Transcutaneous,noninvasiveP O 2 monitoring in adults during exercise and hypoxemia

A new, commercially available, transcutaneous (tc)P _{O 2} monitor was tested in adult females and in laboratory animals to assess its applicability in measuring arterial oxygen tension during physiological stress. Observed values on dogs correlated well with direct measurements of arterialP _{O 2} and with previous data obtained from measurements of arterial blood during exercise and hypoxemia. In our female subjects the unit responded rapidly to changes in inspired ambient oxygen and electrical stability was excellent during maximal exercise tests. TranscutaneousP _{O 2} decreased to an average of 87.8 Torr during maximum exercise breathing 20.9% O₂, and to 32 Torr while breathing 12.6% O₂ at maximum work. Two distinct patterns of response in tcP _{O 2} were observed during hypoxic and normoxic exercise. The technique appears to have substantial future application both in clinical and physiological investigation involving adult subjects.     

Modulation of adipokine production, glucose uptake and lactate release in human adipocytes by small changes in oxygen tension

Adipose tissue becomes hypoxic in obesity, and cell culture studies have demonstrated that hypoxia leads to major changes in adipocyte function. Studies on the response of adipocytes to low O₂ tension have employed marked hypoxia (1% O₂). Here, we have examined the effects of modest hypoxia, utilising differing concentrations of O₂ (1–21%), on adipokine production and glucose uptake by human adipocytes. Incubation with 10% O₂ (24 h) increased expression of the leptin, vascular endothelial growth factor (VEGF) and Angptl4 genes, while leptin expression was elevated even at 15% O₂ (compared to ‘normoxia’—21% O₂). Overall, there was a concentration-dependent increase in the expression of these genes as O₂ fell, with the highest mRNA level evident at 1% O₂. Parallel changes were observed in the secretion of leptin, VEGF and IL-6 into the medium, an increased release being evident at 10% O₂ (15% O₂ for leptin). Adiponectin gene expression was reduced at 15% O₂ and below, while adiponectin release was significantly reduced at 5% O₂. Both 2-deoxy-d-glucose uptake and lactate release showed progressive increases as O₂ concentration fell, being significantly raised at 10% and 5% O₂, respectively. The alterations in substrate transport were accompanied by parallel changes in transporter gene expression, GLUT1 and MCT1 mRNA level increasing from 15% and 10% O₂, respectively. These results indicate that marked responses to reduced O₂ concentration are exhibited by human adipocytes at O₂ levels well above those associated with hypoxia and employed in cell culture studies. Adipocytes are sensitive to small changes in O₂ tension.     

A compartmental model for oxygen transport in brain microcirculation

A compartmental model is formulated for oxygen transport in the cerebrovascular bed of the brain. The model considers the arteriolar, capillary and venular vessels. The vascular bed is represented as a series of compartments on the basis of blood vessel diameter. The formulation takes into account such parameters as hematocrit, vascular diameter, blood viscosity, blood flow, metabolic rate, the nonlinear oxygen dissociation curve, arterial PO₂, P₅₀ (oxygen tension at 50% hemoglobin saturation with O₂) and carbon monoxide concentration. The countercurrent diffusional exchange between paired arterioles and venules is incorporated into the model. The model predicts significant longitudinal PO₂ gradients in the precapillary vessels. However, gradients of hemoglobin saturation with oxygen remain fairly small. The longitudinal PO₂ gradients in the postcapillary vessels are found to be very small. The effect of the following variables on tissue PO₂ is studied: blood flow, PO₂ in the arterial blood, hematocrit, P₅₀, concentration of carbon monoxide, metabolic rate, arterial diameter, and the number of perfused capillaries. The qualitative features of PO₂ distrbution in the vascular network are not altered with moderate variation of these parameters. Finally, the various types of hypoxia, namely hypoxic, anemic and carbon monoxide hypoxia, are discussed in light of the above sensitivity analysis.     

