Differential depression of myocardial contractility by halothane and isoflurane in vitro

Depressant effects of halothane and isoflurane on isolated right ventricular guinea pig papillary muscle bathed in Tyrode's solution at 37 degrees C were examined. Contractions were elicited by stimulation through external field electrodes while tension was recorded continuously and the intracellular cardiac action potential (AP) was monitored simultaneously by microelectrodes. The time differential of tension (dT/dt) and of membrane potential (V) was determined electronically and recorded also. Contractions after rest and at stimulation rates of 0.1, 0.25, 0.5, 1, 2, and 3 Hz were studied. With normal APs, isoflurane (1.3 and 2.5%) depressed peak tension significantly less at high frequencies than did equivalent doses of halothane (0.75 or 1.5%). Isoflurane depressed dT/dt max less than halothane at all frequencies. At 0.3 Hz stimulation, isoflurane (1-4%) significantly increased the normal AP duration by 7-11%. Slow calcium-dependent APs and accompanying contractions were studied in partially depolarized muscles (-40 to -45 mV resting potential in 26 mM K+ Tyrode's solution) stimulated with 0.1 microM isoproterenol. Following rest and at 0.1, 0.25, 0.5, 1, 2, and 3 Hz, both isoflurane (1.3% or 2.5%) and enflurane (1.7% or 3.5%) markedly depressed the late-peaking slow AP contraction observed with low-frequency stimulation. Halothane (0.75% or 1.5%) caused a similar contractile depression (40-60%) at all frequencies. In contrast, isoflurane depressed early peaking tension and the dT/dt max at frequencies greater than 1 Hz significantly less than did halothane or enflurane. At 0.3 Hz, 2% and 4% isoflurane caused 9% and 17% depression of slow AP maximum rate of depolarization (Vmax), but significantly prolonged the AP duration. Isoflurane altered the pattern of tension development in a different manner than halothane, suggesting differing mechanisms of myocardial depression by these anesthetics.     

Effects of halothane and isoflurane on isolated human ventricular myocardium

Segments of viable human left ventricular trabeculae were obtained at the time of endocardial resection for intractable ventricular ectopy. Muscle segments which showed suitable and reproducible contractions in 26 mM K Tyrode solution with 1 microM isoproterenol were electrically stimulated after rest, and at frequencies of 0.1, 0.25, 0.5, and 1 Hz. Effects of 0.75% halothane and 1.3% isoflurane on peak tension, maximum rate of tension development (dT/dt-max), and on slow (calcium dependent) action potential (AP) characteristics were studied. Halothane depressed peak tension, dT/dt-max, and slow AP maximum rate of depolarization (Vmax) at all frequencies, and caused a significantly greater depression of peak tension and dT/dt-max at 0.5-1 Hz than after rest and at 0.1-0.25 Hz. Isoflurane did not significantly depress slow AP Vmax, showed no frequency dependent contractile depression, and depressed dT/dt-max less than halothane at 0.5 and 1 Hz. Halothane and isoflurane caused differing depression in the pattern of developed tension. The differential depression by halothane and isoflurane of human ventricular myocardium was similar to that previously observed in isolated animal ventricular tissue.     

Depressant effects of volatile anesthetics upon rat and amphibian ventricular myocardium: insights into anesthetic mechanisms of action

