Department of Physiology, School of Medicine, University of Maryland, Baltimore, Maryland
Submitted 23 June 2006
; accepted in final form 10 November 2006
Arteries that have developed myogenic tone ...(MT) are in a markedly different physiological state compared with those that have not, with higher cytosolic Ca 2+ and altered activity of several signal transduction pathways. In this study, we sought to determine whether 1 -adrenoceptor-induced Ca 2+ signaling is different in pressurized arteries that have spontaneously developed MT (the presumptive physiological state) compared with those that have not (a common experimental state). At 32°C and intraluminal pressure of 70 mmHg, cytoplasmic Ca 2+ was steady in most smooth muscle cells (SMCs). In a minority of cells (34%), however, at least one propagating Ca 2+ wave occurred. 1 -Adrenoceptor activation (phenylephrine, PE; 0.110.0 µM) caused strong vasoconstriction and markedly increased the frequency of Ca 2+ waves (in virtually all cells). However, when cytosolic Ca 2+ was elevated experimentally in these arteries (K + 20 mM), PE failed to elicit Ca 2+ waves, although it did elevate Ca 2+ (F/F 0 ) further and caused further vasoconstriction. During development of MT, the cytosolic Ca 2+ (F/F 0 ) in individual SMCs increased, Ca 2+ waves disappeared (from SMCs that had them), and small Ca 2+ ripples (frequency 0.05 Hz) appeared in 13% of cells. PE elicited only spatially uniform increases in Ca 2+ and a smaller change in diameter (than in the absence of MT). Nevertheless, when cytosolic Ca 2+ and MT were decreased by nifedipine (1 µM), PE did elicit Ca 2+ waves. Thus 1 -adrenoceptor-mediated Ca 2+ signaling is markedly different in arteries with and without MT, perhaps due to the elevated Ca 2+ , and may have a different molecular basis. 1 -Adrenoceptor-induced vasoconstriction may be supported either by Ca 2+ waves or by steady elevation of cytoplasmic Ca 2+ , depending on the amount of MT.
phenylephrine; confocal microscopy; calcium waves; smooth muscle; imaging
Address for reprint requests and other correspondence: W. G. Wier, Dept. of Physiology, Univ. of Maryland, 655 West Baltimore St., Baltimore, MD 21201 (e-mail: gwier001{at}umaryland.edu )
We investigated the origin of spontaneous transient inward current (STIC) oscillations in descending vasa recta (DVR) pericytes. In cells clamped at -80 mV, angiotensin II (ANG II; 10 nmol/l) induced ...oscillations with mean amplitude and frequency of -65.5 pA and 1.2 Hz. Simultaneous recording of cytoplasmic calcium (Ca(2+)(CYT)) and membrane current oscillations verified their synchrony and the correlation of their amplitudes. Confocal recording in fluo-4-loaded DVR showed that ANG II can induce either stable pericyte Ca(2+)(CYT) elevation or oscillations, while decreasing adjacent endothelial Ca(2+)(CYT). Oscillating currents reversed sign at -30.2 mV and were blocked by niflumic acid, implicating charge transfer via Cl(-) ion. Removal of extracellular Ca(2+), blockade of Ca(2+) influx with SKF96365 (30 micromol/l), ryanodine (30 micromol/l), or caffeine (10 mmol/l) inhibited oscillations. In contrast, they were insensitive to removal of extracellular Na(+) and exposure to either nifedipine (1 micromol/l) or 2-aminoethoxydiphenyl borate (10 micromol/l). Ouabain (100 nmol/l) increased basal pericyte Ca(2+)(CYT) and the frequency of resting STICs but did not affect the larger oscillations that followed ANG II stimulation. We conclude that Ca(2+)(CYT) oscillations stimulate Cl(-) currents. The former are most likely maintained by repetitive cycles of ryanodine-sensitive SR Ca(2+) release and SKF96365-sensitive store refilling.
This paper explores the problem of optimal calculation of electrical parameters in solar cells using three well-known operative points provided by manufacturers considering a single-diode model. ...These are open circuit, short circuit, and maximum power point; with these points is formulated a nonlinear non-convex optimization problem that deals with the minimization of mean square errors associated with variables evaluated at these points, i.e., open-circuit voltage, short circuit current, and current in the maximum power point, respectively. A sine-cosine algorithm is addressed in this research to solve the resulting optimization problem. Numerical results provided by the sine-cosine algorithm show objective functions lower than 1 × 10−12, which confirms the efficiency and robustness of the proposed approach. All the numerical validations are conducted via MATLAB software.
