: (1) rate of force redevelopment following rapid shortening and restretching (ktr); and (2) isometric stiffness at maximal activation and in rigor. The fraction of attached cross-bridges (alpha fs) and apparent rate constants for cross-bridge attachment (fapp) and detachment (gapp) were derived assuming a two-state model for cross-bridge cycling. Compared to the adult, the force-pCa curve for neonatal cardiac muscle was significantly shifted to the left. Neonatal cardiac muscle also displayed significantly smaller alpha fs, slower ktr and fapp; however, gapp was not significantly different between age groups. These data indicate that weaker force production in neonatal cardiac muscle involves, at least in part, less efficient cross-bridge cycling kinetics.

Tramadol in the treatment of postanesthetic shivering.

BACKGROUND: As an inhibitor of the reuptake of serotonin and norepinephrine in the spinal cord, the mechanism of action of tramadol resembles that of nefopam, which has been used in the treatment of postanesthetic shivering. METHODS: In a randomized, placebo-controlled, double-blind study, we assessed the effects of tramadol (0.5 mg.kg-1, 1 mg.kg-1 and 2 mg.kg-1 i.v.) or normal saline on shivering after a standardized general anesthesia in 40 adult patients, ASA physical status I or II (group 1), and in 64 adult patients regardless of the foregoing general anesthesia and ASA physical status (group 2). RESULTS: Tramadol 1 mg.kg-1 or more abolished shivering completely 5 min after treatment in all patients of groups 1 and 2. In group 1, the three dosages of tramadol were not statistically different in lowering the severity and prevalence of postanesthetic shivering. Tramadol 0.5 mg.kg-1 was significantly slower than tramadol 1 or 2 mg.kg-1 in tempering the severity as well as lowering the prevalence of postanesthetic shivering in group 2. CONCLUSION: Tramadol's distinct features in the treatment of shivering reside in its high safety profile and weak sedative properties, particularly in patients with poor cardiorespiratory reserve, in outpatients and on recurrence of shivering.

Mechanism of the negative inotropic effect of thiopental in isolated ferret ventricular myocardium.

BACKGROUND: Thiopental's myocardial depressant effects are well known and most likely involve some alteration in intracellular Ca2+ homeostasis. The aim of this study was to investigate the mechanisms of thiopental's negative inotropic effects and its underlying mechanism in isolated ferret ventricular myocardium (which shows physiologic characteristics similar to human ventricular myocardium), and in frog ventricular myocardium, in which Ca2+ ions for myofibrillar activation are derived almost entirely from transsarcolemmal influx. METHODS: The authors analyzed the effects of thiopental after beta-adrenoceptor blockade on variables of contractility and relaxation, and on the free intracellular Ca2+ transient detected with the Ca(2+)-regulated photoprotein aequorin. Thiopental's effects also were evaluated in ferret right ventricular papillary muscles in which the sarcoplasmic reticulum (SR) function was impaired by ryanodine and in frog ventricular strips with little or no SR function. RESULTS: At concentration > or = 10(-4) M, which is in the high range of the clinically encountered free plasma thiopental concentrations, thiopental decreased contractility and the amplitude of the intracellular Ca2+ transient. At equal peak force, peak aequorin luminescence in 10(-4) M thiopental and [Ca2+]0 > 2.25 mM was slightly smaller than that in control conditions at [Ca2+]o = 2.25 mM. This indicates that thiopental causes a small increase in myofibrillar Ca2+ sensitivity. After inactivation of sarcoplasmic reticulum Ca2+ release with 10(-6) M ryanodine, a condition in which myofibrillar activation depends almost exclusively on transsarcolemmal Ca2+ influx, thiopental caused a further decrease in contractility and in the amplitude of the intracellular Ca2+ transient, and thiopental's relative negative inotropic effect was not different from that in control muscles not exposed to ryanodine. Thiopental, > or = 10(-4) M, decreased contractility in frog ventricular myocardium. CONCLUSIONS: These findings indicate that the direct negative inotropic effect of thiopental results from a decrease in intracellular Ca2+ availability. At least part of thiopental's action is caused by inhibition of transsarcolemmal Ca2+ influx. These effects become apparent at concentrations routinely present during intravenous induction with thiopental.

Mechanism of the negative inotropic effect of propofol in isolated ferret ventricular myocardium.

