Inhibitory Effect Of Isoflurane Research Articles

MiR-652-3p Suppressed the Protective Effects of Isoflurane Against Myocardial Injury in Hypoxia/Reoxygenation by Targeting ISL1.

This research is concentrated on investigating the role and mechanism of miR-652-3p in the protective effects of isoflurane (ISO) against myocardial ischemia-reperfusion (I/R) injury. H9c2 cells underwent pretreatment with varying concentrations of ISO, and subsequently, a hypoxia/reoxygenation (H/R) model was constructed. The levels of miR-652-3p, ISL LIM homeobox 1 (ISL1), and inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α) were evaluated through reverse transcription polymerase chain reaction (RT-qPCR). Enzyme-linked immunosorbent assay was employed to investigate concentrations of myocardial injury markers, such as creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI). Cell counting kit-8 was used to evaluate cell viability, while flow cytometry was utilized to measure apoptosis. Additionally, a dual luciferase reporter assay was conducted to validate the targeting relationship between ISL1 and miR-652-3p. Herein, we confirmed thatthe level of miR-652-3p wasgradually increased with prolonged hypoxia; nevertheless, this increase was suppressed by ISO pretreatment (P < 0.05). Additionally, ISO pretreatment prevented the decrease in cell viability, increase in apoptosis, and overproduction of IL-6, TNF-α, CK-MB, and cTnI induced by H/R (P < 0.05). However, the inhibitory effects of ISO were counteracted by the increased levels of miR-652-3p (P < 0.05). ISL1 is a potential target of miR-652-3p. H/R induction suppressed ISL1 levels compared to the control, but ISO treatment increased its expression (P < 0.05). Overexpression of ISL1 inhibited the elimination of the protective effect of ISO on myocardial damage induced by the elevation of miR-652-3p (P < 0.05). The findings of this research confirm that miR-652-3p attenuated the protective effect of ISO on cardiomyocytes in myocardial ischemia by targeting ISL1.

Sevoflurane and isoflurane inhibit KCl-induced, Rho kinase-mediated, and PI3K-participated vasoconstriction in aged diabetic rat aortas

BackgroundThe mechanism of volatile anesthetics on vascular smooth muscle (VSM) contraction in the setting of diabetes mellitus (DM) remains unclear. The current study was designed to determine the effects of sevoflurane (SEVO) and isoflurane (ISO) on phosphoinositide 3-kinase (PI3K) and Rho kinase (ROCK) mediated KCl-induced vasoconstriction in aged type 2 diabetic rats.MethodsKCl-induced (60 mM) contractions were examined in endothelium-denuded aortic rings from aged T2DM Otsuka Long-Evans Tokushima Fatty (OLETF) rats (65–70 weeks old), control age-matched nondiabetic Long-Evans Tokushima Otsuka (LETO) rats and young Wistar rats (6–8 weeks old). The effects of SEVO or ISO (1–3 minimum alveolar concentration, MAC) on KCl-induced vasoconstriction, as well as those of LY294002 (PI3K inhibitor) and Y27632 (ROCK inhibitor) were measured in aortic rings from the three groups using an isometric force transducer.ResultsKCl induced rapid and continuous contraction of aortic smooth muscle in the three groups, and the contraction was more obvious in OLETF rats.SEVO and ISO inhibited KCl-induced vasoconstriction in a concentration-dependent manner and were suppressed by LY294002 (10 µM) and Y27632 (1 µM). SEVO had a stronger inhibitory effect on the aortas of young Wistar rats than ISO, especially at 2 MAC and 3 MAC (P < 0.05). In aged rats, the inhibitory effect of ISO was stronger than that of SEVO, especially OLETF rats. There was no significant difference in the effects of different concentrations of ISO on arterial contraction among the three groups (P > 0.05). The effects of 1 MAC SEVO on Wistar rats and 3 MAC SEVO on OLETF rats, however, were noticeably and significantly different (P < 0.05).Compared with the control condition, LY294002 and Y27632 had the most noticeable effect on the KCl-induced contraction of aortic rings in OLETF rats (P < 0.01).ConclusionSEVO (3 MAC), ISO (1, 2, 3 MAC), LY294002 and Y27632 have more significant inhibitory effect on the contraction of vascular smooth muscle in aged T2MD rats. The mechanism of SEVO and ISO in vascular tension in T2DM is partly due to changes in PI3K and/or Rho kinase activity.