To clarify the mechanisms by which volatile anesthetics may depress myocardial contractility, the depressant effects of equivalent concentrations of isoflurane, enflurane and halothane were compared in rat and frog ventricular myocardium, preparations which differ markedly in excitation-contraction coupling. In Tyrode solution, right ventricular papillary muscles from rat exhibited very large, rapidly developing contractions after rest, with a subsequent negative force-frequency relation as the stimulation rate was increased to 0.1, 0.25, 0.5, 1, 2, and 3 Hz. The large contractions after rest and at 0.1 Hz were depressed by 0.75% halothane and 1.7% enflurane to about 60% of control, but less so by 1.3% isoflurane (approximately 0.8 MAC). Halothane at 1.5% was more depressant than 2.5% isoflurane at all stimulation rates, while 3.5% enflurane caused intermediate depression (approximately 1.6 MAC). Contractions in frog ventricular strips were studied in Ringer solution following rest and at stimulation rates of 0.1, 0.25, 0.5, and 1 Hz, in the absence and presence of equivalent anesthetic concentrations. At 0.1 to 1 Hz, isoflurane was less depressant than equivalent concentrations of halothane. Enflurane (1.7%) was less depressant than 0.75% halothane at 0.1 and 0.25 Hz; 3.5% enflurane was more depressant than 2.5% isoflurane at 1 Hz. Anesthetic effects on sustained contractures were also studied in frog ventricular strips that were superfused for 4-5 min with 40, 60, 80, and 100 mM K Ringer solution. Contractures induced by 80 and 100 mM K solution were depressed more by halothane (to 60% of control) than by isoflurane or enflurane (approximately 85% of control). However, only enflurane depressed the contractions at 1 Hz more than the sustained contractures in 100 mM K Ringer. The Ca2+ for activating contractions in rat ventricle is derived largely from the sarcoplasmic reticulum, the intracellular Ca2+ accumulation and release organelle. In contrast, Ca2+ for activating contractions in the frog ventricle originates primarily from the external medium. These results suggest that halothane is more potent than isoflurane in reducing the amount of Ca2+ rapidly released from the sarcoplasmic reticulum (as observed in rat), as well as in depressing entry of extracellular Ca2+ to activate myofibrils (as in frog). Enflurane appears to have intermediate potency with actions distinct from halothane and isoflurane. The greater potency of halothane may also be due in part to greater direct depression of actin-myosin ATPase.     

Differential effects of halothane, enflurane, and isoflurane on Ca2+ transients and papillary muscle tension in guinea pigs.

These studies were designed to examine the effects of inhalational anesthetics on rapid changes in myocardial intracellular Ca2+ and Ca2+ sensitivity of the contractile apparatus. The effects of halothane, enflurane, and isoflurane on rapid changes in intracellular Ca2+ (Ca2+ transients as measured with bioluminescent protein aequorin) and contractile characteristics were compared in guinea pig right ventricular papillary muscles. In addition to examination of their potencies at equianesthetic concentrations, the effects of these agents on alterations in Ca2+ sensitivity at myofilaments were also investigated. The negative inotropic effects of halothane (0.65 and 1.15%) and enflurane (1.0 and 2.2%) were dose-dependent and closely related to a decrease in Ca2+ transients. In the presence of isoflurane (0.77 and 1.6%), the contractile force decreased in a dose-dependent manner, but the decrease was significantly less as compared to that with equianesthetic concentrations of halothane and enflurane. An additional feature observed in the presence of isoflurane was a dissociation between intracellular Ca2+ availability and contractile force. Although the magnitude of the Ca2+ transients did not change when the percentage of isoflurane was increased from 0.77 to 1.6, the contractile force decreased. Because of these findings, the effects of halothane (1.2%), enflurane (2.2%), and isoflurane (1.6%) on the relationship between intracellular Ca2+ and tension developed in the papillary muscle were examined in order to assess myofibrillar responsiveness to Ca2+. The results indicate that only isoflurane slightly but significantly shifted the Ca2+/isometric tension curve toward higher intracellular Ca2+ concentrations; no differences were observed in the absence and presence of equianesthetic concentrations of halothane and enflurane.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of halothane, enflurane, and isoflurane on calcium current in isolated canine ventricular cells.

The effects of halothane, enflurane, and isoflurane on voltage-dependent Ca2+ channel current (ICa) were compared in canine ventricular cells by the whole-cell voltage-clamp technique. ICa was elicited in each cell by progressively depolarizing pulses, from -80 or -40 mV to more positive membrane potentials. The peak amplitude and inactivation rate of the inward current were analyzed before, during, and after the external application of equianesthetic concentrations (0.5, 1.0, and 2.0 MAC) of halothane, enflurane, or isoflurane. The concentrations of these agents in the Krebs' solution were as follows (percentage in the gas phase): halothane 0.36, 0.68, and 1.50%; isoflurane 0.50, 1.00, and 1.90%; and enflurane 0.66, 1.36, and 2.39%. Halothane, enflurane, and isoflurane rapidly reduced peak ICa amplitude at all voltages studied, resulting in a depression of the entire current-voltage relationship for ICa activation. This depression was concentration-dependent and completely reversible upon wash-out of the anesthetic agents. Quantitatively, the three anesthetic agents produced a similar inhibition of peak ICa at approximately equianesthetic concentrations. Inactivation of ICa during 200-ms depolarizing pulses was not affected by two lower concentrations of the anesthetic agents, but was accelerated by the highest concentration of enflurane used. These findings suggest that the negative inotropic and chronotropic actions of halothane, enflurane, and isoflurane on the ventricular myocardium are related, at least in part, to their inhibition of ICa at the sarcolemma. However, since all three anesthetic agents depressed ICa amplitude similarly, their quantitatively different effects on cardiac performance are due most likely to differences in actions at other cellular sites.     

