Physiological mechanism of digital vasoconstriction training

Recent work in our laboratory has shown that vasodilation produced during temperature biofeedback training is mediated through a nonneural, beta-adrenergic mechanism. Here we sought to determine if the effects of feedback training for vasoconstriction are produced through a neural or nonneural pathway and whether other measures of physiological activity are correlated with these changes. Nine normal subjects received temperature feedback vasoconstriction training in which feedback was delivered only during periods of successful performance. In a subsequent session, the nerves to one finger were blocked with a local anesthetic while finger blood flow was recorded from this and other fingers. Vasoconstriction occurred during feedback in the intact fingers but not in the nerve-blocked finger and was accompanied by increased skin conductance and heart rate. These data demonstrate that temperature feedback vasoconstriction training is mediated through an efferent, sympathetic nervous pathway. In contrast, temperature feedback vasodilation training is mediated through a nonneural, beta-adrenergic mechanism.     

Physiological mechanism of digital vasoconstriction training

Recent work in our laboratory has shown that vasodilation produced during temperature biofeedback training is mediated through a nonneural, beta-adrenergic mechanism. Here we sought to determine if the effects of feedback training for vasoconstriction are produced through a neural or nonneural pathway and whether other measures of physiological activity are correlated with these changes. Nine normal subjects received temperature feedback vasoconstriction training in which feedback was delivered only during periods of successful performance. In a subsequent session, the nerves to one finger were blocked with a local anesthetic while finger blood flow was recorded from this and other fingers. Vasoconstriction occurred during feedback in the intact fingers but not in the nerve-blocked finger and was accompanied by increased skin conductance and heart rate. These data demonstrate that temperature feedback vasoconstriction training is mediated through an efferent, sympathetic nervous pathway. In contrast, temperature feedback vasodilation training is mediated through a nonneural, beta-adrenergic mechanism.This work was supported by research grant HL-30604 from the National Heart, Lung, and Blood Institute.     

Effect of alterations in ambient temperature on blood flow in the skin.

The effect of changing ambient temperature on skin temperature was recorded in human subjects; also, its effect on blood flow was measured using venous occlusion and optical plethysmography. When cold stimulus was removed in stages using a heating cabinet, it was found that a biphasic flow response occurred in the fingers with each step change in temperature. There was a rapid transient rise followed by a decline to an equilibrium flow level. The transient rise occurred even when the temperature rose from 37 to 40 degrees C, although at this level the equilibrium remained unchanged. It is suggested that the transient rise was due to stimulation of Hensel's dynamic warmth receptors, whereas the rise in equilibrium temperature was due to removal of cold stimulus, which at low ambient temperatures maintains reflex vasoconstriction through activation of static cold receptors. Upper arm skin responded to removal of cold stimulus by a fall in temperature. Immersion of a different limb in cold water produced vasoconstriction in fingers but vasodilatation in the upper arm skin. It is suggested that this may be due to neurogenic vasodilatation, though the present work gives no indication as to pathways.     

Oscillatory processes in lymph microcirculation in the human skin

This study was the first to use laser Doppler flowmetry followed by wavelet analysis in order to estimate oscillations in lymph microcirculation in 30 subjects with (n = 13) or without (n = 17) edema of the distal part of the upper limb. Lymph flow in the human skin exhibited clear dominance of pacemaker phase oscillations in the frequency ranges of 0.021–0.042 and 0.016–0.035 Hz in the skin of the palm surface of the finger nail bone and in the skin of the forearm, respectively. Edema was associated with an increase in the peak frequencies and normalized maximum amplitudes (Al/Ml, where Al is the mean value of the maximum amplitude of phase oscillations, and Ml is the value of the averaged lymph flow expressed in perfusion units). Low-amplitude oscillations were recorded rarer in the myogenic, endothelial, and respiratory ranges. We did not find any cardiac pulse rhythm in the wavelet spectrum of the lymph flow. We did not find any interaction between the Al/Ml value and the skin temperature. In the group of subjects without edema, under physiological conditions only, we found a negative correlation between the Al/Ml value and the amplitudes of myogenous proper blood flow oscillations, which reflected the number of functional capillaries and activity of oxidative metabolism in the tissue. In the group with edema, we did not find any correlations between the indices of lymph flow and blood flow. The values of normalized amplitude and frequency of phase oscillations may be used as efficient diagnostic tools in the studies on lymph microcirculation.     

