We have measured the direct effects of propofol 10(-7)-10(-4) mol litre-1 on isolated canine cerebral, coronary, mesenteric, femoral and renal arteries. In arterial strips precontracted submaximally with potassium chloride or prostaglandin F2 alpha (PGF2 alpha), propofol induced further contractions at low concentrations (10(-6)-10(-5) mol litre-1) and relaxation at high concentrations (10(-4) mol litre-1). Intrafat, which contains soya bean oil, egg phosphatide and glycerol in similar concentration to the emulsion formulation of propofol, had a small relaxant effect at a concentration corresponding to propofol 10(-4) mol litre-1. In humans, clinically relevant plasma concentrations of propofol have been reported to be 1-5 x 10(-5) mol litre-1, 97-99% of which is bound to plasma proteins. Therefore, the results obtained in this study demonstrated that clinically relevant concentrations of propofol did not have direct vasodilator effects.

Six new xenicane diterpenes have been isolated from the acetone extract of the soft coral Xenia florida. Two of them are diterpenes containing a bicyclic [4.3.1] ring system. Three of them seem to be precursors for diterpenes possessing the bicyclic [4.3.1] ring system. One is a common monocarbocyclic diterpene with a cyclononane skeleton.

Recently, it has been shown that endoplasmic reticulum (ER) stress causes apoptosis. However, the mechanism of the ER stress-dependent pathway is not fully understood. In human neuroblastoma SH-SY5Y cells, we detected a caspase-12-like protein that has a molecular mass (approximately 60 kDa) similar to that of mouse caspase-12. Thapsigargin, an inhibitor of ER-associated Ca(2+)-ATPase, induced the degradation of caspase-12-like protein. In addition, the degradation of caspases-9 and -3, cleavage of poly(ADP-ribose) polymerase, DNA fragmentation, and cell death were also observed. Pretreatment with phorbol-12-myristate-13-acetate, which induces the expression of antiapoptotic Bcl-2, inhibited thapsigargin-induced degradation of caspases-9 and -3, but not caspase-12-like protein degradation. A caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp(OCH(3))-CH(2)F, inhibited the degradation of caspase-12-like protein, but not that of caspases-9 and -3. These results suggest that thapsigargin may induce the activation of both ER- and mitochondria-dependent pathways in human SH-SY5Y cells.

The findings that sevoflurane suppressed the effects of arachidonic acid, but not those of prostaglandin G2 and STA2, suggest strongly that sevoflurane inhibited TXA2 formation by suppressing cyclooxygenase activity. Halothane appeared to suppress both TXA2 formation and binding to its receptors. Sevoflurane has strong antiaggregatory effects at subanesthetic concentrations (greater than 0.13 mM; i.e., approximately 0.5 vol/%), whereas halothane has similar effects at somewhat greater anesthetic concentrations (0.49 mM; i.e., approximately 0.54 vol/%). Isoflurane at clinical concentration (0.84 mM; i.e., approximately 1.82 vol/%) does not affect platelet aggregation significantly.

Volatile anaesthetics inhibit endothelium-dependent relaxation, but the underlying mechanism(s) have not been clarified. In an attempt to elucidate the mechanism(s), we determined the effects of halothane, isoflurane and sevoflurane on relaxation induced by acetylcholine and sodium nitroprusside (SNP) and the cGMP formation elicited by exogenous nitric oxide (NO) and SNP in rat aortas. Acetylcholine (10(-7)-10(-5) M)-induced relaxation was attenuated by halothane (2%), isoflurane (2%) and sevoflurane (4%). SNP (10(-8) M)-induced relaxation was reduced by halothane (2%), but not by isoflurane (2%) or sevoflurane (4%). The cGMP level of NO-stimulated aorta was reduced by halothane (2%) and sevoflurane (4%), but not by isoflurane (2%). The cGMP level of SNP (10(-7) M)-stimulated aorta was reduced by halothane (2%), but not by isoflurane (2%) and sevoflurane (4%). We conclude that the mechanisms responsible for the inhibition of endothelium-dependent relaxation differ among anaesthetics. Isoflurane inhibits the relaxation mainly by inhibiting the formation of NO in the endothelium. In contrast, the effect of halothane on endothelium-dependent relaxation may be largely due to the inhibition of action of NO in the vascular smooth muscle and the effect of sevoflurane may be to inactivate NO or to inhibit the action of NO.