Mechanisms of action of halogenated anesthetics on isolated cardiac muscle

The mechanisms responsible for the direct negative inotropic effects of the three currently used volatile anesthetics (halothane, enflurane and isoflurane) are reviewed. These agents interfere at each step of excitation-contraction coupling, i.e. sarcolemmal membrane, sarcoplasmic reticulum and contractile proteins. At the myofilament level, they decrease both calcium sensitivity and maximal developed force of cardiac skinned fibers of various species, a preparation in which all functional membranes are destroyed and thus allowing to study the direct effects of volatile anesthetics on myocardial contractile proteins. The effects of the three volatile anesthetics are similar at equipotent concentrations. The site of action seems to involve the regulatory proteins of the thin myofilament, especially troponin-tropomyosin complex. At the sarcolemmal level, all three anesthetics decrease Ca++ entry through the voltage-dependent calcium channels, an effect that seems slightly more important for both halothane and enflurane than for isoflurane. However, these two sites of action (contractile proteins and sarcolemmal membrane) are not sufficient to explain their overall negative inotropic effect. The third site of action involves the sarcoplasmic reticulum. Halothane and enflurane produce an initial liberation of Ca++ from internal stores, while isoflurane does not. All three agents decrease the net uptake of Ca++ and increase the permeability of sarcoplasmic reticulum to Ca++, similar to the effect of caffeine. However, the resulting effect, i.e. a reduction of sarcoplasmic reticulum Ca++ content occurs at clinical concentrations of halothane or enflurane, while much higher concentrations of isoflurane are required to produce a similar reduction. This differential effect on the sarcoplasmic reticulum function (which is quantitative but not qualitative) seems to be mainly responsible for the lesser negative inotropic effect of isoflurane as observed in intact cardiac muscles of various species including humans. The knowledge of the mechanisms of action of volatile anesthetics is important for understanding the potential consequences associated with their use in patients receiving cardiac drugs, especially calcium blockers and phosphodiesterase inhibitors.     

Depression of atrial rate, atrioventricular nodal conduction, and cardiac contraction by diltiazem and volatile anesthetics in isolated hearts

The direct effects of isoflurane, halothane, and enflurane alone or combined with diltiazem were examined in 49 isolated perfused guinea pig hearts. Recording electrodes were placed in the right atrium and left ventricular septal wall to measure spontaneous atrial rate and atrioventricular conduction time (AVCT). The right atrium was paced at 3-7 Hz (n = 10) to examine rate-dependent effects on AVCT, Wenckebach's periodicity, and ventricular response rates with atrioventricular (AV) block. Isovolumetric left ventricular pressure (LVP) was measured with a saline-filled balloon placed through the mitral valve. Hearts were perfused with oxygenated Krebs-Ringer's solution at 55 mmHg equilibrated with low or high concentrations of isoflurane (0.7 and 1.5%), halothane (0.5 and 1%), or enflurane (1.1 and 2.2%). Hearts were also perfused with a low or high concentration of diltiazem (75 and 150 ng/ml) alone and during anesthetic exposure. Significant findings of combined exposure were as follows: 1) the low isoflurane, halothane, or enflurane concentration plus a low or high diltiazem concentration decreased LVP compared with control and diltiazem alone; low isoflurane plus the high diltiazem concentration decreased LVP more than isoflurane alone. The high isoflurane, halothane, or enflurane concentration plus the low or the high diltiazem concentration decreased LVP from control, anesthetics and diltiazem alone. Diltiazem plus halothane or enflurane decreased LVP more than diltiazem plus isoflurane. 2) Diltiazem plus low or high isoflurane, halothane, or enflurane concentrations decreased spontaneous atrial rate from control and the agents alone, except the high isoflurane concentration plus the low diltiazem concentration was not greater than that of isoflurane alone. Diltiazem plus halothane or enflurane decreased atrial rate more than diltiazem plus isoflurane. 3) Low and high diltiazem concentration plus low isoflurane, halothane, or enflurane concentrations did not prolong AVCT more than the individual agents alone, but low or high diltiazem plus high isoflurane, halothane, or enflurane concentrations increased AVCT more than each anesthetic alone. In nonpaced hearts, AV block occurred only with high diltiazem plus low enflurane (23%) concentrations and the high enflurane concentration (31%). 4) In hearts paced at 5 and 6 Hz, AVCT increased above controls during a low or high concentrations of diltiazem, during enflurane, and during the low or high concentration of diltiazem plus enflurane; AVCT increased more with the low concentration of diltiazem plus enflurane than with the low diltiazem concentration alone.(ABSTRACT TRUNCATED AT 400 WORDS)     

