Effects of halothane, isoflurane and sevoflurane on calcium-related contraction in porcine coronary arteries

Background: Volatile anaesthetics have a direct inhibitory effect upon epicardial coronary arterial smooth muscles (1–4). The site and mode of their action at the cellular level need to be clarified, which was the purpose of our study. The present investigation attempted to answer the question in what way volatile anaesthetics influence Ca²⁺-related contraction in isolated porcine epicardial coronary to understand their intracellular mechanism. Methods: Isolated helical strips of porcine epicardial coronary artery without endothelium were suspended for isotonic contraction recordings in Krebs-Ringer's solution. 9.4×10^-2 MK+, 2.5×10^-1 M Ca²⁺-induced shortening of the strips was regarded as the reference value (100%). After incubation in Ca²⁺-free solution with 10^-3 M ethlene glycol bis (β-aminoethyl ether)-N, N-tetraacetic acid (EGTA) for 60 minutes, the muscle strips were exposed to increasing Ca²⁺ concentrations (10^-4-10^-2) either in the presence or absence of 1.5 or 2.5 minimum alveolar concentration (MAC) halothane, isoflurane or sevoflurane, with 9.4×10^-2 M K⁺ bath solution. Results: All three drug groups produced apparent biphasic effects with a cumulative increase of Ca²⁺ concentration compared with control groups. An initial increase at low Ca²⁺ concentration was followed by a decrease of Ca²⁺-activated contractions. Isoflurane affected Ca²⁺-induced contraction significantly more than halothane and sevoflurane. Conclusions: The results imply that volatile anaesthetics influence Ca²⁺-dependent activity of coronary smooth muscle by complex mechanisms, which involve promotion of intracellular Ca²⁺ release and other mechanisms that alter sensitivity to calcium.     

Dose effect of sevoflurane and isoflurane anesthetics on cortical blood flow during controlled hypotension in the pig

BACKGROUND: The ability of the brain to preserve adequate cerebral blood flow (CBF) during alterations in systemic perfusion pressure is of fundamental importance. At increasing concentrations, isoflurane and sevoflurane have been known to alter CBF, which may be disadvantageous for patients with increased intracranial pressure. The aim was to examine the effects of isoflurane and sevoflurane at increasing minimum alveolar concentrations (MAC) on CBF, during controlled hypotension. METHODS: We studied eight pigs during variations in perfusion pressure induced by caval block (100, 60, 50, and 40 mmHg) under normocapnia. CBF was measured locally in a defined area (4 x 5 measurement points covering 1 cm(2)) of the motor cortex using laser Doppler perfusion imaging. Physiological variables, assessed by analysis of arterial O(2) and CO(2), hemoglobin and hematocrit, were controlled. CBF was measured during propofol (10 mg x kg(-1)x h(-1)) and fentanyl (0.002 mg x kg(-1)x h(-1)) anesthesia, and then during anesthesia with either isoflurane or sevoflurane (given in random order) at increasing MAC (0.3-1.2). After a washout period, the measurements were repeated with the other gas. RESULTS: CBF was significantly higher in the cortex during normotensive (control) settings, MAP approximately 100 mmHg, compared with during hypotension (MAP 40-60 mmHg). Neither different anesthetic nor MAC or local measurement sites were found to influence CBF at any perfusion pressure. CONCLUSION: In this experimental model, the effect of hypotension on CBF was not altered by the anesthetics used [isoflurane, sevoflurane (MAC 0.3-1.2) or propofol (10 mg x kg(-1)x h(-1))]. In this aspect (cortical tissue perspective), these volatile agents appear as suitable as propofol for neurosurgical anesthesia for patients at risk.     

