The science of ‘signal transduction mechanisms’ is the most dramatically progressing field in cell biology during the past several years. Guanine nucleotide- binding proteins (G-proteins) have been identified in almost all cells in every tissue, and their major roles are known to transduce various intracellular signals by interacting between receptor molecules and effector enzymes or ion channels. They regulate synaptic transmission, contractions of cardiac and smooth muscles, secretions of endocrine and exocrine cells, translation system of the messenger RNA, and mitotic cell cycles [17, 21, 58, 61].
This paper describes basic structures and functions of G-proteins and focuses on their modulatory or regulatory actions for ionic channels in the plasma membrane while attempting to put forward some possible unifying concept from the diverse information that has accumulated.

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Lung capacity and maximum oxygen uptake (V_{O2 max}) were measured directly in 167 healthy males, from all the main races in Malaysia. Their ages ranged from 13 to 59 years. They were divided into five age groups (A to E), ranging from the second to the sixth decade. Lung capacities were determined using a dry spirometer and V_{O2 max} was taken as the maximum rate of oxygen consumption during exhaustive exercise on a cycle ergometer. Mean forced vital capacity (FVC) was 3.3±0.5l and it correlated negatively with age. Mean V_{O2 max} was 3.2±0.2l•min^-1 (56.8±3.5ml•kg^-1•min^-1) in Group A (13-19 years) compared to 1.7±0.2l•min^-1(28.9±2.9ml•kg^-1•min^-1) in Group E (50-59 years). Regression analysis revealed an age-related decline in V_{O2 max} of 0.77ml•kg^-1min^-1•year^-1. Multiple regression of the data gave the following equations for the prediction of an individual's V_{O2 max}: V_{O2 max} (l•min^-1)=1.99±0.035 (weight)-0.04 (age), V_{O2 max} (ml•kg^-1 min^-1)=67.7-0.77 (age), where age is in years, weight in kg. In terms of V_{O2 max} as an index of cardiopulmonry performance, Malaysians have a relatively lower capacity when related to the Swedish norms or even to those of some Chilean workers. Malaysians were, however, within the average norms of the American Heart Association's recommendations. Age-related decline in V_{O2 max} was also somewhat higher in the Malaysians.

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In male Wistar rats, microinjection cannulae were stereotaxically implanted in the ventromedial and paraventricular hypothalamic nuclei. After control recordings of spontaneous motor activity for 4-6 days, vasoactive intestinal peptide (VIP) was injected in a dose of 1.0μg and a volume of 2.0μl into these nuclei at 1100 or 1900h, and the activity during the 3-h period following was compared with that on the control days in individual animals. VIP injection produced an increase when injected at 1100h, and a decrease when injected at 1900h. Thus, a time-dependent fluctuation in the VIP effect on the hypothalamic neuronal activity was suggested.

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The effects of training by running (sprint or endurance) on the mitochondrial volume, number, and succinate dehydrogenase (SDH) activity of different types of single muscle fibers, and on the elemental composition of soleus and extensor digitorum longus muscles were studied employing histochemical, electron microscopic, and electron probe-micro analysis (EPMA). Newly weaned male Wistar rats were trained on a motor-driven treadmill endurance exercise for 14 weeks. The relative mitochondrial volume per single muscle fiber of slow-twitch oxidative (SO) fiber was significantly increased following endurance training (p<0.01). There was no significant correlation between mitochondrial volume and number of SO fibers following endurance exercise training. Following sprint training, both mitochondrial volume and number of fast- twitch oxidative glycolytic (FOG) fibers increased significantly (p<0.01), with significant correlation (r=0.69) between these parameters. SDH activity was higher in the order of SO, FOG, and fast-twitch glycolytic (FG) fibers following endurance training; however, the activity was higher in the order FOG, SO, and FG fibers following sprint training. The potassium concentration in cytoplasm of the soleus muscle showed a tendency to decrease following both types of training. These results suggest that the oxidative capacity of each type of muscle fiber does not always increase equally following training. Changes in mitochondrial number and volume in response to the two different types of training differed according to the type of fiber.