Oxygen and reactive oxygen species in articular cartilage: modulators of ionic homeostasis

Articular cartilage is an avascular tissue dependent on diffusion mainly from synovial fluid to service its metabolic requirements. Levels of oxygen (O₂) in the tissue are low, with estimates of between 1 and 6%. Metabolism is largely, if not entirely, glycolytic, with little capacity for oxidative phosphorylation. Notwithstanding, the tissue requires O₂ and consumes it, albeit at low rates. Changes in O₂ tension also have profound effects on chondrocytes affecting phenotype, gene expression, and morphology, as well as response to, and production of, cytokines. Although chondrocytes can survive prolonged anoxia, low O₂ levels have significant metabolic effects, inhibiting glycolysis (the negative Pasteur effect), and also notably matrix production. Why this tissue should respond so markedly to reduction in O₂ tension remains a paradox. Ion homeostasis in articular chondrocytes is also markedly affected by the extracellular matrix in which the cells reside. Recent work has shown that ion homeostasis also responds to changes in O₂ tension, in such a way as to produce significant effects on cell function. For this purpose, O₂ probably acts via alteration in levels of reactive oxygen species. We discuss the possibility that O₂ consumption by this tissue is required to maintain levels of ROS, which are then used physiologically as an intracellular signalling device. This postulate may go some way towards explaining why the tissue is dependent on O₂ and why its removal has such marked effects. Understanding the role of oxygen has implications for disease states in which O₂ or ROS levels may be perturbed.     

Disparate response of articular- and auricular-derived chondrocytes to oxygen tension

Purpose/Aim: To determine the effect of reduced (5%) oxygen tension on chondrogenesis of auricular-derived chondrocytes. Currently, many cell and tissue culture experiments are performed at 20% oxygen with 5% carbon dioxide. Few cells in the body are subjected to this supra-physiological oxygen tension. Chondrocytes and their mesenchymal progenitors are widely reported to have greater chondrogenic expression when cultured at low, more physiological, oxygen tension (1–7%). Although generally accepted, there is still some controversy, and different culture methods, species, and outcome metrics cloud the field. These results are, however, articular chondrocyte biased and have not been reported for auricular-derived chondrocytes. Materials and Methods: Auricular and articular chondrocytes were isolated from skeletally mature New Zealand White rabbits, expanded in culture and differentiated in high density cultures with serum-free chondrogenic media. Cartilage tissue derived from aggregate cultures or from the tissue engineered sheets were assessed for biomechanical, glycosaminoglycan, collagen, collagen cross-links, and lysyl oxidase activity and expression. Results: Our studies show increased proliferation rates for both auricular and articular chondrocytes at low (5%) O₂ versus standard (20%) O₂. In our scaffold-free chondrogenic cultures, low O₂ was found to increase articular chondrocyte accumulation of glycosaminoglycan, but not cross-linked type II collagen, or total collagen. Conversely, auricular chondrocytes accumulated less glycosaminoglycan, cross-linked type II collagen and total collagen under low oxygen tension. Conclusions: This study highlights the dramatic difference in response to low O₂ of chondrocytes isolated from different anatomical sites. Low O₂ is beneficial for articular-derived chondrogenesis but detrimental for auricular-derived chondrogenesis.     

Hypoxic pulmonary steady-state diffusing capacity for CO and cardiac output in rats born at a simulated altitude of 3500 m

Summary In rats born in the low pressure chamber from sea level parents a higher hypoxic steady-state pulmonary diffusing capacity for CO was found as compared with controls of similar body weight. This difference could be explained by a difference in age or by an increase of blood O₂ capacity. There was no difference in alveolar ventilation and alveolar-arterial O₂ pressure differences, a lower cardiac output, no difference in arterial O₂ tension, no difference in arterial O₂ content but a decreased mixed-venous O₂ content as compared with control rats measured at hypoxia. A shift of the standard blood O₂ dissociation curve to the right was found in the simulated high altitude exposed rats. Calculated mixed-venous O₂ pressure was not altered in these rats; since arterial O₂ pressure was the same no difference in mean tissue capillary O₂ pressure may be presumed as compared with control animals. The results suggest that the first generation of rats exposed to simulated high altitude for their whole life is not only less adapted than animals exposed in their youth (as described in previous work) but that the ability to promote the O₂ transport in time of need in rats born in the low pressure chamber is probably even inferior to that of the controls.     