Angiotensin is not required for hypoxic constriction in salt solution-perfused rat lungs

It has been reported that angiotensin II is specifically required for hypoxic vasoconstriction in rat lungs perfused with physiological salt solution. However, studies with other preparations indicate that angiotensin II does not play a necessary role in the mechanism of hypoxic vasoconstriction. In an attempt to resolve this disagreement I investigated in salt solution-perfused rat lungs whether vasoactive agents other than angiotensin II would induce hypoxic vasoconstriction, and, if so, whether the effect was due to selective action on the hypoxic mechanism or to a nonspecific increase in vascular reactivity. The results showed the development of hypoxic pressor responses after addition to perfusate of plasma, angiotensin II, KCl, vanadate, 4-aminopyridine, or norepinephrine plus propranolol. In contrast, addition of saline (control), ouabain, or tetraethylammonium chloride did not induce hypoxic vasoconstriction. Saralasin inhibited the effect of angiotensin II, but not that of plasma. Induction of responsiveness to hypoxia was associated with an increase in normoxic perfusion pressure and with potentiation of pressor responses to KCl. These results suggest that angiotensin II does not play a unique, integral role in the hypoxic mechanism, but instead is only one of many substances that will induce hypoxic pressor reactivity by reversing the vascular hyporeactivity of salt solution-perfused rat lungs.     

Blood Flow Characteristics and Tissue Nutrition in Apparently Ischaemic Feet

Blood flow in the apparently ischaemic feet of patients with atherosclerotic peripheral vascular disease was only weakly pulsatile but the volume of the resting total foot blood flow was higher than normal. No biochemical evidence of overall regional ischaemia or tissue anoxia was found to explain the aetiology of chronic nutritional skin lesions in these clinically ischaemic feet. The physiological effectiveness of a regional blood flow ultimately depends on its ability to perfuse the tissues, and in this respect it is suggested that pulse and pressure are more important than mere volume. It is further suggested that ischaemic or anoxic nutritional skin lesions develop in the presence of localized tissue perfusion failure and not from any overall regional blood flow insufficiency.     

CCK-8 induces fever-like regulated hyperthermia and symptoms of sickness behavior in mice: A biotelemetric study

In earlier studies it has been found that rats respond to intracerebroventricular (i.c.v.) injection of cholecystokinin-octapeptide (CCK-8) with a febrile response characterized by rises of heat production and core temperature together with tail-skin vasoconstriction mediated by CCK2 receptors. Biotelemetric investigations of the same species have additionally shown that CCK-induced fever is accompanied by decreased locomotor activity. Similar data for mice have not been reported so far. In the present studies C57BL/6 mice were infused i.c.v. for 3 days with CCK-8 to see effects on body core temperature, locomotor activity, food intake and body weight. Biotelemetric monitoring disclosed a rise in daylight core temperature and a fall of night-time locomotor activity both lasting beyond the time of i.c.v. infusions. Food intake was suppressed only during infusion, while a significant decrease of body weight was sustained after the end of CCK-8 infusion. It is concluded that similar to rats mice also respond to i.c.v. infusion of CCK-8 with a fever-like (regulated) hyperthermia and some components of sickness behavior as measured by biotelemetry, and thus a CCK-mediated mechanism may contribute to fever genesis also in mice.     

Training to vasodilate in a cooling environment: a valid treatment for Raynaud's phenomenon?

While many reports indicate that voluntary modification of skin temperature is possible and may be useful in the treatment of Raynaud's phenomenon, little attention has been paid to the ecological validity of training skin temperature increases when a considerable amount of vasodilation of digital vessels may already exist (room temperature, 22-24 degrees C). Patients with Raynaud's vasospastic attacks may benefit from learning to avoid attacks when they are impending by voluntarily vasodilating the vessels of their digits under conditions when vasoconstriction has begun. The results in 14 patients with primary and secondary Raynaud's phenomenon indicated that (a) patients learned to voluntarily increase digital skin temperatures in a "cooling" environment during documented vasoconstriction, and (b) there was a 31% decrease in the occurrence of vasospastic attacks following such learning. These data suggest that a new methodology may be useful in the biofeedback treatment of Raynaud's phenomenon, but further research is needed to determine the specific mechanism(s) involved, and the limits to its usefulness.     