Altered levels of the 20S proteasome maturation factor Ump1 affect the response of Saccharomyces cerevisiae to the volatile anesthetic isoflurane

Volatile anesthetics have been used in modern medicine for over 160 years, but their sites and mechanisms of action remain unclear. While many effects of these agents are characterized, how these effects relate to the physiological state of anesthesia has not been elucidated. Volatile anesthetics affect all cells and tissues tested, including mammalian, plant, bacterial, and yeast cells. In yeast, these drugs arrest cell division in a manner that parallels their actions in mammals. To gain further insight into the cellular activities of these compounds, genes were isolated that, when overexpressed or deleted from the genome, alter the response of Saccharomyces cerevisiae (budding yeast) to the volatile anesthetic isoflurane. One of the genes we identified is UMP1, which encodes a chaperone required for maturation of the 20S proteasome complex in yeast. Overexpression of UMP1 renders yeast cells more resistant to the growth inhibitory effects of isoflurane, while deletion of the gene renders cells more sensitive than wild type cells. This suggests an important role for the proteasome in responding to volatile anesthetics in yeast, and may provide clues as to how these drugs exert their effects in more complex eukaryotes, including mammals.

Anesthesia-Induced Hypothermia Attenuates Early-Phase Blood-Brain Barrier Disruption but Not Infarct Volume following Cerebral Ischemia.

Blood-brain barrier (BBB) disruption is thought to facilitate the development of cerebral infarction after a stroke. In a typical stroke model (such as the one used in this study), the early phase of BBB disruption reaches a peak 6 h post-ischemia and largely recovers after 8–24 h, whereas the late phase of BBB disruption begins 48–58 h post-ischemia. Because cerebral infarct develops within 24 h after the onset of ischemia, and several therapeutic agents have been shown to reduce the infarct volume when administered at 6 h post-ischemia, we hypothesized that attenuating BBB disruption at its peak (6 h post-ischemia) can also decrease the infarct volume measured at 24 h. We used a mouse stroke model obtained by combining 120 min of distal middle cerebral arterial occlusion (dMCAo) with ipsilateral common carotid arterial occlusion (CCAo). This model produced the most reliable BBB disruption and cerebral infarction compared to other models characterized by a shorter duration of ischemia or obtained with dMCAO or CCAo alone. The BBB permeability was measured by quantifying Evans blue dye (EBD) extravasation, as this tracer has been shown to be more sensitive for the detection of early-phase BBB disruption compared to other intravascular tracers that are more appropriate for detecting late-phase BBB disruption. We showed that a 1 h-long treatment with isoflurane-anesthesia induced marked hypothermia and attenuated the peak of BBB disruption when administered 6 h after the onset of dMCAo/CCAo-induced ischemia. We also demonstrated that the inhibitory effect of isoflurane was hypothermia-dependent because the same treatment had no effect on ischemic BBB disruption when the mouse body temperature was maintained at 37°C. Importantly, inhibiting the peak of BBB disruption by hypothermia had no effect on the volume of brain infarct 24 h post-ischemia. In conclusion, inhibiting the peak of BBB disruption is not an effective neuroprotective strategy, especially in comparison to the inhibitors of the neuronal death signaling cascade; these, in fact, can attenuate the infarct volume measured at 24 h post-ischemia when administered at 6 h in our same stroke model.

NOD2 mediates isoflurane preconditioning-induced protection of myocardial injury

Anesthetic cardioprotection reduces myocardial infarct size following ischemia–reperfusion injury. However, the underlying mechanisms that drive ischemia–reperfusion injury in cardiomyocytes remain unclear. In this study, we report that isoflurane, a commonly used inhaled anesthetic, can protect cardiomyocytes from anoxia/reoxygenation injury by a nucleotide binding oligomerization domain containing 2 (NOD2)-dependent mechanism. The results showed that isoflurane increased cell viability, and decreased autophagosome generation in primary cardiomyocytes under anoxia/reoxygenation conditions. In addition, western blot revealed that isoflurane reduces the expression of NOD2. Overexpression of NOD2 is accompanied by an increased expression of autophagy-related genes, decreased cell viability, and enhanced expression of phosphorylation p38-mitogen-activated protein kinase (p38MAPK), while NOD2 knockdown exerted the opposite effect. Following preconditioning with SB203580, a p38MAPK inhibitor, the inhibitory effect of isoflurane on cardiomyocytes autophagy was further enhanced, which suggests that p38MAPK is involved in the mechanism of cardioprotection provided by isoflurane. These findings reveal a novel mechanism underlying isoflurane-afford protection of myocardial injury.