Secretory activity of the coronary artery endothelial cells in conditions of the peritoneal dialysis

IntroductionEndothelial dysfunction is frequent in patients treated with peritoneal dialysis and may lead to cardiac complications. We evaluated the effect of effluent dialysates and serum on the function of coronary artery endothelial cells (CAEC).MethodsHuman CAEC in in vitro culture were exposed to serum and dialysates from 24 patients treated with continuous ambulatory peritoneal dialysis (CAPD) and secretion of interleukin-6 (IL6), von Willebrand factor (vWF), tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) were measured. Modulation of the secretory activity of CAEC by Sulodexide, mixture of glycosaminoglycans: heparin sulfate and dermatan sulfate, was studied.ResultsSerum from CAPD patients stimulated synthesis of IL6 (+93%), vWF (+18%), and PAI-1 (+20%) and did not change t-PA secretion in CAEC. Dialysates stimulated secretion of IL6 (+89%), vWF (+29%), and PAI-1 (+31%) and did not change t-PA synthesis. Dialysates collected in 12 patients after 6 months more strongly stimulated synthesis of IL6 (+37%) and PAI-1 (+7%). Sulodexide suppressed the secretory activity of CAEC stimulated by the studied sera: IL6 (–38%), vWF (–19%), t-PA (–13%), and PAI-1 (–12%).ConclusionsSerum and the dialysate from CAPD patients induce inflammatory and prothrombotic reaction in coronary arterial endothelial cells. The general pattern of the observed effects for serum and dialysates was similar but the intensity of the effects was not identical. Sulodexide reduced these effects.     

A comparison of the inhibitory effects of four volatile anaesthetics on the metabolism of chlorzoxazone, a substrate for CYP2E1, in rabbits

Background: Halothane inhibits in vitro and in vivo activity of cytochrome P-450 (CYP) 2E1. There are several fluorinated volatile anaesthetics besides halothane, and most of them are defluorinated by CYP2E1. It is unclear whether other fluorinated anaesthetics inhibit the in vivo activity of CYP2E1.
Methods: We compared the inhibitory effects of therapeutic concentrations of four inhalational anaesthetics, halothane, enflurane, isoflurane, and sevoflurane, on chlorzoxazone metabolism in rabbits receiving artificial ventilation.
Results: All four inhalational anaesthetics decreased arterial blood pressure and increased plasma chlorzoxazone concentration. However, no significant differences in the plasma chlorzoxazone concentration were found between the four anaesthetics. The estimated chlorzoxazone clearance increased after beginning inhalation with all four agents, but no significant difference in clearance was noted between agents.
Conclusions: At therapeutic concentrations, the in vivo inhibitory effect on chlorzoxazone metabolism was similar for all four inhalational anaesthetics examined, even though their chemical characteristics and extent of hepatic metabolism differ considerably.     

Adverse airway events during brief nasal inhalations of volatile anaesthetics: the effect of humidity and repeated exposure on incidence in volunteers preselected by response to desflurane

Twelve volunteers known to have airways that responded adversely to 2.0 MAC desflurane were recruited. Each volunteer inhaled three single breaths of each of 0.5, 1.0 and 2.0 MAC of sevoflurane, halothane, isoflurane, desflurane and balance air, with breaths of air between, whilst breathing nasally through a face mask attached to one of three filters that provided three different levels of humidification. The incidence of any adverse airway events was recorded. The anaesthetic inhaled significantly affected the incidence of adverse airway events (p < 0.001), with the least to most irritant being sevoflurane, halothane, isoflurane and desflurane. Increasing the concentration of anaesthetic also significantly increased the incidence of adverse airway events (p < 0.001). The filter used, and hence the level of humidification, did not affect the incidence of adverse airway events (p = 0.09), but repeated exposure caused a significant reduction in the incidence of adverse airway events (p < 0.001).     

S(+)-ketamine, but not R(-)-ketamine, reduces postischemic adherence of neutrophils in the coronary system of isolated guinea pig hearts.