We hypothesized that in salt-dependent forms of hypertension, endogenous ouabain acts on arterial smooth muscle to cause enhanced vasoconstriction. Here, we tested for the involvement of the arterial ...endothelium and perivascular sympathetic nerve terminals in ouabain-induced vasoconstriction. Segments of rat mesenteric or renal interlobar arteries were pressurized to 70 mmHg at 37 degrees C and exposed to ouabain (10(-11)-10(-7) M). Removal of the endothelium enhanced ouabain-induced vasoconstriction by as much as twofold (at an ouabain concentration of 10(-9) M). A component of the ouabain-induced vasoconstriction is due to the enhanced spontaneous release of norepinephrine (NE) from nerve terminals in the arterial wall. The alpha(1)-adrenoceptor blocker prazosin (10(-6) M) decreased ouabain-induced vasoconstrictions by as much as 50%. However, neither the contraction induced by sympathetic nerve activity (SNA) nor the NE release evoked by SNA (measured directly by carbon fiber amperometry) was increased by ouabain (<10(-7) M). Nevertheless, the converse case was true: after brief bursts of SNA, vasoconstrictor responses to ouabain were transiently increased (1.75-fold). This effect may be mediated by neuropeptide Y and Y(1) receptors on smooth muscle. In arteries lacking the endothelium and exposed to prazosin, ouabain (10(-11) M and greater) caused vasoconstriction, indicating a direct effect of very "low" concentrations of ouabain on arterial smooth muscle. In conclusion, in intact arteries, the endothelium opposes ouabain (10(-11)-10(-7)M)-induced vasoconstriction, which is caused by both enhanced spontaneous NE release and direct effects on smooth muscle. Ouabain (<10(-7)M) does not enhance SNA-mediated contractions, but SNA enhances ouabain-induced contractions. The effects of endogenous ouabain may be accentuated in forms of hypertension that involve sympathetic nerve hyperactivity and/or endothelial dysfunction.
Confocal microscopy of fluo-4 fluorescence in pressurized rat mesenteric small arteries subjected to low-frequency electrical field stimulation revealed Ca2+ transients in perivascular nerves and ...novel, spatially localized Ca2+ transients in adjacent smooth muscle cells. These muscle Ca2+ transients occur with a very brief latency to the stimulus pulse (most <3 ms). They are wider (approximately 5 micro m) and last longer (t(1/2), 145 ms) than Ca2+ sparks. They are abolished by the purinergic receptor (P2X) antagonist suramin, but they are totally unaffected by the alpha1 adrenoceptor antagonist prazosin or by capsaicin (which inhibits the function of perivascular sensory nerves). We conclude that these novel Ca2+ transients represent Ca2+ entering smooth muscle cells through P2X receptors activated by ATP released from sympathetic nerves, and we therefore call them "junctional Ca2+ transients" or jCaTs. As expected from spontaneous neurotransmitter release, jCaTs also occur spontaneously, with characteristics identical to evoked jCaTs. Visualization of sympathetic neurotransmission shows that purinergic components dominate at low frequencies of sympathetic nerve fiber activation.
The use of alpha-2 adrenergic agonists for analgesia is limited due to a narrow therapeutic window. Definition of the role of alpha receptor subtypes in alpha agonist mediated analgesia may identify ...strategies to separate the analgesic from sedative and cardiovascular effects.
Analgesic activity of brimonidine, clonidine, and tizanidine was investigated in wild-type C57B/6, alpha-2A, and alpha-2C knockout mice with allodynia induced by N-methyl-D-aspartate or sulprostone. The alpha receptor selectivity of the alpha agonists was assessed using functional in vitro recombinant assays.
Brimonidine, clonidine, and tizanidine reduced N-methyl-D-aspartate- and sulprostone-induced allodynia in wild-type mice, but not alpha-2A knockout mice. In alpha-2C knockout mice, brimonidine and tizanidine reduced allodynia in both models, whereas clonidine only reduced N-methyl-D-aspartate-induced allodynia. In vitro, clonidine and tizanidine activated alpha-1 and alpha-2 receptors with similar potencies, whereas brimonidine was selective for alpha-2 receptors. In alpha-2C knockout mice with sulprostone-induced allodynia, blockade of clonidine's alpha-1 receptor agonist activity restored clonidine's analgesic efficacy. In wild-type mice, the analgesic potency of intrathecal clonidine and tizanidine was increased 3- to 10-fold by coadministration with the alpha-1A-selective antagonist 5-methylurapidil without affecting sedation. Following intraperitoneal administration, the therapeutic window was negligible for clonidine and tizanidine, but greater for brimonidine. 5-Methylurapidil enhanced the therapeutic window of intraperitoneal clonidine and tizanidine approximately 10-fold.
