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      A Time-Response Model for Analysis of Drug Transport and Blood Flow Response during Iontophoresis of Acetylcholine and Sodium Nitroprusside

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          Abstract

          Background/Aims: The analysis of blood flow responses to iontophoresis of vasoactive drugs is often limited to evaluation of maximum responses. In this study, a time-response model is proposed for the blood flow responses to vasoactive drugs applied by iontophoresis. Methods: The microvascular bed is represented as a single compartment with a zero-order influx of the drugs from the electrode and a first-order clearance due to diffusion and blood flow. The blood flow response to the local drug dose is described using the E<sub>max</sub> model. Results: The model accurately describes the blood flow responses to acetylcholine and sodium nitroprusside during a single iontophoretic current pulse. There is a significant clearance out of the microvascular bed during iontophoresis which depends on the type of drug administered. Conclusion: The model enables an accurate estimation of response parameters such as ED50 and maximum response, even if the true maximum blood flow is not obtained. The results suggest that due to clearance from the microvascular bed, the local drug dose during a single pulse of current is not linearly proportional to current strength multiplied by pulse duration.

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          Most cited references 11

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          Kinetics of pharmacologic response. I. Proposed relationships between response and drug concentration in the intact animal and man.

           J.G. Wagner (1968)
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            A protocol for iontophoresis of acetylcholine and sodium nitroprusside that minimises nonspecific vasodilatory effects.

            Iontophoresis of vasoactive substances is a promising tool for studying pharmacological aspects of the (patho)physiology of the microvasculature. However, nonspecific microvascular responses are a common problem in most protocols used. We studied the effect of current density (mA/cm2), charge density (mC/cm2), drug concentration (mass %) and vehicle concentration (M) on the nonspecific vasodilatation during iontophoresis of sodium chloride, acetylcholine (ACh) and sodium nitroprusside (SNP). We found that nonspecific vasodilatation depended on current density and charge density in both anodal and cathodal iontophoresis. The responses to ACh and SNP were dependent on current density, charge density and drug concentration. We found that by limiting current density (<0.01 mA/cm2) and charge density (<7.8 mC/cm2) and with adjusted concentrations for drugs and vehicles, it is possible to prevent nonspecific effects during iontophoresis of ACh and SNP, while maximum drug effects (plateaus in the dose-response curves) are still obtained. These new findings are important for future iontophoresis studies in which vasoactive drugs are used to assess microvascular function because the presented approach has advantages compared to older techniques, which mainly have attempted to suppress or compensate for the nonspecific responses during iontophoresis by the use of local anaesthetics or the measurement of drug-minus-vehicle responses, both of which present well-known experimental shortcomings.
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              Assessment of microvascular endothelial function in human skin.

              Endothelial dysfunction is an important factor in many cardiovascular diseases, and is commonly associated with impaired endothelium-mediated vasodilatation. Information about the mechanisms behind this dysfunction has come largely from animal studies or, in humans, through invasive techniques that are not specific to one vascular bed. We have developed protocols to assess endothelial function non-invasively in the cutaneous microcirculation by measuring blood flow responses to four receptor-specific vasoactive compounds. Cumulative doses of acetylcholine, methacholine, bradykinin and substance P were administered iontophoretically to the forearm skin of healthy volunteers on two to three occasions. Dose-dependent increases in skin microvascular blood flow in response to these drugs were measured with laser Doppler imaging. Vascular responses to acetylcholine and methacholine were reasonably consistent, with coefficients of variation of approx. 17%. The coefficients of variation for bradykinin and substance P were much poorer, as high as 70% for some doses. This might partly be a consequence of the more unpredictable effects of histamine release in the vasoactive behaviour of these two agonists. Although it might be advantageous to find other agonists with which to test the function of different receptor pathways, we have shown that just acetylcholine and methacholine can currently be used with iontophoresis to allow sensitive and reproducible assessment of endothelial function.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2009
                June 2009
                25 November 2008
                : 46
                : 4
                : 270-277
                Affiliations
                Departments of aMedicine and Care, bBiomedicine and Surgery, and cHand and Plastic Surgery and Intensive Care, Faculty of Health Sciences, Linköping University Hospital, Linköping, Sweden
                Article
                176042 J Vasc Res 2009;46:270–277
                10.1159/000176042
                19033689
                © 2008 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 3, Tables: 1, References: 16, Pages: 8
                Categories
                Research Paper

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