Reduced response of the hypothalamo-pituitary-adrenal axis to alpha1-agonist stimulation during lactation.

To determine whether altered noradrenergic activation of the hypothalamo-pituitary-adrenal (HPA) axis contributes to the attenuated neuroendocrine response to stress observed during lactation, the effect of intracerebroventricular injection of the alpha1-agonist methoxamine (100 microg) was compared between virgin and lactating rats. Virgin rats showed significant increases in plasma corticosterone after methoxamine, reaching 317 +/- 44 ng/ml at 10 min and remaining significantly elevated for more than 120 min, but lactating rats showed no significant increase in corticosterone levels. Furthermore, methoxamine induced an increase in paraventricular nucleus (PVN) CRF messenger RNA expression in virgin, but not lactating, animals. Both groups of rats exhibited comparable elevations in plasma PRL after methoxamine treatment. Arginine vasopressin messenger RNA expression within the parvocellular PVN was greater in the lactating animals than in the virgin controls, but methoxamine injection was without further effect. Studies performed on ovariectomized virgin rats and ovariectomized rats receiving estradiol or progesterone replacement failed to reproduce the attenuated HPA responses seen after methoxamine treatment, although methoxamine-induced PRL levels were greatly increased by estradiol, probably arising from an effect on hormone synthesis. In vitro electrophysiological recordings of PVN neurons in hypothalamic slices from proestrous virgin and lactating rats showed that 45-52% of neurons in both groups exhibited excitatory responses to 10(-4) M methoxamine, but there was a differential response to 10(-5) M methoxamine, with PVN neurons from lactating animals failing to show a response. These data show a selective down-regulation of alpha1-mediated activation of the HPA axis in lactating animals. This may contribute to the attenuated stress-induced activation of the HPA axis during lactation.

AY-31,906, a novel high ceiling diuretic: characterization of its relative potassium-sparing actions in rats and dogs.

AY-31,906, exo-2-amino-4-[(bicyclo[2.2.1]hept-2-yl)amino-N-[[1- methylethyl)amino]carbonyl]-5-pyrimidinesulfonamide, exhibited potent diuretic and natriuretic activity in rats and dogs. After p.o. administration, AY-31,906 was 1.5- and 12.3-times more potent as a natriuretic than furosemide in rats and dogs, respectively, whereas it was 0.5- and 6.1-times as potent after i.v. administration. The maximum natriuretic effect of AY-31,906 in both species was similar to that observed with furosemide. At equiactive natriuretic p.o. doses in both species, AY-31,906 produced a greater increase in the urinary ratio of Na/K than furosemide, indicating a relative potassium-sparing effect. AY-31,906 produced significant increases in the fractional excretion of sodium and chloride in dogs at a dose that produced no statistically significant changes in the fractional excretion of potassium, glomerular filtration rate or renal plasma flow. After p.o. administration, the onset of activity of AY-31,906 occurred within the 1st hr in both rats and dogs and preliminary data demonstrated that the activity lasted for approximately 2 hr in rats and 4 hr in dogs. Clearance studies in conscious dogs suggest that AY-31,906 inhibited electrolyte reabsorption in the ascending limb of the loop of Henle and, unlike furosemide, AY-31,906 had no activity at the proximal tubule. These results indicate that AY-31,906 is a potent, high ceiling diuretic with relative potassium-sparing properties. The compound is well absorbed after p.o. administration with diuretic activity occurring in the 1st hr.

Analgesia after hip replacement surgery: comparison of nalbuphine with morphine.

Two groups of 40 patients undergoing hip replacement received either nalbuphine 0.3 mg kg-1 or morphine 0.15 mg kg-1 i.m. on up to three occasions: 1 h before operation, as soon as requested after operation, and 3 h subsequently if required. Pain intensity was assessed by the patient as severe, moderate or none, and pain relief by a "blind" nurse observer as slight, moderate or complete. Assessments of pain and sedation were carried out at 30-min intervals for 2 h and at 1-h intervals thereafter for up to 6 h. Six patients who received nalbuphine and eight who received morphine before operation required no postoperative analgesia. Ten patients in the nalbuphine group and two in the morphine group failed to obtain adequate pain relief (P less than 0.05) and were given i.v. morphine.

Administration of vecuronium, atracurium and pancuronium in divided doses: effect on onset and duration of action.

The time to onset of neuromuscular block (as assessed by single twitch stimulation at 0.1 Hz) and the duration to 25% recovery of twitch height were measured after administration of vecuronium 0.1 mg kg-1, atracurium 0.5 mg kg-1 or pancuronium 0.1 mg kg-1, administered either as a single bolus or in divided doses, 10% being administered 4 min prior to the remaining 90%. The patients were anaesthetized with thiopentone, nitrous oxide in oxygen and i.v. fentanyl. There was no significant difference between the single- and divided-dose groups, either in the onset times (2.8 and 2.9 min for vecuronium, 2.7 and 2.4 min for atracurium and 3.3 min each for pancuronium for single- and divided-dose groups, respectively) or the duration to 25% recovery of twitch height (35 and 29 min for vecuronium, 45 and 39 min for atracurium and 87 and 93 min for pancuronium for single- and divided-dose groups, respectively).

Quantification of train-of-four responses during recovery of block from non-depolarising muscle relaxants.

Train-of-four (TOF) responses were assessed in 70 patients (seven groups of ten patients each) during recovery of neuromuscular block from atracurium (226 or 452 micrograms/kg), vecuronium (40 or 80 micrograms/kg), pancuronium (60 or 120 micrograms/kg) and tubocurarine (450 micrograms/kg) in order to quantify the height of T1 (first response in the TOF sequence) at which T2, T3 and T4 (2nd, 3rd and 4th response in TOF sequence) reappear. Patients were anaesthetised with thiopentone, nitrous oxide in oxygen and fentanyl. There were small but significant differences between relaxants. The clinically useful parameter, i.e. the 4th response in the TOF sequence, appeared at approximately 30% height of the first response (T1) rather than at 25% as generally believed. It is suggested that the third response in the TOF sequence, which reappeared at an average height of T1 of about 25% be used for administration of further supplements of muscle relaxants since abdominal muscle relaxation becomes inadequate at this stage.

Influence of "priming" on the potency of non-depolarizing neuromuscular blocking agents.

Dose-response curves have been constructed to determine the ED50 and ED95 (doses required to produce a 50% and a 95% block, respectively) following administration of a small "priming" dose of atracurium 50 micrograms kg-1, vecuronium 10 micrograms kg-1 or pancuronium 10 micrograms kg-1. The myoneural blockers were administered subsequently as a single bolus. The results were compared with previously published work on these drugs, in which no priming dose had been administered. The respective ED50 and ED95 values in the primed and control groups were 122 and 126 micrograms kg-1 and 208 and 226 micrograms kg-1, respectively, for atracurium; 26 and 23 micrograms kg-1 and 42 and 39 micrograms kg-1, respectively, for vecuronium; and 31 and 30 micrograms kg-1 and 56 and 60 micrograms kg-1, respectively, for pancuronium. The values showed no significant differences between the respective primed and control groups. Contrary to previous suggestions, our results show no enhancement of blockade when these drugs were administered in divided doses.