Non-thermal factors are important in the control of skin blood flow during exercise only under high physiological strain

Several authors have argued that skin blood flow (SkBF) during exercise is less than during rest at the same levels of body core and whole-body skin temperatures (Tc and Tsk). Since such an effect does not prevent SkBF during exercise from rising above pre-exercise levels, it is sometimes called a relative cutaneous vasoconstriction. Such a vasoconstriction is considered to be either part of a thermoregulatory adjustment during exercise (elevated thermoregulatory "set-point") or a compensatory response to allow adequate perfusion of exercising muscle. In this paper, some of the pertinent experimental evidence is reviewed, and the following conclusions are reached: the evidence does not support a change in thermoregulatory set-point during exercise; under conditions of high physiological strain (high Tsk and intense exercise), there is quite clearly a relative cutaneous vasoconstrictor effect of exercise; the evidence does not support such an effect under more moderate conditions; and it is likely that, under mild to moderate conditions, other compensatory cardiovascular responses are sufficient to allow adequate perfusion of exercising muscle and are invoked in preference to relative cutaneous vasoconstriction, which has been demonstrated only at higher levels of strain. The thermoregulatory SkBF required during sustained exercise is thus maintained as much as possible.     

Are non-thermal factors important in the cutaneous vascular response to exercise? A proponent's view.

Direct forearm blood flow measurements showed that the threshold for vasodilation is shifted to a higher core temperature and that the slope describing the relationship between skin blood flow and core temperature is reduced during submaximum exercise in comparison with supine resting conditions. These changes in skin blood flow characteristics have been shown to be proportionately related to work load in at least one study, but not in others. With heavy exercise, indirect evidence was obtained for the elicitation of vasoconstriction after body core temperature had attained a level of 39 degrees C; this caused a dramatic rise of T core to above 40 degrees C. In other studies, such terminal vasoconstriction was not observed; the subjects stopped exercising (75 percent VO2 max), independently of its duration, when rectal temperature had reached about 39 degrees C. Such inconsistent results in regard to the importance of extrathermal control of skin blood flow may be traced to variations in the motivational and emotional state; moreover, a phenomenon described as "short-term adaptation" may be responsible for some discrepant results. In conclusion, there is evidence for the concept that blood pressure control by peripheral vasoconstriction may have, under certain circumstances, preference over the demands of temperature regulation.     

Clonidine induces nitric oxide- and prostaglandin-mediated vasodilation in healthy human skin.

Sustained sympathetic activation not only leads to vasoconstriction but also might induce paradox vasodilation. This study was performed to explore whether and how alpha(2)-receptor stimulation mediates this vasodilation. We investigated 11 healthy subjects in 33 dermal microdialysis (MD) sessions. After nerve trunk blockade, MD fibers were inserted and perfused with physiological saline until skin trauma-related vasodilation subsided. Thereafter, fibers were perfused with either clonidine solutions (10(-3), 5 x 10(-4), 10(-4) mol/l), N(G)-monomethyl-l-arginine (L-NMMA; nitric oxide synthase blocker), acetylsalicylic acid (ASA; cyclooxygenase blocker), or combinations of these. Laser-Doppler scanning of the investigated skin revealed that clonidine not only induces vasoconstriction but subsequently also vasodilation with higher concentrations (P < 0.001). In contrast, both L-NMMA and ASA induced vasoconstriction (P < 0.001). By coapplication of 10(-3) mol/l clonidine with L-NMMA or ASA, vasodilation was partially prevented (P < 0.001). Our results demonstrate that sustained alpha(2)-receptor stimulation induces vasodilation in a dose-dependent way, which is mediated by nitric oxide and prostaglandin mechanisms in human skin.     

PAF potentiates protamine-induced lung edema: role of pulmonary venoconstriction

We studied the synergistic interaction between platelet-activating factor (PAF) and protamine sulfate, a cationic protein that causes pulmonary endothelial injury, in isolated rat lungs perfused with a physiological salt solution. A low dose of protamine (50 micrograms/ml) increased pulmonary artery perfusion pressure (Ppa) but did not increase wet lung-to-body weight ratio after 20 min. Pretreatment of the lungs with a noninjurious dose of PAF (1.6 nM) 10 min before protamine markedly potentiated protamine-induced pulmonary vasoconstriction and resulted in severe lung edema and increased lung tissue content of 6-keto-prostaglandin F1 alpha, thromboxane B2, and leukotriene C4. Pulmonary microvascular pressure (Pmv), measured by double occlusion, was markedly increased in lungs given PAF and protamine. These potentiating effects of PAF were blocked by WEB 2086 (10(-5) M), a specific PAF receptor antagonist. Pretreatment of the lungs with a high dose of histamine (10(-4) M) failed to enhance the effect of protamine on Ppa, Pmv, or wet lung-to-body weight ratio. Furthermore, PAF pretreatment enhanced elastase-, but not H2O2-, induced lung edema. To assess the role of hydrostatic pressure in edema formation, we compared lung permeability-surface area products (PS) in papaverine-treated lungs given either protamine alone or PAF + protamine and tested the effect of mechanical elevation of Pmv on protamine-induced lung edema. In the absence of vasoconstriction, PAF did not potentiate protamine-induced increase in lung PS. On the other hand, mechanically raising Pmv in protamine-treated lungs to a level similar to that measured in lungs given PAF + protamine did not result in a comparable degree of lung edema. We conclude that PAF potentiates protamine-induced lung edema predominantly by enhanced pulmonary venoconstriction. However, a pressure-independent effect of PAF on lung vasculature cannot be entirely excluded.     