Polymorphonuclear neutrophils (PMN) play a crucial role in the initiation of reperfusion injury. In a previous study, we found that ketamine reduced the postischemic adherence of PMN to the intact coronary system of isolated guinea pig hearts. Because ketamine is a racemic mixture (1:1) of two optical enantiomers, we looked for possible differences in action between the stereoisomers. Seventy-six guinea pig hearts were perfused in the "Langendorff" mode under conditions of constant flow (5 mL/min) using modified Krebs-Henseleit buffer. After 15 min of global warm ischemia, freshly isolated human PMN (10(6)) were infused as a bolus into the coronary system during the second minute of reperfusion. PMN adhesion was expressed as the numeric difference between PMN recovered in the effluent and those applied. Series A hearts received 5 microM S(+), 5 microM R(-), or 10 microM racemic ketamine starting 20 min before ischemia and during reperfusion. In Series B hearts, 10 microM nitro-L-arginine, an inhibitor of NO synthase, was added to the perfusate. In Series C, PMN were preincubated for 15 min with 5 microM S(+)- or R(-)-ketamine. Coronary vascular leak was assessed by measuring the rate of formation of transudate on the epicardial surface. Ischemia/reperfusion without anesthetics increased coronary PMN adherence from 25.5% +/-2.3% (basal) to 35.3%+/-1.5% of the number applied. S(+)-ketamine reduced postischemic adherence in each series (A, 25.5%+/-5.1%; B, 22.5%+/-1.7%; C, 25.3%+/-7.7%), as did racemate (A, 26.4%+/-3.7%). Although 5 microM R(-)-ketamine had no effect on adhesion (A, 30.5%+/-6.7%; B, 34.3%+/-5.1%; C, 34.3%+/-4.3%), it significantly increased vascular leak in the presence of NOLAG. These findings indicate stereoselective differences in biological action between the two ketamine isomers: S(+)-ketamine inhibited PMN adherence, R(-)-ketamine worsened coronary vascular leak in reperfused isolated hearts. IMPLICATIONS: In this study, we demonstrated stereoselective differences in the biologic action of the two ketamine isomers in an animal model of myocardial ischemia. Polymorphonuclear neutrophil adherence to the coronary vasculature after ischemia was inhibited by S(+)-ketamine, whereas R(-)-ketamine increased coronary vascular fluid leak.     

Comparison of the direct effects of sevoflurane,isoflurane and halothane on isolated canine coronary arteries

We have demonstrated previously, using dog epicardial arteries of different sizes, that isoflurane, like adenosine, is preferentially a small coronary artery dilator, whereas halothane, like nitroglycerin, is a large artery dilator. The present study was designed to compare the direct effects of sevoflurane with those of isoflurane and halothane. Proximal large coronary arteries with an outer diameter (o.d.) of 2.5–3.2 mm and distal small arteries of 0.6–0.9 mm o.d. were isolated from dogs and then cut into vascular rings. They were precontracted with KCl (20 mM), and their relaxant responses to anaesthetics were compared relative to the maximal responses induced by papaverine. Sevoflurane, halothane and isoflurane (1–3 human MAC) induced dose-dependent relaxation of these arteries. The relaxant response to sevoflurane did not differ between large and small arteries. However, the relaxant response of the large arteries to halothane (1.5–2.3%) was greater than that of small arteries (P < 0.01) and the response of small arteries to isoflurane (3.5%) was greater than that of large arteries (P < 0.05). In large arteries, the potency of the relaxant effect at equivalent human MAC could be ranked as halothane ≥ sevoflurane > isoflurane, and, in small epicardial arteries as isoflurane > sevoflurane ≫ halothane. We conclude that, unlike isoflurane, sevoflurane is not a preferential dilator of small coronary arteries. Nous avons déjà démontré sur des artères canines épicardiques de différents calibres, que l’isoflurane, comme l’adénosine est un dilatateur préférentiel des petites artères coronaires, alors que l’halothane, comme la nitroglycérine, est un dilatateur des grosses artères. L’étude présente vise à comparer les effets directs du sévoflurane avec ceux de l’isoflurane et de l’halothane. Chez le chien, on isole et sectionne en anneaux de grosses artères coronaires d’un diamètre externe de 2,5 à 3,2 mm et des petites artères coronaires distales de 0,6 à 0,9 mm. Elles sont préalablement contractées avec du KCl (20 mM) et leurs propriétés relaxantes en présence d’anesthésiques sont comparées à la réponse maximale provoquée par la papavérine. Il n’y a pas de différence entre le sévoflurane, l’halothane et l’isoflurane (MAC 1–3 humain); ils provoquent tous une relaxation artérielle qui dépend de la dose. L’effet relaxant du sévoflurane est identique que ce soit sur les grosses ou les petites artères. Cependant, la relaxation des grosses artères en réponse à l’halothane (1,5–2,3%) est plus importante que celle des petites artères (P < 0,01) et la réponse des petites artères à l’isoflurane (3,5%) est plus marquée que celle des grosses artères (P < 0,05). Pour les grosses artères, la puissance de l’effet relaxant à un MAC humain équivalent pourrait être classifiée dans l’ordre: halothane ≥ sévoflurane > isoflurane; et sur les petites artères épicardiques ainsi: isoflurane > sévoflurane ≫ halothane. Nous concluons que contrairement à l’isoflurane, le sévoflurane n’est pas un dilatateur préférentiel des petites artères coronaires.     

