PST 2238: A new antihypertensive compound that modulates Na,K-ATPase in genetic hypertension. (1/315)

A genetic alteration in the adducin genes is associated with hypertension and up-regulation of the expression of renal Na, K-ATPase in Milan-hypertensive (MHS) rats, in which increased ouabain-like factor (OLF) levels are also observed. PST 2238, a new antihypertensive compound that antagonizes the pressor effect of ouabain in vivo and normalizes ouabain-dependent up-regulation of the renal Na-K pump, was evaluated for its ability to lower blood pressure and regulate renal Na,K-ATPase activity in MHS genetic hypertension. In this study, we show that PST 2238, given orally at very low doses (1 and 10 microg/kg for 5-6 weeks), reduced the development of hypertension in MHS rats and normalized the increased renal Na,K-ATPase activity and mRNA levels, whereas it did not affect either blood pressure or Na,K-ATPase in Milan-normotensive (MNS) rats. In addition, a similar antihypertensive effect was observed in adult MHS rats after a short-term treatment. In cultured rat renal cells with increased Na-K pump activity at Vmax due to overexpression of the hypertensive variant of adducin, 5 days of incubation with PST 2238 (10(-10-)-10(-9) M) lowered the pump rate to the level of normal wild-type cells, which in turn were not affected by the drug. In conclusion, PST 2238 is a very potent compound that in MHS rats reduces blood pressure and normalizes Na-K pump alterations caused by a genetic alteration of the cytoskeletal adducin. Because adducin gene mutations have been associated with human essential hypertension, it is suggested that PST 2238 may display greater antihypertensive activity in those patients carrying such a genetic alteration.  (+info)

Effects of an intubating dose of succinylcholine and rocuronium on the larynx and diaphragm: an electromyographic study in humans. (2/315)

BACKGROUND: Paralysis of the vocal cords is one objective of using relaxants to facilitate tracheal intubation. This study compares the neuromuscular blocking effect of succinylcholine and rocuronium on the larynx, the diaphragm, and the adductor pollicis muscle. METHODS: Electromyographic response was used to compare the neuromuscular blocking effect of succinylcholine and rocuronium on the laryngeal adductor muscles, the diaphragm, and the adductor pollicis muscle. Sixteen patients undergoing elective surgery were anesthetized with propofol and fentanyl, and their tracheas were intubated without neuromuscular blocking agents. The recurrent laryngeal and phrenic nerves were stimulated at the neck. The electromyographic response was recorded from electrodes placed on the endotracheal tube and intercostally before and after administration of 1 mg/kg succinylcholine or 0.6 mg/kg rocuronium. RESULTS: The maximum effect was greater at the adductor pollicis (100 and 99%) than at the larynx (96 and 97%) and the diaphragm (94 and 96%) after administration of succinylcholine and rocuronium, respectively (P < or = 0.05). Onset time was not different between the larynx (58+/-10 s), the diaphragm (57+/-8 s), and the adductor pollicis (54+/-13 s), after succinylcholine (all mean +/- SD). After rocuronium, onset time was 124+/-39 s at the larynx, 130+/-44 s at the diaphragm, and 115+/-21 s at the adductor pollicis. After succinylcholine administration, time to 90% recovery was 8.3+/-3.2, 7.2+/-3.5, and 9.1+/-3.0 min at the larynx, the diaphragm, and the adductor pollicis, respectively. Time to 90% recovery after rocuronium administration was 34.9+/-7.6, 30.4+/-4.2, and 49.1+/-11.4 min at the larynx, the diaphragm, and the adductor pollicis, respectively. CONCLUSION: Neuromuscular blocking effect of muscle relaxants on the larynx can be measured noninvasively by electromyography. Although the larynx appears to be resistant to muscle relaxants, we could not demonstrate that its onset time differed from that of peripheral muscles.  (+info)

sgk is an aldosterone-induced kinase in the renal collecting duct. Effects on epithelial na+ channels. (3/315)

