Simultaneous comparison of nicotinic receptor antagonists on three nicotinic acetylcholine receptors.

The relative potencies of several nicotinic cholinoceptor antagonists in producing tetanic fade and reduction of striated muscle contraction were investigated in the isolated guinea-pig oesophagus as well as the guinea-pig and rat phrenic nerve-diaphragm preparations. Contractile smooth muscle responses to vagal stimulation, which involves ganglionic activation, were also measured simultaneously with striated muscle responses in the oesophagus. The relative potency for inhibiting the response of oesophageal smooth muscle to vagal stimulation (20 Hz) was trimetaphan > mecamylamine > hexamethonium > tubocurarine > pancuronium. For oesophageal striated muscle, production of tetanic fade at 100 Hz and reduction in peak tetanic tension at 20 or 100 Hz showed a similar relative potency; pancuronium > tubocurarine > mecamylamine > trimetaphan > hexamethonium and similar results were obtained in the guinea-pig diaphragm for the antagonists investigated (pancuronium, tubocurarine and mecamylamine). In the rat phrenic nerve-diaphragm preparation, production of tetanic fade at 50 Hz and reduction in twitch or tetanic tension all showed the relative potency; tubocurarine > pancuronium > mecamylamine > trimetaphan > hexamethonium. These findings indicate differences in the nicotinic cholinoceptor subtypes involved in vagal ganglionic responses and those in tetanic fade.

Nicotinic acetylcholine receptors on capsaicin-sensitive nerves.

To study the density of nicotinic acetylcholine receptors on primary afferents and central nociceptive pathways, [3H](-)-nicotine binding was conducted in the cerebral cortex and spinal cord including dorsal roots and ganglia (DRG), of control rats and rats desensitized by neonatal capsaicin treatment. [3H](-)-nicotine binding in capsaicin-treated rats was reduced in cerebral cortex by 35% and spinal cord+DRG by 46% (p < 0.05). Functionally, both iontophoretically applied acetylcholine- and capsaicin-evoked flares (measured by laser Doppler flowmetry) were reduced in capsaicin-treated animals (p < 0.05); similarly, electrical stimulation-evoked flares were significantly lower in the same group, compared with controls (p < 0.05). These data provide direct evidence that many neuronal nicotinic acetylcholine receptors are associated with capsaicin-sensitive peptidergic neurones, including primary afferents, DRG and central nociceptive pathways.

Behavioural deviance in children with early treated phenylketonuria.

A sample of 99 early treated phenylketonuric children showed higher levels of behavioural deviance than 197 matched controls. For boys this excess of behavioural deviance persisted when IQ was taken into account. For phenylketonuric girls however it was restricted to those with IQs less than 70. The type of behavioural deviance shown by the boys over the whole IQ range was predominantly neurotic. The levels of behavioural deviance found in phenylketonuric children were among the highest that have been reported for children with various handicapping conditions.

Effect of stopping low-phenylalanine diet on intellectual progress of children with phenylketonuria.

Forty-seven patients at the Hospital for Sick Children, London, who had phenylketonuria and were on a low-phenylalanine diet (21 early-treated--that is, treatment started before the age of 4 months--and 26 late-treated) were placed on a normal diet between the ages of 5 and 15 years. They showed significant falls in mean IQ of about six points after the diet was withdrawn. Twenty-two similar patients (five early-treated and 17 late-treated) at the Universitäts-Kinderklinik, Heidelberg, who were placed on a relaxed low-phenylalanine rather than a normal diet, showed smaller and non-significant falls in mean IQ. During the period of strict diet none of the patients in London or Heidelberg showed any consistent falls in IQ. These results suggest that complete withdrawal of the low-phenylalanine diet during childhood leads to a fall in intellectual progress in many patients.

Acute respiratory failure and obesity with normal ventilatory response to carbon dioxide and absent hypoxic ventilatory drive.

We measured hypoxic and hypercapnic ventilatory drive in a 64 year old woman with acute respiratory failure, congestive heart failure and obesity when she was in remission. She had a ventilatory response to carbon dioxide (CO2) comparable to that in six obese women without hypoventilation but no ventilatory response to hypoxia or to vital capacity breaths of 15 per cent CO2 in N2. Following weight loss, her ventilatory response to CO2 increased but hypoxic ventilatory response to CO2 increased but hypoxic ventilatory drive remained absent. These findings indicate that attenuation of hypoxic ventilatory drive caused by loss of peripheral chemoreceptor function can be a predisposing factor in the development of acute respiratory failure associated with obesity.