All of the experimental results described above can be categorized as follows: 1) the relationship between glucose levels and pancreatic and adrenal nerve activities; 2) innervations of the liver and their role in the regulation of blood glucose level; 3) central integration of blood glucose level; 4) glucose-sensitive afferent nerve fibers in the liver and regulation of blood glucose; 5) oral and intestinal inputs involved in reflex control of blood glucose level. We showed that an increase in blood glucose content produced an increase in the activity of the pancreatic branch of the vagus nerve, whereas it induced a decrease in the activity of the adrenal nerve. It was also shown that a decrease in blood glucose activated the sympatho-adrenal system and suppressed the vago-pancreatic system. It seems rational that these responses are involved in the maintenance of blood glucose level. Studies on the innervation of the liver led us to a conclusion that sympathetic innervation of the liver might play a role in eliciting a prompt hyperglycemic response through liberation of norepinephrine from the nerve terminals, and that the vagal innervation synergically worked with the humoral factor (insulin) for glycogen synthesis in the hyperglycemic condition. The glucose-sensitive afferents from the liver seem to initiate a reflex control of blood glucose level. The gustatory information on EIR response, reported by. STEFFENS [68], is supported by the electrophysiological observations. MEI'S reports [30] also indicated the importance of information from the intestinal glucoreceptors in the reflex control of insulin secretion. The role of integrative functions of the hypothalamus and brainstem through neuronal networks on neural control of blood glucose levels is also evident. A schematic diagram of the nervous networks involved in the regulation of the blood glucose levels is shown in Fig. 3.

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The secretory response of the exocrine pancreas via endogenous secretin (IRS) by intraduodenal instillation of hydrochloric acid (HCl) and various monocarboxylic acid solutions was studied in anesthetized piglets. The secretion induced by HCl solutions of various concentrations containing 250mM NaCl occurred when pH of the solutions was lower than 1.5. After instillation of the HCl solution of pH 1.0, juice flow and protein output increased 26 times and 9 times, respectively, as compared with basal levels. Such pancreatic responses paralleled an increase in plasma IRS concentration in the portal vein. The pancreatic response induced by a lactic acid solution occurred when pH of the solutions was lower than 3.8. The juice flow and protein output stimulated by a lactic acid solution of 250mM and pH 2.0 were 16 and 8 times higher than the basal levels. The responses to the lactic acid solution of pH 2.0 increased concentration dependently, and were followed by an increase in IRS concentration in the portal vein. The pancreatic exocrine responses induced by other monocarboxylic acid solutions (250mM) of pH 2.0 were in the following order: formic acid>lactic acid>pyruvic acid_??_acetic acid>butyric acid>propionic acid. Lactamide, an analogous substance of lactic acid, did not evoke any pancreatic secretion. The results indicate the possibility that pancreatic exocrine response induced by HCl is dependent upon hydrogen ion, while the response induced by monocarboxylic acid is not always dependent on dissociation constant of acid.

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The brainstem of anesthetized cats was electrically stimulated to examine the changes in the intracranial pressure (ICP). There were pressor and depressor sites, which preferentially produced an immediate increase and decrease in ICP in association with the arterial pressor and depressor responses, respectively. A preferential increase in ICP was also observed by stimulation of some depressor sites. The stimulus-induced ICP responses were usually different from the secondary ICP changes due to nonneurogenic alteration of arterial blood pressure (BP) as evoked by arterial bleeding and infusion of saline solution; the stimulus-induced increase in ICP was greatly enhanced when the stimulation to the pressor sites was applied at lowered BP levels and at moderately elevated ICP levels. In addition, when a gradual elevation in ICP was spontaneously observed with the lowering of the BP level, the pressor site-induced increase in ICP exceeded 70-100mmHg at the peak plateau-like waves, regardless of the magnitude of accompanying arterial pressor response. We propose that the stimulus-induced ICP responses cannot be explained merely by the metabolic changes, the decreased intracranial compliance, and the secondary transmural action on the intracranial space of the arterial pressor and depressor responses. A neurogenic mechanism that directly affects intracranial blood diameter may be involved in the ICP responses, especially those observed, at a lower BP level, in addition to extracranic action of sympathetic and parasympathetic nerve activities.

