Control of skin blood flow during exercise.
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):303-12.Control of skin blood flow during exercise.1, .1Laboratory for Human Performance Research, Pennsylvania State University, University Park 16802.AbstractWhen body temperature rises, skin blood flow (SkBF) increases to effect transfer of metabolic heat from the core to the skin. This convective heat transfer is never more important than during dynamic exercise. Control of SkBF involves a complex interaction of regulatory systems (body temperature, blood pressure, metabolism, etc.) and efferent mechanisms (passive withdrawal of constrictor tone, reflex vasoconstriction, active vasodilation). The purpose of this paper is to provide an updated review of this complex control system--control that allows for maintenance of blood pressure and perfusion of active muscle without adverse impact on thermoregulation. Also discussed are vasomotor mechanisms, various components of exercise that are important in the control of SkBF (e.g., intensity, posture, and duration of exercise), and the influences of such factors as blood volume and tonicity, aerobic fitness and heat acclimation, and age.PMID: 1549024
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Methodology article
Effects of some anesthetic agents on skin microcirculation evaluated by laser Doppler perfusion imaging in mice
Sara Gargiulo*†, Matteo Gramanzini†, Raffaele Liuzzi, Adelaide Greco, Arturo Brunetti and Giancarlo Vesce
Corresponding author:
† Equal contributors
Institute of Biostructures and Bioimages of the National Council of Research, Via T. De Amicis 95, Naples 80145, Italy
Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini 5, Naples 80145, Italy
CEINGE scarl, Via G. Salvatore 486, Naples 80145, Italy
Department of Veterinary Medicine and Animal Productions, University of Naples Federico II, Via Delpino 1, Naples 80137, Italy
For all author emails, please .
BMC Veterinary Research 2013, 9:255&
doi:10.48-9-255
The electronic version of this article is the complete one and can be found online at:
Received:9 September 2013
Accepted:2 December 2013
Published:17 December 2013
& 2013 Gargiulo et al.; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Background
Anesthetic agents alter microcirculation, influencing tissue oxygenation and delivery
of vital substrates. Laser Doppler perfusion imaging is a widespread technique in
the field of microvascular research that can evaluate noninvasively and in real time
the effects of environmental conditions, physical manipulations, diseases and treatments
on peripheral perfusion. This study aims to evaluate laser Doppler perfusion imaging
as a means to detect changes in skin microcirculation induced by some popular anesthetic
agents in a murine model. Twenty-four age- and gender-matched healthy CD1 mice were
examined by laser Doppler perfusion imaging. The skin microcirculatory response was
measured at the level of plantar surfaces during isoflurane anesthesia with or without
subsequent dexmedetomidine or acepromazine. At the end of the procedure, dexmedetomidine
was reversed by atipamezole administration.
In all mice, skin blood flow under isoflurane anesthesia did not show significant
differences over time (P = 0.1). The serial perfusion pattern and values following
acepromazine or dexmedetomidine administration differed significantly (P & 0.05).
Conclusions
We standardized a reliable laser Doppler perfusion imaging protocol to non-invasively
assess changes in skin microcirculation induced by anesthesia in mice, considering
the advantages and drawbacks of this technique and its translational value.
