The brain stem neural mechanism for central regulation of breathing is regarded as a complex neuronal mechanism consisting of several functional subsystems subserving different functions. One of its functions is the generation of the respiratory rhythm. Evidence indicates with certainty that the subsystem for respiratory rhythm-generating mechanisms is located in the medullary structure outside the DRG and VRG regions which have been postulated for many years as the hypothetical site generating respiratory rhythm. DRG and VRG are thought to be premotor neuron pools.
Rhythmic activity originating in the medulla is dominant in terms of the spontaneity over other rhythmic activity in the pontine mechanisms as well as those in the spinal cord. Evidences for heterogeneity of functional properties of respiratory neurons in the brain stem are demonstrated. Possible functional differentiation among respiratory neurons is suggested. Neuronal mechanisms involving respiratory neurons identified as members of primary respiratory neuron populations or neuronal networks consisting of various types of respiratory neurons located in the lateral region of the bulbar reticular formation may play important roles in generation of respiratory rhythms. Precise neural processes within the neuronal mechanisms for respiratory rhythm generation are rather equivocal and remain to be determined by further investigation.

View full abstract

Mean arterial pressure and three regional blood flows-renal, superior mesenteric, and hindquarter flows-were monitored in conscious normotensive control rats (NCR), in two-kidney, one-clip (two-kidney), and in one-kidney, one-clip (one-kidney) hypertensive rats. After administering captopril, an angiotensin-converting enzyme inhibitor, mean arterial pressure decreased in all three groups. However, lowering of arterial pressure was not statistically significant in any of the groups. Renal flow increased significantly in the intact artery of two-kidney hypertensive rats, whereas it did not significantly increase in the clipped artery of one-kidney hypertensive rats and in the intact artery of NCR. Superior mesenteric flow increased significantly only in one-kidney hypertensive rats. Hindquarter flow did not significantly change in the three groups. Regional resistance reduced significantly in not only renal but also in superior mesenteric vascular area in two-kidney hypertensive rats, whereas it did not reduce significantly in these two vascular areas in one-kidney hypertensive rats and in NCR. The present findings show that the renin-angiotensin-mediated vasoconstriction plays a role in not only renal but also in superior mesenteric vascular area in two-kidney hypertensive rats, whereas it hardly plays a role in these three vascular beds in one-kidney hypertensive rats.

View full abstract

We found previously that in in vitro tube form preparations of isolated intestine of streptozotocin (STZ) diabetic rats, frequency of spontaneous intraluminal pressure waves was significantly reduced in duodenum when compared with normal controls. In order to elucidate further the diabetic intestinal disorders, we examined the frequency and amplitude of spontaneous length changes and contractile responses to acetylcholine (ACh) and substance P (sP) in isolated intestinal segments of normal and experimental diabetic rats. In comparison with normal controls, we could confirm the significantly decreased frequency of spontaneous length changes in isolated longitudinal and circular muscle preparations of diabetic duodenum (1 month after STZ injection). Furthermore, amplitude of spontaneous length changes was significantly decreased in circular muscle preparations of duodenum, jejunum, and ileum but not in colon nor in longitudinal muscle preparations. Doseresponse curves revealed that both ACh and sP responses were significantly decreased in longitudinal and circular muscle preparations of diabetic duodenum, jejunum, and ileum but not in colon. Mechanisms of reduced contractility of diabetic intestinal smooth muscle in response to ACh and sP were discussed.

View full abstract

Intracellular pH was measured with single- or double-barreled liquid ion-exchanger microelectrodes in the bullfrog sartorius muscle perfused in vitro. A neutral carrier ligand was used for pH sensor of microelectrodes. Average slopes of the single-barreled microelectrodes were -56.4±1.34mV/pH (n=30) and the double-barreled -52.6±1.34 mV/pH (n=65). While changing acid-base parameters of bathing media (pHe from 6.7 to 8.4, P_CO2 from 3.7 to 37mmHg, and HCO₃^- concentrations from 5 to 75mM), paired muscle cell pH (pHi) and membrane potential (EM) values were determined at 23°C. In control conditions (pHe=7.6, HCO₃^-=15mM, P_CO2=11mmHg), pHi and EM (n=20) averaged 6.99±0.04 (S.E.) and -69.2±2.2mV, respectively. A negative correlation was observed between pHiand EM (correlation coefficient r= -0.564, p<0.002). The change in EM per unit pH change was approximately -30mV, indicating that the H⁺ distribution across the cell membrane only incompletely obeys the Donnan rule. The pHi varied more or less with pHe. Namely, changes in pHe and P_CO2 at constant HCO₃^- produced relatively large changes in pHi, but elevation of pHe and P_CO3^- at constant P_CO2 produced relatively minor rise in pHi. The stability of pHi or the size of buffer capacity were proportional to external HCO₃^- concentrations. These data suggested that a transmembrane distribution of buffer pairs depends largely on non-ionic diffusion of CO₂- HCO₃^- buffer system and partly on ion fluxes of HCO₃^- or H⁺.

