PI3K/Akt-Independent NOS/HO Activation Accounts for the Facilitatory Effect of Nicotine on Acetylcholine Renal Vasodilations: Modulation by Ovarian Hormones

Abstract

We investigated the effect of chronic nicotine on cholinergically-mediated renal vasodilations in female rats and its modulation by the nitric oxide synthase (NOS)/heme oxygenase (HO) pathways. Dose-vasodilatory response curves of acetylcholine (0.01–2.43 nmol) were established in isolated phenylephrine-preconstricted perfused kidneys obtained from rats treated with or without nicotine (0.5–4.0 mg/kg/day, 2 weeks). Acetylcholine vasodilations were potentiated by low nicotine doses (0.5 and 1 mg/kg/day) in contrast to no effect for higher doses (2 and 4 mg/kg/day). The facilitatory effect of nicotine was acetylcholine specific because it was not observed with other vasodilators such as 5′-N-ethylcarboxamidoadenosine (NECA, adenosine receptor agonist) or papaverine. Increases in NOS and HO-1 activities appear to mediate the nicotine-evoked enhancement of acetylcholine vasodilation because the latter was compromised after pharmacologic inhibition of NOS (L-NAME) or HO-1 (zinc protoporphyrin, ZnPP). The renal protein expression of phosphorylated Akt was not affected by nicotine. We also show that the presence of the two ovarian hormones is necessary for the nicotine augmentation of acetylcholine vasodilations to manifest because nicotine facilitation was lost in kidneys of ovariectomized (OVX) and restored after combined, but not individual, supplementation with medroxyprogesterone acetate (MPA) and estrogen (E2). Together, the data suggests that chronic nicotine potentiates acetylcholine renal vasodilation in female rats via, at least partly, Akt-independent HO-1 upregulation. The facilitatory effect of nicotine is dose dependent and requires the presence of the two ovarian hormones.

Ovarian hormones modulate endothelin A and B receptor expression

“…Thus it is apparent that the E 2 and P work co-operatively to modulate inner medullary ET A and ET B receptor expression, because individual supplementation of each hormone was less effective in restoring receptor expression. This is consistent with previous studies reporting synergism between of E 2 and P on renovascular tone control [10]. Overall, this work provides evidence that the ET-1 system is highly influenced by the sexhormonal status in females.…”

Punicalagin Induces Nrf2/HO‐1 Expression via Upregulation of PI3K/AKT Pathway and Inhibits LPS‐Induced Oxidative Stress in RAW264.7 Macrophages

“…NO is another important molecule regulated by the Nrf2-mediated pathway, whose excessive generation has been shown to result in oxidative stress and inflammation during an LPS challenge [ 37 , 47 ]. Previous studies have indicated that the PI3K/Akt pathway is a potential target of medicines that exhibit an NO inhibition effect in LPS-induced macrophages [ 48 , 49 ]. Hence, we investigated whether PI3K/Akt signaling also modulates the inhibition property of PUN on NO generation in macrophages.…”

The renin-angiotensin system modulates endotoxic postconditioning of exacerbated renal vasoconstriction in preeclamptic offspring

“…The procedure described in our previous studies 19 , 76 , 77 has been used to assess the renal vasoconstrictor responsiveness to Ang II and phenylephrine. After the induction of anesthesia with i.p.…”

“…The rat isolated perfused kidney. The procedure described in our previous studies 19,76,77 has been used…”