An appropriate inspiratory flow pattern can enhance CO2 exchange, facilitating protective ventilation of healthy lungs.

BACKGROUND: In acute lung injury, CO2 exchange is enhanced by prolonging the volume-weighted mean time for fresh gas to mix with resident alveolar gas, denoted mean distribution time (MDT), and by increasing the flow rate immediately before inspiratory flow interruption, end-inspiratory flow (EIF). The objective was to study these effects in human subjects without lung disease and to analyse the results with respect to lung-protective ventilation of healthy lungs. METHODS: During preparation for intracranial surgery, the lungs of eight subjects were ventilated with a computer-controlled ventilator, allowing breath-by-breath modification of the inspiratory flow pattern. The durations of inspiration (TI) and postinspiratory pause (TP) were modified, as was the profile of the inspiratory flow wave (i.e. constant, increasing, or decreasing). The single-breath test for CO2 was used to quantify airway dead space (VDaw) and CO2 exchange. RESULTS: A long MDT and a high EIF augment CO2 elimination by reducing VDaw and promoting mixing of tidal gas with resident alveolar gas. A heat and moisture exchanger had no other effect than enlarging VDaw. A change of TI from 33 to 15% and of TP from 10 to 28%, leaving the time for expiration unchanged, would augment tidal elimination of CO2 by 14%, allowing a 10% lower tidal volume. CONCLUSIONS: In anaesthetized human subjects without lung disease, CO2 exchange is enhanced by a long MDT and a high EIF. A short TI and a long TP allow significant reduction of tidal volume when lung-protective ventilation is required. CLINICAL TRIAL REGISTRATION: NCT01686984.

Anaesthetic conserving device AnaConDa: dead space effect and significance for lung protective ventilation.

BACKGROUND: The anaesthetic conserving device AnaConDa (ACD) reflects exhaled anaesthetic agents thereby facilitating the use of inhaled anaesthetic agents outside operating theatres. Expired CO2 is, however, also reflected causing a dead space effect in excess of the ACD internal volume. CO2 reflection from the ACD is attenuated by humidity. This study tests the hypothesis that sevoflurane further attenuates reflection of CO2. An analysis of clinical implications of our findings was performed. METHODS: Twelve postoperative patients received mechanical ventilation using a conventional heat and moisture exchanger (HME, internal volume 50 ml) and an ACD (100 ml), the latter with or without administration of sevoflurane. The ACD was also studied with a test lung at high sevoflurane concentrations. Reflection of CO2 and dead space effects were evaluated with the single-breath test for CO2. RESULTS: Sevoflurane reduced but did not abolish CO2 reflection. In patients, the mean dead space effect with 0.8% sevoflurane was 88 ml larger using the ACD compared with the HME (P<0.001), of which 38 ml was due to CO2 reflection. Our calculations show that with the use of the ACD, normocapnia cannot be achieved with tidal volume <6 ml kg(-1) even when respiratory rate is increased. CONCLUSIONS: An ACD causes a dead space effect larger than its internal volume due to reflection of CO2, which is attenuated but not abolished by sevoflurane administration. CO2 reflection from the ACD limits its use with low tidal volume ventilation, such as with lung protection ventilation strategies. CLINICAL TRIAL REGISTRATION: Clinical Trials NCT01699802.

Circulating glycosaminoglycan species in septic shock.

BACKGROUND: Glycosaminoglycans (GAGs) are negatively charged polysaccharides present, e.g., on the luminal face of the blood vessels as heparan sulphate (HS) and hyaluronic acid (HA), in the interstitium as HA, and in neutrofils and plasma as chondroitin sulphate (CS) and HA. Total plasma levels of GAG are increased in human septic shock, but the origin and pathophysiological implications are unclear. In order to determine the source of circulating GAG in sepsis, we compared plasma levels of HS, HA, CS and keratan sulphate (KS) in patients with septic shock and controls. METHODS: HS and KS were measured with enzyme-linked immunosorbent assay, and HA and CS disaccharides with liquid chromatography tandem mass spectrometry in plasma obtained from patients admitted to intensive care fulfilling criteria for septic shock as well as from matched control patients scheduled for neurosurgery. RESULTS: Median levels of HS and HA were fourfold increased in septic shock and were higher in patients that did not survive 90 days (threefold and fivefold for HS and HA, respectively). Median CS levels were unaltered, while KS levels were slightly decreased in sepsis patients. HS and HA levels correlated with levels of interleukin-6 and interleukin-10. Except for HA, GAG levels did not correlate to liver or kidney sequential organ function score. CONCLUSION: Median plasma level of HS and HA is increased in septic shock patients, are higher in patients that do not survive, and correlates with inflammatory activation and failing circulation. The increased levels could be due to vascular damage.

