Diabetes-associated alterations in volatile anesthetic actions on contractile response to norepinephrine in isolated mesenteric resistance arteries.

BACKGROUND: Clinical concentrations of volatile anesthetics significantly influence contractile response to the sympathetic neurotransmitter norepinephrine although its precise mechanisms remain unclarified. In this study, we investigated its possible alterations in diabetes, as well as its underlying mechanisms. METHODS: Isometric force was recorded in small mesenteric arteries from streptozotocin-induced diabetic and age-matched control rats. RESULTS: The concentration-response curve for acetylcholine-induced endothelium-dependent relaxation was shifted to the right in diabetic arteries compared with controls. The concentration-response curve for norepinephrine-induced contraction was shifted to the left and upward by both endothelial denudation and diabetic induction. In the presence of endothelium, isoflurane or sevoflurane enhanced norepinephrine-induced contraction in control arteries but not in diabetic arteries; however, in its absence, both anesthetics identically inhibited norepinephrine-induced contraction in both groups. In control arteries, the isoflurane- or sevoflurane-induced enhancement was not affected by adrenomedullin22-52, calcitonin gene-related peptide8-37, 18beta-glycyrrhetinic acid, N-nitro l-arginine, ouabain, Ba, indomethacin, losartan, ketanserin, BQ-123, and BQ-788. CONCLUSIONS: In diabetes, vascular responses to acetylcholine, norepinephrine, and volatile anesthetics are altered in mesenteric resistance arteries, presumably reflecting endothelial dysfunction and possibly underlying circulatory instability during administration of either anesthetic. Some endothelial mechanisms that are impaired in diabetes would be involved in the anesthetic-induced enhancement of norepinephrine-induced contraction. However, the vasoregulatory mechanism mediated by adrenomedullin, calcitonin gene-related peptide, myoendothelial gap junction, nitric oxide, endothelium-derived hyperpolarizing factor, cyclooxygenase products, angiotensin II, serotonin, or endothelin-1, all of which have been suggested to be impaired in diabetes, would not be involved in the enhancement.

The mechanisms of the direct action of etomidate on vascular reactivity in rat mesenteric resistance arteries.

BACKGROUND: Etomidate minimally influences hemodynamics at a standard induction dose in young healthy patients, but can cause significant systemic hypotension at higher doses for induction or electroencephalographic burst suppression (i.e., cerebral protection) in patients with advanced age or heart disease, and during cardiopulmonary bypass. However, less is known about its action on systemic resistance arteries. METHODS: Using an isometric force recording method and fura-2-fluorometry, we investigated the action of etomidate on vascular reactivity in small mesenteric arteries from young (7-8 wk old, n = 179) and aged (96-98 wk old, n = 10) rats. RESULTS: In the endothelium-intact strips from young rats, etomidate enhanced the contractile response to norepinephrine or KCl (40 mM) at 3 microM but inhibited it at higher concentrations (>or=10 microM). The enhancement was still observed after treatment with N(G)-nitro l-arginine, tetraethylammonium, diclofenac, nordihydroguaiaretic acid, losartan, ketanserin, BQ-123, or BQ-788, but was not observed in aged rats. In the endothelium-denuded strips from young rats, etomidate (>or=10 microM) consistently inhibited the contractile response to norepinephrine or KCl without enhancement at 3 microM. In the fura-2-loaded, endothelium-denuded strips from young rats, etomidate inhibited norepinephrine- or KCl-induced increases in both intracellular Ca(2+) concentration ([Ca(2+)]i) and force. Etomidate still inhibited the norepinephrine-induced increase in [Ca(2+)]i after depletion of the intracellular Ca(2+) stores by ryanodine, which was sensitive to nifedipine. Etomidate had little effect on norepinephrine- or caffeine-induced Ca(2+) release from the intracellular stores or Ca(2+) uptake into the intracellular stores. During stimulation with norepinephrine or KCl, etomidate had little effect on the [Ca(2+)]i-force relation at low concentrations (

Reliability of temperatures measured at standard monitoring sites as an index of brain temperature during deep hypothermic cardiopulmonary bypass conducted for thoracic aortic reconstruction.