Muscle intracellular oxygenation during exercise: optimization for oxygen transport,metabolism, and adaptive change

Exercise is the example par excellence of the body functioning as a physiological system. Conventionally we think of the O₂ transport process as a major manifestation of that system linking and integrating pulmonary, cardiovascular, hematological and skeletal muscular contributions to the task of getting O₂ from the air to the mitochondria, and this process has been well described. However, exercise invokes system responses at levels additional to those of macroscopic O₂ transport. One such set of responses appears to center on muscle intracellular PO₂, which falls dramatically from rest to exercise. At rest, it approximates 4 kPa, but during heavy endurance exercise it falls to about 0.4–0.5 kPa, an amazingly low value for a tissue absolutely dependent on the continual supply of O₂ to meet very high energy demands. One wonders why intracellular PO₂ is allowed to fall to such levels. The proposed answer, to be presented in the review, is that a low intramyocyte PO₂ is pivotal in: (a) optimizing oxygen’s own physiological transport, and (b) stimulating adaptive gene expression that, after translation, enables greater exercise capacity—all the while maintaining PO₂ at levels sufficient to allow oxidative phosphorylation to operate sufficiently fast enough to support intense muscle contraction. Thus, during exercise, reductions of intracellular PO₂ to less than 1% of that in the atmosphere enables an integrated response that fundamentally and simultaneously optimizes physiological, biochemical and molecular events that support not only the exercise as it happens but the adaptive changes to increase exercise capacity over the longer term.     

纵向应力作用下的血管重建

在体血管除了受到血压和剪切血流外,还受到显著的纵向张力作用。纵向张力影响血管的生理功能及其对血压和血流的响应。虽然对血压和血流改变时的血管重建已有了很多了解,但对血管纵向应变及其相应的血管组织重建却了解甚少。本文总结了血管纵向张力和应变的在体观测结果,以及血管对纵向应力改变的细胞和组织层次的响应与适应性重建。增加纵向张力导致组织重建,过度减少纵向张力会导致血管发生屈曲。纵向张力作用下血管组织重建的研究将增强对血管正常生理功能和病理变化的认识。     

Role of O2-sensitive K and Ca channels in the regulation of the pulmonary circulation: Potential role of caveolae and implications for high altitude pulmonary edema

High altitude pulmonary edema (HAPE) is a potentially fatal complication in response to exposure to low O₂ at high altitudes. Hypoxia, by causing pulmonary vasoconstriction, increases pulmonary vascular resistance and pulmonary arterial pressure, both of which are features in the pathogenesis of HAPE. Uneven hypoxic pulmonary vasoconstriction is thought to be responsible for increased capillary pressure and leakage, resulting in edema. O₂-sensitive ion channels are known to play pivotal roles in determining vascular tone in response to hypoxia. K⁺, Ca²⁺ and Na⁺ channels are ubiquitously expressed in both endothelial and smooth muscle cells of the pulmonary microvasculature, subfamilies of which are regulated by local changes in P_O2. Hypoxia reduces activity of voltage-gated K⁺ channels and down-regulates their expression leading to membrane depolarization, Ca²⁺ influx in pulmonary artery smooth muscle cells (by activating voltage-dependent Ca²⁺ channels) and vasoconstriction. Hypoxia up-regulates transient receptor potential channels (TRPC) leading to enhanced Ca²⁺ entry through receptor- and store-operated Ca²⁺ channels. Altered enrichment of ion channels in membrane microdomains, in particular in caveolae, may play a role in excitation–contraction coupling and perhaps in O₂-sensing in the pulmonary circulation and thereby may contribute to the development of HAPE. We review the role of ion channels, in particular those outlined above, in response to low O₂ on vascular tone and pulmonary edema. Advances in the understanding of ion channels involved in the physiological response to hypoxia should lead to a greater understanding of the pathogenesis of HAPE and perhaps in the identification of new therapies.     

Diffusional shunting of oxygen in saline-perfused isolated rabbit heart is negligible

Diffusional shunting of oxygen in the saline-perfused heart was studied by comparing the time course of the coronary venous concentrations of oxygen and an intravascular indicator following a simultaneous step-like change in their arterial concentrations. To this end 7 rabbit hearts were perfused according to Langendorff with Tyrode solution at a perfusion flow rate of 3.8±1.4 ml·min^–1·g^–1 (wet weight) at 37°C. In the reference situation arterial (Pa _{O 2}) and venous oxygen tensions (Pv _{O 2}) were about 610 and 290 mmHg, respectively. Step changes inPa _{O 2} were made to a 60 mmHg lower level and back. Simultaneously the arterial concentration of albumin-bound indocyanine green, an intravascular indicator, was changed. No deflection inPvO₂ was detected before the venous dye concentration changed. The venous dye concentration crossed 5% of its step amplitude 4 s after the arterial change, on average 2.3 s beforePv _{O 2} crossed its 5% level. We conclude that shunt diffusion of oxygen from arterioles to venules and from arterial to venous ends of the capillary bed is negligible in saline-perfused hearts and thus cannot explain the high value ofPv _{O 2} in these preparations.     

