Adenosine receptor inhibition with theophylline attenuates the skin blood flow response to local heating in humans

Abstract

Mechanisms underlying the robust cutaneous vasodilatation in response to local heating of human skin remain unresolved. Adenosine receptor activation has been shown to induce vasodilatation via nitric oxide, and a substantial portion of the plateau phase to local heating of human skin has been shown to be dependent on nitric oxide. The purpose of this study was to investigate a potential role for adenosine receptor activation in cutaneous thermal hyperaemia in humans. Six subjects were equipped with four microdialysis fibres on the ventral forearm. Sites were randomly assigned to receive one of the following four treatments: (1) lactated Ringer solution to serve as a control; (2) 4 mm theophylline, a competitive, non-selective A 1 /A 2 adenosine receptor antagonist; (3) 10 mm N ω -nitro-l-arginine methyl ester (l-NAME) to inhibit NO synthase; or (4) combined 4 mm theophylline + 10 mm l-NAME. Following baseline measurements, each site was locally heated from a baseline temperature of 33• C to 42• C at a rate of 1 • C (10 s) −1 , and skin blood flow was monitored via laser-Doppler flowmetry (LDF). Cutaneous vascular conductance (CVC) was calculated as LDF divided by mean arterial pressure and normalized to maximal values (CVC max ) via local heating to 43• C and infusion of 28 mm sodium nitroprusside. The initial peak was significantly reduced in theophylline (68 ± 2% CVC max ) and l-NAME sites (54 ± 5% CVC max ) compared with control sites (81 ± 2% CVC max ; P < 0.01 and P < 0.001, respectively). Combined theophylline + l-NAME (52 ± 5% CVC max ) reduced the initial peak compared with control and theophylline sites, but was not significantly different compared with l-NAME sites. The secondary plateau was attenuated in theophylline (77 ± 2% CVC max ), l-NAME (60 ± 2% CVC max ) and theophylline + l-NAME (53 ± 1% CVC max ) compared with control sites (94 ± 2% CVC max ; P < 0.001 for all conditions). The secondary plateau was reduced in l-NAME compared with theophylline sites (P < 0.001), and combined theophylline + l-NAME further reduced the secondary plateau compared with theophylline-(P < 0.001) and l-NAME-only sites (P < 0.05). These data suggest that adenosine receptor activation directly contributes to cutaneous thermal hyperaemia, as evidenced by the reduced initial peak and secondary plateau in theophylline sites. These data further suggest that a portion of the NO response may be explained by adenosine receptor activation; however, a substantial portion of the NO response is independent of adenosine receptor activation.

Adenosine receptor inhibition attenuates the decrease in cutaneous vascular conductance during whole‐body cooling from hyperthermia

“…Although occurring at larger doses, Fieger & Wong (2010) mentioned a 'nonspecific vasodilatation' following the administration of theophylline. No significant differences were observed in the subsequent relative decreases of CVC during the first cooling period.…”

“…The theophylline concentration used was based on that reported by Fieger & Wong (2010, 2012, while that for L-NAME was chosen based on previous studies (Minson et al 2001;Fieger & Wong, 2010). Infusions were maintained for a 45 min period to ensure the establishment of each blockade (Minson et al 2001;Fieger & Wong, 2010).…”

“…Although the role of adenosine has been examined in other tissues of the human body, there is relatively little known about its influence on cutaneous blood flow. Recent studies have examined the contribution of adenosine to vasodilatation induced by local (Fieger & Wong, 2010) and whole-body heating (Fieger & Wong, 2012). Although these studies showed a contribution of adenosine during local heating, no direct contribution was observed during whole-body heating.…”

Retrodialysis: A Review of Experimental and Clinical Applications of Reverse Microdialysis in the Skin

“…The data of these researchers suggested that adenosine receptor activation directly contributes to cutaneous thermal hyperemia and that a portion of the NO response may be explained by adenosine receptor activation. However, a substantial portion of the NO response is independent of adenosine receptor activation [77]. Additionally, neurokinin-1 receptors contribute to both the axon reflex component and the secondary plateau phase of cutaneous thermal hyperemia [78].…”

“…Fieger and Wong [77] investigated the potential role of adenosine receptor activation in cutaneous thermal hyperemia because adenosine receptor activation induces vasodilatation via NO and because a substantial portion of the plateau phase of local heating of human skin depends on NO. The data of these researchers suggested that adenosine receptor activation directly contributes to cutaneous thermal hyperemia and that a portion of the NO response may be explained by adenosine receptor activation.…”