Ang-(1–7) activates the NO/cGMP and ATP-sensitive K+ channels pathway to induce peripheral antinociception in rats

Abstract

Angiotensin-(1–7) is a bioactive component of the renin–angiotensin system that is formed endogenously and induces nitric oxide release in several tissues. The l-arginine/NO/cyclic GMP pathway and ATP-sensitive K+ channels have been proposed as the mechanism of action for the peripheral antinociception of several groups of drug and endogenous substances, including opioids, non-steroidal analgesics, acetylcholine and others. The aim of the present study was to investigate the involvement of the l-arginine/NO/cGMP and KATP+ pathway on antinociception induced by angiotensin-(1–7). Paw pressure in rats was used to induce hyperalgesia via an intraplantar injection of prostaglandin E2 (2μg/paw). Ang-(1–7) (2, 3 and 4μg/paw) elicited a local peripheral antinociceptive effect that was antagonized by the nonselective NO synthase (NOS) inhibitor l-NOarg and the selective neuronal NOS (nNOS) inhibitor l-NPA. The selective inhibition of endothelial (eNOS) and inducible (iNOS) NOS by l-NIO and l-NIL, respectively, was ineffective at blocking the effects of a local Ang-(1–7) injection. In addition, the level of nitrite in the homogenized paw tissue, as determined by a colorimetric assay, indicated that exogenous Ang-(1–7) is able to induce NO release. The soluble guanylyl cyclase inhibitor ODQ and the specific blocker of ATP-sensitive K+ channels glibenclamide (40, 80 and 160μg/paw) antagonized the Ang-(1–7) response. The results provide evidence that Ang-(1–7) most likely induces peripheral antinociceptive effects via the l-arginine/NO/cGMP pathway and KATP+ pathway activation.