In Vitro Effects of Desflurane, Sevoflurane, Isoflurane, and Halothane in Isolated Human Right Atria

Background: Direct myocardial effects of volatile anesthetics have been studied in various animal species in vitro. This study evaluated the effects of equianesthetic concentrations of desflurane, sevoflurane, isoflurane, and halothane on contractile parameters of isolated human atria in vitro.

Methods: Human right atrial trabeculae, obtained from patients undergoing coronary bypass surgery, were studied in an oxygenated (95% O2-5% CO2) Tyrode's modified solution ([Ca2+]o = 2.0 mM, 30[degrees]C, stimulation frequency 0.5 Hz). The effects of equianesthetic concentrations (0.5, 1, 1.5, 2, and 2.5 minimum alveolar concentration [MAC]) of desflurane, sevoflurane, isoflurane, and halothane on inotropic and lusitropic parameters of isometric twitches were measured.

Results: Isoflurane, sevoflurane, and desflurane induced a moderate concentration-dependent decrease in active isometric force, which was significantly lower than that induced by halothane. In the presence of adrenoceptor blockade, the desflurane-induced decrease in peak of the positive force derivative and time to peak force became comparable to those induced by isoflurane. Halothane induced a concentration-dependent decrease in time to half-relaxation and a contraction-relaxation coupling parameter significantly greater than those induced by isoflurane, sevoflurane and desflurane.     

Volatile Anesthetics Affect Calcium Mobilization in Bovine Endothelial Cells

Background: The site where volatile anesthetics inhibit endothelium-dependent, nitric oxide-mediated vasodilation is unclear. To determine whether anesthetics could limit endothelium-dependent nitric oxide production by inhibiting receptor-mediated increases in cytosolic Calcium2+, experiments were performed to see if the inhalational anesthetics halothane, isoflurane, and enflurane affect intracellular Calcium2+ ([Ca2+]i) transients induced by the agonists bradykinin and adenosine triphosphate in cultured bovine aortic endothelial cells.

Methods: Bovine aortic endothelial cells, which had been loaded with the fluorescent Calcium2+ indicator Fura-2, were added to medium preequilibrated with volatile anesthetic (1.25% and 2.5% for isoflurane, 1.755 and 3.5% for enflurane, and 0.75% and 1.5% for halothane). In Calcium2+ -containing medium, intracellular Calcium sup 2+ transients were elicited in response to bradykinin (10 nM and 1 micro Meter) or adenosine triphosphate (1 micro Meter and 100 micro Meter).

Results: Both bradykinin and adenosine triphosphate triggered a rapid rise to peak [Ca2+]i followed by a gradual decline to a plateau above the resting level. Although basal [Ca2+]i was unaltered by the anesthetics, both halothane and enflurane, in a dose-dependent manner, depressed the peak and plateau of the [Ca2+] sub i transient elicited by 10 nM bradykinin, whereas isoflurane had no effect. When [Ca2+]i transients were elicited by 1 micro Meter bradykinin, halothane (1% and 5%) did not alter peak and plateau levels. Halothane and enflurane also decreased [Ca2+]i transients evoked by 1 micro Meter and 100 micro Meter adenosine triphosphate, whereas isoflurane also had no effect in this setting.     

Cardiovascular effects of acute changes in extracellular ionized calcium concentration induced by citrate and CaCl2 infusions in chronically instrumented dogs, conscious and during enflurane, halothane, and isoflurane anesthesia