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Graded hypoxia (FET_O2 14-6%) and hypercapnia (FET_CO2 6-10%), which were applied for 45s and 2min, respectively, to urethane anesthetized and artificially ventilated rats produced an increase in adrenal sympathetic efferent nerve activity in parallel with increases in adrenaline and noradrenaline secretion measured in the adrenal venous effluent. Percentage increases in adrenaline and noradrenaline were almost equal. In rats whose carotid sinus nerves (CSN) were bilaterally cut, hypoxia did not produce any effect on adrenal sympathetic nerve activity or catecholamine secretion. In contrast, excitatory adrenal nerve and catecholamine secretory responses to hypercapnia remained unchanged in CSN denervated rats. After severing a splanchnic nerve whose branches innervated the adrenal gland, while maintaining the resting level of catecholamine secretion by low-frequency stimulation of the peripheral end of the splanchnic nerve, hypoxia did not produce any increase in catecholamine secretion. Hypercapnia (FET_CO2 8 and 10%), however, induced catecholamine secretion from denervated adrenal medulla, although the magnitude of the response was significantly lower than that in animals with adrenal nerve intact. It is concluded that hypoxia stimulates the adrenal medulla via the carotid chemoreceptor reflex whereas hypercapnia acts mainly via mechanisms besides carotid chemoreceptors such as central chemoreceptors with some direct stimulatory effect on the adrenal medulla. The functional significance of these dual mechanisms of sympathoadrenal excitation during hypoxia and hypercapnia is discussed.

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To determine the relationship between periodic breathing (PB) during sleep at high altitude and ventilatory chemosensitivities, we studied nine Japanese climbers who participated in the expedition to the Kunlun Mountains (7, 167m) in China in 1986. At sea level, ventilatory response to hypoxia (HVR) by isocapnic progressive hypoxia test and to hypercapnia (HCVR) by Read's method were examined. At altitude 5, 360m, respiratory movements of the chest and abdominal wall, Sa_O2, ECG, and HR were monitored. Seven climbers manifested PB during sleep. There was a significant correlation between PB during sleep and HVR and HCVR (p<0.05). All the climbers showed severe desaturation during sleep. There was a significant negative correlation between degree of desaturation during sleep and HVR (p<0.05). A negative correlation was also detected between PB and the degree of desaturation during sleep. We concluded that ventilatory chemosensitivities play an important role in eliciting PB and that climbers with high HVR can maintain their arterial oxygenation during sleep, due to hyperventilation induced by PB, which is considered an advantageous adaptation for lowland sojourners.

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Atrial temperature (T_at), heat production (M), mean arterial blood pressure (BP), and feeding (FA) and locomotor (LA) activities were measured over a 24-h period in spontaneously hypertensive rats (SHR) and their normotensive controls (Wistar Kyoto rats; WKY) at an ambient temperature of 24°C. Clear day-night changes in all variables were observed in both groups except for BP and LA in SHR. During the day (0600-1800h), SHR moved more frequently and seemed to eat more food than WKY. However, the total amount of food consumed for the 2 consecutive days was the same in both SHR and WKY. Compared with WKY, average M and BP during the day and at night and FA and LA during the day were significantly higher in SHR. The responses of T_at for a 24-h period, M during the day and for a 24-h period, and BP during the day to FA were significantly enhanced in SHR. There were no such significant differences of responses in T_at, M, and BP to LA between SHR and WKY. The results suggest that SHR is hyper-responsive in metabolism and blood pressure to feeding activity, particularly in the daytime, but not to locomotion.

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Blood flow in the superior mesenteric artery was observed with a chronically implanted electromagnetic flow probe in two-kidney, one-clip renovascular hypertensive rats (2K1C), one-kidney, one-clip renovascular hypertensive rats (1K1C), and normotensive control rats (NCR) in the conscious state. Arterial pressure was recorded with an indwelling catheter. Superior mesenteric resistance was calculated as arterial pressure divided by superior mesenteric flow. In all three groups of rats, superior mesenteric resistance remained almost unchanged when arterial pressure decreased markedly on ganglionic blockade with hexamethonium bromide. However, subsequent injection of a vasopressin antagonist (Manning compound) decreased superior mesenteric resistance significantly in 2K1C but not in 1K1C and NCR. Injection of vasopressin antagonist alone was without effect on arterial pressure and superior mesenteric flow in the three rat groups. Only 2K1C were judged to have appreciable sympathetic tone in resistance vessels of the superior mesenteric area, which was blocked by hexamethonium but compensated for by secondarily secreted vasopressin.