Carbon dioxide rebreathing with the anaesthetic conserving device, AnaConDa®.

BACKGROUND: The anaesthetic conserving device (ACD) AnaConDa(®) was developed to allow the reduced use of inhaled agents by conserving exhaled agent and allowing rebreathing. Elevated has been observed in patients when using this ACD, despite tidal volume compensation for the larger apparatus dead space. The aim of the present study was to determine whether CO(2), like inhaled anaesthetics, adsorbs to the ACD during expiration and returns to a test lung during the following inspiration. METHODS: The ACD was attached to an experimental test lung. Apparent dead space by the single-breath test for CO(2) and the amount of CO(2) adsorbed to the carbon filter of the ACD was measured with infrared spectrometry. RESULTS: Apparent dead space was 230 ml larger using the ACD compared with a conventional heat and moisture exchanger (internal volumes 100 and 50 ml, respectively). Varying CO(2) flux to the test lung (85-375 ml min(-1)) did not change the measured dead space nor did varying respiratory rate (12-24 bpm). The ACD contained 3.3 times more CO(2) than the predicted amount present in its internal volume of 100 ml. CONCLUSIONS: Our measurements show a CO(2) reservoir effect of 180 ml in excess of the ACD internal volume. This is due to adsorption of CO(2) in the ACD during expiration and return of CO(2) during the following inspiration.

Larger tidal volume increases sevoflurane uptake in blood: a randomized clinical study.

BACKGROUND: The rate of uptake of volatile anesthetics is dependent on alveolar concentration and ventilation, blood solubility and cardiac output. We wanted to determine whether increased tidal volume (V(T)), with unchanged end-tidal carbon dioxide partial pressure (P(ET)CO(2)), could affect the arterial concentration of sevoflurane. METHODS: Prospective, randomized, clinical study. ASA physical status (2) and II patients scheduled for elective surgery of the lower abdomen were randomly assigned to one of the two groups with 10 patients in each: one group with normal V(T) (NV(T)) and one group with increased V(T) (IV(T)) achieved by increasing the inspired plateau pressure 0.04 cmH(2)O/kg above the initial plateau pressure. A corrugated tube added extra apparatus dead space to maintain P(ET)CO(2) at 4.5 kPa. The respiratory rate was set at 15 min(-1), and sevoflurane was delivered to the fresh gas by a vaporizer set at 3%. Arterial sevoflurane tensions (P(a)sevo), F(i)sevo, P(ET)sevo, P(ET)CO(2), P(a)CO(2), V(T) and airway pressure were measured. RESULTS: The two groups of patients were similar with regard to gender, age, weight, height and body mass index. The mean P(ET)sevo did not differ between the groups. Throughout the observation time, arterial sevoflurane tension (mean ± SE) was significantly higher in the IV(T) group compared with the NV(T) group, e.g. 1.9 ± 0.23 vs. 1.6 ± 0.25 kPa after 60 min of anesthesia (P<0.05). CONCLUSION: Ventilation with larger tidal volumes with isocapnia maintained with added dead-space volume increases the tension of sevoflurane in arterial blood.

Mutation screening of the RYR1-cDNA from peripheral B-lymphocytes in 15 Swedish malignant hyperthermia index cases.

