Nitric oxide (NO) is involved in numerous physiological functions. Besides its role as an endothelium-dependent relaxing factor (EDRF), NO inhibits platelet aggregation, contributes to cytotoxicity against bacteria, is active in synaptic transmission within the brain, etc. NO synthase (NOS) is distributed in brain regions related to the regulation of cardiovascular functions. NO has been inferred not only to act directly on vascular vessels, but also to regulate circulation within the brain. In this review paper, we mainly consider the functions of NO in the cardiovascular center of the medulla oblongata. That is, we describe the anatomical distribution of NOS in the brain, effects of intravenous and intracerebroventricular administration of NOS inhibitors on the circulation, effects of microinjection of NO donors and NOS inhibitors into the nucleus tractus solitarius (NTS) and ventrolateral medulla (VLM), the results of electrophysiological studies on these areas, and finally, the data obtained by new molecular biological techniques.

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Haloperidol (HPL), a widely used antipsychotic drug, is known to induce serious ventricular arrhythmias. However, the mechanism underlying their induction is not clear. We therefore examined the effects of HPL on the intracellular Ca²⁺ ([Ca²⁺]_i) transient and on cell motion in cultured cardiac myocytes, as well as the pathways involving the HPL-induced abnormality of Ca²⁺ homeostasis. HPL prolonged the diastolic phase of the Ca²⁺ transient, with a mid-diastolic re-elevation of [Ca²⁺]_i. The re-elevation of [Ca²⁺]_i was shown to be provoked by Ca²⁺ release from sarcoplasmic reticulum (SR), which can trigger delayed afterdepolarization, the major arrhythmogenic factor. The re-elevation of [Ca²⁺]_i coincided with cell re-contraction during diastole. The induction of this abnormality by HPL appears to be independent of the mechanisms of the antipsychotic action.

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To study the limbic control of nociception, we examined the effect of conditioning stimulation of the central amygdaloid nucleus (ACE) on tooth pulp–driven (TPD) neurons in the first somatosensory cortex (SI). Cats were anesthetized with N₂O–O₂ (2 : 1) and 0.5% halothane, and immobilized with tubocurarine chloride. The tooth pulp test stimulus was applied by a single rectangular pulse (0.5 ms in duration and 3–5 times the threshold intensity for the jaw-opening reflex). Conditioning stimuli to the ACE consisted of trains of 33 pulses (300 μA) delivered at 330 Hz at intervals of 8–10 s. In 35 out of 61 of the slow (S)-type TPD neurons with latencies of more than 20 ms, conditioning stimulation in the ACE, especially in the medial division, markedly reduced the firing response to the pulpal stimulation. The inhibition of the firing rate in the S-type neurons was 74% of the control. In these S-type neurons, the neurons that were inhibited had significantly longer latencies compared to the non-inhibited neurons (45.0 ± 17.6 ms, n = 32 vs. 34.8 ± 10.5 ms, n = 26). In contrast, the ACE conditioning stimulation affected only one out of 18 fast-type TPD neurons with latencies of less than 20 ms. In addition, ACE stimulation had no effect on the spontaneous discharges of either S-type or F-type neurons. The ACE inhibitory effect on S-type neurons was not diminished by naloxone administration (1 mg/kg, i.v.), while the blockade of histamine H₁-receptor by diphenhydramine hydrochloride (0.5 mg/kg, i.v.) partially reversed the inhibitory effect. These results suggest that the ACE inhibits ascending nociceptive information to the SI and that this inhibition is mediated in part by histamine (H₁) receptors. It seems likely that the antinociceptive effect is a neurophysiological basis for stress-induced analgesia (SIA).

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The effects of tetrandrine (Tet) on the contractile function and microvascular permeability in stunned rat myocardium in vivo were studied. Stunned myocardium was induced by 15 (MS₁₅ group) or 20 (MS₂₀ group) min of myocardial ischemia plus 60 min of reperfusion. The following was shown. (1) FITC-BSA concentration was 166.0 ± 7.9 μg/g myocardium in the control group. The concentrations in ischemic myocardium increased by 35.4 and 45.6% in MS₁₅ and MS₂₀ groups, respectively (p < 0.05). (2) Administration of Tet (64.2 and 96.3 μmol/kg, i.p.) 20 min before ischemia not only ameliorated the contractile function, but also reduced the FITC-BSA concentrations in ischemic myocardium. At 60 min after reperfusion, the contractile function parameters in Tet-treated groups were significantly superior to those in corresponding stunning groups. FITC-BSA concentrations in Tet-treated groups were lower than those in stunning groups. Then, there was already no significant difference in FITC-BSA concentrations between Tet-treated groups and the control group. The FITC-BSA concentrations at the end of experiments were correlated negatively with dp/dt_max (r = −0.83, p < 0.01). (3) Tet inhibited KCl-induced calcium influx in isolated cardiomyocytes. The results suggest that Tet given before ischemia may be involved in the reduction of microvascular permeability in stunned myocardium, which might be associated with its calcium channel blocking effect.

