No independent, but an interactive, role of calcium-activated potassium channels in human cutaneous active vasodilation

Abstract

In human cutaneous microvasculature, endothelium-derived hyperpolarizing factors (EDHFs) account for a large portion of vasodilation associated with local stimuli. Thus we sought to determine the role of EDHFs in active vasodilation (AVD) to passive heating in two protocols. Whole body heating was achieved using water-perfused suits (core temperature increase of 0.8-1.0°C), and skin blood flow was measured using laser-Doppler flowmetry. In the first protocol, four sites were perfused continuously via microdialysis with: 1) control; 2) tetraethylammonium (TEA) to block calcium-activated potassium (KCa) channels, and thus the actions of EDHFs; 3) N-nitro-l-arginine methyl ester (l-NAME) to inhibit nitric oxide synthase (NOS); and 4) TEA + l-NAME (n = 8). Data are presented as percent maximal cutaneous vascular conductance (CVC). TEA had no effect on AVD (CVC during heated plateau: control 57.4 ± 4.9% vs. TEA 63.2 ± 5.2%, P = 0.27), indicating EDHFs are not obligatory. l-NAME attenuated plateau CVC to 33.7 ± 5.4% (P < 0.01 vs. control); while TEA + l-NAME augmented plateau CVC compared with l-NAME alone (49.7 ± 5.3%, P = 0.02). From these data, it appears combined blockade of EDHFs and NOS necessitates dilation through other means, possibly through inward rectifier (KIR) and/or ATP-sensitive (KATP) potassium channels. To test this second hypothesis, we measured AVD at the following sites (n = 8): 1) control, 2) l-NAME, 3) l-NAME + TEA, and 4) l-NAME + TEA + barium chloride (BaCl2; KIR and KATP blocker). The addition of BaCl2 to l-NAME + TEA reduced plateau CVC to 32.7 ± 6.6% (P = 0.02 vs. l-NAME + TEA), which did not differ from the l-NAME site. These data combined demonstrate a complex interplay between vasodilatory pathways, with cross-talk between NO, KCa channels, and KIR and/or KATP channels.

Keywords: endothelium-derived hyperpolarizing factors; inward rectifier potassium channels; nitric oxide; thermoregulation; whole body heating.

Fig. 1.

A: response of cutaneous vascular conductance (CVC) to passive heating relative to the rise in oral temperature (ΔT_or) for protocol 1. Infusion of tetraethylammonium (TEA) had no effect on the CVC response compared with the control site, whereas infusion with N-nitro-l-arginine methyl ester (l-NAME) attenuated CVC. Combined infusion of TEA + l-NAME augmented the response compared with the l-NAME site. *P < 0.05 from the control site; †P < 0.05 from the TEA site; ‡P < 0.05 from the l-NAME site. B: response of CVC relative to ΔT_or for protocol 2. The addition of barium chloride (BaCl₂) to l-NAME + TEA attenuated CVC compared with the l-NAME + TEA, back to the level of the l-NAME alone site. *P < 0.05 from the control site; †P < 0.05 from the l-NAME site; ‡P < 0.05 from the l-NAME + TEA site. C: rise in mean skin temperature (T_sk) relative to changes in ΔT_or, averaged across subjects in protocols 1 and 2. Data are presented as means ± SE of %CVC_max.

Fig. 2.

The plateau in CVC observed at the end of heat stress for protocols 1 and 2. Heat stress resulted in rise in core temperature ranging from 0.8 to 1.0°C. Drugs include tetraethylammonium (TEA), N-nitro-l-arginine methyl ester (l-NAME), and barium chloride (BaCl₂). The dotted line represents the average plateau CVC for the control site between the two protocols. Data are presented as means ± SE of %CVCmax. *P < 0.05 from the control site within each protocol; †P < 0.05 between drug sites within each protocol.