To provide information regarding the cause of the muscle rigidity in malignant hyperthermia-susceptible (MHS) pigs, the Ca-induced Ca-release mechanism of the sarcoplasmic reticulum (SR), the Ca uptake by the SR, and the Ca-activated tension production of the contractile system were examined in skinned skeletal muscle fibers from MHS and normal pigs. In muscles of MHS pigs, the rate of Ca-induced Ca release was significantly higher than in normal muscle. The potentiation effect on Ca-induced Ca release by halothane and caffeine did not differ appreciably between MHS and normal fibers. The rate of Ca uptake by the SR and the Ca sensitivity of the contractile system of MHS fibers were not different from those of normal fibers, and halothane in an anesthetic concentration exerted no effect on them. Dantrolene inhibited the Ca-induced Ca release at 38 degrees C. These results suggest that the principal cause of malignant hyperthermia (MH) in MHS pigs is due to the enhancement of the Ca-induced Ca-release mechanism of the SR of the skeletal muscle.

Experiments on perfused adrenal glands of guinea‐pigs were carried out to study the catecholamine output induced by veratridine in the presence of hexamethonium and atropine. Veratridine (10 μm to 200 μm) caused a dose‐dependent increase in catecholamine output. The addition of veratridine to the perfusion medium for a period of 3 min caused an increase in catecholamine output which reached a maximum 5 min to 10 min after withdrawal of the drug. The catecholamine output then gradually declined and reached near resting values within 30 minutes. It was never sustained for a longer period, even when veratridine was infused for 1 hour. Veratridine failed to increase the catecholamine output in the absence of extracellular Ca2+. However, the addition of Ca2+ after an infusion of veratridine (100 μm) in the absence of Ca2+ caused an increase in the catecholamine output which was proportional to the concentration of Ca2+ (0.55 mm to 8.8 him) used. Veratridine did not increase the catecholamine output in the absence of extracellular Na+ ions, NaCl being replaced by equimolar choline chloride or LiCl. Veratridine also failed to evoke catecholamine output in a Na+‐ffee solution in which Na+ was replaced by sucrose; this was the case even in the presence of a high concentration of Ca2+ (8.8 mm). Tetrodotoxin (0.1 μm) and excess Mg2+ (20 mm) reversibly inhibited the catecholamine output induced by veratridine. Ouabain (10 μm) significantly potentiated the veratridine‐induced catecholamine output. It is suggested that Na+‐dependent Ca2+ influx as well as voltage‐dependent Ca2+ influx mechanisms may be involved in the catecholamine output induced by veratridine.

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SUMMARY1. The effect of ouabain on the noradrenaline output from peripheral adrenergic neurones has been studied using isolated guinea-pig vasa deferentia.2. Exposure to ouabain (10-4 M) causes a gradual increase in the noradrenaline output. The effect occurs after a delay of 20 min and reaches a maximum during the period from 40-60 min.3. In the absence of external Ca, exposure to ouabain fails to produce an increase in the noradrenaline output. However, the reintroduction of Ca (2.5 mM) after a 1 hr exposure to ouabain in Ca-free media causes a rapid rise in noradrenaline output which reaches a maximum within the first 20 min. 4. After a 1 hr exposure to a low concentration of ouabain (10-5 m) the reintroduction of Ca is almost ineffective in increasing the noradrenaline output. When the concentration of ouabain is increased, the reintroduction of Ca becomes effective and causes a maximum effect with 10-4 M ouabain. In the presence of a constant amount of ouabain (10-4 M) the noradrenaline output induced by the reintroduction of Ca increases over the range 0-2-2-5 mM.5. In the presence of ouabain (10-4 M) the Ca-induced noradrenaline output increases in a linear fashion with increasing Na concentrations from 25 to 143 mm, as long as NaCl is replaced with equimolar choline chloride or isotonic sucrose.6. In the presence of the lowest effective concentration of sodium (25 mM) the noradrenaline output induced by the reintroduction of Ca after a 1 hr exposure to ouabain is potentiated by LiCl. However, in the complete absence of Na+ ions, there is no Li-dependent increase in the Ca-induced noradrenaline output.7. It is suggested that ouabain may cause an increase in noradrenaline output by an effect on the Na-dependent Ca influx system.