Keywords: Mic A M Laser Doppler perfusion imagingBackground
Microcirculation is the final link between the cardiovascular system and cellular
interfaces and, ultimately, molecular processes. Many studies have investigated the
effect of anesthetics on peripheral and systemic microcirculation in humans
[-], especially their effects on microvascular perfusion, aiming to ensure adequate tissue
oxygenation and nutritional supply. Mice are an ideal model to study anesthetic action
due to their easy manipulation, well-established behavioral and homeostatic responses
to anesthesia, and well-known genetic background. Outbred mouse strains are widely
used in toxicology and pharmacology, and CD1 mice have been employed in anesthesia
[-] on the assumption that most characteristics of interest have a polygenic inheritance
and are related to phenotypic variation in a genetically heterogeneous population
[,]. Moreover, anesthesia is required for most in vivo studies using mouse microcirculatory
models, and the use of diverse anesthetic agents in translational research can interfere
with experimental results
[,]. As an example, pentobarbital
[,], midazolam-medetomidine
[] and isoflurane
[] have been used in preclinical studies on peripheral arterial disease to evaluate
the effects of new angiogenetic therapies. Microcirculatory responses to the most
popular inhalation (halothane, isoflurane) or injectable anesthetics (propofol-fentanyl,
barbiturates and ketamine) have been investigated in rats at the level of intestinal
[], cremaster or dorsal muscle microcirculation
[-] using invasive dorsal microcirculatory chambers or intravital microscopy. So far,
few data have been reported regarding the microvascular effects of the popular laboratory-animal
anesthetic agents acepromazine and dexmedetomidine. Acetylpromazine maleate is an
α-adrenergic receptor antagonist broadly used for sedation and balanced anesthesia
in animals
[]. Concurrent administration of acepromazine reduces the required dose of isoflurane
while potentiating peripheral vasodilation and lowering blood pressure in dogs
[]. The combination of acepromazine with ketamine and xylazine is recommended for a
safe and reliable surgical anesthesia in mice, although it is associated with marked
hypotension
[,]. Dexmedetomidine hydrochloride is a selective α2-adrenoceptor agonist with preferential affinity for α2A and α2B receptors
[]. Perioperative administration of dexmedetomidine hydrochloride reduces the required
doses of isoflurane, thiopental and propofol in humans and animals, and it reduces
the activation of the sympathetic nervous system during surgery, preventing harmful
hemodynamic events such as acute kidney injury
[]. Reliable techniques for measuring perfusion in accessible tissues such as skin may
have significant potential to improve our understanding of microvasculature regulation
under anesthesia. Laser Doppler perfusion imaging (LDPI) is a noninvasive technique
allowing real-time quantification of skin perfusion in two-dimensional color-coded
images. Enhancement of the measured area provides a better evaluation of blood flow
heterogeneity, allowing for the identification of subtle changes in skin perfusion
induced by anesthesia and indicating circulatory status in other areas
[,]. Although LDPI offers a simple and accurate estimate of peripheral perfusion, a standard
method for the study of microcirculatory changes related to anesthesia in mice is
lacking. In the present study, we reviewed several biological variables, such as gender,
environmental variables and operational variables, such as body temperature, skin
district and recording conditions, to develop a LDPI protocol to evaluate the effects
of some anesthetic agents on microcirculation in mice. Our LDPI protocol is a potentially
valuable research tool to detect in vivo real-time microcirculatory changes in preclinical
experiments in mice.
Standardized protocol for animal positioning and LDPI image post-processing and measurement
are described in Figure&
. Sequential perfusion units (PU, volts) values for each group are reported in Table&
as median, minimum and maximum values. No significant differences were seen between
males’ and females’ peripheral blood flow (PBF) at any time point (P & 0.05). The
effects of different anesthetics on peripheral perfusion for each group are presented
in Figure&
. In all mice, mean perfusion under isoflurane anesthesia showed an increasing trend
at 10 and 20&minutes after maintenance (4.25 to 4.55 volts), reaching a steady perfusion
value without significant differences among groups and in later times (P = 0.1). In
contrast, the mean LDPI values following acepromazine (group 1) and dexmedetomidine
administration (group 2) differed significantly. Between 10 and 20&minutes after acepromazine
administration, a significant perfusion increase (P = 0.005) was observed, from 4.55
to 4.85 volts. Dexmedetomidine administration produced a clear biphasic effect, leading
to a significantly reduced (P = 0.0001) blood perfusion (2.47 volts) after 5&minutes,
followed by an increase to 4.32 volts (P = 0.008) after 15&minutes. The latter perfusion
value, close to that under isoflurane anesthesia (P = 0.6), was quite retained (4.34
volts) even following dexmedetomidine reversal by atipamezole (the antidote to the
α2-receptor agonist) (P = 0.9). No significant peripheral perfusion changes were observed
in control mice after up to 30&minutes (4.57 volts) of 1.5% isoflurane anesthesia
(P = 0.11).