A microcomputer program of pulmonary and tissue gas exchange

A microcomputer program written in BASIC for the IBM-PC and compatibles has been developed to analyze the effects of many parameters on the gas exchange and transport phenomena in the lungs and the tissues. The program is designed for use by medical students and residents concerned with gas exchange (anesthesiology, pulmonary diseases, critical care, etc.) to study the steady state effects on blood and tissue oxygen and carbon dioxide levels. The present program consists of two main subroutines: Pulmonary Gas Exchange and Tissue Gas Exchange. Steady state gas exchange at the lungs can be studied using either a three-compartment model or V/Q relationships. The V/Q subroutine uses single or multiple populations of V/Q distributions to determine gas exchange using a log-normal distribution of V/Q ratios. Other variables can be adjusted which determine the arterial and mixed-venous blood gases. These values are then fed into the second part of the program to analyze factors which determine tissue O₂ tension. The Tissue Oxygen Tension subroutine is also subdivided into a modified Krogh-Erlang model, which provides a three-dimensional plot of theoretical capillary and tissue O₂ tensions, and a Piiper model which includes the effect of diffusion shunt on O₂ tensions and treats the tissue as a well-stirred compartment. Minimal and maximal tissue O₂ tensions are calculated using the Piiper model since the intercapillary distance is allowed to vary depending on the O₂ delivery by diffusion. Estimates of blood and tissue O₂ tensions, diffusion/perfusion coefficients, amount of O₂ delivered and the size of the active capillary bed are summarized in a table.     

Influence of hypothermia at different arterial CO2 pressures and local cooling of the spinal cervical cord on the activity of single phrenic motoneurons

Summary In anesthetized guinea pigs the action of acetylcholine, norepinephrine, epinephrine, isoproterenol, and reactive hyperaemia on arterial blood pressure, blood flow in the lower leg (measured by venous occlusion plethysmography), and distribution ofpO₂-values a platinum-O₂-microelectrode was used. By continuous recording of thepO₂ the electrode was moved slowly through the muscle tissue by constant velocity (33 /sec).During the action of norepinephrine, epinephrine, isoproterenol, and following temporary arterial occlusion a linear proportion was found between meanpO₂-values or meanpO₂-gradients and mean blood flow values (between 1.3 and 7.8 ml/min ·100 ml tissue). During the action of acetylcholinepO₂-values decreased in spite of increased blood flow.The reduced number of higherpO₂-values and the decreasedpO₂-gradients appear to indicate a relatively small number of open (perfused) capillaries during the action of acetylcholine. The reduced tissue oxygen delivery is due to enlarged diffusion distances and smaller capillary surface areas.     

Mathematical models of the spatial distribution of retinal oxygen tension and consumption,including changes upon illumination

To better understand oxygen utilization by the retina, a mathematical model of oxygen diffusion and consumption in the cat outer, avascular retina was developed by analyzing previously recorded profiles of oxygen tension (PO₂) as a function of retinal depth. Simple diffusion modelling of the oxygen distribution through the outer retina is possible because the PO₂ depends only on diffusion from the choroidal and retinal circulations and on consumption within the tissue. Several different models were evaluated in order to determine the best one from the standpoints of their ability to represent the data and to agree with physiological reality. For the steady state one-dimensional diffusion model adopted (the special three-layer diffusion model), oxygen consumption was constant through the middle layer and zero in the layers near the choroid and near the inner retina. On the average, the oxygen consuming layer, as found by nonlinear regression for each profile, extended from about 75% to 85% of the retinal depth from the vitreous. This is a narrow band through the mid-region of the photoreceptors. Oxygen consumption of the entire avascular retina, determined from fitting eight PO₂ profiles measured in light-adapted retinas, averaged 2.7 ml O₂(STP)/(100 g tissue · min), while the value determined from fitting thirty-two PO₂ profiles measured in dark-adapted retinas averaged 4.4 ml O₂(STP)/(100 g tissue · min). Consumption in the light was thus only 60% of that in the dark. This suggests that the outer retina is at greater risk of hypoxic injury in the dark than in the light, a fuinding of considerable clinical significance.     