BACKGROUND: Malignant hyperthermia (MH), linked to the ryanodine receptor 1 gene (RYR1) on chromosome 19, is a potentially lethal pharmacogenetic disorder which may lead to a disturbance of intracellular calcium homeostasis when susceptible individuals are exposed to halogenated anaesthetics, suxamethonium, or both. Central core disease (CCD) is a rare dominantly inherited congenital myopathy allelic to MH-susceptibility. METHODS: In this study, 14 unrelated MH-susceptible probands and one CCD patient from Sweden were screened for mutations in the RYR1. Since the RYR1 is also expressed in B-lymphocytes, RYR1-cDNA was transcribed from total RNA extracted from white blood cells. RESULTS: We detected two known RYR1 mutations and two previously described unclassified sequence variants. In addition, six novel sequence variants were detected. All mutations or sequence variants were verified on genomic DNA. Seven of the probands did not show any candidate mutation, although the total coding region of RYR1 was sequenced. Segregation data in in vitro contracture tested family members of three probands support a causative role of three of the novel sequence variants. CONCLUSIONS: Our study contributes to the genetic aetiology of MH in Sweden, but also raises questions about the involvement of genes other than RYR1 since nearly half of the probands did not show any sequence variants in the total coding region of the RYR1.

Wash-in kinetics for sevoflurane using a disposable delivery system (AnaConDa) in cardiac surgery patients.

BACKGROUND: The use of volatile anaesthetics has increased in situations where conventional anaesthetic machines are inadequate or unavailable, for example, cardiac surgery and intensive care. The disposable anaesthetic conserving device, AnaConDa, allows vaporization of liquid volatile anaesthetics from a syringe pump and rebreathing of exhaled anaesthetic. Clinical use requires understanding of device-specific anaesthetic agent kinetics, which are not fully known. We compared the wash-in kinetics for sevoflurane administered by a conventional vaporizer in a non-rebreathing system and the AnaConDa and evaluated if a standard anaesthesia gas monitor gave accurate readings while using the AnaConDa. METHODS: Cardiac surgery patients were randomized to maintenance of anaesthesia with sevoflurane either via a vaporizer or via the AnaConDa (n=8 in each group). Sevoflurane in arterial blood and airway gas was measured with gas chromatography and standard gas monitoring. RESULTS: The initial increase in arterial sevoflurane tension was greater with the vaporizer than with the AnaConDa, but the time to reach 80% of maximum sevoflurane tension was close to 8 min in both groups. End-tidal sevoflurane tension mirrored arterial tension in both groups, whereas measured inspired tension was lower than expired and arterial tensions with the use of the AnaConDa. CONCLUSIONS: The wash-in kinetics for sevoflurane delivered by the AnaConDa are similar to a vaporizer. End-tidal sevoflurane tension accurately reflects arterial tension whereas inspired tension may be underestimated using an AnaConDa.

Endogenous antimicrobial peptide LL-37 induces human vasodilatation.

BACKGROUND: Septic shock includes blood vessel dilatation and activation of innate immunity, which in turn causes release of antimicrobial peptides such as LL-37. It has been shown that LL-37 can attract leucocytes via the lipoxin A(4) receptor (ALX, FPRL1). ALX is also present in vascular endothelial cells. To explore possible ways of pharmacological intervention in septic shock, we investigated if LL-37 can affect vascular tone. METHODS: Human omental arteries and veins were obtained during abdominal surgery, and circular smooth muscle activity was studied in organ baths. Gene expression was studied using reverse transcriptase-polymerase chain reaction. RESULTS: LL-37, at micromolar concentrations, induced a concentration- and endothelium-dependent relaxation in vein but not in artery segments precontracted by endothelin-1. The relaxation was profoundly reduced by potassium chloride (30 mM) to inhibit endothelium-derived hyperpolarizing factor (EDHF), whereas it was less affected by the NOS inhibitor, l-N(G)-nitroarginine methyl ester, and not at all by indomethacin. The ALX agonist, WKYMVm, also induced a relaxation and both the relaxations induced by LL-37 and WKYMVm were inhibited by the ALX antagonist, WRWWWW. ALX was expressed in the vein endothelium. CONCLUSIONS: We demonstrate, for the first time, that the human antimicrobial peptide, LL-37, induces endothelium-dependent relaxation in human omental veins mediated via an effect on endothelial ALX. The relaxation involves the release of nitric oxide and EDHF but not prostanoids. LL-37 released from white blood cells could contribute to blood vessel dilatation during sepsis and treatment with ALX antagonists might be successful.

Male preponderance of patients testing positive for malignant hyperthermia susceptibility.