LDPI scan technique. (A) Animal positioning in sternal recumbency on a light-absorbing pad, with the hind
plantar surfaces symmetrical and perpendicular to the laser beam. (B) LDPI image post-processing and measurement standardized protocol: the mean intensity
of the Doppler signal was registered in ROI encompassing the hind paws and expressed
as numerical value normalized for their area (perfusion color scale 0–5 volts).
Microvascular perfusion values
Representative LDPI images. Peripheral perfusion patterns in mice over time after administration of 3 anesthetic
protocols. Time points with significant differences (P & 0.05) are reported. Group
1 (top row) 10 (A) and 20&minutes after acepromazine injection (B); group 2 (middle row) 5 (C) and 15&minutes after dexmedetomidine injection (D) and 5&minutes after atipamezole administration (E); control group (lower row) 10 (F), 20 (G) and 30&minutes after isoflurane maintenance (H) (perfusion color scale 0–5 volts as reported in Figure&).
Discussion
Anesthetics modulate microcirculation mainly via autonomic sympathetic and parasympathetic
nerves on vascular smooth muscle. Phenothiazine tranquilizers as well as α2-agonists exert their hemodynamic effects mainly by interacting with α-adrenergic-receptors.
Phenothiazines cause vasodilation predominantly by blocking α1 receptors but are also dopamine receptor antagonists
[]. While D1-like dopamine receptors induce relaxation of resistance arteries
[,] D2-like dopamine receptors are typically present on postganglionic sympathetic neurons,
where their excitation leads to a reduction of the neural release of norepinephrine,
inducing a passive fall in vascular resistance and heart rate
[]. Dexmedetomidine is a selective α2-adrenoceptor agonist that shows a dose-dependent, preferential affinity for α2A and α2B receptors
[], evoking a biphasic blood pressure response: a short hypertensive phase mediated
by the α2B receptors, followed by hypotension mediated by the α2A receptors
[,]. The peripheral hemodynamic effects of phenothiazines and of α2-agonists thus differ: while acepromazine causes significant hypotension in isoflurane-anesthetized
[], dexmedetomidine
[,] increases peripheral vascular tone, counteracting the isoflurane-induced vasodilation
and reduction in arterial blood pressure
[]. LDPI permits a noninvasive, real-time measurement of microvascular blood flow using
two-dimensional color-coded images of skin perfusion. The use of laser doppler flowmetry
technique to detect the sympathetic tone during general anesthesia in humans has been
[,,], and translational approaches using LDPI in microvascular perfusion mouse models
offer the advantages of being easy and fast
[]. Moreover, various anesthetics alter blood flow in rodents
[-], so anesthetic regimens used in mouse microcirculatory models should be taken into
account, and they should not adversely affect the vascular bed to be examined. The
main finding in this study is that LDPI is able to evaluate in real time the anesthesia-induced
changes in mouse peripheral microcirculation. The hemodynamic effects recorded during
the different anesthetic protocols were as expected based on previous clinical and
animal studies, although the analyzing techniques were different
[-,]. Because LDPI scans are disrupted by motion
[] and single or combined sedatives have lacked restraining effects in mice, we chose
to perform our study under 1.5% isoflurane anesthesia to record reference perfusion
values. Isoflurane produces only minor effects on murine hemodynamic status
[,]. Costantinides et al. (2011)
[] reported that 1.5% isoflurane produces stable body temperature, mean arterial pressure
(MAP) and heart rate (HR) values in mice, comparable to those observed in awake animals,
so they recommended it for physiological and pharmacological studies of cardiac function
and to facilitate translational research in non-invasive imaging platforms. In the
present study, isoflurane anesthesia yielded a reproducible and stable effect on peripheral
blood perfusion over time (P = 0.1). Acepromazine increased isoflurane plantar perfusion,
as reported by Lemke et al.
