Effects of arterial wall stress on vasomotion

Smooth muscle and endothelial cells in the arterial wall are exposed to mechanical stress. Indeed blood flow induces intraluminal pressure variations and shear stress. An increase in pressure may induce a vessel contraction, a phenomenon known as the myogenic response. Many muscular vessels present vasomotion, i.e., rhythmic diameter oscillations caused by synchronous cytosolic calcium oscillations of the smooth muscle cells. Vasomotion has been shown to be modulated by pressure changes. To get a better understanding of the effect of stress and in particular pressure on vasomotion, we propose a model of a blood vessel describing the calcium dynamics in a coupled population of smooth muscle cells and endothelial cells and the consequent vessel diameter variations. We show that a rise in pressure increases the calcium concentration. This may either induce or abolish vasomotion, or increase its frequency depending on the initial conditions. In our model the myogenic response is less pronounced for large arteries than for small arteries and occurs at higher values of pressure if the wall thickness is increased. Our results are in agreement with experimental observations concerning a broad range of vessels.     

Role of the endothelium on arterial vasomotion

It is well-known that cyclic variations of the vascular diameter, a phenomenon called vasomotion, are induced by synchronous calcium oscillations of smooth muscle cells (SMCs). However, the role of the endothelium on vasomotion is unclear. Some experimental studies claim that the endothelium is necessary for synchronization and vasomotion, whereas others report rhythmic contractions in the absence of an intact endothelium. Moreover, endothelium-derived factors have been shown to abolish vasomotion by desynchronizing the calcium signals in SMCs. By modeling the calcium dynamics of a population of SMCs coupled to a population of endothelial cells, we analyze the effects of an SMC vasoconstrictor stimulation on endothelial cells and the feedback of endothelium-derived factors. Our results show that the endothelium essentially decreases the SMCs calcium level and may move the SMCs from a steady state to an oscillatory domain, and vice versa. In the oscillatory domain, a population of coupled SMCs exhibits synchronous calcium oscillations. Outside the oscillatory domain, the coupled SMCs present only irregular calcium flashings arising from noise modeling stochastic opening of channels. Our findings provide explanations for the published contradictory experimental observations.     

Recruitment of smooth muscle cells and arterial vasomotion

Investigating the recruitment and synchronization of smooth muscle cells (SMCs) is the key to understanding the physical mechanisms leading to contraction and spontaneous diameter oscillations of arteries, called vasomotion. We improved a method that allows the correlation of calcium oscillations (flashing) of individual SMCs with mean calcium variations and arterial contraction using confocal microscopy. Endothelium-stripped rat mesenteric arteries were cut open, loaded with dual calcium fluorescence probes, and stimulated by increasing concentrations of the vasoconstrictors phenylephrine (PE) and KCl. We found that the number and synchronization of flashing cells depends on vasoconstrictor concentration. At low vasoconstrictor concentration, few cells flash asynchronously and no local contraction is detected. At medium concentration, recruitment of cells is complete and synchronous, leading to strip contraction after KCl stimulation and to vasomotion after PE stimulation. High concentration of PE leads to synchronous calcium oscillations and fully contracted vessels, whereas high concentration of KCl leads to a sustained nonoscillating increase of calcium and to fully contracted vessels. We conclude that the number of simultaneously recruited cells is an important factor in controlling rat mesenteric artery contraction and vasomotion.     

Localization of the sites of pulmonary vasomotion by use of arterial and venous occlusion

In this study, we present a new approach for using the pressure vs. time data obtained after various vascular occlusion maneuvers in pump-perfused lungs to gain insight into the longitudinal distribution of vascular resistance with respect to vascular compliance. Occlusion data were obtained from isolated dog lung lobes under normal control conditions, during hypoxia, and during histamine or serotonin infusion. The data used in the analysis include the slope of the arterial pressure curve and the zero time intercept of the extrapolated venous pressure curve after venous occlusion, the equilibrium pressure after simultaneous occlusion of both the arterial inflow and venous outflow, and the area bounded by equilibrium pressure and the arterial pressure curve after arterial occlusion. We analyzed these data by use of a compartmental model in which the vascular bed is represented by three parallel compliances separated by two series resistances, and each of the three compliances and the two resistances can be identified. To interpret the model parameters, we view the large arteries and veins as mainly compliance vessels and the small arteries and veins as mainly resistance vessels. The capillary bed is viewed as having a high compliance, and any capillary resistance is included in the two series resistances. With this view in mind, the results are consistent with the major response to serotonin infusion being constriction of large and small arteries (a decrease in arterial compliance and an increase in arterial resistance), the major response to histamine infusion being constriction of small and large veins (an increase in venous resistance and a decrease in venous compliance), and the major response to hypoxia being constriction of the small arteries (an increase in arterial resistance). The results suggest that this approach may have utility for evaluation of the sites of action of pulmonary vasomotor stimuli.     