BACKGROUND: Malignant hyperthermia susceptibility is diagnosed using an in vitro contracture test (IVCT). In families in which the mutation is known, genetic tests are also available. The inheritance pattern is regarded as autosomal dominant, which predicts equal proportions of men and women affected. The aim of this study was to investigate whether there were sex differences in the diagnostic outcome of the 1407 patients tested for malignant hyperthermia in Sweden between 1985 and 2005. METHODS: Information about sex, diagnosis, IVCT result and kinship was analysed. Comparisons were made between the two sexes. Probands and relatives were analysed separately in order to eliminate bias caused by the type of surgery performed in the two sexes. RESULTS: Males, more than females, revealed a pathological outcome in IVCT. Amongst male relatives, the fraction of pathological outcome in IVCT was 0.70 [95% confidence interval (CI), 0.66-0.74]; the corresponding value for females was 0.40 (95% CI, 0.36-0.44). CONCLUSION: A significant difference was observed in the sex distribution of outcome of IVCT, with significantly more males revealing a pathological IVCT. This indicates the influence of one or several factors related to sex in the outcome of IVCT, for example different expression of calcium handling proteins in the sexes, a complex pattern of inheritance or unknown environmental factors.

Effects of sevoflurane on sympathetic neurotransmission in human omental arteries and veins.

BACKGROUND: Sevoflurane reduces blood pressure, the regulation of which requires an intact sympathetic neurotransmission. This study was designed to evaluate the effect of sevoflurane on the coupling between peripheral sympathetic neurones and vascular smooth muscle in isolated human omental vessels. METHODS: Segments of arteries and veins were exposed to sevoflurane 1%, 2% and 4% (corresponding to approximately 0.5, 1 and 2 MAC in humans, respectively). The vessels were studied in vitro to determine the effects on (i) isometric contraction during electrical field stimulation (EFS) or in the presence of exogenous norepinephrine (NE); (ii) electrical field stimulated release of [(3)H]-NE from vessel segments previously incubated with [(3)H]-NE; (iii) uptake of [(3)H]-NE. RESULTS: In artery segments, sevoflurane 4% attenuated the contraction induced by both EFS and exogenous NE. In vein segments, sevoflurane 4% attenuated only the EFS-induced contractions. Sevoflurane 1% and 2% had no effect. The release of [(3)H]-NE was inhibited by sevoflurane 2% and 4% in arteries and by sevoflurane 1%, 2% and 4% in veins. Sevoflurane had no effect on the uptake of [(3)H]-NE in either vessel. CONCLUSIONS: Sevoflurane depresses sympathetic neuromuscular transmission in human omental vessels by reducing neuronal NE release and NE sensitivity in arteries and by reducing NE release in veins. This could contribute to the hypotension seen during sevoflurane anaesthesia, at least at concentrations above 1 MAC.

Effects of human cathelicidin antimicrobial peptide LL-37 on lipopolysaccharide-induced nitric oxide release from rat aorta in vitro.

BACKGROUND: Lipopolysaccharides (LPS), released by Gram-negative bacteria, cause vascular expression of inducible nitric oxide synthase (iNOS) leading to nitric oxide (NO) production and septic shock. Human cathelicidin antimicrobial peptide (LL-37) can bind and neutralize LPS. We wanted to study whether LL-37 affects LPS or interleukin-1beta (IL-1beta)-induced production, release and function of NO in intact rat aorta rings and cultured rat aorta smooth muscle cells. METHODS: Isolated segments of thoracic aorta and cultured cells were incubated in the presence of LPS, LL-37, LPS + IL-37, IL-1beta, IL-1beta + IL-37 or in medium alone. Smooth muscle contraction in response to phenylephrine and accumulation of the sdegradation products of NO, nitrate and nitrite, were measured on aorta segments. Levels of iNOS were assessed by Western blot and cytotoxic effects were detected by measurement of DNA fragmentation in cultured cells. Number of viable cells were determined after Trypan blue treatment. RESULTS: Both LPS and IL-1beta reduced contractility in response to phenylephrine and increased NO production as well as iNOS expression. LL-37 inhibited the LPS depression of vascular contractility induced only by LPS. LL-37 reduced both the LPS- and IL-1beta-induced NO production and iNOS expression. LL-37 at high concentrations induced DNA fragmentation and decreased the number of living cells. CONCLUSION: IL-37 reduces NO production induced by LPS and IL-1beta. The reduction does not seem to result only from neutralization of LPS but also from a cytotoxic effect, possibly via induction of apoptosis.

