Studies with iontophoretic administration of drugs to human dermal vessels in vivo: cholinergic vasodilatation is mediated by dilator prostanoids rather than nitric oxide.
OBJECTIVE
Impaired function of the vascular endothelium has been well documented in hypertension and hypercholesterolaemia. However, the 'gold standard' method for assessing endothelial function, using intra-arterial 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 iontophoresis to assess endothelial function in human dermal vessels in vivo.


METHODS
In healthy male volunteers, we delivered acetylcholine (ACh) and sodium nitroprusside (SNP) to dermal vessels of the forearm using iontophoresis, and measured vasodilatation using laser Doppler fluximetry. Drugs were diluted in a methylcellulose gel vehicle which did not induce vasodilatation. To assess the contribution of nitric oxide and vasoactive prostanoids to cholinergic dilatation, the procedure was repeated during brachial artery infusion of the nitric oxide synthase inhibitor, L-N(G)-monomethyl-arginine (L-NMMA) and after intravenous administration of the cyclooxygenase inhibitor, aspirin. As a control for the vasoconstrictor effect of L-NMMA, which was measured by venous occlusion plethysmography, iontophoresis was repeated during brachial artery infusion of noradrenaline.


RESULTS
Flux increased in response to iontophoresis 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 inhibited 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 contrast to the forearm circulation, dermal vasodilatation in response to iontophoresis of ACh is mediated predominately by a dilator prostanoid rather than by nitric oxide generation. Furthermore, the non-invasive technique of iontophoresis could complement existing invasive tests of endothelial function in future clinical studies.
Noon
J P
JP
Department of Medicine, University of Edinburgh, Western General Hospital, UK.
Walker
B R
BR
Hand
M F
MF
Webb
D J
DJ
D000109:Acetylcholine / Q000008:administration & dosage* / Q000494:pharmacology; D000328:Adult; D001241:Aspirin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007478:Iontophoresis; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D009599:Nitroprusside / Q000008:administration & dosage / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D011453:Prostaglandins / Q000502:physiology*; D012867:Skin / Q000098:blood supply* / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D011453:Prostaglandins; D014662:Vasoconstrictor Agents; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D000109:Acetylcholine; D001241:Aspirin; D009638:Norepinephrine