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The relationship between parotid amylase secretion and the osmolality in the gastric contents of rats fed a pelleted or liquid diet was investigated. In sham-operated rats fed a pelleted diet, amylase activity in the parotid glands decreased, amylase activity in the plasma increased, and there was strong amylase activity in the gastric contents. As a result, both reducing sugar concentration and osmolality in the gastric contents increased. In parotid duct–ligated rats, the feeding of a pelleted diet affected neither parotid nor plasma amylase activity and there was little amylase activity in the gastric contents; this resulted in decreased starch digestion. The amylase activity in the gastric contents of rats fed a liquid diet was lower than that of rats fed the pelleted diet. Both the reducing sugar concentration and osmolality in the gastric contents of rats fed the liquid diet were lower than those of rats fed the pelleted diet. However, both the reducing sugar concentration and osmolality in the gastric contents of rats fed the liquid diet were higher than those in the liquid diet itself. A small quantity of parotid amylase seems to effectively digest a large part of the starch in the stomaches of rats fed the liquid diet. These findings suggest that amylase secreted from parotid glands increases osmolality in the gastric contents via the production of reducing sugars from starch in rats when fed either pelleted or liquid diets.

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We have already reported the linear oxygen consumption per beat (Vo₂)–systolic pressure-volume area (PVA) relation from the curved left ventricular (LV) end-systolic pressure–volume relation (ESPVR) in the cross-circulated rat heart. The Vo₂ intercept (PVA-independent Vo₂) is primarily composed of Vo₂ for Ca²⁺ handling in excitation-contraction (E-C) coupling and basal metabolism. The aim of the present study was to obtain the oxygen cost of LV contractility that indicates Vo₂ for Ca²⁺ handling in E-C coupling per unit LV contractility change in the rat heart. Oxygen cost of LV contractility is obtainable as a slope of a linear relation between PVA-independent Vo₂ and LV contractility. We obtained a composite Vo₂–PVA relation line at a mid-range LV volume (mLVV) under gradually enhanced LV contractility by stepwise increased Ca²⁺ infusion and thus the gradually increased PVA-independent Vo₂ values. As a LV contractility index, we could not use E_max (ESP-V ratio; ESP/ESV) for the linear ESPVR because of the curved ESPVR in the rat LV. A PVA at a mLVV (PVA_mLVV) has been proposed as a good index for assessing rat LV mechanoenergetics. Since the experimentally obtained PVA_mLVV was not triangular due to the curved ESPVR, we propose an equivalent ESP-V ratio at a mLVV, (eESP/ESV)_mLVV, as a LV contractility index. This index was calculated as an ESP-V ratio of the specific virtual triangular PVA_mLVV that is energetically equivalent to the real PVA_mLVV. The present approach enabled us to obtain a linear relation between PVA-independent Vo₂ and (eESP/ESV)_mLVV and the oxygen cost of LV contractility as the slope of this relation.

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In the circular muscle of the guinea-pig gastric antrum, the contribution of glycolysis to spontaneous electrical activity, slow wave, was studied. The slow wave could be maintained without a marked change in glucose-free solution for more than 1 h even when treated with iodoacetic acid (IAA, 0.1–0.5 mm). However, reapplication of glucose following the IAA treatment produced clear inhibitory effects on the slow wave. Lactate release from the tissue was reduced to about 10% of the control by IAA (0.1 mm) in the absence of glucose and there was very slow recovery on glucose reapplication. This suggests that IAA did not block glycolysis completely and that the inhibition of slow wave was mainly due to the accumulation of some metabolites. Small electrical activity often remained during the inhibition by IAA and glucose. When the excitability of the smooth muscle was increased by Co²⁺ application or Na⁺ removal, slow wave-like activity could be generated under the condition in which the slow wave was strongly inhibited by IAA and glucose. These results may be explained by assuming that the accumulation of glycolytic metabolites decreases the excitability of smooth muscle cells and also reduces the driving potential generated in the interstitial cells of Cajal to a subthreshold level for the slow wave in the smooth muscle cells.