Bactericidal/permeability-increasing protein inhibits endotoxin-induced vascular nitric oxide synthesis.

BACKGROUND: Endotoxin (lipopolysaccharide, LPS) up-regulates inducible nitric oxide synthase (iNOS) in blood vessels during septic shock. This promotes the production of nitric oxide (NO), leading to dilation of the vessels. The aim of the study was to investigate the effects of the LPS-binding endogenous antibiotic bactericidal/permeability-increasing protein (BPI) on the action of LPS on the blood vessels wall and to identify possible influence on underlying NO-related mechanisms. METHODS: Isolated segments of rat thoracic aorta and cultured primary smooth muscle cells were incubated for 5-48 h in the presence of the following combinations of compounds: (a) LPS; (b) interleukin-1beta (IL-1beta); (c) BPI; (d) BPI + LPS; (e) BPI + IL-1beta or (f) neither BPI, LPS nor IL-1beta (control). After incubation of intact segments, we measured smooth muscle contraction in response to phenylephrine and accumulation of the NO end products nitrate and nitrite in surrounding medium. Western blot was used to assess the levels of inducible nitric oxide synthase (iNOS) in cultured cells. RESULTS: Both LPS and IL-1beta decreased contractility and increased NO production, as well as iNOS. Co-incubation with BPI attenuated all the effects of LPS but only the effects of prolonged exposure to IL-1beta in cultured cells. CONCLUSION: We conclude that BPI attenuates the LPS-induced changes in vascular reactivity by inhibiting the expression of iNOS resulting in decreased NO formation and restored responsiveness to vasoconstrictors. The data suggest that BPI can prevent circulatory disturbances during Gram-negative sepsis.

Bactericidal activity of human eosinophilic granulocytes against Escherichia coli.

Eosinophils participate in allergic inflammation and may have roles in the body's defense against helminthic infestation. Even under noninflammatory conditions, eosinophils are present in the mucosa of the large intestine, where large numbers of gram-negative bacteria reside. Therefore, roles for eosinophils in host defenses against bacterial invasion are possible. In a system for bacterial viable counts, the bactericidal activity of eosinophils and the contribution of different cellular antibacterial systems against Escherichia coli were investigated. Eosinophils showed a rapid and efficient killing of E. coli under aerobic conditions, whereas under anaerobic conditions bacterial killing decreased dramatically. In addition, diphenylene iodonium chloride (DPI), an inhibitor of the NADPH oxidase and thereby of superoxide production, also significantly inhibited bacterial killing. The inhibitor of nitric oxide (NO) production L-N(5)-(1-iminoethyl)-ornithine dihydrochloride did not affect the killing efficiency, suggesting that NO or derivatives thereof are of minor importance under the experimental conditions used. To investigate the involvement of superoxide and eosinophil peroxidase (EPO) in bacterial killing, EPO was blocked by azide. The rate of E. coli killing decreased significantly in the presence of azide, whereas addition of DPI did not further decrease the killing, suggesting that superoxide acts in conjunction with EPO. Bactericidal activity was seen in eosinophil extracts containing granule proteins, indicating that oxygen-independent killing may be of importance as well. The findings suggest that eosinophils can participate in host defense against gram-negative bacterial invasion and that oxygen-dependent killing, i.e., superoxide acting in conjunction with EPO, may be the most important bactericidal effector function of these cells.

Effects of propofol on substance P-induced relaxation in isolated human omental arteries and veins.

To elucidate if an effect of propofol on endothelium-dependent relaxation could contribute to propofol-induced vasodilation, smooth muscle relaxation of isolated human omental artery and vein segments precontracted by endothelin-1 were measured. Substance P induced a concentration-dependent relaxation (mean +/- SEM) in both artery (63 +/-8.4% of precontraction, n = 9) and vein (60+/-11%, n = 7). The relaxation was enhanced by 10(-6) M propofol (artery, 72+/-9.5%, n = 9; vein, 81+/-12%, n = 7) but not affected by 10(-7), 10(-5) and 10(-4) M propofol. In the presence of Nomega-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor), 10(-6) M propofol still enhanced the substance P-induced relaxation in arteries but not veins, whereas 10(-4) M propofol inhibited the relaxation in both arteries (rightward shift of the concentration-response curve) and veins (28+/-7.5%, n = 8). In the presence of potassium chloride (to prevent hyperpolarization), the enhancement of substance P-induced relaxation by 10(-6) M propofol was abolished in both arteries and veins whereas 10(-5) and 10(-4) M propofol reduced the relaxation in arteries (38+/-13% at 10(-5) M, n = 6; 30+/-11% at 10(-4) M, n = 6) but not in veins. These results demonstrate that propofol, at lower, clinically relevant concentrations, promotes endothelium-dependent relaxation mediated via hyperpolarization in human omental arteries and via both nitric oxide and hyperpolarization in human omental veins.

