In smooth muscle isolated from the guinea‐pig stomach, cyanide (CN) and iodoacetic acid (IAA) were applied to block oxidative phosphorylation and glycolysis, respectively. Effects of IAA on generation of spontaneous mechanical and electrical activities were systematically investigated by comparing those of CN. Spontaneous activity ceased in 10–20 min during applications of 1 mm IAA. On the other hand, application of 1 mm CN also reduced the spontaneous activity, but never terminated it. In the presence of CN the negativity of the resting membrane potential was slightly reduced. When spontaneous activity ceased with IAA, the resting membrane potential was not significantly affected. Also, before ceasing, the amplitude and duration of the spontaneous electrical activity were significantly reduced. The amplitude of the electrotonic potential was, however, not changed by IAA. Further, glibenclamide did not prevent the effects of IAA. These results suggest that, unlike cardiac muscle, activation of metabolism‐dependent K+ channels in stomach smooth muscle does not seem to play a major role in reducing and terminating spontaneous activity during metabolic inhibition. Carbachol‐induced contraction transiently increased, and subsequently decreased gradually during application of IAA. After 50 min application of IAA, when there was no spontaneous activity, the concentrations of phosphocreatine (PCr) and ATP measured with 31P nuclear magnetic resonance decreased to 60 and 80% of the control, respectively, while inorganic phosphate (Pi) concentration paradoxically fell to below detectable levels. During subsequent prolonged application of IAA, high‐energy phosphates steadily decreased. On the other hand, after 50 min CN application, [PCr] and [ATP] decreased to approximately 30 and 80% of the control, respectively, while [Pi] increased by 2.6‐fold. In the presence of either CN or IAA, spontaneous mechanical and electrical activities were reduced or eliminated, although amounts of high‐energy phosphates sufficient to contract smooth muscle remained. It can be postulated that some mechanism(s) related to energy metabolism, but not including ATP‐sensitive K+ channels, plays an important role in generating spontaneous activity in guinea‐pig stomach smooth muscle. During metabolic inhibition the energy metabolism‐dependent mechanism(s) would preserve high‐energy phosphates, and consequently cell viability, by stopping spontaneous activity.

1In the circular muscle of the corpus region of the guinea-pig stomach, the effects ofcatecholamines on mechanical activity were studied with simultaneous recording of membrane potential by use of intracellular microelectrodes. In order to investigate responses mediated through a-adrenoceptors, the P-adrenoceptors were blocked by propranolol (10-6 M) in most experiments. 2 Adrenaline (< 10-M) produced a monophasic contraction with little change in membrane potential. At higher concentrations (>l0-M), adrenaline usually produced an early transient contraction followed by a slow tonic contraction. During the early phase, the membrane was hyperpolarized and slow waves were reduced in amplitude. 3 The phasic contractions superimposed on the late slow phase of the contractile response were higher in frequency and larger in amplitude than in controls before adrenaline application. These changes were associated with an increase in the amplitude and frequency of slow waves, and with a spike-like component appearing on the top of each slow wave. 4 Adrenaline-induced changes in mechanical and electrical activity were inhibited by prazosin, but largely unaffected by yohimbine. In some preparations, there was a transient weak inhibition ofphasic contraction before muscle tone was increased by adrenaline, and this became more pronounced in the presence of yohimbine. 5 Phenylephrine, selective for a,-receptors, produced responses very similar to those of adrenaline, whereas agonists selective for a,-receptors, clonidine and B-HT 920, produced only a small slow contraction without any clear change in membrane potential. 6 It is concluded that in the circular muscle of guinea-pig stomach, the contractile response and changes in the electrical slow wave activity produced by adrenaline are both mediated mainly through the activation of a,-receptors.

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The in vitro electrophysiological properties of a newly synthesised antiarrhythmic agent, AN-132, were evaluated by recording transmembrane action potentials from guinea pig papillary muscles. AN-132 (10-100 mumol.litre-1) caused a dose dependent decrease in the maximum upstroke velocity (Vmax) of the action potential without affecting the resting potential. In the presence of AN-132, trains of stimuli at rates greater than or equal to 0.1 Hz led to an exponential decline in Vmax. This use dependent block was enhanced at higher stimulation frequency. The time constant for the recovery of Vmax from the use dependent block was 39.5-41.2 s. The curves relating membrane potential and Vmax were shifted by AN-132 (100 mumol.litre-1) in the direction of more negative potentials (6.1 mV). In preparations treated with AN-132 (30 and 100 mumol.litre-1), the Vmax of test action potentials preceded by conditioning clamp pulses to 0 mV was progressively decreased with an increasing number of pulses. A single prolonged clamp pulse to 0 mV reduced Vmax much less than multiple brief clamp pulses. These findings suggest than AN-132 has use dependent inhibitory action on the fast sodium channel by binding to the channel mainly during its activated state and that the unbinding rate of the drug during diastole is very slow. This use dependency and its greater inhibition of Vmax in depolarised muscles through the increase in tonic block may play a major role in preventing ventricular arrhythmias.

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