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A comparison was made of effects of Mg, Ca, Sr, or verapamil on the mechanical and electrical activities in the uterine longitudinal muscles of spayed and estrogen-treated rats. The muscle strips taken from spayed rat exhibited spontaneous rhythmic activity in the Locke solution which did not contain Mg, whereas spontaneous activity was less frequent in the preparation taken from estrogen-treated rat. The resting potentials were -54 and -61mV in the spayed and the estrogen-treated preparations, respectively. An initial spike potential followed by plateau potential with abortive spikes on the top was generated in both spayed and estrogen-treated preparations. In the spayed preparation, the frequency of rhythmic contractions was reduced, and the base-line tension was lowered when 0.6mM Mg was added to the solution. The base-line tension was elevated progressively when the external Ca concentration was raised, and reached a maximal value up to 10mM. The amplitude of phasic contraction was progressively increased by increasing Ca concentrations in the range from 1.25 to 5mM, and was reduced by Ca higher than 10mM. In the estrogen-treated preparation, the amplitude of phasic contraction was increased by increasing Ca concentrations in the range from 1.25up to 17.5mM. When the amplitude of phasic contraction was increased, the duration of plateau potential became protracted. Substitution of the external Ca with Sr caused an increase in the spike activity generated on the top of plateau potential. However, the amplitude of phasic contraction was diminished in both the spayed and the estrogen-treated preparations. Verapamil (2μM) caused a stronger depression of electrical and mechanical activity in the spayed preparation. Results were discussed in relation to the genomic effects of estradiol on the membrane properties so as to change the interaction with divalent cations.

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In order to determine the role of glucagon in cold acclimation, the changes in glucagon receptor were investigated in white adipocytes from cold-acclimated rats by establishing a glucagon radioreceptor assay method for isolated white adipocytes. The following conditions were found to be appropriate for specific glucagon receptor binding assay; cell concentration of about 1×10⁵cells/ml, 15min preincubation with glucagons and 30mm-reaction at 25°C in the presence of bacitracin (1mg/ml). Cold acclimation decreased the size and increased the number of epididymal white adipocytes. Cold acclimation increased the number of glucagons receptors of white adipocytes, resulting in 140% in terms of unit cell, and 260% increase per unit surface area and 210% increase per whole tissue. However, the affinity of the binding site for glucagon was not affected. The results suggested that an enhanced metabolic response of cold-acclimated rats to glucagon could be partly explained by the increased number of glucagon receptor in white adipocytes.

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The location of ascending and descending pathways of the straining reflex was studied by making bulbar cuts in dogs. Rhythmic increases, which were elicited simultaneously in nervous outflows to the diaphragm and rectus abdominas by activation of pelvic afferent fibers, were used to indicate rhythmic straining. The increases were not affected by cutting the dorsal funiculus at the bulbospinal junction, but stopped after cutting both lateral funiculi and by longitudinally cutting the roof of the central canal just caudal to the obex. The increases were impaired by unilateral section of the bulbospinal junction, but were abolished completely after successive ipsilateral hemisection of the rostral bulb. Moreover, rhythmic increases, which appeared synchronously with rhythmic straining in unit discharges recorded from the Kolliker-Fuse nucleus and neighboring structures, disappeared after the longitudinal bulbar cut. However, reflex discharges elicited in pelvic vesical and rectal branches by stimulation of corresponding pelvic afferent fibers were not reduced. These results show that the indispensable part of the ascending pathway of rhythmic straining passes through the lateral funiculus and decussates at the lower bulb, but the pathway of micturition and defecation reflexes do not cross at that level.