Effects of propofol on desipramine-sensitive [3H]-noradrenaline uptake kinetics in rat femoral artery.

BACKGROUND: The intravenous anaesthetic propofol inhibits the neuronal uptake of noradrenaline (uptake1) from the vascular sympathetic neuromuscular junction, resulting in an enhancement of the sympathetic neurotransmission. This could be important for maintenance of blood pressure during propofol anaesthesia. The aim of the present study was to determine how propofol influences the kinetics of uptake1. METHODS: Isolated segments of rat femoral arteries were incubated with [3H]-noradrenaline in the presence or absence of propofol and the radioactivity taken up was measured in a scintillation counter. The uptake1 inhibitor, desipramine, was used to delineate the specific neuronal uptake. RESULTS: Desipramine and 10 microM propofol significantly reduced the uptake in segments incubated with 0.1 microM [3H]-noradrenaline. Propofol at 1 microM and 100 microM did not affect the uptake. Non-linear regression analysis of specific uptake yielded Km 0.50 microM, Vmax 1.6 pmol mg(-1) 15 min(-1) and Hill coefficient 1.1. Propofol (1-10 microM) increased the Km value and propofol (10-100 microM) increased the Vmax value concentration-dependently, while the Hill coefficient was not affected. CONCLUSION: Propofol seems to have a biphasic effect on the uptake of noradrenaline in the vascular sympathetic neuromuscular junction. At lower propofol concentrations there is a decrease in the affinity of the noradrenaline transporters. The resulting uptake inhibition is counteracted at higher propofol concentrations by an increase in the efficacy of the uptake.

Effects of propofol on isolated human pial arteries.

BACKGROUND: The intravenous anaesthetic propofol has been reported to increase cerebral vascular resistance in vivo. The underlying mechanisms are not fully understood, but may include effects on metabolism and direct effects on the vascular smooth muscle. The present study was designed to evaluate the direct effects of propofol on human pial arteries. METHODS: We investigated the direct effect of propofol (10(-6)-10(-4) M) on isolated human pial arteries at basal tension as well as the influence on contractions induced by 5-hydroxytryptamine, prostaglandin F2alpha, noradrenaline and potassium chloride. RESULTS: Propofol did not change the basal tension. Propofol at 10(-6) and 10(-5) M did not affect the concentration-response curves of any of the contractile agents tested. Propofol at the supraclinical concentration 10(-4) M reduced the contractions induced by all contractile agents. CONCLUSION: Propofol reduces the tone of human pial arteries in vitro at supraclinical concentrations, but has no effect on the tone at clinically relevant concentrations.

Substance P relaxes rat bronchial smooth muscle via epithelial prostanoid synthesis.

BACKGROUND: Substance P is present in bronchial nerve fibres. The physiological actions of substance P are mediated via tachykinin NK(1) receptors. Immunochemical studies have demonstrated tachykinin NK(1) receptors in the rat airway epithelium. OBJECTIVE: To elucidate how epithelial tachykinin NK(1) receptors affect smooth muscle response to substance P. METHODS: Contractile response of isolated rat bronchial trunk with or without epithelium was recorded. RESULTS: In intact segments precontracted by 5-hydroxytryptamine, relaxation was induced by substance P and the nitric oxide donor, sodium nitroprusside. Removal of the epithelium abolished relaxation induced by substance P but did not affect relaxation induced by sodium nitroprusside. The cyclo-oxygenase inhibitor, indomethacin, but not the nitric oxide synthase inhibitor, L-N(G)-monomethylarginine, reduced the relaxation in response to substance P. CONCLUSIONS: Epithelial tachykinin NK(1) receptors mediate substance-P-induced relaxation of rat bronchial smooth muscle via release of prostanoids but not nitric oxide.

