Potency and recovery characteristics of rocuronium mixed with sodium bicarbonate.

Sodium bicarbonate may be added to rocuronium to decrease pain on injection. However, this mixture may result in the formation of carbon dioxide bubbles. We investigated whether the addition of sodium bicarbonate to rocuronium alters neuromuscular blockade, in 120 patients randomly assigned to receive rocuronium mixed with saline or bicarbonate 8.4%, either in varying doses (for dose-response measurements; 60 patients) or a fixed dose of 600 µg.kg(-1) (for time-course measurements; 60 patients). Sodium bicarbonate resulted in a left-shift of the rocuronium dose-response curve. The effective doses of rocuronium to produce 95% twitch depression were 331.6 (95% CI: 310.4-352.8) and 284.3 (95% CI: 262.0-306.6) µg.kg(-1) mixed with isotonic saline or sodium bicarbonate, respectively (p < 0.001). The mean (SD) onset times of rocuronium 600 µg.kg(-1) were 3.6 (0.6) and 2.7 (0.5) min in the corresponding groups, respectively (p < 0.001). The mean (SD) times to 95% recovery were 35.8 (5.8) and 47.9 (7.1) min, respectively (p < 0.001). We conclude that the mixing of sodium bicarbonate with rocuronium enhances the potency, shortens the onset and prolongs the duration of action.

Urinary N-acetyl-beta-D-glucosaminidase and malondialdehyde as a markers of renal damage in burned patients.

This study was aimed to evaluate renal dysfunction during three weeks after the burn injuries in 12 patients admitted to the Hallym University Hankang Medical Center with flame burn injuries (total body surface area, 20-40%). Parameters assessed included 24-hr urine volume, blood urea nitrogen, serum creatinine, creatinine clearance, total urinary protein, urinary microalbumin, 24-hr urinary N-acetyl-beta-D-glucosaminidase (NAG) activity, and urinary malondialdehyde (MDA). Statistical analysis was performed using repeated measures ANOVA test. The 24-hr urine volume, creatinine clearance, and urinary protein significantly increased on day 3 post-burn and fell thereafter. The urine microalbumin excretion showed two peak levels on day 0 post-burn and day 3. The 24-hr urinary NAG activity significantly increased to its maximal level on day 7 post-burn and gradually fell thereafter. The urinary MDA progressively increased during 3 weeks after the burn injury. Despite recovery of general renal function through an intensive care of burn injury, renal tubular damage and lipid peroxidation of the renal tissue suggested to persist during three weeks after the burn. Therefore, a close monitoring and intensive management of renal dysfunction is necessary to prevent burn-induced acute renal failure as well as to lower mortality in patients with major burns.

Modification of cardiovascular responses to adenosine A1 receptor stimulation in the posterior hypothalamus of anaesthetized rats by cAMP and by GABA(B) receptor blockade.

1 Injection of N(6)-cyclohexyladenosine (CHA; 1, 5 and 10 nmol), an adenosine A1 receptor agonist, into the posterior hypothalamus of rats produced a dose-dependent decrease in blood pressure (BP) and heart rate (HR). 2 Pretreatment with 8-cyclopentyl-1,3-dimethylxanthine (CPDX; 50 nmol), an adenosine A1 receptor antagonist, blocked the depressor and bradycardic effects of CHA (10 nmol). 3 Pretreatment with 8-bromo-cyclic adenosine monophosphate (AMP) (10 nmol), a cAMP analogue, attenuated the depressor and bradycardic effect of CHA (10 nmol); 8-bromo-cyclic guanosine monophosphate (GMP) (10 nmol), a cGMP analogue, did not modify those effects of CHA. 4 In addition, pretreatment with 5-aminovaleric acid (25 nmol), a gamma-aminobutyric acid (GABA)(B) receptor antagonist, attenuated the depressor and bradycardic effects of CHA (10 nmol). 5 These results suggest that adenosine A1 receptors in the posterior hypothalamus have an inhibitory role in the central cardiovascular regulation and that these vasodepressive and bradycardic actions are modified by raised cAMP and by GABA(B) receptor inhibition.

Mediation of the cardiovascular response to spinal gamma-aminobutyric acid(B) receptor stimulation by adenosine A(1) receptors in anesthetized rats.

Cardiovascular inhibitory effects induced by intrathecal (i.t.) administration of adenosine A(1) receptor agonist and its modulation by gamma-aminobutyric acid(B) (GABA(B)) receptor was suggested by our previous report. In this experiment, we examined the mediation of cardiovascular effects of GABA(B) receptor stimulation by adenosine A(1) and A(2) in the spinal cord. I.t. administration of GABA(B) receptor agonist, baclofen (30, 60 and 100 nmol) produced a dose dependent decrease of blood pressure and heart rate. Pretreatment with adenosine A(1) receptor antagonist, 8-cyclopentyl-1,3-dimethylxanthine (50 nmol), attenuated the depressor and bradycardiac effects of baclofen (100 nmol), but not with adenosine A(2) receptor antagonist, 3, 7-dimethyl-1-propargylxanthine (25 nmol). These results suggest that GABA(B) receptors in the spinal cord play an inhibitory role in the central cardiovascular regulation and that the depressor and bradycardiac actions are mediated by adenosine A(1) receptors.

