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Assessment of microvascular effects of vasoactive drugs: Methodological in vivo studies in humansbased on iontophoresis
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cardiovascular disease is the leading cause of death in western societies and endothelial dysfunction is one of the earliest signs seen in the development of such conditions. Thedevelopment of prognostic tools to aid in the prediction of micro- and macrovascular diseasebased on assessment of vascular reactivity is therefore of paramount importance.

Transdermal iontophoresis offers a quick, non-invasive and relatively straightforward way todeliver vasoactive substances in order to provoke a vascular response in man. When combined with either laser Doppler flowmetry (LDF) or tissue viability imaging (TiVi) for quantification of these responses the methodology offers a potentially powerful tool forvascular investigations. The technique has, however, not been established in clinical practice yet and is mostly used in experimental settings. The lack of consensus in what data analysistechnique to use, uncertainty concerning the actual drug dose applied, and the difficulties associated with the assessment of responses to vasoconstrictors may have contributed to thisfact. The aim of this thesis is therefore to address these issues and thus facilitate the use and improve the applicability of transdermal iontophoresis for assessment of cutaneous microvascular function.

More specifically, a non-linear dose-response model (Emax-model) that is commonly used in in vitro investigations of vascular function was applied to the iontophoresis data. The resultsshow that the Emax-model accurately describes the cutaneous vascular responses totransdermally iontophoresed acetylcholine (ACh) and, sodium nitroprusside (SNP). The Emaxmodelgenerates variables that can be used for quantitative statistical analysis of data andenables a more powerful analysis compared to the methods presently used. It is furtherdemonstrated that the maximal dose effect and vascular responses vary between differentprotocols with the same total iontophoretic charge but with different current strengths anddurations. This finding implies that the assumption that the local drug dose is linearlyproportional to the iontophoretic charge (used for estimation of delivered drug dose to themicrovascular bed) may be inaccurate in in vivo investigations and that there is need for amore refined model.

It is also demonstrated that in a vasoconstrictive setting (iontophoresis of noradrenaline andphenylephrine) TiVi is the favourable technique for measuring vascular responses as it issensitive enough to generate data that can be fitted to the Emax-model even without predilatationof the vessels.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2009. , 47 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1125
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-50642ISBN: 978-91-7393-638-5 (print)OAI: oai:DiVA.org:liu-50642DiVA: diva2:271818
Public defence
2009-11-06, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2009-10-13 Created: 2009-10-13 Last updated: 2009-10-13Bibliographically approved
List of papers
1. Assessment of microvascular function by study of the dose‐response effects of iontophoretically applied drugs (acetylcholine and sodium nitroprusside): Methods and comparison with in vitro studies
Open this publication in new window or tab >>Assessment of microvascular function by study of the dose‐response effects of iontophoretically applied drugs (acetylcholine and sodium nitroprusside): Methods and comparison with in vitro studies
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2007 (English)In: Microvascular Research, ISSN 0026-2862, E-ISSN 1095-9319, Vol. 73, no 2, 143-149 p.Article in journal (Refereed) Published
Abstract [en]

Current knowledge about vascular function stems mainly from pharmacological in vitro studies using mounted vascular strips on a strain gauge. We know of no paper that has systematically examined the possibility of assessing the conventional dose–response effects of iontophoresis and laser Doppler investigation of vasoactive substances and compared those relations to data obtained from strips mounted on a strain gauge.

We used the vasoactive substances acetylcholine (endothelium dependent) and sodium nitroprusside (endothelium independent) and an antagonist (atropine) to enable further investigations in the receptor physiology of iontophoresis.

Dose–response curves from the iontophoresis experiments showed close similarity to those obtained by vascular strips mounted on a strain gauge. The coefficient of variation (CV) of the dose–response factors found in iontophoresis (both inter and intra experimental variability) was low. The iontophoretic effective dose of 50% (ED50) for acetylcholine and nitroprusside had only CVs of 25% and 26%, respectively, compared with 71% and 77% for the vascular strips. Acetylcholine-induced response was antagonized by iontophoresis of atropine. Contrary to expectations, this antagonism was not competitive.

The results show that iontophoresis in combination with laser Doppler technology produces reproducible and reliable dose–response curves that picture the vascular effects of vasoactive drugs.

Keyword
Microvascular circulation, Endothelium, Dose–response, Iontophoresis, Laser doppler
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14459 (URN)10.1016/j.mvr.2006.10.004 (DOI)
Available from: 2007-05-04 Created: 2007-05-04 Last updated: 2017-12-13Bibliographically approved
2. Sub-epidermal imaging using polarized light spectroscopy for assessment of skin microcirculation
Open this publication in new window or tab >>Sub-epidermal imaging using polarized light spectroscopy for assessment of skin microcirculation
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2007 (English)In: Skin research and technology, ISSN 0909-752X, E-ISSN 1600-0846, Vol. 13, no 4, 472-484 p.Article in journal (Refereed) Published
Abstract [en]

Background/aims: Many clinical conditions that affect the microcirculation of the skin are still diagnosed and followed up by observational methods alone in spite of the fact that non-invasive, more user-independent and objective methods are available today. Limited portability, high cost, lack of robustness and non-specificity of findings are among the factors that have hampered the implementation of these methods in a clinical setting. The aim of this study is to present and evaluate a new, portable and easy-to-use imaging technology for investigation of the red blood cell (RBC) concentration in the skin microvasculature based on the method of polarization light spectroscopy using modified standard digital camera technology.

