ATP‐induced vasodilation in human skeletal muscle

Abstract

1 The purine nucleotide adenosine-5 0 -triphosphate (ATP) exerts pronounced effects on the cardiovascular system. The mechanism of action of the vasodilator response to ATP in humans has not been elucidated yet. The proposed endothelium-derived relaxing factors (EDRFs) were studied in a series of experiments, using the perfused forearm technique. 2 Adenosine 5 0 -triphosphate (0.2, 0.6, 6 and 20 nmol dl À1 forearm volume min À1 ) evoked a dosedependent forearm vasodilator response, which could not be inhibited by separate infusion of the nonselective COX inhibitor indomethacin (5 mg dl À1 min À1 , n ¼ 10), the blocker of Na þ /K þ -ATPase ouabain (0.2 mg dl À1 min À1 , n ¼ 8), the blocker of K Ca channels tetraethylammonium chloride (TEA, 0.1 mg dl À1 min À1 , n ¼ 10), nor by the K ATP -channel blocker glibenclamide (2 mg dl À1 min À1 , n ¼ 10). All blockers, except glibenclamide, caused a significant increase in baseline vascular tone. The obtained results might be due to compensatory actions of unblocked EDRFs. Combined infusion of TEA, indomethacin and L-NMMA (n ¼ 6) significantly increased the baseline forearm vascular resistance. The ATP-induced relative decreases in forearm vascular resistance were 4875, 6773, 8872, and 9272% in the absence and 2377, 6274, 8972, and 9371% in the presence of the combination of TEA, indomethacin and L-NMMA (Po0.05, repeated-measures ANOVA, n ¼ 6). A similar inhibition was obtained for sodium nitroprusside (SNP, Po0.05 repeated-measures ANOVA, n ¼ 6), indicating a nonspecific interaction due to the blocker-induced vasoconstriction. 3 ATP-induced vasodilation in the human forearm cannot be inhibited by separate infusion of indomethacin, ouabain, glibenclamide or TEA, or by a combined infusion of TEA, indomethacin, and L-NMMA. Endothelium-independent mechanisms and involvement of unblocked EDRFs, such as CO, might play a role, and call for further studies.

Vasodilatory responsiveness to adenosine triphosphate in ageing humans

“…The potential insight gained from our observations of preserved ATP responsiveness with age and the lack of effect of AA on this response in older adults points towards a NO‐independent vasodilator property of ATP. This is consistent with the majority of studies in humans (Rongen et al 1994; Shiramoto et al 1997; Hrafnkelsdottir et al 2001; van Ginneken et al 2004), and we believe highlights the need for future studies designed to further understand the mechanisms by which ATP evokes vasodilatation in humans.…”

“…With respect to ATP‐mediated vasodilatation, the underlying signalling mechanisms are at present unclear as some in vitro studies and one human study suggest a role for both NO and PGs (Burnstock, 1990; Hammer et al 2001; Mortensen et al . 2009), whereas a number of studies in humans (including unpublished observations from our laboratory) indicate that ATP evokes vasodilatation independent of NO and PGs (Rongen et al 1994; Shiramoto et al 1997; Hrafnkelsdottir et al 2001; van Ginneken et al 2004). Collectively, our observations of preserved vasodilatation to exogenous ATP which was unaffected by AA administration in older adults with endothelial dysfunction indirectly supports these previous studies, indicating a minor contribution of NO and PGs to ATP‐mediated vasodilatation in humans.…”

ATP‐mediated vasodilatation occurs via activation of inwardly rectifying potassium channels in humans

“…In this context, elevations in endothelial cell [Ca 2+ ] can increase the synthesis of nitric oxide (NO) and arachidonic acid metabolites such as vasodilating prostaglandins (PGs) and, consistent with this, some in vitro preparations have shown that these substances may contribute to the vasodilator action of ATP (Wihlborg et al 2003; Ellsworth et al 2009). In contrast, the majority of studies in humans indicate that NO and PGs are not the primary mediators and at best have only a modest role in the local dilatory response to intravascular ATP (Rongen et al 1994; van Ginneken et al 2004; Mortensen et al 2009; Crecelius et al 2011 a ). Thus, it appears that ATP‐mediated vasodilatation involves mechanisms beyond these traditional endothelial cell signalling pathways in humans.…”

“…In humans, intravascular ATP can cause profound vasodilatation and moreover may be important for vascular control in that it has the unique ability to limit sympathetically mediated vasoconstriction, similar to what occurs in contracting skeletal muscle (Kirby et al 2008). Thus, given the role of ATP in vasomotor control, there has been substantial interest in understanding the primary downstream signalling mechanisms underlying ATP‐mediated vasodilatation (Rongen et al 1994; van Ginneken et al 2004; Crecelius et al 2011 a ).…”

Purinergic Signaling and Blood Vessels in Health and Disease

“…In human contracting forearm and leg skeletal muscle, activation of ATP/UTPselective P2Y 2 receptors on endothelial cells increases blood flow and blunts sympathetic vasoconstriction elicited via P2X and a 1 receptors (Kirby et al, 2008;Rosenmeier et al, 2008;Mortensen et al, 2009b). ATP evokes vasodilation of human forearm skeletal microvessels (van Ginneken et al, 2004), but perhaps not via NO (Shiramoto et al, 1997).…”