Phenotypic switch of CD8+ T cells reactivated under hypoxia toward IL‐10 secreting,poorly proliferative effector cells

CD8⁺ T cells controlling pathogens or tumors must function at sites where oxygen tension is frequently low, and never as high as under atmospheric culture conditions. However, T‐cell function in vivo is generally analyzed indirectly, or is extrapolated from in vitro studies under nonphysiologic oxygen tensions. In this study, we delineate the role of physiologic and pathologic oxygen tension in vitro during reactivation and differentiation of tumor‐specific CD8⁺ T cells. Using CD8⁺ T cells from pmel‐1 mice, we observed that the generation of CTLs under 5% O₂, which corresponds to physioxia in lymph nodes, gave rise to a higher effector signature than those generated under atmospheric oxygen fractions (21% O₂). Hypoxia (1% O₂) did not modify cytotoxicity, but decreasing O₂ tensions during CTL and CD8⁺ tumor‐infiltrating lymphocyte reactivation dose‐dependently decreased proliferation, induced secretion of the immunosuppressive cytokine IL‐10, and upregulated the expression of CD137 (4‐1BB) and CD25. Overall, our data indicate that oxygen tension is a key regulator of CD8⁺ T‐cell function and fate and suggest that IL‐10 release may be an unanticipated component of CD8⁺ T cell‐mediated immune responses in most in vivo microenvironments.     

Observations on the rhythmic variation in the cat carotid body chemoreceptor activity which has the same period as respiration

1. The activity in carotid body chemoreceptor afferent fibres in the cat has been recorded and found to have a rhythm with the same period as respiration.

2. This rhythm is not an artifact; it is not due to arterial pressure changes with respiration nor to cyclical changes in pulmonary venous admixture. It is caused by changes in blood gas tensions during each respiratory cycle.

3. The amplitude of the rhythm is modified by transient and long-term changes in inspired oxygen or CO₂ so that a rise or fall in O₂ or CO₂ tensions of arterial blood (P_a,O2, P_a,CO2) from the physiological range reduces it. The ratio of the rhythm amplitude to the mean rate of chemoreceptor discharge increases with P_a,O2 over the range 40-240 mm Hg.

4. The rhythm is modified by changes in respiratory frequency and volume.

5. The fluctuations of arterial oxygen tension which have the same period as respiration are shown to be conducted up the vertebral artery at least as far as the vertebro-occipital anastomosis.

6. It is proposed that the chemoreceptor rhythm reflects the moment to moment changes in blood gas tensions.

     

Exercise-induced hypoxemia in athletes: Role of inadequate hyperventilation

Summary These experiments examined the exercise-induced changes in pulmonary gas exchange in elite endurance athletes and tested the hypothesis that an inadequate hyperventilatory response might explain the large intersubject variability in arterial partial pressure of oxygen (P _a0₂) during heavy exercise in this population. Twelve highly trained endurance cyclists [maximum oxygen consumption (VO_2max) range = 65-77 ml·kg^–1·min^–1] performed a normoxic graded exercise test on a cycle ergometer toVO_2max at sea level. During incremental exercise atVO_2max 5 of the 12 subjects had ideal alveolar to arterial P02 gradients (P _A-aO₂) of above 5 kPa (range 5-5.7) and a decline from restingP _aO₂ (P _aO₂) 2.4 kPa or above (range 2.4-2.7). In contrast, 4 subjects had a maximal exercise (P _A-aO₂) of 4.0-4.3 kPa with P _aO₂ of 0.4-1.3 kPa while the remaining 3 subjects hadP _A-aO₂ of 4.3-5 kPa with P _aO₂ between 1.7 and 2.0 kPa. The correlation between P_AO₂ andP _aO₂ atVO_2max was 0.17. Further, the correlation between the ratio of ventilation to oxygen consumption VSP _aO₂ and arterial partial pressure of carbon dioxide VSP _aO₂ atVO_2max was 0.17 and 0.34, respectively. These experiments demonstrate that heavy exercise results in significantly compromised pulmonary gas exchange in approximately 40% of the elite endurance athletes studied. These data do not support the hypothesis that the principal mechanism to explain this gas exchange failure is an inadequate hyperventilatory response.     