Reduction of p38 mitogen-activated protein kinase and cyclooxygenase-2 signaling by isoflurane inhibits proliferation and apoptosis evasion in human papillomavirus-infected laryngeal papillomas.

Human laryngeal papilloma (LP) is a human papillomavirus-induced hyperplastic tumor of the respiratory tract, which is characterized by rapid growth and apoptosis resistance. Isoflurane (ISO) inhibits proliferation and elicits apoptosis in cancer cells. The results of the present study found that the mRNA and protein levels of cyclooxygenase-2 (COX2) were higher in LP tissues than in normal laryngeal samples, and prostaglandin E2 (PGE2) production was increased in LP cells, as determined by quantitative polymerase chain reaction, western blot and radioimmunoassay analyses. Notably, the increase in COX2 and PGE2 levels was significantly abrogated in the ISO-treated LP cells. The inhibitory effects of ISO on COX2 expression and activity depended on the inactivation of p38 mitogen-activated protein kinase (MAPK) in LP cells. By inhibiting the COX2 activity of LP cells, ISO treatment markedly suppressed cell viability and proliferation, as determined using Cell Counting Kit-8, flow cytometry and 5-ethynyl-20-deoxyuridine incorporation assays. Furthermore, ISO treatment promoted cell apoptosis, as demonstrated by flow cytometry, nucleosomal fragmentation and caspase-3 activity assays. Collectively, the present results suggest that COX2 is critical in the progression of LP, and ISO is a potential agent for LP therapy by impeding p38 MAPK/COX2 signaling.

The cellular mechanisms underlying the inhibitory effects of isoflurane and sevoflurane on arginine vasopressin-induced vasoconstriction

Arginine vasopressin (AVP) is a potent vasoconstrictor that is sometimes used for the treatment of refractory vasodilatory shock. AVP constricts vascular smooth muscle by increasing both intracellular calcium concentration ([Ca(2+)](i)) and myofilament Ca(2+) sensitivity. However, the modulation of AVP-mediated vasoconstriction by volatile anesthetics remains to be determined. This study investigates the effects of isoflurane and sevoflurane on AVP-induced vasoconstriction and elucidates the underlying mechanisms, with an emphasis on the Ca(2+)-mediated pathways and Ca(2+) sensitization pathways of rat aortic smooth muscle. The effects of isoflurane and sevoflurane on AVP-induced vasoconstriction and on the AVP-induced increase in [Ca(2+)](i) and Rho activity in rat aorta were investigated by isometric force recording, by measuring [Ca(2+)](i) using fluorescence dye, and by Western blotting techniques. Arginine vasopressin (10⁻⁷M) elicited a transient contractile response that was inhibited by isoflurane and sevoflurane in a concentration-dependent manner. AVP (10⁻⁷ M) induced a transient increase in intracellular Ca(2+) concentration ([Ca(2+)](i)). Isoflurane and sevoflurane also inhibited an AVP-induced increase in [Ca(2+)](i) in a concentration-dependent manner. AVP (10⁻⁷ M) increased the Rho activity that was attenuated by 2 minimum alveolar concentration of sevoflurane (P < 0.01), but not by an equipotent concentration of isoflurane. Arginine vasopressin-induced vasoconstriction is mediated by an increase in [Ca(2+)](i) and by the activation of the Rho-Rho kinase pathway in rat aortic smooth muscle. Although both isoflurane and sevoflurane, at clinically relevant concentrations, attenuate AVP-induced contraction, the cellular mechanisms of their inhibitory effects appear to differ.

