Philippe R. Housmans

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

Background:The aim of this study was to investigate propofols 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. Propofols effects were evaluated in a preparation in which the sarcoplasmic reticulum function was impaired by ryanodine. The effects of propofols solvent, intralipid, on myocardial contractility, relaxation, and the intracellular Ca++ transient also were examined. Results:Propofol, at concentrations of 10 μM or greater, decreased contractility and, at concentrations of 30 μM 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 μM propofol in [Ca++]o>2.25 mM did not differ, which suggests that propofol does not alter myofibrillar Ca++ sensitivity. After inactivatlon of sarcoplasmic reticulum Ca++ release with 1 μM 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, propofols relative negative inotropic effect did not differ from that in control muscles not exposed to ryanodine. Propofols 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 propofols action is attributable to inhibition of transsarcolemmal Ca++ influx.

Comparative effects of halothane, enflurane, and isoflurane at equipotent anesthetic concentrations on isolated ventricular myocardium of the ferret. II: Relaxation

The effects of halothane, enflurane, and isoflurane on myocardial relaxation were compared in papillary muscles of the right ventricle of adult male ferrets at 30° C. The sensitivity of cardiac relaxation to the loading conditions was determined by examining the time course of relaxation before, during, and after exposure to incremental concentrations of halothane (n = 9 muscles), enflurane (n = 9 muscles), and isoflurane (n = 9 muscles) in steps of 0.25 MAC up to 1.5 MAC of halothane and of enflurane and up to 2.0 MAC of isoflurane. Load sensitivity of relaxation was quantified by comparing force and time coordinates at the onset of the isometric relaxation phase in several afterloaded isotonic twitch contractions with relaxation of the isometric twitch. Load sensitivity of relaxation, which is of particular benefit during early rapid filling of the heart, was decreased in a dose-dependent reversible fashion by halothane, enflurane, and, to a lesser extent, by isoflurane. These anesthetics abbreviated isometric relaxation, yet prolonged the time course of muscle lengthening which is suggestive of an impairment of calcium uptake by the sarcoplasmic reticulum and of a decrease in calcium sensitivity of the contractile proteins.

Effects of dexmedetomidine on contractility, relaxation, and intracellular calcium transients of isolated ventricular myocardium

The effects of the highly selective alpha 2-adrenoceptor agonist dexmedetomidine on contractility, relaxation, and the intracellular Ca2+ transients of isolated ventricular myocardium were studied in isolated right ventricular papillary muscles obtained from reserpinized ferrets. Dexmedetomidine (10(-10)-10(-5) M) did not alter amplitude and time variables of isometric, isotonic and zero-load-clamped twitches, except for a slight increase in maximal isotonic relaxation rate at 10(-5) M. Dexmedetomidine (10(-8)-10(-5) M) caused no changes in the intracellular Ca2+ transient detected with aequorin. These results suggest that dexmedetomidine has no intrinsic myocardial contractile effects.

Mechanism of the positive inotropic effect of ketamine in isolated ferret ventricular papillary muscle.

Ketamine is a cardiovascular stimulant through its sympathomimetic effects; however, its direct inotropic effect has been reported as positive in rat and negative in rabbit ventricular myocardium. This study reexamines the effect of ketamine on the contractile properties of mammalian ventricular myocardium. In isolated, electrically stimulated ferret right ventricular papillary muscles, the authors assessed the inotropic effect of ketamine (10(-6) M to 3 x 10(-4) M in 0.5 log M increments) alone and in various pharmacologic conditions designed to delineate ketamines site(s) of action. Ketamine exerted a positive inotropic effect that was maximal at 10(-4) M. Bupranolol (10(-7) M) abolished this positive inotropic effect, whereas phentolamine (10(-6) M) did not. Depletion of norepinephrine stores by reserpine also eliminated ketamines positive inotropic effect, indicating that ketamine caused indirect activation of the beta-adrenoceptor. Ketamine did not exert a positive inotropic effect in the presence of simultaneous inhibition of neuronal norepinephrine uptake with desmethylimipramine (DMI) (5 x 10(-6) M) and extraneuronal uptake with corticosterone (5 x 10(-5) M). It is likely that ketamines action is to inhibit norepinephrine uptake at the neuroeffector junction rather than to augment norepinephrine release. In the presence of corticosterone, ketamine exerted a smaller positive inotropic effect than that seen with ketamine alone. Ketamine produced a small increase in force development in the presence of DMI, but this did not reach statistical significance. Inhibition of neuronal catecholamine uptake appears to be the predominant mechanism of ketamines positive inotropic effect.