[], and reduced vascular tone and arterial pressure due to its α-blocking action. After
dexmedetomidine administration, a rapid and intense decrease in plantar perfusion
was followed by a longer phase of increased perfusion, in agreement with the typical
biphasic hemodynamic effect of this class of sedatives. In all of the mice, the increased
perfusion recorded 15&minutes after dexmedetomidine administration did not surpass
the perfusion brought about by isoflurane (P = 0.6), and it was noticeably lower than
the perfusion recorded following acepromazine administration (P = 0.01), which did
not increase significantly even after atipamezole injection (P = 0.9). Special care
was taken to avoid methodological bias. To date, the skin has been used as a model
of microcirculation to investigate vascular mechanisms in cardiovascular
[-] or kidney diseases
[] and diabetes
[,]. Autonomic innervation of microvessels in the region of interest
[,,-], somatic stimulation of cutaneous arterial sympathetic nerve activity
[], positioning and body temperature
[] are all crucial factors affecting skin blood flow measured by LDPI. Glabrous skin
areas are highly innervated by noradrenergic sympathetic vasoconstrictor nerves
[,], which are regulated by α-adrenoceptors
[] in several species
[-]. For these reasons, we chose plantar region to investigate blood flow changes brought
about by anesthetic drugs, also avoiding hair clipping, which might affect cutaneous
arterial sympathetic nerve activity and alter LDPI measurements
[]. In our setting, precise hind plantar surface positioning was achieved to keep the
site of interest highly symmetrical and precisely perpendicular to the laser beam
[-]. Moreover, body temperature was monitored by a rectal probe and adjusted between
35.5-36.5°C by an infrared lamp. Our experiments were performed in a temperature-controlled
[], and we started LDPI recordings after each animal had acclimatized. The effects of
sex hormones on vascular tone continue to be a matter of debate
[,]. Stucker et al. (2001)
[] reported in an LDPI study only a tendency toward higher perfusion values in men than
in women, stating that moderate gender differences in skin perfusion between study
groups should be tolerated. Similarly, Kunkel et al. (2007)
[] found that foot skin perfusion in normal human subjects was independent of gender.
In our experience, no significant differences between males and females were found
in the peripheral blood flow in either control or treated animals. In accordance with
the manufacturers’ technical instructions, the room lighting should be kept to a minimum
brightness. We set our lighting discrimination between background and the site of
measurement to the default threshold level of 6.2 volts, adjusting the backscattered
laser light intensity in the range of 7–9 volts, obtaining an optimum quality of data.
To compare perfusion in different images, a user-defined color scale was adopted during
the acquisition process, ranging from 0 to 5 volts (perfusion output value of 0 volts
was calibrated to 0% perfusion, whereas 5 volts was calibrated to 100%). The average
perfusion in each region of interest (ROI) was normalized to the wall plantar surface
area to reduce bias related to unavoidable anatomical and position variance. To further
minimize any data divergence, the hind paw perfusion value for each animal at each
time point was calculated as the average value of both hind paw ROIs.
Conclusions
LDPI is able to evaluate noninvasively and in real time the skin microcirculation
changes induced by general anesthesia in mouse models. LDPI could be useful for studying
the effects of anesthetics on peripheral microcirculation and to avoid the inconsistent
use of anesthetic agents in cardiovascular translational research. Standardization
of an appropriate LDPI procedure is needed in preclinical studies to avoid bias in
experimental results.
Ethical permission
This study was approved by the animal welfare regulation committee (CESA) of the University
“Federico II” of Naples and by the Italian Ministry of Health. It complied with the
Guide for the Care and Use of Laboratory Animals published by the US National Institutes
of Health (NIH Publication No. 85–23, revised 1996).
Study subjects and design
Twenty-four CD1 mice (15 females and 9 males), 8 to 10&weeks old, were randomly assigned
to one of three experimental groups (5 females and 3 males) and sequentially examined
in identical ambient conditions. Skin perfusion was recorded by LDPI under isoflurane
anesthesia combined or not with acepromazine or dexmedetomidine, as well as after
the administration of atipamezole to antagonize dexmedetomidine’s effects.