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In order to elucidate diabetic gastrointestinal disorders, we measured the length, diameter, volume, and intraluminal pressure of the isolated segments of the duodenum, jejunum, ileum, and proximal colon during injection of Tyrode's solution into them, as well as wet weight. Wet weight of the stomach and of each intestinal segment of 3cm length were similar between normal and diabetic preparations, except the duodenum. Wet weight of the diabetic duodenum was significantly heavier than that of normal. However, capacity of all diabetic gastrointestinal segments was significantly larger than that of normal ones, even after corrected for wet weight (ml/g wet weight). During saline injection, normal intestinal Contrarily, diabetic ones were distended more circumferentially than normal, as well as longitudinally. Pressure-volume relationships showed that pressure inside of the diabetic gastrointestinal tract increased much more moderately than that of normal one according to volume increase during saline injection. Similarly, tension inside of diabetic intestinal segments increased much more moderately than that of normal ones. Chord and slope compliance of diabetic gastrointestinal tract was generally larger than those of normal one. Histologically, there are no remarkable differences in cross-sectional area between normal and diabetic intestinal segments after usual fixation without intraluminal fixative injection. However, diabetic segments were much more remarkably dilated than normals were, when fixed after fixative injection. Greater compliance or distensibility of the diabetic gastrointestinal tract seemed to be one basic ground for dilatation, atony, larger appearance, transit delay, and motile disorders of the diabetic gastrointestinal tract.

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We have studied the effects of various pancreatic secretagogues on free cytosolic calcium ([Ca²⁺]_i) and amylase release in dispersed rat pancreatic acini, to determine the role of [Ca²⁺]_i; in stimulated enzyme secretion from the exocrine pancreas. Dispersed rat pancreatic acini were loaded with the new Ca²⁺ -sensitive fluorescent indicator, fura-2. Resting [Ca²⁺]_i was 110±2nM (a mean±SE.). Carbachol, caerulein, bombesin, and neuromedin B and C each caused a rapid increase in [Ca²⁺]_i; maximal increases of 100 to 400-500nM were reached within 20s following the secretagogue addition, and this was followed by a return to a lower sustained level within 2min. When enzyme secretion from the acini was monitored as a function of time using a perifusion system, secretagogue-induced amylase release took a biphasic pattern consisting of an initial burst phase for a several minutes and a second sustained phase during stimulation. Although sustained amylase secretion occurred at near resting [Ca²⁺]_i, the peak [Ca²⁺]_i correlated with the amount of stimulated amylase release as well as with the initial release, during submaximal and maximal stimulation by these agents. At supramaximal concentrations of carbachol and caerulein, amylase release, but not the increase in [Ca²⁺]_i, was attenuated. On the other hand, in response to supramaximal concentrations of bombesin, and neuromedin B and C, both the amount of amylase released and the peak [Ca²⁺]_i were similar to those obtained in response to maximal concentrations. From a standpoint of time course analysis of enzyme secretion, both the first burst phase and the second sustained phase were inhibited during stimulation by 10^-3M carbachol, compared with 10^-5M carbachol, while supramaximal stimulation by neuromedin C caused a pattern of amylase release similar to that produced by maximal stimulation. These data suggest that in pancreatic acinar cells an increase in [Ca²⁺]_i plays an important role in stimulus-secretion coupling; however, other factors may be indispensable in regulating enzyme secretion. Furthermore, it is suggested that there is a difference in the intracellular messenger system between carbachol and caerulein, and neurotransmitters belonging to the bombesin family, especially during supramaximal stimulations.

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The inhibitory effects of CR-1409, a new glutaramic acid derivative developed as a cholecystokinin (CCK) receptor antagonist, on caerulein-stimulated amylase secretion and on intracellular Ca²⁺ ([Ca²⁺]_i) mobilization were studied in isolated rat pancreatic acini. Pancreatic acini were prepared by collagenase digestion method and loaded with 1μM fura-2/AM for measurement of the intracellular free Ca²⁺ concentration. Amylase release was examined by a perifusion method. Stimulation with 10^-10M caerulein, 10^-5M carbachol, or 10^-8M gastrin-releasing peptide (GRP) led to biphasic amylase release and increase in [Ca²⁺]_i. CR-1409 at 1 and 5μM inhibited, by 50 and 84%, respectively, the amylase secretion and increase in [Ca²⁺]_i induced by 10^-10M caerulein, and 25μM CR-1409 completely inhibited both amylase secretion and increase in [Ca²⁺]_i induced by caerulein. However, 25μM CR-1409 did not inhibit unstimulated secretion of amylase or the secretions induced by carbachol and GRP, which are also mediated by changes in intracellular Ca²⁺. We conclude that CR-1409 acts as a specific inhibitor of the CCK receptor in the pancreas, and is useful in studies on the involvement of the release and action of CCK in vitro.

