Assessment of microvascular effects of vasoactive drugs Methodological in vivo studies in humans based on iontophoresis

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. The development of prognostic tools to aid in the prediction of microand macrovascular disease, based on assessment of vascular reactivity, is therefore of paramount importance. Transdermal iontophoresis offers a quick, non-invasive, and relatively straightforward way to deliver 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 for vascular investigations. The technique has, however, not been established in clinical practice yet and is mostly used in experimental settings. The lack of consensus on what data analysis technique to use, uncertainty concerning the actual drug dose applied, and the difficulties associated with the assessment of responses to vasoconstrictors, may have contributed to this. 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), which is commonly used in in vitro investigations of vascular function, was applied to the iontophoresis data. The results show that the Emax-model accurately describes the cutaneous vascular responses to transdermally iontophoresed acetylcholine (ACh) and sodium nitroprusside (SNP). The Emaxmodel generates variables that can be used for quantitative statistical analysis of data, and enables a more powerful analysis in comparison with the methods presently used. It is further demonstrated that the maximal dose effect and vascular responses vary between different protocols with the same total iontophoretic charge but with different current strengths and durations. This finding implies that the assumption that the local drug dose is linearly proportional to the iontophoretic charge (used for estimation of delivered drug dose to the microvascular bed) may be inaccurate for in vivo investigations and that there is need for a more refined model. It is also demonstrated that in a vasoconstrictive setting (iontophoresis of noradrenaline and phenylephrine) TiVi is the favourable technique for measuring vascular responses as it is sensitive enough to generate data that can be fitted to the Emax-model even without predilatation of the vessels. The results from this thesis may contribute to eventually establish transdermal iontophoresis as a widespread clinical tool for detection of vascular function.