Contractile force and resting tension in the presence of halothane and increased extracellular potassium or decreased extracellular pH in isolated guinea pig atria

To gain a better understanding of the direct actions of halothane on myocardial function in ischaemia, we studied the effects of increasing extracellular potassium concentration and decreasing extracellular pH (acidosis), alone or in combination with halothane, on the contractile force and resting tension in isolated atria. Guinea pig left atria were superfused with Tyrode’s solution and stimulated at 1 Hz. Isometric contractile force and resting tension were measured using a force displacement transducer. Perfusate potassium concentrations were increased from 5.4 mmol · L⁻¹ to either 8.1 mmol · L⁻¹ or 10.8 mmol · L⁻¹ by adding KCl to the standard Tyrode’s solution, and its pH was decreased from 7.4 to either 7.0 or 6.5 by decreasing bicarbonate. In standard Tyrode’s solution (potassium 5.4 mmol · L⁻¹, pH 7.4), halothane 0.5–2% reduced contractile force in a dose-dependent manner (P < 0.05); the effective concentration of halothane for 50% inhibition of contractile force (IC₅₀) was 1.3%. Both increasing extracellular potassium and decreasing extracellular pH decreased the contractile force in a potassium-or pH-dependent fashion. The negative inotropism of halothane (1%) was not altered by increasing potassium concentrations, whereas 1% halothane caused a greater decrease in contractile force at pH 6.5 than at pH 7.4. Halothane (1%) enhanced the acidosis (pH 6.5)-induced increases in resting tension. Arrhythmias were produced in one of eight preparations during acidosis, while four of eight preparations demonstrated arrhythmias during acidosis in the presence of halothane. These data suggest that acidosis and halothane may have a synergistic interaction on the contractile force and resting tension of the atria. The increase in resting tension observed during acidosis/ halothane conditions suggests than an increase in cytosolic calcium is associated with these synergistic interactions between acidosis and halothane. Pour mieux comprendre l’action direct de l’halothane sur la fonction myocardique pendant l’ischémie, nous avons étudié les effets de l’augmentation du potassium extracellulaire et de la diminution du pH extracellulaire (acidose), seuls ou en association avec l’halothane, sur la force contractile et la tension de repos d’oreillettes isolées. Des oreillettes gauches de cobaye furent perfusées avec une solution de Tyrode et stimulées à 1 Hz. La force contractile isométrique et la tension de repos ont été mesurées avec un transducteur de force de déplacement. Les concentrations de potassium perfusées ont été augmentées de 5,4 mmol · L⁻¹ à 8,1 mmol · L⁻¹ ou à 10,8 mmol · L⁻¹ par l’ajout de KCl à la solution standard de Tyrode, et son pH abaissé de 7,4 à 7,0 ou 6,5 par baisse des bicarbonates. Avec la solution standard de Tyrode (potassium 5,4 mmol · L⁻¹, pH 7,4), l’halothane (0.5–2%) diminue la force contractile proportionnellement à la dose (P < 0,05); la concentration efficace d’halothane requise pour produire une inhibition de 50% de la force contractile (IC_5O) a été de 1,3%. L’augmentation du potassium extracellulaire et la diminution du pH extracellulaire réduisent toutes les deux la force contractile proportionnellement au potassium ou au pH. L’inotropisme négatif de l’halothane (1%) n’est pas modifié par l’augmentation de la concentration de potassium alors que l’halothane produit une diminution plus importante de la force contractile à un pH de 6,5 que de 7,4. L’halothane (1%) exagère l’augmentation de la tension de repos induite par l’acidose (pH 6,5). Des arrythmies sont apparues sur une des huit préparations pendant l’acidose en présence d’halothane. Ces données suggèrent que l’acidose et l’halothane pourraient avoir une activité synergique sur le force contractile et la tension de repos des oreillettes. L’augmentation de la tension de repos observée pendant l’acidose combinée à l’halothane suggère l’association d’une augmentation du calcium cytosolique avec des interactions synergiques entre l’acidose et l’halothane.