No abstract

Platelet aggregation is impaired during anaesthesia with sevoflurane but not with isofluranePurpose: Halothane suppresses platelet aggregation in vitro and ex vivo, and prolongs bleeding time. In a previous in vitro study we demonstrated ~ sevoflurane had a more suppressive effect on platelet aggregation than did halo~hane. The present study i~ whel~ the clinical use of sevollurane aliected plamlet al~,regation ex vivo. Methods: Thirty-eight patients undergoing minor elective surgery were divided randomly into sevoflurane and isoflurane groups. Anaesthesia was induced with thiopentone iv, and was malntainecl with sevoflurane or isoflurane with nitrous oxide. Blood was collected to measure platelet aggregation induced by adenosine diphosphate (ADP) and epinephrine. The first (control) blood collection was performed in the operating room before induction of anaesthesia, and the second 5-I 0 rain after tracheal intubation but before the start of surgery, when the end-expiratory sevoflurane or isoflurane concentrations had stabilised at I-I .S times the minimum alveolar concentration (MAC) and mean arterial pressures were between 80-I 20% of preanaesthetic values. Results: In all samples obtained during sevoflurane anaesthesia (n = 15), ADP and epinephrine could not induce secondary a~regation, although they did induce primary a~egation. In contrast, in the isoflurane group, both primary and secondary aggregation were observed in 14 out of 15 patients, and secondary aggregation was abolished in only one of the samples obtained during anaesthesia. Conclusion: Sevoflurane, but not isoflurane, alters platelet aggregation in the clinical situation, possibly by suppression of thromboxane A~ formation.Objectif: Uhalothane inhibe l'agr~tion plaquettalre in v/fro et in vivo et prolonge le temps de saignement. Nous avons antEdeurernent d~montr6 que le s(~voflurane avalt un effet inhibiteur in vitro plus important sur l'a~t~tion plaquettaire que l'halothane. La prOsente ~ude a pour but de v&ifier si l'usage clinique du s~voflurane affecte ragr~gation plaquettalre in vivo. M&hodes : Trente-huit patients soumis ~ une chirurgie Elective mineure r~partis au hasard en groupe s~voflu-rane et groupe isoflurane participaient A l'&ude, l'anesth~sie &ait induite au thiopental/v, et entretenue au s~-voflurane ou A l'isoflurane avec du protoxyde d'azote. Du sang 6tait recueilli pour la mesure de l'agr~gation plaquettaire induite par le diphosphate d'ad~nosine (ADP) et l'6pin~phrine. Le premier 6chantillon sanguin (contr61e) c~tait recueilli en salle d'op&ation avant rinduction de l'anesth~sie et le second, 5-10 rain aprEs l'intubation irachicle et avant le d~but de rintervention apr(~s stabilisation des concentrations t61&expiratoires de s~voflurane et d'isoflurane A I-1,5 lois la concentration alv~,olaire minimale (MAC) de rn~me que de la pression artErielle moyenne A 80-120% des valeurs pr~anestl~siques. R~ultats : MalgrE une agr6gation primaire, I'ADP et l'6pin6phrine n'ont induit l'agr~ation secondaire dans aucun des Echantillons rec...

The DNA replication-related element binding factor (DREF) plays an important role in regulation of cell proliferation in Drosophila, binding to DRE and activating transcription of genes carrying this element in their promoter regions. Overexpression of DREF in eye imaginal discs induces a rough eye phenotype in adults, which can be suppressed by half dose reduction of the osa or moira (mor) genes encoding subunits of the BRM complex. This ATP-dependent chromatin remodeling complex is known to control gene expression and the cell cycle. In the 5′ flanking regions of the osa and mor genes, DRE and DRE-like sequences exist which contribute to their promoter activities. Expression levels and promoter activities of osa and mor are decreased in DREF knockdown cells and our results in vitro and in cultured cells indicate that transcription of osa and mor is regulated by the DRE/DREF regulatory pathway. In addition, mRNA levels of other BRM complex subunits and a target gene, string/cdc25, were found to be decreased by knockdown of DREF. These results indicate that DREF is involved in regulation of the BRM complex and thereby the cell cycle.