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During vertebrate embryogenesis, blastoderm cells at the gastrula stage migrate to new locations for subsequent development. The cellular mechanism of migration was studied in medaka (Oryzias latipes) embryos at the early gastrula stage. When fibronectin was applied iontophoretically or by the puff method, cell surface protrusion known as pseudopods and a local [Ca²⁺]_i rise at the site of application were observed in approximately half of the isolated blastoderm cells. When the pseudopod adhered to the substrate, the cell body moved toward the direction of the pseudopod as [Ca²⁺]_i declined and the pseudopod was withdrawn. Local puff application of ionomycin, a Ca²⁺ ionophore, in the presence of external Ca²⁺ induced protrusions of the plasma membrane similar to pseudopods, suggesting that the [Ca²⁺]_i rise itself is causing pseudopod formation. On the other hand, fibronectin induced pseudopods even in the absence of external Ca²⁺, suggesting the mobilization of Ca²⁺ from internal stores. In accordance with this interpretation, fibronectin failed to induce [Ca²⁺]_i rises after pretreatment with thapsigargin, a blocker of Ca²⁺-ATPase in the endoplasmic reticulum. Furthermore, chelating internal Ca²⁺ with BAPTA prevented fibronectin from inducing pseudopods. U-73122, a blocker of phospholipase C, completely suppressed both the [Ca²⁺]_i rise and morphological changes accompanied with fibronectin application, suggesting involvement of the inositol phosphate pathway. On the other hand, caffeine evoked a [Ca²⁺]_i rise in a great majority of the fibronectin-responsive cells and the percentage of fibronectin-responsive cells was greatly reduced by a blocking dose of ryanodine. These results suggest that fibronectin activates phospholipase C and the initial [Ca²⁺]_i rise through IP₃ receptors further activates ryanodine receptors, achieving the local [Ca²⁺]_i rise. The decay time course of [Ca²⁺]_i after fibronectin application was prolonged in the absence of external Na⁺. DCB, an inhibitor of Na⁺/Ca²⁺ exchangers, also prolonged the time course of the [Ca²⁺]_i decay, suggesting the contribution of Na⁺/Ca²⁺ exchangers. Cytochalasin D, an inhibitor of actin polymerization by binding to the barbed end of F-actin, induced swelling in fibronectin-responsive cells and prevented fibronectin from inducing pseudopod formation without suppressing the [Ca²⁺]_i rise. These results support the hypothesis that fibronectin facilitates cell migration via pseudopod formation during gastrulation.

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Exhaled nitric oxide (NO) level decreases after corticosteroid treatment in asthmatics, but the effect of a leukotriene receptor antagonist, pranlukast, on exhaled NO has not been elucidated. Pranlukast treatment in mild persistent asthmatics for 4 weeks decreased the exhaled NO level, which did not differ from the levels in healthy subjects.

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The effects of depolarizing conditions resulting from increasing extracellular K⁺ concentration or nystatin treatment on intracellular Ca²⁺ concentration ([Ca²⁺]_i) were studied in guinea pig antral mucous cells following acetylcholine (ACh) stimulation. ACh stimulation evoked a biphasic increase in [Ca²⁺]_i, that is, an initial transient increase followed by a plateau. Depolarizing conditions reduced the [Ca²⁺]_i in the plateau phase during ACh stimulation. However, pertussis toxin (PTX, a G protein inhibitor) treatment caused [Ca²⁺]_i in the ACh-evoked plateau phase to increase under depolarizing conditions, while it had no effect on [Ca²⁺]_i under hyperpolarized conditions. Based on these observations, Ca²⁺ permeable channels are regulated by a G protein which is activated by depolarized conditions and inhibited by hyperpolarized conditions and PTX; activation of the G protein (depolarization) causes Ca²⁺ permeable channels to inhibit, and in turn, inhibition of the G protein (hyperpolarization) causes them to activate.

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Twelve trained young males (age: 24 ± 5 years) performed an incremental test to exhaustion during which capillary blood and saliva samples were obtained to determine the blood lactate (LT) and salivary amylase (T_sa) thresholds. The root mean–square voltage of electromyographic activity (rms-EMG) of the vastus lateralis muscle was also recorded to detect the electromyographic threshold (EMG_T). No significant difference was found between the exercise intensity corresponding to the LT, T_sa or EMG_T.

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