Characterization of 5-hydroxytryptamine receptors mediating circular smooth muscle contraction in the human umbilical artery.

The study was performed to characterize pharmacologically the contractile 5-hydroxytryptamine (5-HT) receptors in the circular smooth muscle of the isolated human umbilical artery. Effects of agonists and antagonists for different 5-HT receptor subtypes were studied in intact endothelium vessel segments. All agonists induced concentration-dependent circular smooth muscle contractions. The potency was in declining order 5-HT > alpha-methyl-5-HT > sumatriptan >/= 2-methyl-5-HT. The effects of 5-HT and alpha-methyl-5-HT were antagonized by ketanserin, as well as methiothepin. The contractile effect of sumatriptan was antagonized by methiothepin but not by ketanserin. The 5-HT3 receptor antagonist, MDL 72222, did not affect the contraction by any of the agonists, including 2-methyl-5-HT. It is concluded that the 5-HT-induced contraction in the circular smooth muscle of the human umbilical artery seems to be mediated by a mixed population of 5-HT1-like receptors and 5-HT2 receptors.

Differential effect of propofol on sympathetic neurotransmission in isolated human omental arteries and veins.

1. The present study was undertaken to elucidate the effect of propofol on sympathetic neurotransmission in isolated human omental vessels. 2. Segments of both arteries and veins were exposed to 0, 10(-7), 10(-6), 10(-5) or 10(-4)M propofol, and studied in vitro to determine effects on: (i) isometric tension after electrical field stimulation (EFS) or after exogenous administration of noradrenaline (NA); (ii) EFS-stimulated release of [3H]-NA from vessel segments preincubated with [3H]-NA; (iii) uptake of [3H]-NA. 3. Propofol at 10(-6) M enhanced EFS-induced contraction in artery segments, 10(-7) and 10(-5) M had no effect, and 10(-4) M propofol depressed EFS-induced contraction in both artery and vein segments. 4. Propofol did not affect the response to exogenous NA in artery and vein segments. 5. EFS-stimulated release of [3H]-NA was depressed by 10(-5) and 10(-4) M propofol in artery segments, and by 10(-4) M in vein segments. 6. Uptake of [3H]-NA was depressed by 10(-6)-10(-4) M propofol in artery but not in vein segments. 7. The results suggest that sympathetic neurotransmission is enhanced at clinical concentrations (10(-6) M) of propofol in human omental arteries, but not veins. This may be due to an increased availability of NA in the neuromuscular junction resulting from a reduced presynaptic reuptake. Propofol at probably supraclinical concentrations (10(-5)-10(-4) M) impairs the sympathetic neurotransmission in both human omental arteries and veins, probably due to an inhibitory effect on the NA release from the sympathetic nerves.

Endothelium-derived prostanoids reduce 5-hydroxytryptamine-induced contraction in the human uterine artery.

The contribution of endothelium-linked mechanisms to the contraction induced by 5-hydroxytryptamine (5-HT) was investigated in the isolated human uterine artery. 5-HT contracted the uterine artery concentration-dependently. Removal of the endothelium or treatment with the cyclooxygenase inhibitor indomethacin potentiated the contractile response to 5-HT. The nitric oxide synthase inhibitor L-N(G)-monomethyl-arginine (L-NMMA) did not influence the contraction induced by 5-HT. Indomethacin did not affect the response to 5-HT in endothelium-denuded vessels. The 5-HT1 receptor agonist 5-carboxyamidotryptamine (5-CT) did not relax precontracted arteries. Removal of the endothelium did not change the response to 5-HT in the presence of the 5-HT(1B/D) receptor antagonist GR127935 and the 5-HT1A and 5-HT1B receptor antagonist -pindolol. The 5-HT1B receptor antagonist SB224289 did not affect the contraction induced by 5-HT. The results indicate that the 5-HT-induced contraction in the human uterine artery is accompanied by the release of an endothelium-derived relaxing factor (EDRF). This EDRF seems to be a prostanoid, probably prostacyclin (PGI2). The endothelium-linked mechanism seems to be mediated via a 5-HT1 receptor, but it is not possible to further classify the receptor subtype by the information obtained in this study.