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Effects of saphenous nerve stimulation and hemorrhage on discharge activity of parvocellular neurosecretory (PC) cells of the paraventricular hypothalamic nucleus (PVN) were studied in anesthetized rats. The PC cells were identified in the PVN with the criteria that units recorded in the PVN showed an antidromically conducted spike after median eminence but not after posterior pituitary stimulation of 0.45mA intensity and were demonstrated histologically to be located in the parvocellular regions of the PVN. Saphenous nerve stimulation at 4Hz repetition and of 3mA intensity increased the discharge rate of 13 of the 52 PC cells tested. These excited cells exhibited a synaptically mediated excitation during post-stimulus period on peristimulus time histograms constructed during 1Hz stimulation. Hemorrhage (4ml/kg b.w.) activated 7 of the 10 PC cells tested which had been excited by saphenous nerve stimulation. Both saphenous nerve stimulation and hemorrhage increased immunoreactive adrenocorticotropic hormone (ACTH) in the plasma in the anesthetized rats. These data support the view that synergistic potentiation of ACTH secretion reported to occur after noxious and hypovolemic stimuli depends at least in part on the interaction between afferent neural signals originating from noxious and cardiovascular receptors on their way up to corticotropin-releasing factor (CRF)-secreting PVN neurons.

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Vasopressin-prostaglandin (PG) interaction, especially the role of the inhibitory effects of PGE₂ on vasopressin action, was studied using toad urinary bladders. The PGH₂, at 1×10^-7M, inhibited vasopressin-stimulated water flow (MARUMO, 1982); PGE₂ inhibited the water flow at 10^-8M, but PGD₂, PGF_2α, and PGI₂ did not do so even at 10^-7M. Thus, PGE₂ has a physiological effect in contrast to other PGs converted from PGH₂. Indomethacin enhanced both the vasopressin- and cyclic AMP-stimulated water flow across the toad bladder. However, the half maximum activation dose for vasopressin was 2×10^-10M, but for cyclic AMP, as much as 3×10^-8M. The PGE₂ inhibited both vasopressin- and cyclic AMP-stimulated water flow. However, PGE₂ inhibited vasopressin action in a dose-dependent manner which was not noted as a PGE₂ effect on cyclic AMP action. The W-7, which is a specific inhibitor of calmodulin, suppressed cyclic AMP-stimulated water flow in a dose-dependent manner. Thus, PGE₂ may suppress vasopressin-stimulated water flow at a site of cyclic AMP generation under physiological conditions. Thromboxane B₂ (TXB₂) enhanced vasopressin-stimulated water flow but not cyclic AMP-stimulated one. Thus PGE₂ and TXB₂ may be concluded as negative or positive modulators of vasopressin action in the toad bladder on the step(s) as the site of cyclic AMP generation under physiological conditions.

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Serial, measurements of extracellular fluid (ECF), and plasma volumes were evaluated in dogs before and during general anaesthesia with sodium pentobarbitone and under controlled conditions of arterial pH, p_O2, p_CO2, and blood pressure. Sodium pentobarbitone anaesthesia caused an early, significant rise in ECF volume with a fall in haematocrit, plasma protein, and plasma potassium concentrations. Plasma osmolality and sodium concentrations were unchanged. The lack of change in ECF sodium concentration suggests that the total ECF sodium content increased in parallel with the expansion of this compartment. Sodium bound to macromolecules in the interstitial space or to bone is suggested as a possible source of sodium ions. It is unlikely that intracellular sodium stores contribute to a significant extent in these changes. During prolonged anaesthesia plasma volume progressively increased while total ECF volume returned towards control values. This work clarifies previous observations and suggests that major fluid movements occur during sodium pentobarbitone anaesthesia primarily associated with altered cell membrane properties and generalised haemodynamic changes.