Experimental protocol
Animals were acclimated for 15&min at a room temperature of 27 ± 3°C before anesthetic
induction. During LDPI recording, the ambient lighting was kept at a minimum. Body
temperature was monitored by a rectal temperature probe (Harvard Apparatus(R), MLT1404)
and closely adjusted to 35.5 ± 0.5°C by an infrared lamp kept 60&cm away from the
body surface. On the basis of a critical revision of the existing literature, peripheral
perfusion was measured at the level of the hairless, highly sympathetic innervated
plantar surfaces
[,]. Animals were placed in sternal recumbency on the light-absorbing pad provided by
the apparatus company, positioning the hind plantar surfaces symmetrically and perpendicularly
to the laser beam (Figure&
). Isoflurane induction and maintenance were identical for all mice: each animal was
weighed on a precision scale and transferred from a holding cage to a small rodent
anesthetic chamber (isoflurane 4% in 2&L/min oxygen) (ISOFLURANE-VET(R), MERIAL ITALIA
S.p.A.(R)). When deeply anesthetized, animals were placed in sternal recumbency on the
recording bed and fitted with a facial mask delivering isoflurane 1.5% in 1&L/min
oxygen. LDPI scans were recorded 10 and 20&minutes after isoflurane maintenance. Subsequent
group treatments were carried out according to the schedule below, with precise time
intervals between the LDPI recordings based on the pharmacodynamics of the different
anesthetic agents:
Group 1 (8 subjects): Acepromazine (PREQUILLAN(R), FATRO S.p.A.(R)) 5&mg/kg (= 0.99&mg/kcal)
was administered intraperitoneally (IP), followed by two LDPI scans at an interval
of ten minutes.
Group 2 (8 subjects): Dexmedetomidine (DEXDOMITOR(R), Pfizer Italia Srl(R)) 1&mg/kg (= 0.19&mg/kcal)
was administered IP, followed by two LDPI scans after 5 and 15&minutes. Finally, dexmedetomidine
was reversed by injecting the α2-adrenoceptor antagonist atipamezole (ATIPAM, Fatro(R)) 2.5&mg/kg (= 0.49&mg/kcal) IP,
and a further LDPI scan was performed after 5&minutes.
Group 3 “control” (8 subjects): an additional LDPI scan was recorded 30&minutes after isoflurane
maintenance.
Laser Doppler imaging system
The Periscan(R) apparatus displayed the blood perfusion signal both as a numerical PU
(volts) and as a color-coded image ranging from dark blue (low perfusion) to bright
red (high perfusion). The settings used in the present study were laser beam power
= 1&mV; wavelength = 670& pixel size = 0.25 × 0.25&mm2; scanner head distance =15& scanning area = 3 × 2 cm2; scanning time = 2&minutes.
Data processing
The mean intensity of the Doppler signal was quantified using proprietary software
in a fixed ROI, encompassing the corresponding hind paw regions, normalized for the
areas of the hind paws and expressed as numerical values (volts) to reduce the bias
related to unavoidable anatomical and position variance. To further minimize any data
divergence, the hind paw perfusion value for each animal at each time point was calculated
as the average value of both hind paw ROIs.
Data analysis
Statistical analysis was carried out using the software SPSS 18.0.2. (SPSS, Chicago,
IL). To compare inter-group differences, one way Friedman ANOVA was used. A post hoc
analysis with Dunn’s test was performed when appropriate. A linear generalized model
(LGM) for repeated measurements (two-way ANOVA) was used to assess perfusion patterns
at different times within groups. A P value &0.05 was considered statistically significant.
Abbreviations
HR: H IP: I LDPI: Laser Doppl MAP:
Me PU: P ROI: Region of interest.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
SG, MG, AB and GV conceived and designed this study, as well as contribuited to data
interpretation and drafted the manuscript. SG, MG, and GV carried out the experiments.
AG took part in the data collection. SG and MG analysed and arranged data for statistical
analysis. RL performed the statistical analyses. SG and MG made equal contribution
to this study and should be considered first authors. All authors read and approved
the final manuscript.
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