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The effect of putative K channel blockers on anion secretion has been studied in primary monolayer cultures of rat epididymal cells using the short circuit current technique. Under basal conditions, monolayers had a transepithelial potential difference of about 2-3mV, apical side negative and a short circuit current (SCC) of about 2μA•cm^-2. The transepithelial resistance was about 500Ω•cm². Addition of adrenaline (0.23μM, basolaterally) caused the SCC to rise to a peak value of about 10.5μA•cm^-2 and then stabilized at about 4μA•cm^-2 after 15min. This rise in the short circuit current has previously been shown to be due to an increase in net anion secretion from the basolateral to the apical medium. In tissues stimulated with adrenaline, addition of barium (Ba) to the apical side did not affect the adrenaline-induced SCC, but addition to the basolateral side caused a dose-dependent inhibition of the current with an IC₅₀ value (concentration required to inhibit 50% of the current) of 0.92mM. At Ba concentration of 5mM, the adrenaline-induced SCC was completely abolished. There was no effect on transepithelial resistance. Addition of tetraethylamonium (TEA) (16mM) to the apical or basolateral side had no significant effect on the adrenaline-stimulated SCC. Lidocaine and quinidine inhibited the adrenaline-stimulated SCC when added either to the apical or basolateral bathing solution. The IC₅₀ values for lidocaine were 0.42mM and 0.35mM for basolateral and apical application, respectively. The IC₅₀ values for quinidine were 0.062mM and 0.050mM for basolateral and apical application, respectively. In all cases there was no change in tissue resistance. It is proposed that in the basolateral membrane of the epididymal cells, there is a component which is sensitive to putative K channel blockers. It is likely that it is a K channel. As in other secretory cells, this channel plays an important role in secretion.

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Changes in acinar cell volume during secretion were observed in the perfused rat mandibular gland by the video-enhanced contrast (VEC) microscopy. The acinar cell shrank (81.3±4.9% (mean ±S.D., n=5)) during acetylcholine stimulation and swelled (107.4±2.3% (n=5)) after cessation of the stimulation. These evidences suggested that a large amount of fluid is transported via transcellular route in the salivary gland.

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The enzyme activities of intra- and extrafusal fibers in the tibialis anterior muscle of rats during postnatal development have been investigated. Muscle fibers 1 day after birth showed a uniform reaction for adenosine triphosphatase (ATPase), succinate dehydrogenase (SDH), and α-glycerophosphate dehydrogenase (α-GPD) activities. Fast-twitch (F) and slow-twitch (S) fibers with ATPase activity were found at 9 and 11 days. Thereafter, the type shift of muscle fibers from S to F was observed in the deep and middle portions. Fast-twitch oxidative glycolytic (FOG), fast-twitch glycolytic (FG), and slow-twitch oxidative (SO) fibers with ATPase, SDH, and α-GPD activities were found at 15 (the superficial portion) and 17 days (the deep and middle portions). The histochemical differentiation of intrafusal muscle fibers (7 and 9 days) was found earlier than that of extrafusal muscle fibers.

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A lipophilic anion, tetraphenylboron (TPB^-)-induced Ca²⁺ release from fragmented sarcoplasmic reticulum (SR) of frog skeletal muscle was monitored by chlortetracycline fluorescence. TPB^- caused change in surface charge of the membrane and in the protein conformation with a time course similar to that of the Ca²⁺ release. Tetraphenylarsonium (TPA⁺) inhibited these effects of TPB^-. Change in surface charge of SR is suggested to cause conformational change in SR membrane proteins, and then result in Ca²⁺ release from the SR.

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Human neutrophils were separated into two fractions using a continuous density gradient of Percoll solution. A marked decrease in O₂^- production was observed in the low-density neutrophil fraction. There was little erythrocyte contamination in the high-density neutrophil fraction (<0.5%), and thus the hypotonic or ammonium chloride lysis of erythrocytes was not necessary.

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This paper describes the development of a computer-controlled system that controls inspired CO₂ or end-tidal P_CO2 (PET_CO2) to follow preprogrammed functions such as step, sinusoid, and pulse, under normoxic, hyperoxic, and hypoxic conditions. The system uses a proportional-integral (PI) controller that was optimized by adjusting the PI parameters so as to minimize the integral-time of absolute error (ITAE) performance parameter.

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