To study the cardiovascular effects of low blood ionized calcium ion concentrations [Ca2+] induced by citrate infusion followed by high [Ca2+], induced by CaCl2 infusion awake and during enflurane (2.5% ET), halothane (1.2% ET), and isoflurane (1.6% ET) anesthesia, dogs were chronically instrumented to measure heart rate, aortic, left atrial, and left ventricular (LV) blood pressures, and cardiac output. In conscious dogs low [Ca2+] (decreased 0.35 mM); increased heart rate (HR) and mean aortic pressure (MAP) and decreased stroke volume (SV) and LV dP/dtmax. Low [Ca2+] increased HR during all three anesthetics and decreased LV dP/dtmax except during isoflurane anesthesia. Low [Ca2+] produced more hemodynamic depression during enflurane anesthesia than during anesthesia with halothane or isoflurane increasing left atrial pressure and decreasing MAP and SV. The differences seen were partially related to decreased systemic vascular resistance during halothane and isoflurane anesthesia. In conscious dogs following high [Ca2+] (increased 0.37 mM); only MAP and LV dP/dtmax increased. LVdP/dtmax was also increased by high [Ca2+] during all three anesthetics without a change in MAP. Cardiac output increased during halothane and isoflurane anesthesia but was unchanged during enflurane. It would appear that the hemodynamic sensitivity for the effects of changing [Ca2+] was enflurane greater than halothane greater than isoflurane greater than awake. The results suggest that the effects of changes in [Ca2+] induced by citrate and CaCl2 infusion are modified by the three volatile anesthetics.     

In vitro effects of desflurane, sevoflurane, isoflurane, and halothane in isolated human right atria

BACKGROUND: Direct myocardial effects of volatile anesthetics have been studied in various animal species in vitro. This study evaluated the effects of equianesthetic concentrations of desflurane, sevoflurane, isoflurane, and halothane on contractile parameters of isolated human atria in vitro. METHODS: Human right atrial trabeculae, obtained from patients undergoing coronary bypass surgery, were studied in an oxygenated (95% O2-5% CO2) Tyrode's modified solution ([Ca2+]o = 2.0 mM, 30 degrees C, stimulation frequency 0.5 Hz). The effects of equianesthetic concentrations (0.5, 1, 1.5, 2, and 2.5 minimum alveolar concentration [MAC]) of desflurane, sevoflurane, isoflurane, and halothane on inotropic and lusitropic parameters of isometric twitches were measured. RESULTS: Isoflurane, sevoflurane, and desflurane induced a moderate concentration-dependent decrease in active isometric force, which was significantly lower than that induced by halothane. In the presence of adrenoceptor blockade, the desflurane-induced decrease in peak of the positive force derivative and time to peak force became comparable to those induced by isoflurane. Halothane induced a concentration-dependent decrease in time to half-relaxation and a contraction-relaxation coupling parameter significantly greater than those induced by isoflurane, sevoflurane and desflurane. CONCLUSIONS: In isolated human atrial myocardium, desflurane, sevoflurane, and isoflurane induced a moderate concentration-dependent negative inotropic effect. The effect of desflurane on time to peak force and peak of the positive force derivative could be related to intramyocardial catecholamine release. At clinically relevant concentrations, desflurane, sevoflurane, and isoflurane did not modify isometric relaxation.     

Comparison of end-systolic pressure-length relations and preload recruitable stroke work as indices of myocardial contractility in the conscious and anesthetized, chronically instrumented dog

Development of an index of myocardial contractility that is both load independent and easily quantified in vivo has been a difficult task. Recently, three measures of contractile state have been advocated that appear to fulfill these requirements: the end-systolic pressure-length relationship (ESPLR), the ESPLR area, and regional preload recruitable stroke work (PRSW). Because the effects of halothane and isoflurane on these indices of contractility have yet to be studied, the purpose of this investigation was to compare the effects of these volatile anesthetics on contractile function as evaluated via these techniques in chronically instrumented dogs. Because autonomic nervous system tone substantially influences systemic hemodynamics in vivo, experiments were performed in the presence of pharmacologic blockade of the autonomic nervous system. Four groups comprised the 36 experiments that were performed with nine dogs. Following inhalational induction, the dogs were maintained on 1.5 MAC and 2 MAC of halothane or isoflurane. Pressure-length loops were generated after 1 h of equilibration using preload reduction via partial inferior vena caval occlusion or afterload augmentation by a phenylephrine infusion. The PRSW and ESPLR were then calculated, respectively. Slope and length intercept variables obtained from the ESPLR failed to significantly change from control with increasing levels of anesthetic depth despite substantial decreases in other indices of contractility. However, combination of slope and length intercept parameters into the ESPLR area model proved to be a sensitive and easily calculable measure of depressed myocardial function. Similarly, regional PRSW slope precisely reflected changes in contractile state when halothane (62 +/- 10 for control to 30 +/- 6 erg.cm-2.10(-3).mm-1 at 2 MAC) or isoflurane (83 +/- 14 for control to 55 +/- 8 erg.cm-2.10(-3).mm-1 at 2 MAC) were administered. The PRSW slope also demonstrated a significant difference in depressed contractility when equianesthetic concentrations of halothane and isoflurane were compared (63 +/- 7% of control with halothane versus 86 +/- 4% of control with isoflurane at 1.5 MAC; 50 +/- 5% of control with halothane versus 70 +/- 6% of control with isoflurane at 2 MAC). The ESPLR area also accurately demonstrated the differential depression in contractile function suggested by recent in vitro studies when equianesthetic doses of halothane and isoflurane were compared in vivo. Therefore, while ESPLR slope and length intercept variables fail as indices of myocardial contractility, ESPLR area and regional PRSW slope were shown to be useful indicators of contractile state in the conscious and anesthetized dog.     

