British journal of pharmacology
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The mechanisms by which haemoglobin and methaemoglobin inhibit the vasodilator actions of glyceryl trinitrate, sodium azide, nitric oxide, and the bovine retractor penis inhibitory factor (IF) were studied on rabbit endothelium-denuded aortic rings. Methaemoglobin was less effective than haemoglobin against each vasodilator, it was more effective at inhibiting the relaxation to azide than that to glyceryl trinitrate. Glyceryl trinitrate was neither bound nor inactivated when passed through columns of haemoglobin-agarose or methaemoglobin-agarose. ⋯ Neither the acid-activated nor the inactive forms of IF were bound or inactivated when passed through columns of methaemoglobin-agarose. Neither form of IF was retained on passage through columns of haemoglobin-agarose, but the resulting activity in the eluates was less than control, was unstable and, unlike the original activity, decayed rapidly on ice. The greater ability of haemoglobin, compared to methaemoglobin, to inhibit vasodilatation induced by IF might therefore reflect the greater ability of haemoglobin to interact with this vasodilator and inactivate it.
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K+ (2.4-15.6 mmol l-1) antagonized the positive inotropic effect of dihydro-ouabain. The concentration-effect curves became steeper with the shift to higher concentrations of the glycoside. At 1.2 mmol l-1 Ca2+, an increase in K+ from 2.4 to 12 mmol l-1 required tenfold higher concentrations of dihydro-ouabain to produce equal inotropic effects. ⋯ Diminution of Vmax of the action potential was observed only at K+ concentrations greater than 5.9 mmol l-1, whereas the resting membrane potential was continuously depolarized over the entire range of K+ concentrations. The results support the view that the reduction in receptor affinity cannot be the sole cause of the antagonism between the glycoside and K+. Impairment of passive Na+ influx during diastole, due to the K+-dependent depolarization of the resting membrane potential, contributed to about one half of the glycoside-K+ antagonism.
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Excitatory junction currents produced by glutamate were recorded with an extracellular electrode at the neuromuscular junction of the crayfish. Pentobarbitone, phenobarbitone, diazepam, chlordiazepoxide and procaine had only minimal effects on current decay at concentrations which are highly effective in other preparations. The glutamate synapse in the crayfish appears relatively resistant to these drugs. In contrast, ether and halothane increased the rate of decay of the currents at concentrations which are comparable to those occurring during anaesthesia.
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The effects of the steroid anaesthetic alphaxalone on acetylcholine (ACh)-induced ionic channels were studied in voltage clamped 'myoballs' in culture. Alphaxalone produced a reversible blockade of the ACh-evoked inward current, ED50 = 6.0 microM. ⋯ In double pulse conditioning experiments, alphaxalone produced an additional inhibition with a time constant of recovery (550 ms) much longer than the time constant of recovery of the normal desensitization (250 ms). It was concluded that alphaxalone blocks active (open) ionic channels.
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1 The effects of 4-aminopyridine (4AP) on the output of acetylcholine (ACh) from the cerebral cortex were investigated in unanaesthetized freely moving rats and in anaesthetized rats by means of the ;cup technique'. ACh was determined by bioassay on the dorsal muscle of the leech.2 In unanaesthetized rats intraperitoneal injection of 4AP (3 mg/kg) had no effect on the cortical output of ACh.3 After injection of morphine (10 mg/kg s.c.), which depressed the spontaneous output of ACh, 4AP increased the cortical output to a level significantly higher than that determined before morphine injection.4 In rats anaesthetized with either urethane or pentobarbitone, drugs known to decrease cortical output of ACh, 4AP (i.v. or i.p.) elicited a significant increase in the output of ACh. ⋯ Moreover, the 4AP-induced increase in cortical ACh output was not related to changes in respiratory frequency.6 In summary systemic administration of 4AP in subconvulsive doses (1 and 3 mg/kg) increased cortical output of ACh in rats anaesthetized with urethane or pentobarbitone or after injection of morphine, but not in untreated freely moving rats. It is suggested that the anaesthetic agents and morphine may cause an imbalance between excitatory and inhibitory central pathways, and that this imbalance may play a role in their depressant effect on cortical output of ACh and/or in the 4AP-induced facilitation described in this paper.