Role of central neuronal nicotinic receptor in the inhibitory effect of isoflurane on synaptic long-term potentiation in hippocampal slices of rats

To determine effect of central neuronal nicotinic receptor on synaptic long-term potentiation (LTP) in the CA1 area of rats hippocampal slices. Brain slice preparation transverse hippocampal slices were obtained from male Sprague-Dawley rats that were ether-anesthetized and decapitated. The hippocampus was rapidly removed, and slices were prepared in ice-cold artificial cerebrospinal fluid (ACSF), oxygenated with 95% O2 - 5% CO2. Seventy-seven slices were randomly divided into 11 equal groups (n = 7 each): group LTP; group isoflurane 0.125; group isoflurane 0.25; group isoflurane 0.5; group nicotine 0.1; group nicotine 1.0; group nicotine 10.0; group nicotine 1.0 + isoflurane 0.25; group nicotine 10.0 + isoflurane 0.25; group mecamylamine; group mecamylamine + isoflurane 0.125. One recording electrode was positioned in the pyramidal cell layer of the CA1 area of rats hippocampal slices to simultaneously record evoked population spikes (PS). For LTP induction, high-frequency stimulation (HFS) conditioning pulses (100 Hz/s) were applied to the Schaffer collateral-commissural pathway of hippocampus using a bipolar stimulating electrode. The changes of PS amplitude after HFS were analyzed in each group. The PS amplitude of the rats hippocampal slices in group LTP after HFS was significantly increased by (52 +/- 12)% compared with that of pre-HFS indicating the successful induction of LTP. Compared with group LTP, the PS amplitudes decreased significantly in group isoflurane 0.125, 0.25 and 0.5 after HFS (P < 0.01) and increased significantly in group nicotine 1.0 and 10.0 (P < 0.01), but the PS amplitudes in group nicotine 0.1 was not significantly changed after HFS (P > 0.05). The PS amplitudes after HFS in group nicotine 1.0 + isoflurane 0.25 and group nicotine 10.0 + isoflurane 0.25 was dramatically increased compared with the value of group isoflurane 0.25 (P < 0.01), but did not differ significantly from group LTP (P > 0.05). The PS amplitudes after HFS in group mecamylamine has no significant difference compared with the value of group isoflurane 0.125, but it was significantly lower than that in group LTP (P < 0.01). The PS amplitudes after HFS in group mecamylamine + isoflurane 0.125 significantly decreased compared with the value of group isoflurane 0.125 and group LTP (P < 0.05 or P < 0.01). The inhibition of LTP induction may contribute to isoflurane-induced deficits in memory, and the underlying mechanism is involved in the inhibition of nicotinic acetylcholine receptor activation in hippocampus of rats.

The Mechanism Behind the Inhibitory Effect of Isoflurane on Angiotensin II-Induced Vascular Contraction Is Different from That of Sevoflurane

Angiotensin II (Ang II)-induced vascular contraction is mediated both by a Ca(2+)-mediated signaling pathway and a Ca(2+) sensitization mechanism. We recently demonstrated that sevoflurane inhibits the contractile response to Ang II, mainly by inhibiting protein kinase C (PKC) phosphorylation that regulates myofilament Ca(2+) sensitivity, without significant alteration of intracellular Ca(2+) concentration ([Ca(2+)](i)) in rat aortic smooth muscle. The current study was designed to determine the mechanisms by which isoflurane inhibits Ang II-induced contraction of rat aortic smooth muscle. The effects of isoflurane on vasoconstriction, increase in [Ca(2+)](i), and phosphorylation of PKC in response to Ang II (10(-7) M) were investigated, using an isometric force transducer, a fluorometer, and Western blotting, respectively. Ang II elicited a transient contraction of rat aortic smooth muscle that was associated with an increase in [Ca(2+)](i) and PKC phosphorylation. Isoflurane (1.2%-3.5%) inhibited Ang II-induced contraction of rat aortic smooth muscle in a concentration-dependent manner (P < 0.05 at 1.2%, P < 0.01 at 2.3% and 3.5% isoflurane, n = 6). Isoflurane also inhibited elevation of [Ca(2+)](i) in response to Ang II (P < 0.01 at 2.3% and 3.5% isoflurane, n = 6), but failed to affect Ang II-induced phosphorylation of PKC at concentrations up to 3.5% (n = 7). These results suggest that, unlike sevoflurane, the inhibitory effect of isoflurane on Ang II-induced contraction is mainly mediated by attenuation of the Ca(2+)-mediated signaling pathway.