The effects of volatile anesthetics on calcium regulation by malignant hyperthermia-susceptible sarcoplasmic reticulum.

To clarify the mechanism by which volatile anesthetics initiate malignant hyperthermia (MH), we examined the effect of halothane, isoflurane, and enflurane on Ca2+ uptake and release by sarcoplasmic reticulum vesicles isolated from MH-susceptible (MHS) and normal pig muscle. Clinical concentrations of these anesthetics (0.1-0.5 mM) stimulated sarcoplasmic reticulum ATP-dependent Ca2+ uptake (maximal at approximately 4 mM), whereas 10-20 times the clinical anesthetic concentration inhibited Ca2+ uptake. There was no significant difference between MHS and normal sarcoplasmic reticulum in any aspect of Ca2+ uptake. Ca2+ release from 45Ca(2+)-filled sarcoplasmic reticulum vesicles in a 10(-8) M Ca(2+)-containing medium (pH 7.0) was significantly stimulated at clinical concentrations of all three volatile anesthetics (anesthetic concentration for the 50% stimulation of Ca2+ release = 0.096-0.22 mM); however, the rate constant for Ca2+ release from MHS sarcoplasmic reticulum was in all cases significantly greater than that from normal sarcoplasmic reticulum. Furthermore, 0.5 mM halothane had no effect on Ca2+ release from normal sarcoplasmic reticulum at pH values less than 6.8, although it could still significantly stimulate Ca2+ release from MHS sarcoplasmic reticulum even at pH 6.4; similar results were obtained for isoflurane and enflurane. These studies thus demonstrate that the interaction of volatile anesthetics with the sarcoplasmic reticulum Ca(2+)-release channel is altered in MHS porcine muscle such that the channel may be activated even at a Ca2+ concentration or pH that would be expected to maintain the channel in the closed state.     

Effect of K+ channel blockade with tetraethylammonium on anesthetic-induced relaxation in canine cerebral and coronary arteries.

The mechanism by which volatile anesthetics produce their direct effects on vascular smooth muscle remains unknown. The authors previously reported that volatile anesthetics decrease both Ca2+ and K+ currents, however the role of Ca(2+)-activated K+ channels during the vasorelaxation by anesthetics has not been investigated. The purpose of this study was to determine whether blockade of the K+ channel alters the response to volatile anesthetics. Responses were studied in canine middle cerebral arteries and proximal and distal canine coronary arteries. Vascular rings (2-mm length) were suspended in tissue baths, and isometric tension was recorded. Rings were constricted with 40 mM KCl and prostaglandin F2 alpha (middle cerebral arteries only) and subsequently exposed to enflurane (3.25%), halothane (1.35%), and isoflurane (2.1%). Volatile anesthetics produced vasorelaxation with relative potency in order: enflurane > halothane > isoflurane. The procedure was repeated in the presence of the K+ channel blocker tetraethylammonium chloride (TEA, 20 mM). In all groups of vessels TEA alone elicited either no increase or only a transient increase in tension, however constrictions to both agonists were augmented in the presence of TEA. The presence of TEA significantly augmented anesthetic-induced vasorelaxation in small and large coronary vessels and in middle cerebral arteries. However, this effect was more pronounced in the cerebral as compared to coronary arteries. Constrictions produced in cerebral vessels by 15 microM prostaglandin F2 alpha were comparable with constrictions produced by 5 microM prostaglandin F2 alpha in the presence of TEA. The subsequent relaxant response of these vessels to enflurane was also comparable in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Depression of myocardial contractility in vitro by bupivacaine, etidocaine, and lidocaine