A model of smooth muscle cell synchronization in the arterial wall

Vasomotion is a rhythmic variation in microvascular diameter. Although known for more than 150 years, the cellular processes underlying the initiation of vasomotion are not fully understood. In the present study a model of a single cell is extended by coupling a number of cells into a tube. The simulated results point to a permissive role of cGMP in establishing intercellular synchronization. In sufficient concentration, cGMP may activate a cGMP-sensitive calcium-dependent chloride channel, causing a tight spatiotemporal coupling between release of sarcoplasmic reticulum calcium, membrane depolarization, and influx of extracellular calcium. Low [cGMP] is associated only with unsynchronized waves. At intermediate concentrations, cells display either waves or whole cell oscillations, but these remain unsynchronized between cells. Whole cell oscillations are associated with rhythmic variation in membrane potential and flow of current through gap junctions. The amplitude of these oscillations in potential grows with increasing [cGMP], and, past a certain threshold, they become strong enough to entrain all cells in the vascular wall, thereby initiating sustained vasomotion. In this state there is a rhythmic flow of calcium through voltage-sensitive calcium channels into the cytoplasm, making the frequency of established vasomotion sensitive to membrane potential. It is concluded that electrical coupling through gap junctions is likely to be responsible for the rapid synchronization across a large number of cells. Gap-junctional current between cells is due to the appearance of oscillations in the membrane potential that again depends on the entrainment of sarcoplasmic reticulum and plasma membrane within the individual cell.     

Voltage-mediated mechanism for calcium wave synchronization and arrhythmogenesis in atrial tissue

A wide range of atrial arrythmias are caused by molecular defects in proteins that regulate calcium (Ca) cycling. In many cases, these defects promote the propagation of subcellular Ca waves in the cell, which can perturb the voltage time course and induce dangerous perturbations of the action potential (AP). However, subcellular Ca waves occur randomly in cells and, therefore, electrical coupling between cells substantially decreases their effect on the AP. In this study, we present evidence that Ca waves in atrial tissue can synchronize in-phase owing to an order-disorder phase transition. In particular, we show that, below a critical pacing rate, Ca waves are desynchronized and therefore do not induce substantial AP fluctuations in tissue. However, above this critical pacing rate, Ca waves gradually synchronize over millions of cells, which leads to a dramatic amplification of AP fluctuations. We exploit an underlying Ising symmetry of paced cardiac tissue to show that this transition exhibits universal properties common to a wide range of physical systems in nature. Finally, we show that in the heart, phase synchronization induces spatially out-of-phase AP duration alternans which drives wave break and reentry. These results suggest that cardiac tissue exhibits a phase transition that is required for subcellular Ca cycling defects to induce a life-threatening arrhythmia.     

Multiple factors in Mendelian inheritance

Ohne Zusammenfassung     

Phase synchronization and coherence resonance of stochastic calcium oscillations in coupled hepatocytes

The frequency of free cytosolic calcium concentration ([Ca(2+)]) oscillations elicited by a given agonist concentration differs between individual hepatocytes. However, in multicellular systems of rat hepatocytes and even in the intact liver, [Ca(2+)] oscillations are synchronized and highly coordinated. In this paper, we have investigated theoretically the effects of gap junction permeable to calcium and of the total Ca(2+) channel number located on endoplasmic reticulum on intercellular synchronization. Figures of ratio between mean oscillating frequency of coupled cells describe visually the process of phase-locking. By virtue of a set of phase analysis, we can observe a gradual transition from synchronous behavior to nonsynchronous behavior. Furthermore, a signal-to-noise ratio in two dimensional parameter space (coupling strength-total Ca(2+) channel number) has suggested that, coherence resonance will occur for appropriate noise and coupling.     