OBJECTIVE: It is essential to estimate the brain temperature of patients during deliberate deep hypothermia. Using jugular bulb temperature as a standard for brain temperature, we evaluated the accuracy and precision of 5 standard temperature monitoring sites (ie, pulmonary artery, nasopharynx, forehead deep-tissue, urinary bladder, and fingertip skin-surface tissue) during deep hypothermic cardiopulmonary bypass conducted for thoracic aortic reconstruction. METHODS: In 20 adult patients with thoracic aortic aneurysms, the 5 temperature monitoring sites were recorded every 1 minute during deep hypothermic (<20 degrees C) cardiopulmonary bypass. The accuracy was evaluated by the difference from jugular bulb temperature, and the precision was evaluated by its standard deviation, as well as by the correlation with jugular bulb temperature. RESULTS: Pulmonary artery temperature and jugular bulb temperature began to change immediately after the start of cooling or rewarming, closely matching each other, and the other temperatures lagged behind these two temperatures. During either situation, the accuracy of pulmonary artery temperature measurement (0.3 degrees C-0.5 degrees C) was much superior to the other measurements, and its precision (standard deviation of the difference from jugular bulb temperature = 1.5 degrees C-1.8 degrees C; correlation coefficient = 0.94-0.95) was also best among the measurements, with its rank order being pulmonary artery > or = nasopharynx > forehead > bladder > fingertip. However, the accuracy and precision of pulmonary artery temperature measurement was significantly impaired during and for several minutes after infusion of cold cardioplegic solution. CONCLUSIONS: Pulmonary artery temperature measurement is recommended to estimate brain temperature during deep hypothermic cardiopulmonary bypass, even if it is conducted with the sternum opened; however, caution needs to be exercised in interpreting its measurements during periods of the cardioplegic solution infusion.

Cellular and molecular mechanisms regulating vascular tone. Part 1: basic mechanisms controlling cytosolic Ca2+ concentration and the Ca2+-dependent regulation of vascular tone.

General anesthetics cause hemodynamic instability and alter blood flow to various organs. There is mounting evidence that most general anesthetics, at clinical concentrations, influence a wide variety of cellular and molecular mechanisms regulating the contractile state of vascular smooth muscle cells (i.e., vascular tone). In addition, in current anesthetic practice, various types of vasoactive agents are often used to control vascular reactivity and to sustain tissue blood flow in high-risk surgical patients with impaired vital organ function and/or hemodynamic instability. Understanding the physiological mechanisms involved in the regulation of vascular tone thus would be beneficial for anesthesiologists. This review, in two parts, provides an overview of current knowledge about the cellular and molecular mechanisms regulating vascular tone-i.e., targets for general anesthetics, as well as for vasoactive drugs that are used in intraoperative circulatory management. This first part of the two-part review focuses on basic mechanisms regulating cytosolic Ca2+ concentration and the Ca2+-dependent regulation of vascular tone.

Cellular and molecular mechanisms regulating vascular tone. Part 2: regulatory mechanisms modulating Ca2+ mobilization and/or myofilament Ca2+ sensitivity in vascular smooth muscle cells.

Understanding the physiological mechanisms regulating vascular tone would lead to better circulatory management during general anesthesia. This two-part review provides an overview of current knowledge about the cellular and molecular mechanisms regulating the contractile state of vascular smooth muscle cells (i.e., vascular tone). The first part reviews basic mechanisms controlling the cytosolic Ca2+ concentration in vascular smooth muscle cells, and the Ca2+-dependent regulation of vascular tone. This second part reviews the regulatory mechanisms modulating Ca2+ mobilization and/or myofilament Ca2+ sensitivity in vascular smooth muscle cells-including Rho/Rho kinase, protein kinase C, arachidonic acid, Ca2+/calmodulin-dependent protein kinase II, caldesmon, calponin, mitogen-activated protein kinases, tyrosine kinases, cyclic nucleotides, Cl- channels, and K+ channels.

General anesthetics and vascular smooth muscle: direct actions of general anesthetics on cellular mechanisms regulating vascular tone.