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 Isoflurane on Parasympathetic Vasodilatation in the Rat Submandibular Gland

Volatile anesthetics have been known to suppress parasympathetic reflex vasodilatation in the lower lip and palate. However, in the submandibular gland, little is known about the effects of these anesthetics on the parasympathetic vasodilatation elicited by reflex and direct (i.e., non-reflex) activation of the parasympathetic vasodilator mechanisms. Although both parasympathetic vasodilatations were inhibited by isoflurane in a concentration- and time-dependent manner, the effects of continuous administration of the alpha(1)-adrenoceptor agonist methoxamine were markedly different: The reflex vasodilatation was not affected by methoxamine, while the direct vasodilatation was significantly reduced. Picrotoxin (GABA(A) receptor antagonist) attenuated the inhibitory effect of isoflurane on direct vasodilatation and the systemic arterial blood pressure. These findings suggest that the isoflurane-induced inhibitory effects on direct vasodilatation are produced by a decrease of peripheral vascular tone by GABAergic mechanisms, whereas those on the reflex vasodilatation are produced exclusively by the inhibition of the reflex center.

The vascular relaxing effects of sevoflurane and isoflurane are more important in hypertensive than in normotensive rats

The vascular response to anesthetics is altered in hypertensive patients since the functional and structural integrities of vascular smooth muscle and endothelium are deranged. The effects of anesthetics on angiotensin II (Ang II)-induced changes in vascular tone are not well understood. We investigated the effects of sevoflurane and isoflurane on Ang II-induced vasoconstriction in spontaneously hypertensive rats (SHR). The dose-dependent effects of sevoflurane and isoflurane on the Ang II-induced contraction of aortic rings, in the presence and absence of an intact endothelium, were investigated in normotensive Wistar-Kyoto rats (WKY) and SHR and compared using isometric force transducers. Ang II (10(-9)-10(-6) M) induced a similar transient phasic contraction of endothelium-intact rings from the two rat strains in a dose-dependent manner. Removal of the endothelium augmented the Ang II-elicited phasic contraction, to a greater extent in the SHR group than in the WKY group. Sevoflurane and isoflurane (1-3 minimum alveolar concentration) concentration-dependently inhibited the Ang II-induced contraction of endothelium-intact rings from WKY; an effect that was greatly enhanced following removal of the endothelium. A greater degree of attenuation of the Ang II-induced contraction of both endothelium-intact and -denuded rings by the two anesthetics was observed in the SHR group. The inhibitory effects of isoflurane on the Ang II-induced contraction of aortic rings from both strains appeared to be stronger than that of sevoflurane at equipotent concentrations. Our finding that the inhibitory effects of isoflurane and sevoflurane on Ang II-induced vasoconstriction are enhanced in SHR may, at least in part, account for the anesthesia-induced systemic hypotension frequently seen in hypertensive patients.

The Inhibitory Effects of Isoflurane on Protein Tyrosine Phosphorylation–modulated Contraction of Rat Aortic Smooth Muscle

Tyrosine kinase-catalyzed protein tyrosine phosphorylation plays an important role in initiating and modulating vascular smooth muscle contraction. The aim of the current study was to examine the effects of isoflurane on sodium orthovanadate (Na3VO4), a potent protein tyrosine phosphatase inhibitor-induced, tyrosine phosphorylation-mediated contraction of rat aortic smooth muscle. The Na3VO4-induced contraction of rat aortic smooth muscle and tyrosine phosphorylation of proteins including phospholipase Cgamma-1 (PLCgamma-1) and p44/p42 mitogen-activated protein kinase (MAPK) were assessed in the presence of different concentrations of isoflurane, using isometric force measurement and Western blotting methods, respectively. Na3VO4 (10(-4) m) induced a gradually sustained contraction and significant increase in protein tyrosine phosphorylation of a set of substrates including PLCgamma-1 and p42MAPK, all of which were markedly inhibited by genistein (5 x 10(-5) m), a tyrosine kinase inhibitor. Isoflurane (1.2-3.5%) dose-dependently depressed the Na3VO4-induced contraction (P < 0.05-0.005; n = 8). Isoflurane also attenuated the total density of the Na3VO4-induced, tyrosine-phosphorylated substrate bands and the density of tyrosine-phosphorylated PLCgamma-1 band and p42MAPK band (P < 0.05-0.005; n = 4) in a concentration-dependent manner. The findings of the current study, that isoflurane dose-dependently inhibits both the Na3VO4-stimulated contraction and tyrosine phosphorylation of a set of proteins including PLCgamma-1 and p42MAPK in rat aortic smooth muscle, suggest that isoflurane depresses protein tyrosine phosphorylation-modulated contraction of vascular smooth muscle, especially that mediated by the tyrosine-phosphorylated PLCgamma-1 and MAPK signaling pathways.