Alpha-1A receptor agonist activity can counterbalance alpha-2 receptor agonist-induced analgesia. Greater alpha-2 selectivity may enhance the therapeutic window of alpha-2 agonists in the treatment of pain.
Conventional protection schemes have proven insufficient for the protection of Active Distribution Networks (ADN). Novel protection schemes with an adaptive approach should be developed to guarantee ...the protection of ADN under all their operating conditions. This paper proposes an ADN adaptive protection methodology, which is based on an intelligent approach fault detector over locally available measurements. This approach uses Machine Learning (ML) based techniques to reduce the strong dependence of the adaptive protection schemes on the availability of communication systems and to determine if, over a fault condition, an Intelligent Electronic Device (IED) should operate considering the changes in operational conditions of an ADN. Additionally, the methodology takes into account different and remarkable recommendations for the use of ML techniques. The proposed methodology is validated on the modified IEEE 34-nodes test feeder. Additionally, it takes into consideration typical features of ADN and micro-grids like the load imbalance, reconfiguration, changes in impedance upstream from the micro-grid, and off-grid/on-grid operation modes. The results demonstrate the flexibility and simplicity of the methodology to determine the best accuracy performance among several ML models. Besides, they show the methodology’s versatility to find the suitable ML model for IEDs located on different zones of an ADN. The ease of design’s implementation, formulation of parameters, and promising test results indicate the potential for real-life applications.
•The methodology is flexible and adaptable to protect different network context.•Protection based in communication—less approach with emphasis in relevant operating conditions.•Points recommendations for adaptive protection design based on Machine Learning techniques.•Shows strong influence between of Intelligent Electronic Devices and the intelligent models.
Two-photon fluorescence microscopy and conscious, restrained optical biosensor mice were used to study smooth muscle Ca
2+
signaling in ear arterioles. Conscious mice were used in order to preserve ...normal mean arterial blood pressure (MAP) and sympathetic nerve activity (SNA). ExMLCK mice, which express a genetically-encoded smooth muscle-specific FRET-based Ca
2+
indicator, were equipped with blood pressure telemetry and immobilized for imaging. MAP was 101 ± 4 mmHg in conscious restrained mice, similar to the freely mobile state (107 ± 3 mmHg). Oscillatory vasomotion or irregular contractions were observed in most arterioles (71%), with the greatest oscillatory frequency observed at 0.25 s
−1
. In a typical arteriole with an average diameter of ~35 μm, oscillatory vasomotion of a 5–6 μm magnitude was accompanied by nearly uniform Ca
2+
oscillations from ~0.1 to 0.5 μM, with maximum Ca
2+
occurring immediately before the rapid decrease in diameter. Very rapid, spatially uniform “Ca
2+
flashes” were also observed but not asynchronous propagating Ca
2+
waves. In contrast, vasomotion and dynamic Ca
2+
signals were rarely observed in ear arterioles of anesthetized exMLCK biosensor mice. Hexamethonium (30 μg/g BW, i.p.) caused a fall in MAP to 74 ± 4 mmHg, arteriolar vasodilation, and abolition of vasomotion and synchronous Ca
2+
transients.
Summary
: MAP and heart rate (HR) were normal during high-resolution Ca
2+
imaging of conscious, restrained mice. SNA induced continuous vasomotion and irregular vasoconstrictions via spatially uniform Ca
2+
signaling within the arterial wall. FRET-based biosensor mice and two-photon imaging provided the first measurements of Ca
2+
in vascular smooth muscle cells in arterioles of conscious animals.
The effects of estrogens on pain perception remain controversial. In animal models, both beneficial and detrimental effects of non-selective estrogens have been reported. ERb-131 a non-steroidal ...estrogen receptor beta ligand was evaluated in several pain animal models involving nerve injury or sensitization. Using functional and binding assays, ERb-131 was characterized as a potent and selective estrogen receptor beta agonist.
In vivo, ERb-131 was devoid of estrogen receptor alpha activity as assessed in a rat uterotrophic assay. ERb-131 alleviated tactile hyperalgesia induced by capsaicin, and reversed tactile allodynia caused by spinal nerve ligation and various chemical insults. Moreover, ERb-131 did not influence the pain threshold of normal healthy animals. Thus, estrogen receptor beta agonism is a critical effector in attenuating a broad range of anti-nociceptive states.
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