General anesthetics threaten cardiovascular stability by causing changes in cardiac function, vascular reactivity, and cardiovascular reflexes and significantly alter distribution of cardiac output to various organs. Their overall impact is often systemic hypotension, which is attributable to myocardial depression, peripheral vasodilation, and attenuated sympathetic nervous system activity. However, one could be more causative than the others, depending on anesthetic agents and cardiovascular factors inherent in patients (e.g., coexisting heart disease). It is generally believed that most general anesthetics attenuate sympathetic nervous system outflow from the central nervous system, thereby decreasing vascular resistance in peripheral circulations. Indeed, in previous in vivo studies, during administration of various general anesthetics, vascular resistance was decreased in most peripheral circulations; however, it was unaffected or increased in some peripheral circulations. General anesthetics may act directly on vascular smooth muscle and/or endothelial cells in various vascular beds, influencing total peripheral and/or regional vascular resistance, and hence organ blood flow. This article reviews previously reported direct (i.e., nonneural) vascular actions of general anesthetics and discusses their underlying mechanisms, their in vivo relevance, and the future of research for general anesthetic vascular pharmacology.

[Quantitative assessment of pressure relief at the sacral area in adults lying supine on the operating room table].

BACKGROUND: It is important to prevent development of the pressure ulcers in patients undergoing lengthy surgery, particularly at areas of skin overlying bony prominences. This study was designed to investigate distribution of the interface pressure (IP) over the body area (from the head to pelvic area) in supine adults and also evaluate the ability of a polyurethane-made cushion to reduce the IP at their sacral area. METHODS: Utilizing a recently developed device to measure the IP (ERGO-CHECK, ABW Co., Germany), we evaluated distribution of the IP (estimated per 3 x 4 cm2 area) over the body area in healthy volunteers (n=31) and patients under general anesthesia (n=6) lying supine on the operating room (OR) table. RESULTS: In all the subjects, the highest IP was generated at the sacrum; 62.5 +/- 23.8 (mean +/- SD) and 35.7 +/- 5.5 mmHg in the volunteers and patients, respectively. The polyurethane-made, "doughnut" cushion (5 cm in thickness) inserted between the pelvic area and the OR table significantly reduced (P < 0.05) the IP at the sacrum in both groups: the IPs after the insertion in the volunteers and patients were 35.1 +/- 11.1 and 25.6 +/- 6.5 mmHg, respectively. In addition, the insertion significantly reduced (P < 0.05) the high-risk area (i.e., area of IP > 32 mmHg) in both groups. CONCLUSIONS: Quantitative assessment of the IP would be useful in evaluating precisely the effectiveness of various types of pillows, cushions, or mattresses designed to reduce the IP.

[Changes in serum Na+ and blood hemoglobin levels during three types of transurethral procedures for the treatment of benign prostatic hypertrophy].

BACKGROUND: Transurethral holmium YAG laser resection of the prostate (HoLR-P) and transurethral electrovaporization of the prostate (TUV-P) have recently received increasing attention as an effective minimally invasive approach for the treatment of prostatic hypertrophy. However, less information is available regarding the intraoperative changes in the serum Na+ and blood hemoglobin levels during either HoLR-P or TUV-P. METHODS: Intraoperative changes in serum Na+ and blood hemoglobin levels were investigated in 17 patients undergoing transurethral resection of the prostate (TUR-P, n = 7), HoLR-P (n = 7) or TUV-P (n = 3). The 3% D-sorbitol solution was used as the irrigating fluid in all the patients. RESULTS: In three patients, severe hyponatremia (118-123 mEq x l(-1)) developed abruptly (< or = 15 min) at various time points during TUR-P with (n = 1) or without (n = 2) cystostomy. However, no clinical symptoms were observed after development of the hyponatremia in those awake patients. No large (> 10 mEq x l(-1)) decreases in the Na+ level were observed in any of the patients undergoing HoLR-P or TUV-P. In patients undergoing TUR-P and HoLR-P, percent changes in serum Na+ level significantly correlated with those in blood hemoglobin level, but not with the resection time; the slopes were significantly larger than unity. CONCLUSIONS: The TUR syndrome is less likely to occur during HoLR-P or TUV-P. During TUR-P, the onset of severe hyponatremia appears to be unpredictable, and may not necessarily be accompanied by clinical symptoms. Frequent measurements of the serum Na+ level appear essential for early detection of severe hyponatremia.

Changes in body temperature during profound hypothermic cardiopulmonary bypass in adult patients undergoing aortic arch reconstruction.