Room D, 10/17/2000 9: 00 AM - 11: 00 AM (PS) Inhibitory Effects of Isoflurane and Nonimmobilizing Halogenated Compounds on Neuronal Nicotinic Receptors

<b>Room D, 10/17/2000 9: 00 AM - 11: 00 AM (PS) Inhibitory Effects of Isoflurane and Nonimmobilizing Halogenated Compounds on Neuronal Nicotinic Receptors</b>

Modulation of the Cardiac Sodium Current by Inhalational Anesthetics in the Absence and Presence of β-Stimulation

Cardiac dysrhythmias during inhalational anesthesia in association with catecholamines are well known, and halothane is more "sensitizing" than isoflurane. However, the underlying mechanisms of action of volatile anesthetics with or without catecholamines on cardiac Na channels are poorly understood. In this study, the authors investigated the effects of halothane and isoflurane in the absence and presence of beta-stimulation (isoproterenol) on the cardiac Na+ current (INa) in ventricular myocytes enzymatically isolated from adult guinea pig hearts. A standard whole-cell patch-clamp technique was used. The INa was elicited by depolarizing test pulses from a holding potential of -80 mV in reduced Na+ solution (10 mM). Isoproterenol alone depressed peak INa significantly by 14.6 +/- 1.7% (means +/- SEM). Halothane (1.2 mM) and isoflurane (1.0 mM) also depressed peak INa significantly by 42.1 +/- 3.4% and 21.3 +/- 1.9%, respectively. In the presence of halothane, the effect of isoproterenol (1 microM) was potentiated, further decreasing peak INa by 34.7 +/- 4.1%. The halothane effect was less, although significant, in the presence of a G-protein inhibitor (GDPbetaS) or a specific protein kinase A inhibitor [PKI-(6-22)-amide], reducing peak INa by 24.2 +/- 3.3% and 24 +/- 2.4%, respectively. In combination with isoflurane, the effect of isoproterenol on INa inhibition was less pronounced, but significant, decreasing current by 12.6 +/- 3.9%. GDPbetaS also reduced the inhibitory effect of isoflurane. In contrast, PKI-(6-22)-amide had no effect on isoflurane INa inhibition. These results suggest two distinct pathways for volatile anesthetic modulation on the cardiac Na+ current: (1) involvement of G proteins and a cyclic adenosine monophosphate (cAMP)-mediated pathway for halothane and, (2) a G-protein-dependent but cAMP-independent pathway for isoflurane. Furthermore, these studies show that the inhibition of cardiac INa by isoproterenol is enhanced in the presence of halothane, suggesting some form of synergistic interaction between halothane and isoproterenol.

Isoflurane inhibits nicotinic acetylcholine receptor-mediated 22Na+ influx and muscarinic receptor-evoked cyclic GMP production in cultured bovine adrenal medullary cells