View full abstract

We studied the effect of stretch on the membrane potentials and ultrastructure of isolated ventricular papillary muscles of guinea pigs. The muscles were stimulated at 0.5Hz and stretched stepwise from slack length (90% of L_max) to 100% (mild stretch), 110-120% (moderate stretch), and 130-140% of L_max (severe stretch), under microscopic control. In control Tyrode solution (K⁺=5.4mM, Ca²⁺=1.8mM, Mg²⁺=0.5mM), the mild to moderate stretch significantly depolarized the resting potential (RP) by about 6mV as compared to that in slack length, whereas the severe stretch hyperpolarized the membrane by about 5mV. The latter finding was new and was focused on in later experiments. Both the hyperpolarization and depolarization became more marked when [K⁺]₀ was decreased to 1.35- 2.7mM, and became less with elevated [K⁺]₀ to 10.8-21.6mM, thereby suggesting the participation of altered K⁺ conductance (gK) with these changes in the RP. Perfusion with low [Ca²⁺]₀ (0.45mM) enhanced the depolarization but eliminated the hyperpolarization; high [Ca²⁺]₀ (7.2mM) inhibited the depolarization without effect on the hyperpolarization. D- 600 (1μM), caffeine (10mM), and ryanodine (1μM), all of which may produce decreases in [Ca²⁺]i, abolished the hyperpolarization with inconsistent effects on the depolarization. Moderate to severe stretches decreased the maximum rate of rise of action potential (V_max), by shifting the V_max-RP relationship toward hyperpolarizing direction. The shift could be reversed partially after increasing [Mg²⁺]₀ to 8.0mM. Electron microscopic examination revealed that the sarcoplasmic reticulum (SR) remained intact with mild to moderate stretches with significant lengthening of sarcomere length, while with a severe stretch, the SR showed a structural disarrangement with a non-uniform lengthening of sarcomere length. Our observations suggest that stretch-induced hyperpolarization is probably mediated by the increase in gK, presumably secondary to the increase in [Ca²⁺]i. Ca²⁺ may be released from the SR upon mechanical stretch of the organelle.

View full abstract

In the isolated frog muscle, the proteinaceous venom extracted from jellyfish (genus Aurelia) produced 1) a complete and irreversible block of indirectly and directly elicited muscle twitch and 2) an irreversible depolarization of the muscle membrane. This venom-induced depolarization was effectively reversed or prevented by the substitution of choline for sodium in Ringer solution, but not by the introduction of tetrodotoxin (TTX), a sodium channel blocker. The mechanism of muscle membrane depolarization appears to involve probably an increase in membrane permeability to sodium ion as shown by the decrease in membrane resistance. These results suggest that the venom forms a pore which has sodium selectivity or activates a TTX-insensitive sodium channel which is different from the known sodium channel.

View full abstract

The ionic mechanisms of automaticity in spontaneously active preparations (n=38) from "diseased" human atria were investigated. The cycle length (CL) of the automatic action potential (AAP) ranged from 0.6 to 4.5s (mean ± S.D.: 2.0±1.0s). The AAP from preparations obtained from non-digitalized patients (group 1, n=29) showed various CLs, in that 16 patients had a CL longer than 2.0s (slow-type AAP) while in tissues from the other 13 patients, the CL was 2.0s or less (fast-type AAP). On the other hand, all preparations obtained from the digitalized patients prior to cardiac surgery (group 2, n=9) had the fast-type AAP (CL_??_2.0s). The slow-type AAP was accelerated and changed to the fast one after application of ouabain (1μM) or by perfusing with 50% [Na+]₀ Tyrode solution. Ryanodine (1μM), a specific inhibitor of calcium release from the sarcoplasmic reticulum (SR), markedly lengthened the CL of fast-type AAP, without affecting the slow-type AAP. In contrast, caffeine (15mM) shortened the CL of the slow-type AAP and remarkably lengthened the CL of the fast-type AAP, as is the case in ryanodine. The rate of slow-type AAP was enhanced with an increase in [Ca²⁺+]₀ and depressed with a decrease in [Ca²⁺+]₀ or with application of diltiazem, a Ca²⁺+ channel blocker. The slow-type AAP was changed to the fast-type AAP by stretching the preparation by about 20%. In vitro preparations excised from patients with dilated atria revealed a shorter CL of AAPs. We conclude that in "diseased" human atrial preparations, the ionic mechanism responsible for generation of slow- and fast-type automaticity differs. Slow automaticity (CL>2.0s) perhaps relates to activation of the slow inward Ca²⁺+ current, while the fast-type automaticity (CL_??_2.0s) is linked to cyclic increases in [Ca²⁺+]i.