PURPOSE: Our aim was to characterize changes in body temperatures during profound hypothermic cardiopulmonary bypass (CPB) conducted with the sternum opened. METHODS: In ten adult patients who underwent profound hypothermic (< 20 degrees C) CPB for aortic arch reconstruction, pulmonary arterial temperature (PAT), nasopharyngeal temperature (NPT), forehead deep-tissue temperature (FHT), and urinary bladder temperature (UBT) were recorded every 1 min throughout the surgery. In addition, the CPB venous line temperature (CPBT), a reasonable indicator of mixed venous blood temperature during CPB and believed to best reflect core temperature during stabilized hypothermia on CPB, was recorded during the period of total CPB. RESULTS: PAT began to change immediately after the start of cooling or rewarming, closely matching the CPBT ( r = 0.98). During either situation, the other four temperatures lagged behind PAT ( P < 0.05); however, NPT followed PAT more closely than the other three temperatures ( P < 0.05). During stabilized hypothermia, PAT, NPT, and FHT, but not UBT, closely matched the CPBT, with gradients of less than 0.5 degrees C. CONCLUSION: During induction of profound hypothermia and its reversal on total CPB with the heart in situ, a PA catheter thermistor, presumably because of its placement immediately behind the superior vena cava, would provide a reliable measure of the mixed venous blood temperature. During stabilized profound hypothermia, PAT, NPT, and FHT, but not UBT, serve as a reliable index of core temperature.

[Usefulness of monitoring forehead deep-tissue temperature as an index of core temperature in adult patients undergoing laparotomies under general anesthesia--investigation in operating rooms with air-movement control system using vertical flow].

BACKGROUND: Acute changes in air temperature in the vicinity of the patents' forehead may impair clinical usefulness of the forehead deep-tissue thermometry. We thus investigated usefulness of monitoring the forehead deep-tissue temperature as an index of core temperature in 12 adult patients undergoing laparotomies in operating rooms with air-movement control system using vertical flow. METHODS: Nasopharyngeal, forehead deep-tissue, palm deep-tissue, and fingertip skin-surface temperatures were recorded during surgery every 5 minutes in operating rooms where room temperature was thermostatically controlled at approximately 25 degrees C. The patients were not actively warmed with forced-air warmers, but covered with cotton blankets where possible. The deep-tissue and fingertip skin-surface temperatures were compared with the nasopharyngeal temperature using regression and Bland and Altman's analyses. RESULTS: The four temperatures continued decreasing during surgery, and the nasopharyngeal temperature decreased to below 36 degrees C 2 hours after induction of anesthesia. Only the forehead deep-tissue temperature satisfactorily correlated with the nasopharyngeal temperature (r = 0.76, n = 300, P < 0.0001). The difference between nasopharyngeal and forehead temperatures was +0.26 degree C, and its standard deviation was 0.34 degree C. CONCLUSIONS: The forehead deep-tissue temperature has sufficient accuracy and precision for clinical use in operating rooms with air-movement control system using vertical flow. However, the core temperature appears to be slightly underestimated with the forehead deep-tissue thermometry.

Mechanisms of direct inhibitory action of isoflurane on vascular smooth muscle of mesenteric resistance arteries.

BACKGROUND: Isoflurane has been shown to directly inhibit vascular reactivity. However, less information is available regarding its underlying mechanisms in systemic resistance arteries. METHODS: Endothelium-denuded smooth muscle strips were prepared from rat mesenteric resistance arteries. Isometric force and intracellular Ca2+ concentration ([Ca2+]i) were measured simultaneously in the fura-2-loaded strips, whereas only the force was measured in the beta-escin membrane-permeabilized strips. RESULTS: Isoflurane (3-5%) inhibited the increases in both [Ca2+]i and force induced by either norepinephrine (0.5 microM) or KCl (40 mM). These inhibitions were similarly observed after depletion of intracellular Ca2+ stores by ryanodine. Regardless of the presence of ryanodine, after washout of isoflurane, its inhibition of the norepinephrine response (both [Ca2+]i and force) was significantly prolonged, whereas that of the KCl response was quickly restored. In the ryanodine-treated strips, the norepinephrine- and KCl-induced increases in [Ca2+]i were both eliminated by nifedipine, a voltage-gated Ca2+ channel blocker, whereas only the former was inhibited by niflumic acid, a Ca2+-activated Cl- channel blocker. Isoflurane caused a rightward shift of the Ca2+-force relation only in the fura-2-loaded strips but not in the beta-escin-permeabilized strips. CONCLUSIONS: In mesenteric resistance arteries, isoflurane depresses vascular smooth muscle reactivity by directly inhibiting both Ca2+ mobilization and myofilament Ca2+ sensitivity. Isoflurane inhibits both norepinephrine- and KCl-induced voltage-gated Ca2+ influx. During stimulation with norepinephrine, isoflurane may prevent activation of Ca2+-activated Cl- channels and thereby inhibit voltage-gated Ca2+ influx in a prolonged manner. The presence of the plasma membrane appears essential for its inhibition of the myofilament Ca2+ sensitivity.