The early phase of the stimulatory effect of aldosterone on sodium reabsorption in renal epithelia is thought to involve activation of apical sodium channels. However, the genes initiating this effect are unknown. We used a combination of polymerase chain reaction-based subtractive hybridization and differential display techniques to identify aldosterone-regulated immediate early genes in renal mineralocorticoid target cells. We report here that aldosterone rapidly increases mRNA levels of a putative Ser/Thr kinase, sgk (or serum- and glucocorticoid-regulated kinase), in its native target cells, i.e. in cortical collecting duct cells. The effect occurs within 30 min of the addition of aldosterone, is mediated through mineralocorticoid receptors, and does not require de novo protein synthesis. The full-length sequences of rabbit and mouse sgk cDNAs were determined. Both cDNAs show significant homology to rat and human sgk (88-94% at the nucleotide level, and 96-99% at the amino acid level). Coexpression of the mouse sgk in Xenopus oocytes with the three subunits of the epithelial Na+ channel results in a significantly enhanced Na+ current. These results suggest that sgk is an immediate early aldosterone-induced gene, and this protein kinase plays an important role in the early phase of aldosterone-stimulated Na+ transport.  (+info)

Augmentation of the rocuronium-induced neuromuscular block by the acutely administered phenytoin. (4/315)

BACKGROUND: The effects of an acute administration of phenytoin on the magnitude of the rocuronium-induced neuromuscular block were evaluated. METHODS: Twenty patients (classified as American Society of Anesthesiologists physical status I or II) scheduled for craniotomy were studied: 15 received phenytoin during operation (10 mg/kg), and the others served as controls. Anesthesia was induced with thiopental and fentanyl and maintained with nitrous oxide (65%) in oxygen and end-tidal isoflurane (1%). The ulnar nerve was stimulated supramaximally and the evoked electromyography was recorded using a neuromuscular transmission monitor. Continuous infusion of rocuronium maintained the neuromuscular block with first twitch (T1) between 10 and 15% for 45 min before the start of an infusion of either phenytoin or NaCl 0.9%. Twitch recordings continued for 60 min thereafter. Arterial blood samples were collected at the predefined time points (four measurements before and four after the start of the infusion) to determine the concentrations of phenytoin and rocuronium and the percentage of rocuronium bound to plasma proteins. RESULTS: The first twitch produced by an infusion of rocuronium remained constant during the 15 min before and the 60 min after the start of the saline infusion. After the phenytoin infusion, the twitch decreased progressively, but the plasma concentrations and the protein-bound fraction of rocuronium did not change. CONCLUSION: Phenytoin acutely augments the neuromuscular block produced by rocuronium without altering its plasma concentration or its binding to plasma proteins.  (+info)

Rapid tracheal intubation with rocuronium: a probability approach to determining dose. (5/315)

BACKGROUND: Rapid tracheal intubation with rocuronium has not been studied using a probability-based approach. The authors aimed to predict doses of rocuronium giving 90% and 95% probability of in intubation within 60 s and to estimate their durations of action. METHODS: After premedication with midazolam, 2 mg, anesthesia was induced in 80 subjects with fentanyl, 2 microg/kg, followed 3 min later by propofol, 2 mg/kg. Patients received randomly rocuronium, 0.0, 0.4, 0.8, or 1.2 mg/kg (n = 20/ dose). Laryngoscopy began 40 s later, aiming for intubation at 60 s, and conditions were graded perfect, acceptable, or unacceptable, with the first two conditions being successful intubation. Anesthesia was maintained with isoflurane 0.5-1.0% (end-tidal) and fentanyL Duration of action was time until reappearance of the first tactile train-of-four response. The dose versus fraction of patients with successful intubation was analyzed by logistic regression. Doses giving 90% and 95% (D90 and D95) probability of successful intubation were calculated. RESULTS: intubation was successful in 7, 11, 18, and 19 patients in the 0.0, 0.4, 0.8, and 1.2 mg/kg groups, respectively. The D90 and D95 doses (95% confidence limits in parentheses) were 0.83 (0.59-1.03) and 1.04 (0.76-1.36) mg/kg, respectively. Estimated time until first tactile train-of-four response after D90 and D95 doses was 32 and 46 min, respectively. CONCLUSIONS: After induction with fentanyl and propofol, rocuronium, 1.04 mg/kg gives 95% probability of successful intubation at 60 s.  (+info)

Intramuscular rocuronium in infants and children: a multicenter study to evaluate tracheal intubating conditions, onset, and duration of action. (6/315)