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Veratridine (0.1 mM) was found to be effective in producing an increase in the catecholamine output from perfused guinea‐pig adrenal glands in the presence of high concentrations of hexamethonium (1.83 mM) and atropine (28.8 μM). The response to veratridine was abolished by removal of either Na+ or Ca2+ from perfusion media and by the addition of tetrodotoxin (0.1 μM). It is suggested that the response to veratridine may be due to an increase in the tetrodotoxin‐sensitive Na+ permeability of chromaffin cell membranes.

1 Transmural electrical stimulation (TMS) of longitudinal smooth muscle strips taken from the cardiac portion of the pig stomach produced biphasic responses consisting of initial contractions followed by relaxations. The excitatory component was enhanced by neostigmine and abolished by atropine. After atropine treatment, TMS and nicotine or 1,1-dimethyl-4-phenyl-piperazinium, caused a relaxation or a relaxation followed by an after-contraction. All of these responses were abolished or reduced reversibly with tetrodotoxin and cocaine, while hexamethonium only abolished the response to ganglion-stimulating agents. 2 The relaxation caused by TMS reached a maximum amplitude at 5-10 Hz, and was entirely resistant to the effects of a-and P-adrenoceptor blocking agents, or a combination of them, and also to guanethidine. These results strongly suggested that the relaxation was elicited by stimulation of intramural non-adrenergic inhibitory neurones. 4 Stimulation of the intramural inhibitory neurones of the tissue consistently evoked an inhibitory junction potential, which showed a summation during repetitive stimulation. One the other hand, ATP elicited mainly a small depolarization of a few mV. 5 When the desensitization to ATP of the muscle was achieved in the presence of atropine and guanethidine, the relaxation induced by stimulation of the non-adrenergic inhibitory neurones could be evoked without any modification. 6 Dipyridamole neither potentiated the inhibitory responses due to stimulation of the intramural inhibitory neurones nor showed any consistent effect on the ATP-induced response. 7 From these results, it is unlikely that ATP, or any related compound, is the transmitter substance of the intramural inhibitory neurones in the longitudinal smooth muscle of the pig stomach.

SUMMARY1. Effects of apamin on electrical and mechanical activities and cyclic nucleotide accumulation in response to vasoactive intestinal peptide (VIP) and intramural nerve stimulation were investigated in isolated circular strips of the rat stomach in the presence of atropine and guanethidine.2. Circular muscles generated rhythmic contractions and slow waves in the antrum but not in the fundus. Intramural nerve stimulation and VIP caused frequency-and dose-dependent relaxation of fundic strips and inhibition of spontaneous contractions of antral strips. Apamin partly reduced the responses to intramural nerve stimulation but not those to VIP.3. In the antrum, apamin reduced inhibitory junction potentials (IJPs) evoked at the nadir of slow waves but not at their zenith. In the fundus, apamin partly decreased the amplitude of IJPs. Repetitive nerve stimulation was associated with an apamin-sensitive hyperpolarization and apamin-resistant decrease in the slow wave amplitude in the antrum.4. VIP caused a dose-dependent hyperpolarization of fundic circular muscle membrane. In the antrum, VIP inhibited spike potentials superimposed on slow waves and it decreased the slow wave amplitude in about half of the preparations. These electrical responses to VIP were resistant to apamin.5. Intramural nerve stimulation evoked an apamin-resistant output of VIP from muscle strips, which no longer occurred after tetrodotoxin or removal of extracellular c2+. Ca26. Intramural nerve stimulation and VIP elicited apamin-resistant increases in cyclic AMP and cyclic GMP accumulations. The effects of VIP on cyclic AMP were greater than those on cyclic GMP. The effects of intramural nerve stimulation on cyclic GMP were faster in onset than those of cyclic AMP.7. It is suggested that VIP is a neurotransmitter of the intramural inhibitory nerves concerned in the apamin-resistant relaxation of the rat stomach.