Effect of acute hypoxia on muscle blood flow, VO2p, and [HHb] kinetics during leg extension exercise in older men

The adjustment of pulmonary oxygen uptake (VO_2p), heart rate (HR), limb blood flow (LBF), and muscle deoxygenation [HHb] was examined during the transition to moderate-intensity, knee-extension exercise in six older adults (70 ± 4 years) under two conditions: normoxia (FIO₂ = 20.9 %) and hypoxia (FIO₂ = 15 %). The subjects performed repeated step transitions from an active baseline (3 W) to an absolute work rate (21 W) in both conditions. Phase 2 VO_2p, HR, LBF, and [HHb] data were fit with an exponential model. Under hypoxic conditions, no change was observed in HR kinetics, on the other hand, LBF kinetics was faster (normoxia 34 ± 3 s; hypoxia 28 ± 2), whereas the overall [HHb] adjustment ( $ \tau^{\prime } = {\text{TD}} + \tau $ ) was slower (normoxia 28 ± 2; hypoxia 33 ± 4 s). Phase 2 VO_2p kinetics were unchanged (p < 0.05). The faster LBF kinetics and slower [HHb] kinetics reflect an improved matching between O₂ delivery and O₂ utilization at the microvascular level, preventing the phase 2 VO_2p kinetics from become slower in hypoxia. Moreover, the absolute blood flow values were higher in hypoxia (1.17 ± 0.2 L min^?1) compared to normoxia (0.96 ± 0.2 L min^?1) during the steady-state exercise at 21 W. These findings support the idea that, for older adults exercising at a low work rate, an increase of limb blood flow offsets the drop in arterial oxygen content (CaO₂) caused by breathing an hypoxic mixture.     

白藜芦醇苷对低氧大鼠肺血管构型重建的影响

目的:观察白藜芦醇苷对慢性常压低氧性肺动脉高压(HPH)大鼠肺血管构型重建的影响并探讨可能的机理。方法:29只健康SD大鼠随机分为正常对照组、单纯低氧组和低氧加白藜芦醇苷(PD)组。各组内按照肺小血管外径分为I组(30μm-100μm)和II组(101μm-200μm)。右心导管法检测大鼠肺动脉压力(mPAP)、微量滴定法检测血浆和肺匀浆中磷脂酶A₂(PLA₂)活性、光镜下观察肺小血管中膜厚度(MT%)和中膜面积(MA%)的变化。结果:低氧3周后大鼠mPAP、血浆及肺匀浆中PLA₂活性、肺小血管MA%、I组MT%显著高于对照组,II组MT%无显著性改变。低氧加PD预处理后上述改变明显轻于单纯低氧组。结论:PD可有效防治慢性常压低氧性大鼠肺动脉压力的升高,其机理与抑制大鼠肺血管构型重建有关。     

Tissue remodeling of rat pulmonary artery in hypoxic breathing. II. Course of change of mechanical properties

When cells and the matrix of a tissue remodel, the mechanical properties of the tissue do change. The mechanical properties are expressed by constitutive equations. In this article the remodeling of the constitutive equation of the pulmonary artery is studied. The remodeling was induced in a rat breathing a gas whose oxygen concentration was suddenly decreased as a step function of time and maintained constant (17.2%, 13.6%, or 10%) afterwards. Since the mathematical form of the constitutive equation has been identified in earlier papers, we need to determine only the elastic constants that change in the process of tissue remodeling. We consider arteries subjected to blood pressure and longitudinal stretch, and limit ourselves to two-dimensional problems involving only circumferential and longitudinal stress and strain. In the neighborhood of an in vivo state, the perturbations of stresses and strains are related by linear, anisotropic, tensor equations involving three elastic constants: the incremental Young's modulus in the circumferential direction Y , that in the longitudinal direction Y_zz, and the cross modulus Y_z Over a 24 h period, changes of Y between 164 and 187 kN/m² Y_zz between 64 and 92 kN/m² and Y _z between 61 and 88 kN/m² are statistically insignificant. © 2001 Biomedical Engineering Society. PAC01: 8719Rr, 8719Uv