Multiple synchronization strategies in rhythmic sensorimotor tasks: phase vs period correction

To characterize synchronisation strategies in the tracking of auditory rhythm with rhythmic finger tapping, the adaptation process after unexpected step changes of an interstimulus interval (ISI) of 500 ms was investigated. Step changes of 2% (10 ms), 4% (20 ms), and 10% (50 ms) of ISI were applied to the stimulus sequence. Synchronisation patterns of 5 subjects were analyzed based on synchronisation error (SE) and interresponse intervals (IRI). A strategy shift contigent upon the size of the introduced step change was detected. After small ISI changes, rapid IRI matching to the new ISI was accompanied by temporarily enlarged SE values, which slowly returned to preferred SE values before the step change. Large ISI changes showed quick SE adaptations accompanied by a temporary overcorrection of IRI. Response asymmetry between ISI decreases and increases emerged, showing a stronger adaptation during ISI increases. A two-dimensional difference equation was formulated to simulate the time series of intertap intervals and explain the control process during IRI and SE adjustments. The system constants were optimized to minimalize the deviations between the computed and the observed response trajectories, consisting of the time series of SE and IRI. It was shown that a successful model fit using a linear two-dimensional difference equation was based on the size and direction of the ISI changes. MANOVA procedures showed that differences in equation parameters during small and large step changes were statistically significant (P<0.05). It is therefore suggested that a uniform model accounting for synchronization responses to all step changes would require the introduction of nonlinear system properties. Received: 20 August 1997/Accepted in revised form: 9 June 1998     

Multiple primary cancers in Denmark 1943-80; influence of possible underreporting and suggested risk factors

The risk of developing a second primary cancer was studied among 171,749 men and 208,192 women who were reported to the Danish Cancer Registry between 1943 and 1980. Only those who survived at least two months were included in the analysis, and more than 1.7 million person-years of observation were accrued. Altogether, 15,084 second primary cancers developed, of which 13,231 were in organs other than the initial or adjacent site [relative risk (RR) = 1.01]. Adjustment for possible underreporting of multiple primary cancers increased the RR to 1.24, which stresses the need for detailed knowledge of registration procedures interpreting results from cancer registries. The unadjusted RR for all sites increased with time, from 0.94 during the first decade of follow-up (excluding the first year) to 1.13 among 30-year survivors, whereas the adjusted RR increased from 1.08 to 1.41. Elevated risks were observed for sites thought to have a common etiology. For example, cancers of smoking-related sites were increased in both directions following cancers of the oral cavity, respiratory tract, and urinary organs. For cancers suspected to have a hormone- or dietary fat-related association, significant reciprocal relationships were seen among cancers of the endometrium, ovary, and colon. Cancer treatment probably is an important factor in second cancer development, even when judged indirectly in the present study. For example, radiotherapy may have been responsible for an elevated risk of subsequent cancers of the thyroid, breast, colon, rectum, bladder, and connective tissue in long-term survivors. Chemotherapy may have increased the risk of subsequent leukemias. Our data further indicate that cancer patients have no general susceptibility to develop new malignant tumors, although high rates may be found for particular sites sharing common risk factors. Conversely, the occurrence of one cancer does not appear to protect against developing a new cancer.     

Electrophysiological factors in the influence of nitrate and ammonium ions on calcium uptake and translocation in tomato plants

Abstract Tomato plants (Lycopersicon esculentum Mill. cv. San Marzano), grown in dilute nutrient solutions containing (in meq ˙ 1^-1) 0.5 NaNO₃, 0.5 NH₄NO₃ or 0.25 (NH₄)₂ SO₄ as the nitrogen source, were detopped for collection of xylem sap and measurement of trans-root electrical potentials. The plant parts and the xylem exudate were subsequently analysed for mineral content. The commonly observed effects of NH₄⁺ were noted, including reduction of calcium concentration in the xylem sap, and of calcium content in stems and leaves, compared with NO₃^-fed plants. This effect was attributed principally to the less negative trans-root electrical potential measured in NH₄⁺-fed plants, and the resultant reduction of inward driving force on passively moving divalent cations.     