The effects of local anesthetics in depressing myocardial contractility were studied in isolated guinea pig right ventricular papillary muscles. Bupivacaine and etidocaine, 4 and 10 microM, showed reverse frequency-dependent depression of contractility, that is, less significant depression of contractility at higher stimulation frequencies (2-3 Hz) than at lesser frequencies (less than 1 Hz). Lidocaine, 40 microM, demonstrated a similar trend. In contrast, the normal action potential maximum rate of depolarization (Vmax), a measure of sodium channel conductance, was significantly more depressed at 2-3 Hz by bupivacaine and etidocaine than by lidocaine. Consequently, contractile depression could be overcome only at higher stimulation frequencies, at which conduction was depressed. To explore the mechanism of the contractile depression, local anesthetic effects were studied on slow (calcium channel-mediated) action potentials in partially depolarized papillary muscles. Etidocaine and bupivacaine, 4 and 10 microM, and lidocaine, 40 and 100 microM, caused a marked depression of the late-peaking contractile responses, attributed to Ca2+ release from the sarcoplasmic reticulum. In contrast, only 10 microM bupivacaine caused any significant depression of the slow action potential rate of depolarization (to 89% of control), consistent with a possible small depression of Ca2+ entry.     

Comparison of volatile anesthetic actions on intracellular calcium stores of vascular smooth muscle: investigation in isolated systemic resistance arteries

BACKGROUND: Volatile anesthetic actions on intracellular Ca2+ stores (ie., sarcoplasmic reticulum [SR]) of vascular smooth muscle have not been fully elucidated. METHODS: Using isometric force recording method and fura-2 fluorometry, the actions of four volatile anesthetics on SR were studied in isolated endothellum-denuded rat mesenteric arteries. RESULTS: Halothane (> or = 3%) and enflurane (> or = 3%), but not isoflurane and sevoflurane, increased the intracellular Ca2+ concentration ([Ca2+]i) in Ca2+-free solution. These Ca2+-releasing actions were eliminated by procaine. When each anesthetic was applied during Ca2+ loading, halothane (> or = 3%) and enflurane (5%), but not isoflurane and sevoflurane, decreased the amount of Ca2+ in the SR. However, if halothane or enflurane was applied with procaine during Ca2+ loading, both anesthetics increased the amount of Ca2+ in the SR. The caffeine-induced increase in [Ca2+], was enhanced in the presence of halothane (> or = 1%), enflurane (> or = 1%), and isoflurane (> or = 3%) but was attenuated in the presence of sevoflurane (> or = 3%). The norepinephrine-induced increase in [Ca2+], was enhanced only in the presence of sevoflurane (> or = 3%). Not all of these anesthetic effects on the [Ca2+]i were parallel with the simultaneously observed anesthetic effects on the force. CONCLUSIONS: In systemic resistance arteries, the halothane, enflurane, isoflurane, and sevoflurane differentially influence the SR functions. Both halothane and enflurane cause Ca2+ release from the caffeine-sensitive SR. In addition, both anesthetics appear to have a stimulating action on Ca2+ uptake in addition to the Ca2+-releasing action. Halothane, enflurane, and isoflurane all enhance, while sevoflurane attenuates, the Ca2+-induced Ca2+-release mechanism. However, only sevoflurane stimulates the inositol 1,4,5-triphosphate-induced Ca2+ release mechanism. Isoflurane and sevoflurane do not stimulate Ca2+ release or influence Ca2+ uptake.     

The effects of volatile anesthetics on spontaneous contractility of isolated human pregnant uterine muscle: a comparison among sevoflurane, desflurane, isoflurane, and halothane

We examined the effects of equianesthetic concentrations of sevoflurane, desflurane, isoflurane, and halothane on the spontaneous contractility of isolated human pregnant uterine muscles. We also determined if their action was related to potassium channels. Uterine specimens were obtained from normal full-term pregnant women undergoing elective lower-segment cesarean delivery. Longitudinal muscle strips were mounted vertically in tissue chambers. Their isometric tension was recorded while they were exposed to 0.5-3 minimum alveolar concentration (MAC) of volatile anesthetics in the absence and presence of the high conductance calcium-activated potassium channel blocker, tetraethylammonium, or the adenosine triphosphate-sensitive potassium channel (K(ATP))-blocker, glibenclamide. The anesthetics examined produced a dose-dependent depression of contractility. The inhibitory potency of sevoflurane and desflurane was comparable to, whereas that of isoflurane was smaller than, that of halothane: concentrations causing 50% inhibition of the contractile amplitude (ED(50)) were 1.72, 1.44, 2.35, and 1.66 MAC (P < 0.05), respectively. Tetraethylammonium and glibenclamide did not affect the uterine response to the anesthetics, except for glibenclamide, which attenuated the response to isoflurane. These results indicate that the volatile anesthetics have inhibitory effects on the contractility of the human uterus. The inhibitory effect of isoflurane may in part be mediated through activation of K(ATP) channels.     