Modification of cardiovascular response of adenosine A2 receptor agonist by adenylate cyclase in the spinal cord of rats.

This study was performed to investigate the influence of spinal adenosine A2 receptors on the central regulation of blood pressure (BP) and heart rate (HR), and to define whether its mechanism is mediated by adenylate cyclase or guanylate cyclase. Intrathecal (i.t.) administration of drugs at the thoracic level were performed in anesthetized, artificially ventilated male Sprague-Dawley rats. Injection (i.t.) of adenosine A2 receptor agonist, 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA; 1, 2 and 3 nmol) produced a dose dependent decrease of BP and HR. Pretreatment with adenylate cyclase inhibitor, MDL-12,330, attenuated the depressor and bradycardiac effects of CPCA (2 nmol), but not with guanylate cyclase inhibitor, LY-83,583. These results suggest that adenosine A2 receptor in the spinal cord plays an inhibitory role in the central cardiovascular regulation and that the depressor and bradycardiac actions are mediated by adenylate cyclase.

Phenotypes of flavin-containing monooxygenase activity determined by ranitidine N-oxidation are positively correlated with genotypes of linked FM03 gene mutations in a Korean population.

A non-invasive urine analysis method to determine the in-vivo flavin-containing mono-oxygenase (FMO) activity catalysing N-oxidation of ranitidine (RA) was developed and used to phenotype a Korean population. FMO activity was assessed by the molar concentration ratio of RA and RANO in the bulked 8 h urine. This method was used to determine the FMO phenotypes of 210 Korean volunteers (173 men and 37 women, 110 nonsmokers and 100 smokers). Urinary RA/RANO ratio, representing the metabolic ratio and the reciprocal index of FMO activity, ranged from 5.67-27.20 (4.8-fold difference) and was not different between men and women (P = 0.76) or between smokers and nonsmokers (P = 0.50). The frequencies of RA/RANO ratios were distributed in a trimodal fashion. Among the 210 Korean subjects, 93 (44.3%) were fast metabolizers, 104 (49.5%) were intermediate metabolizers and 13 (6.2%) were slow metabolizers. Subsequently, the relationship between the ranitidine N-oxidation phenotypes and FMO3 genotypes, determined by the presence of two previously identified mutant alleles (Glu158Lys: FMO3/Lys158 and Glu308Gly: FMO3/Gly308 alleles) commonly found in our Korean population was examined. The results showed that subjects who were homozygous and heterozygous for either one or both of the FMO3/Lys158 and FMO3/Gly308 mutant alleles had significantly lower in-vivo FMO activities than those with homozygous wild-type alleles (FMO3/Glu158 and FMO3/Glu308) (P < 0.001, Mann-Whitney U-test). Furthermore, the FMO activities of subjects with either FMO3/Lys158 or FMO3/Gly308 mutant alleles were almost identical to those having both FMO3 mutant alleles (FMO3/Lys158 and FMO3/Gly308). These two mutant alleles located, respectively, at exons 4 and 7 in the FMO3 gene appeared to be strongly linked by cis-configuration in Koreans. Therefore, we concluded that presence of FMO3/Lys158 and FMO3/Gly308 mutant alleles in FMO3 gene is responsible for the low ranitidine N-oxidation (FMO3 activity) in our Korean population.

Modification of cardiovascular responses to spinal GABA(B) receptor stimulation by cAMP and by K(ATP) channel blockade in anaesthetized rats.

1. Intrathecal (i.t.) injection of baclofen (30, 60 and 100 nmol), a GABA(B) receptor agonist, produced a dose-dependent decrease in blood pressure (BP) and heart rate (HR). 2. Pretreatment with 5-aminovaleric acid (50 nmol), a GABA(B) receptor antagonist, blocked the depressor and bradycardic effects of baclofen (100 nmol). 3. Pretreatment with 8-bromo-cAMP (10 nmol), a cAMP analogue, attenuated the depressor and bradycardic effects of baclofen (100 nmol), but not with 8-bromo-cGMP (10 nmol), a cGMP analogue. 4. In addition, pretreatment with glipizide (20 nmol), an ATP-sensitive K+ channel (K(ATP)) blocker, attenuated the depressor and bradycardic effects of baclofen (100 nmol). These results suggest that GABA(B) receptors in the spinal cord have an inhibitory role in the central cardiovascular regulation and that these depressive and bradycardic actions are modified by cAMP and by K(ATP) channel blockade.

Rac GTPase activity is essential for EGF-induced mitogenesis.

