1. The effects of the phosphodiesterase inhibitors caffeine, theophylline, isobutylmethylxanthine (IBMX) and rolipram on spontaneous electrical activity (slow waves) were studied in the circular muscle of the guinea‐pig gastric antrum. 2. All the inhibitors reduced slow wave frequency without changing the membrane potential and the slow wave configuration, but at higher concentrations they blocked the slow waves and caused membrane hyperpolarization. In the presence of the inhibitors a low level of irregular electrical activity could be observed in many preparations. 3. Isoprenaline, forskolin, dibutyryl cAMP and 8‐bromo‐cAMP all produced effects essentially similar to those of phosphodiesterase inhibitors. K+ (12 mM) and removal of K+ both depolarized the membrane and these were not affected by IBMX (1‐3 microM). A decrease in frequency caused by IBMX was also not significantly affected by 12 mM K+ or K+ removal and only partially antagonized by TEA or 4‐aminopyridine. 4. These results suggest that an increase in intracellular cAMP inhibits pacemaker activity of slow waves. An increase in K+ conductance does not seem to be a major factor in this inhibition. Slow waves appear to be a compound electrical activity in a group of muscle cells and are likely to be disintegrated by xanthine derivatives.

Japan 1 Caffeine inhibited spontaneous mechanical activity at 0.3-1 mM, but produced a tonic contraction at concentrations higher than 3 mM in the circular muscle of the guinea-pig gastric antrum. In the circular muscle of the rabbit portal vein, caffeine at concentrations higher than 1 mM produced an early phasic contraction followed by a small tonic component. The caffeine-induced contraction was abolished by removal of the external Ca2" more rapidly in the gastric antrum than the portal vein.2 When the preparations were pretreated with ryanodine (1 gM) a sustained contraction developed on wash-out of caffeine (10 mM) both in the gastric antrum and portal vein. This contraction was not affected by nicardipine (3 gxM) or verapamil (3 gM), but was readily abolished by removal of the external Ca2+ or by addition of cobalt (1 mM). Spontaneous electrical activity, the slow wave, in gastric muscles was blocked in the presence of 10 mm caffeine, but reappeared during the sustained contraction. 3 Both the contractions induced directly by caffeine and those produced following caffeine wash-out after ryanodine treatment were accompanied by a maintained increase in intracellular Ca2+ concentration measured with fura-2. 4 The presence or absence of Ca2" during the application of ryanodine did not affect the ability of caffeine to initiate sustained contractions, provided Ca2" was present during the exposure to caffeine. 5 It is concluded that caffeine can induce a sustained contraction after ryanodine treatment both in the guinea-pig gastric antrum and rabbit portal vein, by activating a Ca2+ influx pathway insensitive to organic Ca2+ channel blockers. No clear evidence was obtained for involvement of the Ca2' influx pathway activated through depletion of intracellular Ca2" stores. A hypothesis is proposed that the plasma membrane of these preparations is similar to the sarcoplasmic reticulum membrane in that Ca2+ permeability can be increased almost irreversibly by a combination of caffeine and ryanodine in the presence of the external Ca2+.

1. Circular muscle strips of the guinea-pig gastric muscle produced spontaneous electrical activity in the form of slow waves. The slow wave amplitude , maximum rate of rise, duration, and frequency were 31 mV, 60 mV sec-1 , 4.3 sec, and 4.3 min-1 on average, respectively. These parameters were not appreciably affected by 3μM nifedipine or nicardipine, even following membrane depolarization with 60 mM K+ . 2. Ni2+(1-100μM)increased slow wave amplitude and frequency, but reduced the rate of rise, accompanied by membrane depolarization. The rate of rise and depolarization slowly recovered to the control values in the continuous presence of Ni2+, but slow wave frequency remained high. The recovery after wash-out was very poor particularly when a high concentration of Ni2+ was applied. 3. The effects of Co2+ were fundamentally the same as those of Ni2+. 4. Removal of external Ca2+ slowly reduced the rate of rise and amplitude of the slow waves in the absence and the presence of Ni2+ and Co2+, although the effects were reduced in the presence of these metal ions. 5. Concentrations of Ni2+ and Co2+ greater than 1 mM suppressed the slow waves . However, when the external Na+ was replaced with N-methyl-D-glucamine during the suppression, nearly normal electrical activity was resumed. 6. Since slow waves were not significantly affected by nifedipine (3μM)and Ni2+(100 μM),the inward currents generating slow waves do not seem to flow through L-type Ca2+ channels or typical T-type Ca2+ channels. Slow waves are probably potentiated by Ni2+ and Co2+ acting intracellularly. These ions at higher concentrations seem to inhibit the pacemaker activity more powerfully than they do the inward currents responsible for slow wave generation.