[Changes in acid-base balance and blood lactate levels during radio frequency ablation conducted for the treatment of hepatocellular carcinomata in patients with liver cirrhosis].

BACKGROUND: Radio frequency ablation (RFA) has recently received increasing attention as an effective minimally invasive approach for the treatment of hepatocellular carcinomata (HCCs). However, we experienced a patient with liver cirrhosis (LC, Child-Pugh class B) in whom severe lactic acidosis developed during RFA conducted for the treatment of a HCC (-4.5 cm in diameter). This case prompted us to reevaluate possible injurious effects of RFA on non-tumorous liver tissues in the vicinity of its target in LC patients. METHODS: Intraoperative changes in acid-base balance and blood lactate levels, and postoperative changes in serum transaminases were investigated in LC (Child-Pugh class A) patients undergoing either laparotomic RFA (for the treatment of HCCs [diameter < 3 cm]) or partial hepatectomy (with the aid of the Pringle's manuever), and non-LC patients undergoing pancreatectomy. RESULTS: During the intraoperative period, significant lactic acidosis developed only in the patients undergoing hepatectomy. Core temperature significantly increased following the RFA. Postoperative increases in the transaminases observed in the patients undergoing hepatectomy were far larger than those observed in the patients undergoing either RAF or pancreatectomy. CONCLUSION: RFA, conducted for the treatment of smaller HCCs, appears to be minimally invasive even in the presence of LC (Child-Pugh class A).

[Development of severe lactic acidosis during radio frequency ablation conducted for the treatment of hepatocellular carcinomata in a patient with liver cirrhosis].

A 60-year-old male with liver cirrhosis (Child-Pugh class B) underwent laparotomic radio frequency ablation for the treatment of a solitary hepatocellular carcinoma (-4.5 cm in diameter). Severe lactic acidosis (base excess < -12 mEq.l-1, lactate > 150 mg.dl-1) developed during the intraoperative period, when neither his hemodynamics nor arterial oxygenation was significantly impaired. The blood loss was small (-200 g), and the serum hemoglobin level was maintained -10 g.dl-1 during the procedure. There was no evidence for impairment of either peripheral perfusion or renal function. In addition, there was no evidence for development of either splanchnic ischemia or diabetic ketoacidosis. Thus, the acidosis appeared to be caused by significant impairment of liver function possibly resulting from the ablation (total ablation time = -60 min). The core temperature increased rapidly (-1.5 degrees C/60 hr) immediately after the ablation was started, suggesting that a large amount of heat was produced in the ablated area and/or that the vicinity of the ablated area was richly supplied by blood flow. As a result, intact liver cells in the vicinity of the tumor probably suffered from thermal injuries. In conclusion, depending on preoperative liver function, ablated area, and/or blood flow in the vicinity of ablated area, the ablation may become significantly invasive.

Sevoflurane and bradykinin-induced calcium mobilization in pulmonary arterial valvular endothelial cells in situ: sevoflurane stimulates plasmalemmal calcium influx into endothelial cells.