The calcium requirement and factors causing calcium loss

Studies carried out under strictly controlled conditions during different calcium intakes in adult males have shown that the average calcium balance was only slightly positive (+22 mg/day) during a calcium intake of 800 mg/day, the recommended dietary calcium intake, not taking into consideration dermal losses of calcium. During this calcium intake, the calcium balances were negative in 34% of the subjects studied. Increasing the calcium intake to 1200 mg/day resulted in a significant increase of the calcium balance; further increases to different intake levels up to 2300 mg/day did not improve the calcium balance further. Increasing the phosphorus intake up to 2000 mg/day as well as increasing the protein intake from 1 g/kg body weight to 2 g/kg, given as meat, did not have an adverse effect on calcium metabolism. A variety of drugs, notably aluminum-containing antacids, induced calcium loss. Increasing the calcium intake more than 10-fold from 200 to 2500 mg/day did not lower the blood pressure in a large number of normotensive patients and in a small number of hypertensive patients studied.     

Model of intercellular calcium oscillations in hepatocytes: synchronization of heterogeneous cells.

Hepatocytes respond with repetitive cytosolic calcium spikes to stimulation by vasopressin and noradrenalin. In the intact liver, calcium oscillations occur in a synchronized fashion as periodic waves across whole liver lobules, but the mechanism of intercellular coupling remains unclear. Recently, it has been shown that individual hepatocytes can have very different intrinsic oscillation frequencies but become phase-locked when coupled by gap junctions. We investigate the gap junction hypothesis for intercellular synchronization by means of a mathematical model. It is shown that junctional calcium fluxes are effective in synchronizing calcium oscillations in coupled hepatocytes. An experimentally testable estimate is given for the junctional coupling coefficient required; it mainly depends on the degree of heterogeneity between cells. Intercellular synchronization by junctional calcium diffusion may occur also in other cell types exhibiting calcium-activated calcium release through InsP(3) receptors, if the gap junctional coupling is strong enough and the InsP(3) receptors are sufficiently sensitized by InsP(3).     

Multiple cytosolic calcium buffers in posterior pituitary nerve terminals

Cytosolic Ca²⁺ buffers bind to a large fraction of Ca²⁺ as it enters a cell, shaping Ca²⁺ signals both spatially and temporally. In this way, cytosolic Ca²⁺ buffers regulate excitation-secretion coupling and short-term plasticity of release. The posterior pituitary is composed of peptidergic nerve terminals, which release oxytocin and vasopressin in response to Ca²⁺ entry. Secretion of these hormones exhibits a complex dependence on the frequency and pattern of electrical activity, and the role of cytosolic Ca²⁺ buffers in controlling pituitary Ca²⁺ signaling is poorly understood. Here, cytosolic Ca²⁺ buffers were studied with two-photon imaging in patch-clamped nerve terminals of the rat posterior pituitary. Fluorescence of the Ca²⁺ indicator fluo-8 revealed stepwise increases in free Ca²⁺ after a series of brief depolarizing pulses in rapid succession. These Ca²⁺ increments grew larger as free Ca²⁺ rose to saturate the cytosolic buffers and reduce the availability of Ca²⁺ binding sites. These titration data revealed two endogenous buffers. All nerve terminals contained a buffer with a K_d of 1.5–4.7 µM, and approximately half contained an additional higher-affinity buffer with a K_d of 340 nM. Western blots identified calretinin and calbindin D28K in the posterior pituitary, and their in vitro binding properties correspond well with our fluorometric analysis. The high-affinity buffer washed out, but at a rate much slower than expected from diffusion; washout of the low-affinity buffer could not be detected. This work has revealed the functional impact of cytosolic Ca²⁺ buffers in situ in nerve terminals at a new level of detail. The saturation of these cytosolic buffers will amplify Ca²⁺ signals and may contribute to use-dependent facilitation of release. A difference in the buffer compositions of oxytocin and vasopressin nerve terminals could contribute to the differences in release plasticity of these two hormones.