Methods: The use of orthogonal linear polarization filters over both the flash source and the detector array removes the polarization-retaining light reflected from the epidermal layer. Only the depolarized light backscattered from the papillary dermal matrix reaches the detector array. By separating the RGB color planes of an image acquired in this manner and applying a dedicated image processing algorithm, spectroscopic information about the chromophores in the dermal tissue can be attained. If the algorithm is based on a differential principle in which the normalized differences between the individual values of the red and green color plane are calculated, tissue components with similar spectral signature in both planes are suppressed, while components with different spectral signatures such as RBCs are enhanced.

Results: In vitro fluid models compare well with theory and computer simulations in describing a linear relationship between the imager output signal termed the tissue viability index (TiVi index) and RBC concentration in the physiological range of 0-4% RBC fraction of tissue volume (cc=0.997, n=20). The influence of oxygen saturation on the calculated RBC concentration is limited to within -3.9% for values within the physiological range (70-100% oxygen saturation). Monte Carlo simulations provide information about the sampling depth (about 0.5mm on the average) of the imaging system. In vivo system evaluation based on iontophoresis of acetylcholine displays a heterogeneous pattern of vasodilatation appearing inside the electrode area after about 10min. Topical application of methyl nicotinate and clobetasol propionate further demonstrates the capacity to document the extent and intensity of both an increase (erythema) and a decrease (blanching) in the skin RBC concentration without movement artifact and with compensation for irregularity in pigmentation.

Conclusions: Polarization light spectroscopy imaging for assessment of RBC concentration in the skin microvasculature is a robust and accessible technique for the clinical setting. Additionally, the technique has pre-clinical research applications for investigation of the spatial and temporal aspects of skin erythema and blanching as well as a potential role in drug development, skin care product development and skin toxicological assessment.

Keyword
Biomedical optics, Blanching, Erythema, Microcirculation, Polarizationspectroscopy
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-48066 (URN)10.1111/j.1600-0846.2007.00253.x (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13Bibliographically approved
3. Assessment of microvascular response to iontophoresis ofnoradrenaline and phenylephrine using local heating andlaser Doppler flowmetry
Open this publication in new window or tab >>Assessment of microvascular response to iontophoresis ofnoradrenaline and phenylephrine using local heating andlaser Doppler flowmetry
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Laser-Doppler flowmetry (LDF) is an attractive method to assess blood flow responses butlacks sensitivity to accurately measure low perfusion values during iontophoresis of vasoconstricting drugs without predilatation of the microvascular bed.

The aim of this study was to develop a protocol for iontophoresis of noradrenaline (NA) andphenylephrine (Phe) in the skin, using local heating to predilate the microvascular bed andLDF to measure blood flow responses. Three protocols with the same electrical charge (12mC) but different durations and current strengths (100 s x 0.12 mA, 200 s x 0.06 mA, 300 s x0.04 mA) were used to study the effect of pulse duration and current strength on the responses.

Skin perfusion decreased to 68-78% of the predilatated state with both NA and Phe. Doseresponse plateaus were not obtained with any protocol. The extent of the vasoconstriction depended on the protocol used.

These results suggest that predilatation by local heating appears less suitable duringiontophoresis of NA and Phe, due to limited vascular responses and especially absence of response plateaus, even at high current strengths. The latter leads to difficulties in performing proper dose response analyses. Another interesting finding was that the actual dose of NA and Phe given to the tissue was affected not only by the size of the electrical charge, but local blood flow as well.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-50639 (URN)
Available from: 2009-10-13 Created: 2009-10-13 Last updated: 2010-01-14Bibliographically approved
4. Tissue viability imaging: Microvascular response to vasoactive drugs induced by iontophoresis
Open this publication in new window or tab >>Tissue viability imaging: Microvascular response to vasoactive drugs induced by iontophoresis
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2009 (English)In: Microvascular Research, ISSN 0026-2862, Vol. 78, no 2, 199-205 p.Article in journal (Refereed) Published
Abstract [en]

When one is studying the physiology of the cutaneous microcirculation there is a need for relevant non-invasive and versatile techniques. In this study we used a new optical device, the tissue viability imager (TiVi), to map changes in cutaneous microvascular concentrations of red blood cells during iontophoresis of vasoactive substances (noradrenaline (NA) and phenylephrine (Phe) for vasoconstriction and acetylcholine (ACh) and sodium nitroprusside (SNP) for vasodilatation). We aimed to present data both individually and pooled, using a four-variable logistic dose response model that is commonly used in similar in vitro vascular studies. The accuracy of the TiVi was also investigated by calculating the coefficient of variation and comparing it with similar tests previously done using laser Doppler imaging.

Tests were also performed using the TiVi and LDPI simultaneously to further compare the two methods. Results showed that the TiVi is capable of quantifying vascular responses to iontophorised noradrenaline and phenylephrine without the need to increase background flow first. Fitting the TiVi data to the dose response model resulted in ED50-values with narrow confidence intervals and acceptable r2 values. Mean ED50-values for the TiVi did not differ significantly from similar values obtained using laser Doppler.

Results further seem to suggest that when the blood perfusion increases during vasodilatation in skin the initial phase relies mainly on an increase in red blood cell concentration whereas the further perfusion increase is due to an increase in red blood cell velocity.

Keyword
Cutaneous microcirculation; Iontophoresis; Laser Doppler; Tissue viability imager
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-21238 (URN)10.1016/j.mvr.2009.04.008 (DOI)
Note
Original Publication: Joakim Henricson, Anders Nilsson, Erik Tesselaar, Gert Nilsson and Folke Sjöberg, Tissue viability imaging: Microvascular response to vasoactive drugs induced by iontophoresis, 2009, Microvascular Research, (78), 2, 199-205. http://dx.doi.org/10.1016/j.mvr.2009.04.008 Copyright: Elsevier Science B.V., Amsterdam http://www.elsevier.com/ Available from: 2009-09-30 Created: 2009-09-30 Last updated: 2009-10-30Bibliographically approved

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