The effects of isoflurane on 22Na+ influx, 45Ca2+ influx, catecholamine secretion and cyclic GMP production induced by three kinds of secretagogue (nicotinic agonists, veratridine and a high concentration of K+) have been investigated using cultured bovine adrenal medullary cells. (1) Isoflurane (1-6%) inhibited catecholamine secretion stimulated by carbachol, nicotine and dimethyl-4-phenylpiperazinium in a concentration-dependent manner. Isoflurane suppressed carbachol-evoked 22Na+ influx and 45Ca2+ influx at concentrations similar to those which suppressed catecholamine secretion. The inhibition of catecholamine secretion by isoflurane was not overcome by increasing the concentration of carbachol. (2) The inhibitory effects of isoflurane on veratridine-induced 22Na+ influx, 45Ca2+ influx and catecholamine secretion became evident when the concentration of isoflurane was raised to 4-6%, i.e. 2-3 fold higher than the concentrations (1-2%) employed clinically. (3) High K(+)-evoked 45Ca2+ influx and catecholamine secretion were not affected by isoflurane (1-6%). (4) Isoflurane (1-6%) attenuated the production of cyclic GMP caused by muscarine, but not that caused by atrial natriuretic peptide or by sodium nitroprusside. These results suggest that isoflurane, at clinical anesthetic concentrations, inhibits nicotinic acetylcholine receptor-mediated cell responses as well as muscarinic receptor-mediated cyclic GMP production in adrenal medullary cells.

Effects of Isoflurane on Regulation of Capacitance Vessels under Normotensive and Chronically Hypertensive Conditions

This chapter summarizes several studies that demonstrate that significant differences exist in the reflex regulation of mesenteric capacitance veins in chronic renal wrap hypertensive versus normotensive rabbits. The heart rate response to aortic depressor nerve stimulation and to graded hypoxia has also been equally attenuated by isoflurane in both groups of animals. The two groups of animals also differ significantly in the baseline responses to isoflurane administration. In both groups of animals, 1.5% inhaled isoflurane significantly reduces heart rate and mean arterial pressure and dilated mesenteric capacitance vein diameter. However, in the hypertensive animals, the isoflurane-mediated reduction in arterial pressure has been significantly greater and the isoflurane-mediated increase in mesenteric vein diameter has been significantly less than that observed in the normotensive animals. The present study of the interaction between a volatile anesthetic and the hypertensive condition focused on changes in reflex responses that are mediated primarily by an elevation of sympathetic neural efferent activity. It has been observed that an inhibition of baroreflex and chemoreflex changes in heart rate, blood pressure, and mesenteric vein diameter during the administration of 0.75 minimum alveolar concentration (MAC) isoflurane in normotensive control animals. In addition, isoflurane has been shown to inhibit the relaxation effect of endothelium-derived nitric oxide on vascular smooth muscle cells in in vitro mesenteric vein ring preparations. In the hypertensive animals, the inhibitory effect of isoflurane on the heart rate responses to chemoreflex activation, on the blood pressure responses to both baroreflex and chemoreflex activation and on the mesenteric venodilation in response to aortic depressor nerve stimulation has been the same as in the normotensive control animals. Finally, it should be noted that the action of different anesthetic agents on sympathetically mediated reflex responses, particularly reflex regulation of venous tone, may vary.

P-597 - Inhibitory effect of isoflurane on catecholamine secretion and ion influxes in adrenal medurally cells.

P-597 - Inhibitory effect of isoflurane on catecholamine secretion and ion influxes in adrenal medurally cells.

Isoflurane Does Not Prevent Hepatic Injury Produced by Halothane in Rats

We speculated that the inhibitory effect of isoflurane on the metabolism of halothane might reduce hepatic injury produced by halothane. To test this hypothesis we pretreated male rats with phenobarbital and 24 hr later exposed them to one of three types of anesthesia. One group of rats was anesthetized with 0.6 MAC isoflurane in 21-25% oxygen for 20 min, followed by exposure to 0.3 MAC isoflurane and 0.3 MAC halothane either in 9% oxygen for 46 min (n = 5) or in 12% oxygen for 60 min (n = 11). A second group of rats received 0.3 MAC halothane in 9% oxygen for either 46 min (n = 12) or in 12% oxygen for 60 min (n = 10). The third group received 0.3 MAC isoflurane in 9% oxygen for either 46 min (n = 12) or for 120 min (n = 8). The rats were killed 24 hr after the exposures and liver slides prepared. Histologic examination revealed that rats treated with isoflurane plus halothane, or with halothane alone showed a significant hepatic injury (P less than 0.005) when compared with those treated with isoflurane. Thus isoflurane failed to protect the liver from halothane-induced injury.