Rac, a member of the Rho family GTPases, has been implicated in the regulation of a wide range of biological processes including actin remodeling, cell transformation, G1 cell cycle progression, and gene expression. To determine whether Rac GTPase activity is required for epidermal growth factor-induced mitogenesis, Rat-2 stable cells expressing a dominant-negative Rac1 mutant, RacN17, were prepared. Exposure to EGF exhibited a significantly restricted growth response in Rat-2-RacN17 cells compared to Rat-2 parental cells, suggesting an essential role of Rac in EGF-induced mitogenesis. In contrast, addition of lysophosphatidic acid exerted the same level of growth in Rat-2 and Rat-2-RacN17 cells. To gain further evidence for the essential role of Rac in EGF-induced mitogenesis, we performed the microinjection experiment. EGF-induced DNA synthesis was significantly blocked by microinjection of recombinant RacN17 protein, and not control IgG. Our further study to analyze the downstream mediator of Rac in EGF-signaling to mitogenesis demonstrated that Rac-activated phospholipase A2 plays a critical role. Taken together, our results suggest that the "Rac and Rac-activated PLA2" cascade is one of the major mitogenic pathways induced by EGF.

Mediation of the cardiovascular response of adenosine A1 receptor through a GABA(B) receptor in the spinal cord of the rat.

Cardiovascular inhibitory effects induced by intrathecal (i.t.) administration of adenosine A1 receptor agonist and its modulation by cyclic AMP was suggested by our previous report. In this experiment, we examined the mediation of cardiovascular effects of adenosine A1 receptor by gamma-aminobutyric acid receptors A and B [GABA(A) and GABA(B)] in the spinal cord. I.t. administration of 10 nmol of N6-cyclohexyladenosine (CHA), an adenosine A1 receptor agonist, and pretreatment with bicuculline (10 nmol, i.t), a GABA(A) receptor antagonist, and 5-aminovaleric acid (50 nmol, i.t.), a GABA(B) receptor antagonist, prior to injection of CHA were performed in anesthetized, artificially ventilated Sprague-Dawley rats. I.t. injection of 50 nmol of 5-aminovaleric acid significantly attenuated the inhibitory cardiovascular effects of CHA but 10 nmol of bicuculline did not alter CHA-induced cardiovascular actions. It is suggested that cardiovascular responses of adenosine A1 receptor is mediated by GABA(B) receptor in the spinal cord.

Differential coupling of G alpha q family of G-protein to muscarinic M1 receptor and neurokinin-2 receptor.

The ligand binding signals to a wide variety of seven transmembrane cell surface receptors are transduced into intracellular signals through heterotrimeric G-proteins. Recently, there have been reports which show diverse coupling patterns of ligand-activated receptors to the members of Gq family alpha subunits. In order to shed some light on these complex signal processing networks, interactions between G alpha q family of G protein and neurokinin-2 receptor as well as muscarinic M1 receptor, which are considered to be new therapeutic targets in asthma, were studied. Using washed membranes from Cos-7 cells co-transfected with different G alpha q and receptor cDNAs, the receptors were stimulated with various concentrations of carbachol and neurokinin A and the agonist-dependent release of [3H]inositol phosphates through phospholipase C beta-1 activation was measured. Differential coupling of G alpha q family of G-protein to muscarinic M1 receptor and neurokinin-2 receptor was observed. The neurokinin-2 receptor shows a ligand-mediated response in membranes co-transfected with G alpha q, G alpha 11 and G alpha 14 but not G alpha 16 and the ability of the muscarinic M1 receptor to activate phospholipase C through G alpha q/11 but not G alpha 14 and G alpha 16 was demonstrated. Clearly G alpha q/11 can couple M1 and neurokinin-2 receptor to activate phospholipase C. But, there are differences in the relative coupling of the G alpha 14 and G alpha 16 subunits to these receptors.

Modification of cardiovascular response of adenosine A1 receptor agonist by cyclic AMP in the spinal cord of the rats.

This study was performed to investigate the influence of the spinal adenosine A1 receptors on the central regulation of blood pressure (BP) and heart rate (HR), and to define whether its mechanism is mediated by cyclic AMP (cAMP) or cyclic GMP (cGMP). Intrathecal (i.t.) administration of drugs at the thoracic level were performed in anesthetized, artificially ventilated male Sprague-Dawley rats. Injection (i.t.) of adenosine A1 receptor agonist, N6-cyclohexyladenosine (CHA; 1, 5 and 10 nmol) produced dose dependent decrease of BP and HR. Pretreatment with a cAMP analogue, 8-bromo-cAMP, attenuated the depressor and bradycardiac effects of CHA (10 nmol), but not with cGMP analogue, 8-bromo-cGMP. These results suggest that adenosine A1 receptor in the spinal cord plays an inhibitory role in the central cardiovascular regulation and that this depressor and bradycardiac actions are mediated by cAMP.