Effects of nitrous oxide and isoflurane on the L-type calcium current of rabbit ventricular myocytes and their modulation by beta-adrenoceptor stimulation

BACKGROUND: We compared the effects of nitrous oxide (N2O) plus isoflurane with equianesthetic isoflurane alone on the L-type calcium current (I(Ca,L)), and also investigated their modulation of beta-adrenoceptor stimulation. METHODS: I(Ca,L) was recorded from enzymatically isolated rabbit ventricular myocytes using the whole-cell patch clamp technique. Ventricular myocytes were exposed to prepluses of -40 mV from a holding potential of -80 mV and then to +50 mV in 10 mV increments and thereafter the depolarization pulses that acquire peak currents were applied every 10 seconds. The changes in I(Ca,L) were measured in exposure to experimental gases of 1 MAC:1) 0.5% isoflurane and N2O:O2 (2:1) (I-N20) and 2) 1.15% isoflurane and N2:O2,(2:1) (I-N2). RESULTS: I-N2O and I-N2 depressed the peak I(Ca,L) by 15.6 +/- 9.2 and 14.6 +/- 8.1%, respectively. In the presence of 1 microM isoproterenol or 10 microM forskolin, the depression by I-N20 was significantly suppressed, but not by I-N2. CONCLUSIONS: The results show that I-N2O and I-N2 depressed I(Ca,L) to a similar degree without beta-adrenoceptor stimulation. The depression by I-N2O, however, was modulated by beta-adrenoceptor stimulation. Beta-adrenoceptor stimulation was thus found to modulate the effect of N2O combined with isoflurane rather than equianesthetic isoflurane alone.     

Comparison of the systemic and coronary hemodynamic actions of desflurane, isoflurane, halothane, and enflurane in the chronically instrumented dog

The systemic and coronary hemodynamic effects of desflurane were compared to those of isoflurane, halothane, and enflurane in chronically instrumented dogs. Since autonomic nervous system function may significantly influence the hemodynamic actions of anesthetics in vivo, a series of experiments also was performed in the presence of pharmacologic blockade of the autonomic nervous system. Eight groups comprising a total of 80 experiments were performed on 10 dogs instrumented for measurement of aortic and left ventricular pressure, the peak rate of increase of left ventricular pressure (dP/dt), subendocardial segment length, coronary blood flow velocity, and cardiac output. Systemic and coronary hemodynamics were recorded in the conscious state and after 30 min equilibration at 1.25 and 1.75 MAC desflurane, isoflurane, halothane, and enflurane. Desflurane (+79 +/- 12% change from control) produced greater increases in heart rate than did halothane (+44 +/- 12% change from control) or enflurane (+44 +/- 9% change from control) at 1.75 MAC. Desflurane preserved mean arterial pressure to a greater degree than did equianesthetic concentrations of isoflurane. This result was attributed to a smaller effect on peripheral vascular resistance as compared to isoflurane and greater preservation of myocardial contractility as evaluated by peak positive left ventricular dP/dt and the rate of increase of ventricular pressure at 50 mmHg (dP/dt50) compared to other volatile anesthetics. Increases in diastolic coronary blood flow velocity (+19 +/- 6 and +35 +/- 12% change from control at 1.75 MAC, respectively) and concomitant decreases in diastolic coronary vascular resistance (-41 +/- 12 and -58 +/- 6% change from control at 1.75 MAC, respectively) were produced by desflurane and isoflurane. In the presence of autonomic nervous system blockade, the actions of desflurane and isoflurane were nearly identical with the exception of coronary vasodilation. After autonomic nervous system blockade, isoflurane increased coronary blood flow velocity, but desflurane did not. Furthermore, both desflurane and isoflurane continued to produce less depression of myocardial contractility than did halothane and enflurane. In summary, at equianesthetic concentrations, desflurane and isoflurane produced similar hemodynamic effects; however, in the absence of drugs that inhibit autonomic reflexes, desflurane had less negative inotropic activity and produced less decrease in arterial pressure. The coronary vasodilator actions of desflurane and isoflurane within the limitations of this model were not similar. When the increase in heart rate and rate-pressure product produced by desflurane were prevented in dogs with autonomic nervous system blockade, desflurane produced no change in coronary blood flow velocity.     

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)