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We quantitatively assessed the change of pulmonary microvascular permeability following E, coli endotoxin infusion (1mg/kg) in anaesthetized dogs. We used mathematical analysis to estimate membrane parameters from lung lymph data. Lung lymph was collected from the afferent lymphatic connecting to the left tracheobronchial lymph node whose lymph could be considered to represent an average sample of lung tissue fluid. To separate the effects of changes in the driving pressures and surface area on lymph fluid and protein flux from those in membrane permeability, lymph flow (J_v) was increased greater than 6 times baseline by left atrial pressure (P_1a) elevation until lymph protein concentration (C_L) approached to a constant value independent of J_v. Membrane parameters for plasma total protein, i.e., osmotic reflection coefficient (σ_d), solvent-drag reflection coefficient (σf), permeability surface area product (PS), filtration coefficient (Kfc), were calculated from lung lymphatic data in control (P_1a) elevation alone (n=10), and endotoxin group (n=7). Among these parameters, osmotic reflection coefficient (σ_d) decreased significantly to 0.61 in endotoxin group from the value of 0.71 in control group. This result indicates a moderate increase in pulmonary microvascular permeability following E. coli endotoxin infusion. However, there was no significant difference in the other membrane parameters (σ_f, PS, K_fc) between control and endotoxin group. Based on these results, we conclude that σ_d could quantitatively represent the moderate change of the microvascular permeability in endotoxin-induced lung injury in anaesthetized dogs.

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A study was made of the effects of cycloheximide, an inhibitor of protein synthesis, on the transformations of electrical activity and adrenergic response of the circular muscle of rat uterus during pregnancy and postpartum. Electrical activity proceeded from plateau type on Day 18 of gestation to spike type on Day 22. Excitatory reaction of the contraction to noradrenaline (10^-7, 3×10^-7M) on Day 18 altered to an inhibitory one on Day 22. When pregnant rats were injected intraperitoneally with 50μg cycloheximide daily from Day 18, the changes mentioned above were suppressed and parturition delayed. In the preparations obtained on Day 21, the excitatory effect of 10^-7M noradrenaline on the contraction changed to an inhibitory one by in vitro incubation for 7h with Krebs solution. This transformation was prevented by the incubation with 2μg/ml cycloheximide for 7h. Membrane activity and adrenergic response turned to plateau-dominant action potential with long duration and potentiation of the contraction by noradrenaline (10^-7, 3×10^-7M) 48h after parturition, respectively. Cycloheximide (50μg/day, i.p., immediately after delivery and on the next day) failed to inhibit these postpartum changes. The results suggest that the process of protein synthesis is involved in the alterations in electrical activity and adrenergic response of the circular muscle of rat uterus during late pregnancy stage.

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In pertaining to P_O2 dependency of the pulmonary CO diffusing capacity during rebreathing, the O₂ uptake (V_O2) and cardiac output (Q) were measured at three different P_O2 levels between 100 and 500 Torr. Since the V_O2 measured by an O₂ injection method is strongly influenced in hyperoxia by a gas exchange ratio (R), a simulation method using a R- P_CO2 relation during rebreathing was developed. Gas volume in the lung-bag-system needed in the computation was measured from the difference in O₂ concentration between before and after injecting a known amount of O₂ into the rebreathing circuit. The accuracy of the volume was checked by comparing it with the volume measured successively with a body box. The V_O2 was determined by comparing the simulated O₂ and CO₂ concentrations in rebreathing gas with the measured ones. The V_O2 significantly increased by rebreathing in hyperoxia. To analyze the V_O2 increase, the Q was computed by dividing the V_O2 by the arteriovenous O₂ content difference, which in turn was obtained by dividing the slope of the CO₂ dissociation curve by that of the R-P_CO2 line. The Q was almost linearly related to the V_O2. Since there was no difference in V_O2 in steady state breathing between normoxia and hyperoxia, the increase in V_O2 and Q seemed to occur transiently. This finding is very important in evaluating the P_O2 dependency of the pulmonary diffusing capacity for CO.

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The effects of carotid chemoreceptor stimulating and depressing agents on internal intercostal muscle activity (IIMA) were studied before and after surgical denervation of the carotid sinus nerve (CSN) in the rabbit. An intracarotid injection of 30μg of sodium cyanide (NaCN) during inspiration caused an increase in both IIMA and respiratory rate (RR). In contrast, intracarotid administration of 10μg of dopamine (DA) during inspiration resulted in a decrease in both IIMA and RR. The NaCN- and DA-induced characteristic responses in IIMA were abolished by the section of the CSN. The results indicate that the excitatory and inhibitory responses of IIMA to intracarotid injections of NaCN and DA are mainly mediated through carotid chemoreflexes.