BACKGROUND: This multicenter, assessor-blinded, randomized study was done to confirm and extend a pilot study showing that intramuscular rocuronium can provide adequate tracheal intubating conditions in infants (2.5 min) and children (3 min) during halothane anesthesia. METHODS: Thirty-eight infants (age range, 3-12 months) and 38 children (age range, 1 to 5 yr) classified as American Society of Anesthesiologists physical status 1 and 2 were evaluated at four investigational sites. Anesthesia was maintained with halothane and oxygen (1% end-tidal concentration if <2.5 yr; 0.80% end-tidal concentration if >2.5 yr) for 5 min. One half of the patients received 0.45 mg/kg intravenous rocuronium. The others received 1 mg/kg (infants) or 1.8 mg/kg (children) of intramuscular rocuronium into the deltoid muscle. Intubating conditions and mechanomyographic responses to ulnar nerve stimulation were assessed. RESULTS: The conditions for tracheal intubation at 2.5 and 3 min in infants and children, respectively, were inadequate in a high percentage of patients in the intramuscular group. Nine of 16 infants and 10 of 17 children had adequate or better intubating conditions at 3.5 and 4 min, respectively, after intramuscular rocuronium. Better-than-adequate intubating conditions were achieved in 14 of 15 infants and 16 of 17 children given intravenous rocuronium. Intramuscular rocuronium provided > or =98% blockade in 7.4+/-3.4 min (in infants) and 8+/-6.3 min (in children). Twenty-five percent recovery occurred in 79+/-26 min (in infants) and in 86+/-22 min (in children). CONCLUSIONS: Intramuscular rocuronium, in the doses and conditions tested, does not consistently provide satisfactory tracheal intubating conditions in infants and children and is not an adequate alternative to intramuscular succinylcholine when rapid intubation is necessary.  (+info)

Effects of priming with pancuronium or rocuronium on intubation with rocuronium in children. (7/315)

Rocuronium is a non-depolarizing neuromuscular blocking agent which has a rapid onset and intermediate duration of action. The goal of this study was to compare the neuromuscular blocking actions of rocuronium with and without a priming dose of pancuronium or rocuronium in children. Thirty patients were randomly allocated into 3 groups. Ten patients received a single dose of 0.6 mg/kg rocuronium (Group I). The others received either 0.015 mg/kg pancuronium (Group II) or 0.06 mg/kg rocuronium (Group III) 3 minutes before an intubating dose of 0.54 mg/kg rocuronium was given. Neuromuscular blockade was measured via accelerographic response to single stimulations (1 Hz) of the ulnar nerve until maximal twitch depression was reached followed by train-of-four (TOF) stimuli (2 Hz) at 15 second intervals for the remainder of recovery. Groups were compared with regard to onset time, duration and recovery indices. The onset time and duration of block did not differ significantly between groups. However, the time to recovery in group II (24.5 +/- 9.9 min) was significantly prolonged compared to that in group I (12.7 +/- 3.1 min) or group III (12.7 +/- 3.9 min). We concluded that the use of rocuronium with a preceding dose of either pancuronium or rocuronium provided no advantage for intubation in children.  (+info)

Spontaneous or neostigmine-induced recovery after maintenance of neuromuscular block with Org 9487 (rapacuronium) or rocuronium following an initial dose of Org 9487. (8/315)

We have examined spontaneous and neostigmine-induced recovery after an initial dose of Org 9487 1.5 mg kg-1 followed by three repeat doses of Org 9487, a 30-min infusion of Org 9487 or two incremental doses of rocuronium. Mean clinical duration after incremental doses of Org 9487 0.5 mg kg-1 increased from 12.3 (SD 3.4) min to 14.0 (4.0) and 15.9 (5.9) min (P < 0.01), and after rocuronium from 14.4 (5.2) min to 19.2 (5.9) min (P < 0.01). Times for spontaneous recovery from a T1 of 25% to a TOF ratio of 0.8 after the last bolus dose of Org 9487 and after a 30-min infusion were 72.4 (16.5) and 66.1 (26.9) min compared with 36.7 (15.8) min in the group receiving reocuronium. These times were significantly reduced to 9.9 (4.5), 8.6 (6.1) and 5.7 (2.5) min, respectively, after neostigmine administration at a T1 of 25% (P < 0.05). We conclude that administration of Org 9487 by repeat bolus doses or infusion was associated with slow spontaneous recovery but neostigmine administration resulted in adequate recovery in less than 10 min.  (+info)

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