Kinins locally synthesized in the cardiovascular tissue are believed to contribute to the regulation of cardiovascular homeostasis by stimulating the endothelial cells to release nitric oxide, prostacyclin, or a hyperpolarizing factor via autocrine-paracrine mechanisms. This study was designed to investigate the action of sevoflurane on bradykinin-induced Ca2+ mobilization in endothelial cells in situ. Utilizing fura-2-loaded rat pulmonary arterial valve leaflets, the effects of sevoflurane were examined on bradykinin-induced increases in intracellular Ca2+ concentration ([Ca2+]i) in endothelial cells in situ. In the presence of extracellular Ca2+ (1.5 mM), bradykinin (3-30 microM) produced an initial phasic and a subsequent tonic increase in [Ca2+]i in a concentration-dependent manner. However, it produced only the phasic increase in [Ca2+]i in the absence of extracellular Ca2+. Sevoflurane (5%, 0.67 mM) inhibited both the phasic and tonic responses to bradykinin. In these experiments, sevoflurane (3-5%) generated sustained increases (approximately 20-40% of the bradykinin-induced maximal increase in [Ca2+]i) in the resting [Ca2+]i level. Sevoflurane still increased [Ca2+]i after depletion of the intracellular Ca stores with ionomycin (0.1 microM ). However, the sevoflurane-induced increase in [Ca2+]i was eliminated by removal of the extracellular Ca and attenuated by NiCl (1-3 mM). In conclusion, in the pulmonary arterial valvular endothelial cells, sevoflurane inhibits both bradykinin-induced Ca2+ release from the intracellular stores and bradykinin-induced plasmalemmal Ca2+ influx. In addition, sevoflurane appears to stimulate the plasmalemmal Ca2+ influx and thereby increase the endothelial [Ca2+]i level. Sevoflurane might influence the pulmonary vascular tone through its direct action on the pulmonary arterial valvular endothelial cells.

[Acute renal failure in an infant attributable to arterial cannula malposition during cardiopulmonary bypass via ministernotomy].

A 6-month-old female (4.9 kg) with multiple congenital heart lesions underwent intracardiac repair with the aid of cardiopulmonary bypass (CPB) through a lower half sternotomy. Aortic cannulation, venous cannulation, and cardioplegia cannula insertion were all accomplished through the ministernotomy. During the CPB, in spite of a high perfusion flow rate (182 ml.kg-1.min-1), the systemic arterial pressure was persistently low (mean values = 25-35 mmHg) and the urine output was greatly reduced (< 1 ml.hr-1). In addition, inappropriate increases in the arterial inflow line pressure were recognized. Since abutment of the cannula tip against the aortic intima was suspected, several attempts were made to correct its malpositioning. During the CPB, hemolysis was also found in the mixed venous blood. Since the oliguria and resultant hyperkalemia persisted after weaning from the CPB, peritoneal dialysis was introduced immediately after the surgery. Her renal function gradually recovered postoperatively, and she was finally weaned from the peritoneal dialysis on the 13th postoperative day. Although the ministernotomy has been proposed to be a safe approach for most of cardiac surgeries, it appears to increase the risk for arterial cannula malposition as compared to the standard full-length sternotomy in small pediatric patients.

Protamine relaxes vascular smooth muscle by directly reducing cytosolic free calcium concentrations in small resistance arteries.

Protamine has been suggested to relax vascular smooth muscle by reducing the intracellular Ca2+ concentration ([Ca2+]i). However, there has been no direct evidence that protamine reduces the [Ca2+]i of vascular smooth muscle. We therefore studied the effects of protamine on changes in [Ca2+]i and tension induced by norepinephrine (NE) and high K+ in endothelium-denuded strips from rabbit small mesenteric artery, using fura-2-fluorometry and isometric tension recording methods. Both NE (1 µM) and high K+ (40 mM) produced a transient phasic increase, followed by a tonic increase in [Ca2+]i and tension. Protamine concentration (15-500 µg·ml-1)-dependently inhibited (P<0.05) the phasic and tonic components of both NE- and high K+-induced contraction with IC50 values of ≈50 µg·ml-1. Protamine (50 µg·ml-1) inhibited (P<0.05) the phasic and tonic increases in [Ca2+]i caused by both NE and high K+ by ≈40%-60%. We conclude that the direct vasodilator action of protamine is due, at least in part, to reduction of [Ca2+]i in vascular smooth muscle; this reduction in [Ca2+]i may be due to inhibition of both Ca2+ influx and Ca2+ release from intracellular Ca2+ stores.