View full abstract

Effects of cytochalasins B and D (CB, CD) were examined for the contractions of the longitudinal myometrium of pregnant rat exposed to Krebs solution, 40mM K Krebs, and Ca-free (40mM K) solution containing 5mM Mg. The Ca-free contraction was evoked by applying 3mM ATP. Application of CB caused a prompt inhibition of the contractions: 3μM CB depressed the twitch contraction generated in Krebs solution by 12%, the K-contracture by 6%, and the ATP-induced contraction in the Ca-free solution by 59%. CD (3μM) depressed the K-contracture by 31%, and the ATP-induced contraction in the Ca-free solution by 81%. CB and CD in 3μM hyperpolarized the membrane and depressed the generation of action potential. From the above results, it was discussed that depressant effects of cytochalasins on twitch contractions in Krebs solution are at least in part due to the depression of membrane excitability, whereas contractions evoked in high K solutions are depressed by cytochalasins due to their effects on cytoskeleton.

View full abstract

The time course of the ability of active shortening was compared to that of isometric contractile force during contraction-relaxation cycles of the pedal retractor muscle of Mytilus by measuring the maximal shortening velocity and the rate of force redevelopment after a quick release. The contractile force had its peak at 2s after stimulus initiation and decayed with a half relaxation time of 8.3s at 10°C. At 6s after stimulus initiation, both the maximal velocity of shortening and the rate of force redevelopment had decreased to 30% or less of the initial values, while 70% of peak force was retained. The results suggest a mechanism of economic force maintenance with a reduced rate of crossbridge cycling.

View full abstract

The effects of glycerol (400 to 1, 200mM) treatment on contractions of rat soleus muscles were investigated. Glycerol induced temperature- and concentration-dependent contractures which depended largely on extracellular calcium. Glycerol treatments reduced but did not abolish twitch, tetanus, and potassium contracture tension and these changes were far less at 22 than at 37°C. Caffeine contractures were not altered following glycerol treatment at 22°C, but were at 37°C. It is suggested that the lesser effects of glycerol treatment on the soleus compared to other muscles may be due to its smaller transverse tubule system. Glycerol permeation and thus its osmotic action may be less in the soleus than in other muscles.

View full abstract

In order to investigate the mechanism by which elevated extracellular Ca ions decrease twitch and tetanus tension in frog skeletal muscle we made mechanical and electrophysiological measurements on single fibers or small bundles from twitch muscles. High concentration of Ca caused a hyperpolarization and an increase in the duration of action potential. The mechanical threshold, estimated by using the strength-duration curve, was shifted upward by adding Ca ions. These effects were fully reversible. Steady state twitch tension was slightly increased by replacing Mg and Ni with Ca and decreased by elevating their concentrations, although Ba resulted in a marked twitch augmentation and a positive correlation with the ion concentration. By contrast, the strength-duration curve was shifted upward by Ni while Mg and Ba showed no shift. These evidences point to a failure of the early step of excitation-contraction coupling, including the T-membrane depolarization, as the primary mechanism of action of high concentration of Ca, Mg, and Ni ions, whereas Ba ion has an additional intracellular potentiating effect.

View full abstract

In three groups of subjects we studied heart rate (HR) and ventilatory responses to progressive eucapnic hypoxia, steady-state hypercapnia with and without hypoxia, and hyperoxic and hypoxic breath-holding (BH). Groups were six subjects about 25 years after bilateral carotid body resection (BR), eight subjects of an equally long period after unilateral resection (UR), and three control subjects similar to the study groups in age and pulmonary function (C). During progressive hypoxia, HR increased more in BR than in UR and C subjects. Ventilatory response was lowest in BR subjects (as expected). Steady-state hypoxic hypercapnia (end-tidal P_O2, 60Torr) depressed HR significantly more in C than in BR and UR subjects. Again, ventilatory response was lower in BR than in C subjects. HR progressively increased during BH initiated in hyperoxia (end-tidal P_O2, 200 Torr) and hypoxia (end-tidal P_O2, 70Torr). In the BR group, the HR increment during hypoxia was significantly larger than that during hyperoxia. No such difference was apparent in UR and C groups. Thus, hypoxia with or without hypercapnia tends to accelerate HR in BR subjects whereas either less tachycardia or slowing is seen in UR and C subjects.

View full abstract

In the untrained subjects, inhalation of 4.5-6.0% CO₂ prior to maximal treadmill exercise does not affect physical performance and maximum oxygen uptake, while blood lactate levels during recovery have a tendency to greater decrease in CO₂ breathing than that in the room-air breathing. It was suggested that CO₂ inhalation immediately prior to maximal exercise as applied here is not a useful tool in increasing physical performance.

View full abstract