Inhibition of KATP channel activity augments baroreflex-mediated vasoconstriction in exercising human skeletal muscle

Contracting skeletal muscle produces vasodilatory metabolites which attenuate sympathetically mediated vasoconstriction. This phenomenon was first demonstrated in 1962 by Remensnyder et al. (1962) and was defined as functional sympatholysis. Since that time, a number of investigations have demonstrated functional sympatholysis in rats (Thomas et al. 1994, 1997), dogs (Buckwalter & Clifford, 1999; Ruble et al. 2002) and humans (Hansen et al. 2000a; Dinenno & Joyner, 2003; Wray et al. 2004b). Functional sympatholysis appears to provide a mechanism by which adequate perfusion of the active muscle can occur in the presence of sympathetic vasoconstriction in both active and inactive skeletal muscles and organs and, yet, systemic arterial blood pressure can be supported (Joyner & Thomas, 2003). However, the mechanism by which the contraction-induced modulation of sympathetic vasoconstriction becomes manifest remains obscure. Two prominent mechanisms for causing functional sympatholysis during exercise have been proposed. One involves the endogenous vasodilator nitric oxide (NO), while the other involves the ATP-sensitive potassium (KATP) channel (Hansen et al. 2000b). A body of evidence exists from animal experiments which strongly supports the role of NO as having a role in the phenomenon of functional sympatholysis (Thomas & Victor, 1998; Buckwalter et al. 2004). In contrast, human experiments indicate that NO is not obligatory as the primary mechanism underlying functional sympatholysis (Dinenno & Joyner, 2003). However, it has been shown that KATP channel activity is sensitive to a range of vasodilator metabolites, including NO (Nelson & Quayle, 1995), which may therefore be one of the factors contributing to the activation of the KATP channel in humans during muscle contraction. Activation of potassium channels, which are widely distributed in vascular smooth muscle (Nelson & Quayle, 1995), generally results in hyperpolarization and relaxation of vascular smooth muscle (Quast et al. 1994). Furthermore, it has been demonstrated that KATP channel activity is sensitive to changes in the concentrations of both intra- and extracellular factors such as ATP, nucleotide diphosphates, molecular oxygen (O2), hydrogen ions (H+), adenosine, prostacyclin and NO (Quayle & Standen, 1994; Nelson & Quayle, 1995). Thomas et al. (1997) investigated the possibility that the activation of KATP channels by some metabolic product of skeletal muscle contraction was a key mechanism by which sympathetic vasoconstriction, especially that mediated by the activation of α2 adrenoceptors, was attenuated in contracting skeletal muscle. From studies using anaesthetized rats, they reported that pharmacological activation of KATP channels via diazoxide administration attenuated sympathetic vasoconstriction in resting hindlimb in a dose-dependent manner (Thomas et al. 1997). Furthermore, they demonstrated that functional sympatholysis was sensitive to modulation by changes in the activity of the KATP channel and that contraction-induced sympatholysis was moderately prevented by the KATP channel blocker, glibenclamide (Thomas et al. 1997). Thus, contraction-induced activation of KATP channels appears to be a central mechanism underlying functional sympatholysis in the rat. However, the role of KATP channel activity in modulating sympatholysis in humans remains unknown. Recently, we have identified the effectiveness of functional sympatholysis during disengagement of the carotid baroreflex (CBR) using neck pressure (NP) and the resulting vasoconstrictor response of active skeletal muscle (Keller et al. 2003). Furthermore, in both animals (O'Leary et al. 1991; Collins et al. 2001) and in humans (Ogoh et al. 2003) the importance of baroreflex-mediated control of total vascular conductance in maintaining arterial blood pressure during exercise has been confirmed. However, whether the KATP channel plays a role in the functional sympatholysis observed in the baroreflex-mediated sympathetic vasoconstriction during exercise in humans (Keller et al. 2003) remains to be explored. Therefore, the current investigation was designed to examine the role of the KATP channel in modulating functional sympatholysis in humans. We hypothesize that KATP channel inhibition will restore CBR-mediated vasoconstriction in a vascular bed supplying exercising skeletal muscle. We addressed this hypothesis in humans performing one-legged knee extension exercise, using quantifiable NP stimulation of the carotid baroreceptors with and without ingestion of oral glyburide with the expectation of partially restoring sympathetically mediated vasoconstriction in the exercising leg.