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 ketamines intrinsic negative inotropic effect. Methods:The authors analyzed the effects of ketamine after β-adrenoceptor blockade on variables of contractility and relaxation, and on the free intracellular Ca++ transient detected with the Ca++-regulated photoprotein aequorin. Ketamines 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 ≥ 3.3 × 10−3 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 ketamines relative negative inotropic effect was not different from that in control muscles not exposed to ryanodine. Furthermore, a 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 ketamines action is caused by inhibition of transsarcolemmal Ca++ influx.

Minimum Alveolar Concentrations (MAC) of Halothane, Enflurane, and Isoflurane in Ferrets

The minimum alveolar concentrations (MAC) of isoflurane, enflurane, and halothane were determined in adult male ferrets during controlled ventilation at normothermia (37°C). Mean (±SD) MAC values for isoflurane (n = 8), enflurane (n = 8), and halothane (n = 8) at 37°C were 1.52 ± 0.10%, 1.99 ± 0.18%, and 1.01 ± 0.10%, respectively. Halothane MAC was reduced by 26% in the presence of 70% N2O. At 29.9 ± 0.2°C, the mean MAC value of halothane (0.85 ± 0.11%) was 16% less than MAC at 37°C. The relative potencies of the halogenated anesthetics are of the same order as those reported for large animals and for humans.

Mechanism of the Direct, Negative Inotropic Effect of Etomidate in Isolated Ferret Ventricular Myocardium

BackgroundEtomidate 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 etomidates 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. MethodsThe authors analyzed the effects of etomidate after β-adrenoceptor blockade on variables of contractility and relaxation, and on the free intracellular Ca++ transient detected with the Ca++-regulated photoprotein aequorin. Etomidates 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. ResultsAt concentrations ≥ 3 μg/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 μg/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 etomidates relative negative Inotropic effect was not different from that in control muscles not exposed to ryanodine. Etomidate 10 μg/ml decreased contractility in frog ventricular myocardium. ConclusionsThese 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 etomidates 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.

Role of transsarcolemmal Ca2+ entry in the negative inotropic effect of nitrous oxide in isolated ferret myocardium

The purpose of this study was to investigate the effects of nitrous oxide (N2O) on transsarcolemmal calcium influx in isolated ferret right ventricular myocardium. Using a range of loading conditions, papillary muscles were equilibrated in 50% nitrogen (N2) or 50% N2O in oxygen in the presence and absence of ryanodine, a specific inhibitor of calcium release from the sarcoplasmic reticulum. After equilibration in 50% N2O or 50% N2 in oxygen, peak developed force, peak isotonic shortening, and maximal unloaded velocity of shortening were compared in the presence and absence of 10−6 M ryanodine. Fifty percent N2O caused a significant reduction in contractility in control conditions and a further significant reduction in contractile variables in the presence of 10−6 M ryanodine. We conclude that at least part of the negative inotropic effect of N2O is due to an inhibition of transsarcolemmal calcium influx.

Valvular Heart Disease

Valve surgery is very different from coronary artery bypass grafting (CABG). Over the natural history of valvular heart disease (VHD), the physiologic characteristics change markedly and, in the operating room, physiologic and hemodynamic conditions are quite variable and are readily influenced by anesthetic interventions. For some types of valve lesions it can be relatively difficult to predict preoperatively how the heart will respond to the altered loading conditions associated with valve repair or replacement. It is essential to understand the natural history of each of the major adult-acquired valve defects and how the pathophysiologic conditions evolve. Surgical decision making regarding valve repair or replacement must also be understood, because a valve operated on at the appropriate stage of its natural history will have a good and more predictable outcome than one operated on at a late stage, when the perioperative result can be quite poor. Because pathophysiologic conditions are dynamic and differ significantly among valve lesions, understanding the physiology and natural

The Effects of Halothane, Enflurane, and Isoflurane on the Length—Tension Relation of the Isolated Ventricular Papillary Muscle of the Ferret

The effects of halothane, enflurane, and isoflurane on the length-tension relation were investigated in papillary muscles of the right ventricle of adult male ferrets at 30 degrees C. Isometric twitch contractions were obtained at lengths ranging from the shortest length yielding the greatest active force development under isometric conditions (Lmax) to 86% of Lmax, in two consecutive protocols: first in [Ca2+]o ranging from 0.45 to 2.25 mM, and then in [Ca2+]o 2.25 mM before, during, and after exposure to incremental concentrations of halothane (n = 9 muscles), enflurane (n = 9 muscles), and isoflurane (n = 9 muscles), each in steps of 0.25 MAC to total concentrations up to and including 1.5 MAC. Each of the three anesthetics caused a concentration-dependent decrease in developed force. The relative extent of the negative inotropic effect was not different at various muscle lengths. Because myofibrillar Ca2+ responsiveness (Ca2(+)-affinity of troponin C) decreases at shorter muscle lengths, the results suggest that an alteration in myofibrillar Ca2+ responsiveness by volatile anesthetics is minor relative to the anesthetic-induced decreased intracellular Ca2+ availability in ventricular myocardium.