BACKGROUND: The aim of this study was to investigate propofol's effect on myocardial contractility and relaxation and examine its underlying mechanism of action in isolated ferret ventricular myocardium. METHODS: The effects of propofol on variables of contractility and relaxation and on the free intracellular Ca++ transient detected with the Ca(++)-regulated photoprotein aequorin were analyzed. Propofol's effects were evaluated in a preparation in which the sarcoplasmic reticulum function was impaired by ryanodine. The effects of propofol's solvent, intralipid, on myocardial contractility, relaxation, and the intracellular Ca++ transient also were examined. RESULTS: Propofol, at concentrations of 10 microM or greater, decreased contractility and, at concentrations of 30 of microns or greater, decreased the amplitude of the intracellular Ca++ transient. At equal peak force, control peak aequorin luminescence in [Ca++]o = 2.25 mM and peak aequorin luminescence in 300 microM [Ca++]o = 2.25 mM and peak aequorin luminescence in 300 microM propofol in [Ca++]o > 2.25 mM did not differ, which suggests that propofol does not alter myofibrillar Ca++ sensitivity. After inactivation of sarcoplasmic reticulum Ca++ release with 1 microM ryanodine, a condition in which myofibrillar activation depends almost exclusively on transsarcolemmal Ca++ influx, propofol caused a decrease in contractility and in the amplitude of the intracellular Ca++ transient. Under these conditions, propofol's relative negative inotropic effect did not differ from that in control muscles not exposed to ryanodine. Propofol's solvent, 10% intralipid, exerted a modest positive inotropic effect in this preparation. The intracellular Ca++ transient was unchanged by intralipid. Neither propofol nor intralipid altered the load sensitivity of relaxation. CONCLUSIONS: These findings suggest that the negative inotropic effect of propofol results from a decrease in intracellular Ca++ availability with no changes in myofibrillar Ca++ sensitivity. At least part of propofol's action is attributable to inhibition of transsarcolemmal Ca++ influx.

Mechanism of the direct, negative inotropic effect of etomidate in isolated ferret ventricular myocardium.

BACKGROUND: Etomidate exerts a mild, positive inotropic effect in rat ventricular myocardium, yet has a negative inotropic effect in isolated rabbit ventricular myocardium. The aim of this study was to investigate the mechanisms of etomidate's inotropic effect and its underlying mechanism in isolated ferret ventricular myocardium (which shows similar physiologic characteristics as human ventricular myocardium) and in frog ventricular myocardium, in which Ca++ ions for myofibrillar activation are derived almost entirely from transsarcolemmal influx. METHODS: The authors analyzed the effects of etomidate after beta-adrenoceptor blockade on variables of contractility and relaxation, and on the free intracellular Ca++ transient detected with the Ca+(+)-regulated photoprotein aequorin. Etomidate's effects were also evaluated in ferret right ventricular papillary muscles in which the sarcoplasmic reticulum (SR) function was impaired by ryanodine, and in frog ventricular strips with little or no SR function. RESULTS: At concentrations > or = 3 micrograms/ml, which by far exceed the clinically useful concentration range, etomidate decreased contractility and the amplitude of the intracellular Ca++ transient. At equal peak force, control peak aequorin luminescence in [Ca++]o = 2.25 mM and peak aequorin luminescence in etomidate 10 micrograms/ml and [Ca++]o > 2.25 mM did not differ, which indicates that etomidate does not alter myofibrillar Ca++ sensitivity. After inactivation of sarcoplasmic reticulum Ca++ release with ryanodine 10(-6) M, a condition in which myofibrillar activation depends almost exclusively on transsarcolemmal Ca++ influx, etomidate caused a decrease in contractility and in the amplitude of the intracellular Ca++ transient, and etomidate's relative negative inotropic effect was not different from that in control muscles not exposed to ryanodine. Etomidate 10 micrograms/ml decreased contractility in frog ventricular myocardium. CONCLUSIONS: These findings indicate that the direct negative inotropic effect of etomidate results from a decrease in intracellular Ca++ availability with no changes in myofibrillar Ca++ sensitivity. At least part of etomidate's action is caused by inhibition of transsarcolemmal Ca++ influx. Yet, these effects become apparent only at concentrations that are at least one order of magnitude larger than those encountered in clinical practice.

Mechanism of the direct, negative inotropic effect of ketamine in isolated ferret and frog ventricular myocardium.

BACKGROUND: Ketamine exerts both an indirect, positive inotropic effect and a direct, negative inotropic effect in isolated ferret ventricular myocardium. This negative inotropic effect becomes apparent after inactivation of the sympathetic neuroeffector junction. The aim of this study was to investigate the mechanisms of ketamine's intrinsic negative inotropic effect. METHODS: The authors analyzed the effects of ketamine after beta-adrenoceptor blockade on variables of contractility and relaxation, and on the free intracellular Ca++ transient detected with the Ca(++)-regulated photoprotein aequorin. Ketamine's effects were also evaluated in a preparation in which the sarcoplasmic reticulum (SR) function was impaired by ryanodine, and in frog ventricular myocardium in which the SR is poorly developed. RESULTS: Ketamine at concentrations > or = 3.3 x 10(-5) M decreased contractility and the amplitude of the intracellular Ca++ transient. After inactivation of sarcoplasmic reticulum Ca++ release with 10(-6) M ryanodine, a condition in which myofibrillar activation depends almost exclusively on transsarcolemmal Ca++ influx, ketamine caused a decrease in contractility and in the amplitude of the intracellular Ca++ transient, and ketamine's relative negative inotropic effect was not different from that in control muscles not exposed to ryanodine. Furthermore, > or = 10(-4) M ketamine decreased contractility in frog ventricular myocardium, a species that is almost entirely dependent on transsarcolemmal Ca++ influx for its myofibrillar activation. CONCLUSIONS: These findings indicate that the direct negative inotropic effect of ketamine results from a decrease in intracellular Ca++ availability with no changes in myofibrillar Ca++ sensitivity. At least part of ketamine's action is caused by inhibition of transsarcolemmal Ca++ influx.