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Experiments were done on the tortoise, Testudo hermanni (anesthetized), or on its lung-vagus preparation in which all other internal organs had been removed. By recording the afferent impulse patterns in fine strands of the vagus, three kinds of CO₂-sensitive receptors were demonstrated. (1) Heymans-type chemoreceptors: Afferents originating from thoracic arterial chemorceptors fired randomly at amplitudes below 100μV. Firing frequency increased when the animal was ventilated with CO₂-enriched, nitrogen or hypoxic mixtures, or was given NaCN. (2) Intrapulmonary CO₂ receptors (IPC). In an artificially ventilated tortoise and in lung-vagus preparations where the lung CO₂-fraction (F_CO2) was below 2.5%, single units with a spike amplitude above 200μV fired regularly. When CO₂-enriched air was inspired, impulse frequency decreased markedly, and when the lung was washed with air, it returned to the control frequency following the initial excitation. In lung-vagus preparations the impulse frequency did not change with lung inflation, was null for F_CO2 greater than 2.5-3.5%, and was inversely proportional to lower F_CO2's. (3) Intrapulmonary CO₂-sensitive mechanoreceptors: In anesthetized artificially ventilated tortoises, impulse bursts synchronized with inspiration decreased when the animal inspired 5 or 10% CO₂ in air. In lung-vagus preparations, slowly adapting mechanoreceptor responses provoked by lung inflation were reduced when the lung was inflated with CO₂-enriched air.

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Spontaneously beating sino-atrial node (S-A node) of guinea-pig was superfused with solutions of various osmolarities. The changes in the rate of spontaneous beating and in action potentials were measured. In the solution of normal tonicity, the rate of spontaneous beating was 214±6beats/min (mean±S.E.) and the maximum rate of rise was 9.7±2.5V/s. When extracellular Na⁺ was reduced by 33%, isotonically replaced with sucrose, the heart rate was reduced to 177±8beats/min and the maximum rate of rise was reduced to 7.6±1.2V/s. Decreasing the osmolarity by 30% increased the heart rate by 6% and increasing the osmolarity to 130, 150, and 170% decreased the heart rate to 94, 89, and 73%, respectively, in low Na⁺ medium. The tonicity dependence of the heart rate was not affected by TTX, atropine, phentolamine, or propranolol. When the tonicity was either increased twice or decreased half, the spontaneous beating stopped. Adding either K⁺ or Rb⁺ of 6mM to the solution which was two times as hypertonic as the normal, could activate the beating again. Substances inhibiting the potassium conductance such as tetraethylammonium (TEA), 4-aminopyridine (4-AP), and cesium chloride (CsCl) could also reactivate the spontaneity. Although lowering extracellular Ca²⁺ concentration could reactivate the spontaneity in the hypertonic medium, increasing Mg²⁺ inhibited the reactivation. The contribution of K⁺ current in the effects of changing osmolarity on the spontaneous beating is discussed.

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The effects of exercise training on the catecholamine-stimulated [³H]GDP release in rat adipocyte membranes prelabeled with [³H]GTP and the adenylate cyclase activity were investigated. Exercise training significantly increased the release of [³H]GDP in response to (-)isoproterenol. The adenylate cyclase activity induced by a nonhydrolyzable guanine nucleotide analogue, Gpp(NH)p, was significantly greater in exercise-trained rats.

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Determination of Hüfner's factor and simultaneous measurement of met- and carboxyhemoglobin were performed in 31 human, 16 canine, and 2 murine blood samples. Both measured and corrected values of Hüfner's factor were lower than the theoretical value of 1.39, suggesting the possibility of the presence of unidentifiable inactive hemoglobin(s) in blood.

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Muscle sympathetic nerve activity (MSA) was recorded by microneurographic technique from the human tibial nerve before and during voluntary sustained and rhythmic handgrip exercises. The MSA increased significantly during sustained contractions but not during rhythmic contractions, whereas no differences in resting activity before the two modes of handgrip were seen at rest. The results demonstrate that MSA responses to sustained and rhythmic exercises are distinctly different, showing less sympathetic outflow during rhythmic than during sustained contraction.

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