ATP Released in Response to Angiotensin II Contributes to Vasoconstriction in the Rat Mesenteric Arterial Bed in a Sex‐dependent Manner

Abstract

While vascular tone is affected by multiple mediators released from various component tissues, it has been a long-held belief that the mechanical act of vascular smooth muscle contraction induces ATP release regardless of the stimulus that initiated vasoconstriction. Contrary to this theory, here we present evidence that the release of ATP by vascular smooth muscle is both agonist- and sex-dependent. By utilizing a near-real time luminometric technique developed by our lab, we found that while methoxamine, 5-hydroxytryptamine, and angiotensin II all induced vasoconstriction in the rat mesenteric arterial bed, only angiotensin II caused ATP release. Furthermore, this response was only seen in preparations from male rats, whereas those from female rats showed no ATP release in response to any of the three vasoactive agents tested, indicating a sex difference in this process. When we further investigated the ATP release and perfusion pressure responses to angiotensin II, we found that both were inhibited by losartan, indicating the involvement of AT1 receptors. The nonselective P2 antagonist suramin blocked a significant portion of angiotensin II-stimulated vasoconstriction, suggesting that the action of ATP on P2 receptors may play a critical role in the ability of angiotensin II to cause vasoconstriction. A similar response was seen when angiotensin II was perfused along with NF449, a selective inhibitor of the P2X1 receptor. Angiotensin II-induced ATP release was inhibited by carbenoxolone, a nonspecific gap junction blocker which is known to inhibit pannexin-1 channels, suggesting that this may be the conduit through which this release occurs. Taken together, our findings suggest that activation of vascular AT1 receptors by angiotensin II directly constricts smooth muscle while simultaneously opening carbenoxolone-sensitive channels allowing ATP to be released. This ATP then activates vascular P2X1 receptors, augmenting the AT1-induced vasoconstriction. This process occurs in the mesenteric arterial bed taken from male, but not female, rats.