The role of the surrounding tissue in the propagation of waves through the arterial system.

A theoretical analysis of the flow in arteries is presented, taking into consideration the role played by the surrounding tissues in determining the speed of propagatoion and the damping of the blood pressure pulse. This study was undertaken (a) to exhibit a method of computing the flow properties with a more nearly accurate model, (b) to see if the displacement on the skin would be related to the arterial wall displacement, and hence to pressure, velocity and flow rate of blood in the artery, and if it is likely to be measurable. It was found that the pressure of the 'viscous' part in the surrounding tissue increases the pulse velocity and the damping of the wave over the values found by other models which considered only thick-walled elastic tubes with no surrounding tissue. This study also shows that measurements on the skin can provide information about changes in arterial circulation due to diseases such as: edema, arteriosclerosis and others where the Young's modulus for either the arterial wall or the surrounding tissues is altered.     

Slice It Hot: Acute Adult Brain Slicing in Physiological Temperature

Here we present a protocol for preparation of acute brain slices. This procedure is a critical element for electrophysiological patch-clamp experiments that largely determines the quality of results. It has been shown that omitting the cooling step during cutting procedure is beneficial in obtaining healthy slices and cells, especially when dealing with highly myelinated brain structures from mature animals. Even though the precise mechanism whereby elevated temperature supports neural health can only be speculated upon, it stands to reason that, whenever possible, the temperature in which the slicing is performed should be close to physiological conditions to prevent temperature related artifacts. Another important advantage of this method is the simplicity of the procedure and therefore the short preparation time. In the demonstrated method adult mice are used but the same procedure can be applied with younger mice as well as rats. Also, the following patch clamp experiment is performed on horizontal cerebellar slices, but the same procedure can also be used in other planes as well as other posterior areas of the brain.     

Infrared thermal imaging based study of localized cold stress induced thermoregulation in lower limbs: The role of age on the inversion time

Thermoregulatory control of human body temperature is of paramount importance for normal bodily functions. Exposure of the upper and lower limbs to localized cold stress can cause cold-induced injuries and often lower limbs are more susceptible to damages from cold-induced injuries. In this study, we use infrared thermal imaging to probe localized cold stress induced cutaneous vasoconstriction of lower limbs in 33 healthy subjects. The cold stress is actuated by applying ice to the plantar surfaces of the lower limbs for 180 s and after removal of the cold stress, infrared thermography is utilized to non-invasively monitor the time-dependent variations in vein pixel temperatures on the dorsal surfaces of the stimulated and non-stimulated feet. It is observed that the vein pixel temperature of the stimulated foot showed a non-monotonic variation with time, consisting of an initial decrease and the presence of an inversion time, beyond which temperature is regained. The initial decrease in vein pixel temperature of the stimulated foot is attributed to the reduced blood flow caused by the cold stress induced severe vasoconstriction. Beyond the inversion time, the vein pixel temperature is found to increase due to rewarming of the surrounding skin. Experimental findings indicate that the inversion time linearly increased with the age of the subject, indicating a reduced thermoregulatory efficiency for the aged subjects. This study provides a thermal imaging-based insight into the skin temperature re-distribution during the early stages of blood perfusion in lower limbs, after an exposure to a localized acute cold stress. Statistical analyses reveal that subject height, weight, body-mass index and gender do not influence the inversion time significantly. The experimental findings are important towards rapid evaluation of personnel fitness for deployment in extreme cold environment, treatment of cold-induced injuries and probing of thermoregulatory impairments.     

