Skin blood flow responses to the iontophoresis of acetylcholine and sodium nitroprusside in man: possible mechanisms.

Abstract

1. The mechanisms involved in the human skin blood flow responses to iontophoretic application of acetylcholine (ACh; delivered using an anodal charge) or sodium nitroprusside (SNP; administered with a cathodal charge) are unclear. The aims of this study were to investigate possible contributions of prostaglandin production to the increase in skin blood flow induced following the iontophoresis of ACh and to investigate possible contributions from local sensory nerves to the perfusion responses induced by ACh, SNP and their vehicles. 2. The contribution of prostaglandins to the ACh response was determined in a randomized double-blind study of eight healthy subjects, who were studied on two occasions. Basal responses to ACh were measured before the oral administration of 600 mg soluble aspirin in diluted orange juice (1 occasion) or orange juice (1 occasion) and again 30 min after the drink. The contribution of local sensory nerve activation to the responses to ACh and ACh vehicle (8 subjects) and and to SNP and SNP vehicle (7 subjects) was assessed. EMLA (5%) (a eutectic mixture of lignocaine and prilocaine) and placebo cream were applied to two separate areas on the forearm in a double-blind randomized manner 2 h before drug responses were measured. In all studies the skin microcirculation responses to iontophoretically applied drug vehicle (1 site) and drug (2 sites) were recorded by laser Doppler perfusion imaging. 3 The increase in forearm skin perfusion (P < 0 001) in response to the iontophoresis of ACh minus the response to ACh vehicle was not significantly different following placebo or aspirin administration. The increase in forearm skin red blood cell flux (P < 0 001) in response to the iontophoresis of ACh minus the response to ACh vehicle was not significantly different at the placebo-compared with the EMLA-treated site. The small increase in perfusion (P < 0 01) in response to the iontophoresis of ACh vehicle was significantly inhibited at the EMLA-compared with the placebo-treated site (P < 0 05). The marked increase in perfusion (P < 0 001) in response to the iontophoresis of SNP vehicle was significantly inhibited at the EMLA-compared with the placebo-treated site (P < 0 01). 4. These data suggest that in healthy volunteers: (1) mechanisms other than prostaglandin production and local sensory nerve activation may be involved in the increase in skin perfusion observed following the iontophoretic application of ACh; and (2) stimulation of local sensory nerves may be responsible for the increase in tissue perfusion observed following the iontophoretic application of either ACh vehicle or SNP vehicle.

Transdermal iontophoresis as an in-vivo technique for studying microvascular physiology

“…The nonspecific response at the cathode was found stronger than the response at the anode. Since then, a number of studies have investigated the nonspecific effect, and several explanations have been given (Table 1), including the involvement of prostaglandins (Berliner, 1997;Durand et al, 2004), and sensory nerve stimulation (Morris and Shore, 1996), particularly the axon reflex in primary afferent fibers (Tartas et al, 2005).…”

“…However, nonspecific vasodilatation is an important confounding factor when iontophoresis is used to study the microvasculature, because it introduces a blood flow effect that is not a result of the drug under study. Various strategies have therefore been applied to avoid nonspecific effects, including the use of local anesthetics (Morris and Shore, 1996), special vehicle solutions (Noon et al, 1998) and the limitation of current strength or total iontophoretic charge (Droog et al, 2004).…”

“…In the cutaneous microvasculature, vasodilatation in response to acetylcholine may be mediated by mechanisms other than NO, although the results are conflicting. Prostaglandins may (Khan et al, 1997;Lenasi and Strucl, 2008;Noon et al, 1998) or may not be involved (Berghoff et al, 2002;Morris and Shore, 1996). Also, it has been suggested that acetylcholine induces vasodilation through stimulation of sensory nerves (Berghoff et al, 2002).…”

“…Possible mechanism Evidence References membrane hyperpolarization pH changes difference between anodal and cathodal iontophoresis (Grossmann et al, 1995) (Droog and Sjoberg, 2003) (Asberg et al, 1999) (Ferrell et al, 2002) vasoactive substances in sweat ducts drugs travel primarily through sweat ducts (Morris and Shore, 1996) sensory nerves EMLA partially blocks the response (Morris and Shore, 1996) prostaglandins aspirin partially blocks the response (Berliner, 1997) (Durand et al, 2002) small primary afferent fibers capsaicin partially blocks the response (Durand et al, 2002) …”

Effect of dietary nitrate on blood pressure, endothelial function, and insulin sensitivity in type 2 diabetes

“…17 Much of this impairment may be due to the reduced bioavailability of NO. 18 Increasing the bioavailability of NO to reduce vascular tone and thus BP, and improve insulin sensitivity is an attractive therapeutic target in T2DM.Diets rich in green leafy vegetables lower the risk of cardiovascular disease. [19][20] A recent meta-analysis has shown that diets rich in green leafy vegetables reduce the risk of developing T2DM.…”