STUDIES WITH IONTOPHORETIC ADMINISTRATION OF DRUGS TO HUMAN DERMAL VESSELS IN-VIVO - CHOLINERGIC VASODILATATION IS MEDIATED BY DILATOR PROSTANOIDS RATHER THAN NITRIC-OXIDE

Aims Impaired function of the vascular endothelium has been well docum ented in hypertension and hypercholesterolaemia. However, the 'gold st andard' method for assessing endothelial function, using intra-arteria l drug infusion, is invasive and has only been applied in the forearm and coronary circulations in vivo. The aim of the present study was to establish the non-invasive technique of transdermal drug iontophoresi s to assess endothelial function in human dermal vessels in vivo. Meth ods In healthy male volunteers, we delivered acetylcholine (ACh) and s odium nitroprusside (SNP) to dermal vessels of the forearm using ionto phoresis, and measured vasodilatation using laser Doppler fluximetry. Drugs were diluted in a methylcellulose gel vehicle which did not indu ce vasodilatation. To assess the contribution of nitric oxide and vaso active prostanoids to cholinergic dilatation, the procedure was repeat ed during brachial artery infusion of the nitric oxide synthase inhibi tor, L-N-G-monomethyl-arginine (L-NMMA) and after intravenous administ ration of the cyclooxygenase inhibitor, aspirin. As a control for the vasoconstrictor effect of L-NMMA, which was measured by venous occlusi on plethysmography, iontophoresis was repeated during brachial artery infusion of noradrenaline. Results Flux increased in response to ionto phoresis of ACh (from 45 +/- 9 to 499 +/- 80 units; P<0.0001) and SNP (from 32+/-11 to 607+/-82 units; P<0.0001). Brachial artery infusions of L-NMMA or noradrenaline caused reductions in forearm blood flow (by 43+/-2% and 44+/-2%, respectively) but did not inhibit vasodilatation in response to iontophoresis of ACh or SNP. In contrast, aspirin inhi bited the response to iontophoresis of ACh (from 473+/-81 to 222+/-43 units; P<0.0001) but did not affect the response to SNP (from 348+/-59 to 355+/-58). Conclusions We conclude that in healthy subjects, in co ntrast to the forearm circulation, dermal vasodilatation in response t o iontophoresis of ACh is mediated predominately by a dilator prostano id rather than by nitric oxide generation. Furthermore, the non-invasi ve technique of iontophoresis could complement existing invasive tests of endothelial function in future clinical studies.