Search

Electroacupuncture (EA) can be used to lower high blood pressure (BP) in clinical practice. However, precise mechanisms underlying its effects on elevated BP remain unclear. Our previous studies have shown that EA at the P5-6 acupoints, overlying the median nerve, attenuates elevated BP induced by gastric distension (GD) through influence on rostral ventrolateral medulla (rVLM). Although adenosine is released during neuronal activation in the rVLM, its role in acupuncture-cardiovascular regulation is unknown. The purinergic system is involved in cardiovascular pressor and depressor responses, including via selective activation of A1 and A2 a rVLM receptors, respectively. The action of A2 a receptor stimulation in the central nervous system may be further regulated through an endogenous opioid mechanism. However, it is uncertain whether this putative action occurs in the rVLM. We hypothesized that adenosine in the rVLM contributes to EA modulation of sympathoexcitatory reflexes through an A2 a but not an A1 adenosine receptor-opioid mechanism. EA or sham-EA was applied at the P5-6 acupoints in Sprague-Dawley male rats subjected to repeated GD under anesthesia. We found that EA (n = 6) but not sham-EA (n = 5) at P5-6 significantly (P < 0.05) attenuated GD-induced elevations in BP. EA modulation of sympathoexcitatory cardiovascular reflexes was reversed significantly after rVLM microinjection (50 nl) of 8-SPT (10 mM; non-selective adenosine receptor antagonist; n = 7) or SCH 58261 (1 mM; A2 a receptor antagonist; n = 8; both P < 0.05), but not by DPCPX (3 mM; A1 receptor antagonist; n = 6) or the vehicle (5% dimethylsulfoxide; n = 6). Moreover, microinjection of an A2 a receptor agonist, CGS-21680 (0.4 mM; n = 8) into the rVLM attenuated GD-induced pressor responses without EA, which mimicked EA's inhibitory effects (P < 0.05). After blockade of opioid receptors with naloxone (1 mM) in the rVLM, SCH 58261's reversal of EA's effect on GD-induced pressor responses was blunted, and CGS-21680-mediated inhibitory effect on pressor responses was not observed. Furthermore, neurons labeled with adenosine A2 a receptors were anatomically co-localized with neurons stained with enkephalin in the rVLM. These data suggest that the involvement of rVLM adenosine A2 a receptors in EA modulation of GD-induced pressor reflexes is, at least in part, dependent on the presence of endogenous opioids.

Background & Aims: During fibrosis hepatic stellate cells (HSC) undergo activation, proliferation and senescence but the regulation of these important processes is poorly understood. The adenosine A2A receptor (A2A) is known to be present on HSC, and its activation results in liver fibrosis. In this study, we tested if A2A has a role in the regulation of HSC proliferation, apoptosis, senescence, and the relevant molecular mechanism.Methods: The ability of adenosine to regulate p53 and Rb protein levels, proliferation, apoptosis and senescence was tested in the human HSC cell line LX-2 and rat primary HSC.Results: Adenosine receptor activation down-regulates p53 and Rb protein levels, increases BrdU incorporation and increases cell survival in LX-2 cells and in primary rat HSC. These effects of NECA were reproduced by an adenosine A2A receptor specific agonist (CGS21680) and blocked by a specific antagonist (ZM241385). By day twenty-one of culture primary rat HSC entered senescence and expressed -gal which was significantly inhibited by NECA. Furthermore, NECA induced down regulation of p53 and Rb and Rac1, and decreased phosphorylation of p44-42 MAP Kinase in LX-2 cells and primary rat HSC. These effects were reproduced by the cAMP analog 8-Bromo-cAMP, and the adenylyl cyclase activator forskolin, and were blocked by PKA inhibitors.Conclusions: These results demonstrate that A2A receptor regulates a number of HSC fate decisions and induces greater HSC proliferation, reduces apoptosis and senescence by decreasing p53 and Rb through cAMP-PKA/Rac1/p38 MAPK pathway. This provides a mechanism for adenosine induced HSC regulation and liver fibrosis.