Ultrasound tomography of soft tissues and venous vessels in secondary edema of the upper limbs

The paper is concerned with ultrasound investigation that permits obtaining objective data on changes in the thickness, structure, borders and density of soft tissues in upper limb lymphedema. Moderate thickening of the skin and subcutaneous fat with slight thickening of the latter was noted in patients with mild edema. The thickness of the group of muscles at the shoulder level was decreased in each 3rd patient. Thickening of the skin and subcutaneous fat more than 1.5-fold was noted in edema of average severity. In severe edema the skin and subcutaneous tissue got thicker 2-2.5 times and acquired a dense regular spotty pattern. Echogeneity of the skin was reduced, and it often became merged with the subcutaneous fat. Cavities filled in with edematous fluid were found in the zone of maximum edema. Ultrasound phlebography made it possible to determine the state of major veins in upper limb edema and to abandon roentgenocontrast investigation of veins in a majority of cases.     

Tissue impedance and temperature measurements in relation to necrosis in experimental cryosurgery

Tissue temperature and impedance were measured in dog skin during freezing in situ. The previously frozen skin was removed by punch biopsies 3 days later to permit microscopic evaluation of the extent of necrosis. The histologic observations were related to the temperature and impedance measurements in an effort to determine the usefulness of the monitoring techniques in clinical cryosurgery. Tissue temperature and impedance have a definite relationship in tissue freezing, but the range of temperatures about any impedance values causes some concern. The tissue biopsies showed that an impedance value of at least 10 Mohms is not always associated with tissue death. In these experiments, there was the usual range of temperatures in relation to tissue death, but tissue temperatures of -30 degrees C and colder were always associated with complete necrosis. It is concluded that tissue temperatures are the more accurate and useful monitoring technique to supplement clinical judgment. However, impedance techniques may also be used to monitor therapy, especially if used primarily to monitor depth of therapy, and if controlled by clinical judgment wary of the inaccuracy of the technique.     

The role of adrenergic receptors in Ni2+-induced coronary vasoconstriction

The possible involvement of adrenergic receptors in nickel ion (Ni2+)-induced coronary vasoconstriction was studied on isolated perfused rat hearts and on isolated canine coronary artery strips. The experiments on both models showed that (i) alfa-adrenergic blockade by phenoxybenzamine or phentholamine caused only partial depression of Ni2+-induced coronary vasoconstriction: (ii) beta-adrenergic receptor blockade by propranolol totally prevented Ni2+-action, and (iii) Ni2+ (1 microM) caused significant inhibition of coronary vasodilatation induced by isoproterenol. The experimental results indicate that alfa-adrenoceptors play minor role (if any) in the coronary action mechanism of Ni2+ but it may be mediated by beta-adrenergic mechanisms. Nickel was found to alter the reactivity of coronary beta-adrenoceptors suggesting a possible modulatory role of this trace metal in coronary adrenergic mechanisms.     

Brünnich's guillemots (Uria lomvia) maintain high temperature in the body core during dives

A major challenge for diving birds, reptiles, and mammals is regulating body temperature while conserving oxygen through a reduction in metabolic processes. To gain insight into how these needs are met, we measured dive depth and body temperatures at the core or periphery between the skin and abdominal muscles simultaneously in freely diving Brünnich's guillemots (Uria lomvia), an arctic seabird, using an implantable data logger (16-mm diameter, 50-mm length, 14-g mass, Little Leonardo Ltd., Tokyo). Guillemots exhibited increased body core temperatures, but decreased peripheral temperatures, during diving. Heat conservation within the body core appeared to result from the combined effect of peripheral vasoconstriction and a high wing beat frequency that generates heat. Conversely, the observed tissue hypothermia in the periphery should reduce metabolic processes as well as heat loss to the water. These physiological effects are likely one of the key physiological adaptations that makes guillemots to perform as an efficient predator in arctic waters.     

Exocytotic release from individual granules exhibits similar properties at mast and chromaffin cells.

The effects of temperature on granular secretion were studied in individual bovine adrenal chromaffin and rat peritoneal mast cells. It was found that more molecules are released from individual granules at physiological temperature than at room temperature, where such experiments are normally performed. In mast cells, there is also a dramatic decrease in the time required for exocytosis to be complete at 37 degrees C compared to room temperature. In the presence of some cations, the amount released from individual granules at room temperature from both types of cells could be altered. The amount of secretion decreased with the divalent cation zinc but increased with the monovalent cation cesium. These experiments used two electrochemical techniques: cyclic voltammetry and amperometry. With amperometry, the concentration gradient created by the electrode near the cell further increased the amount of release. Similar responses to changes in the extracellular environment in chromaffin and mast cells suggest that the mechanism of extrusion of the granule contents is similar in both cell types.