Abstract 17612: Central GPR18 Mediates Hypotension via Enhanced PI3K/AKT-ERK1/2-nNOS Signaling and Inhibition of cAMP in the Rostral Ventrolateral Medulla of Conscious Normotensive Rats
Background and objectives: Our previous studies were the first to demonstrate the anatomical expression of GPR18 in tyrosine hydroxylase-immunoreactive neurons in the rostral ventrolateral medulla (RVLM), and to suggest important function for RVLM GPR18 in blood pressure regulation. The latter is supported by the dose-related reductions and elevations in blood pressure (BP) caused by the GPR18 activation by abnormal cannabidiol (Abn CBD) and blockade by O-1918, respectively, in conscious rats. However, the molecular mechanisms for GPR18 restraining influence on BP is not fully understood. In the present study, we tested the hypothesis that activation of RVLM PI3K/AKT-ERK1/2-nNOS network and inhibition of cAMP play a causal role in GPR18 mediated hypotension. Male SD rats (n=5 rats/treatment) received intra-RVLM Abn CBD (0.4 ug/animal) or its vehicle following local selective inhibition of (a) PI3K/AKT phosphorylation (wortmannin), (b) ERK1/2 phosphorylation (PD98059), (c),eNOS (N5-[1-Iminoethyl]-L-ornithine; L-NIO), or (d) nNOS (Nω-propyl-L-arginine; NPLA). Additional experiment was conducted following enhanced cAMP generation (forskolin). At the conclusion of BP measurements, the microinjected and contralateral (control) RVLM were collected for conducting the ex vivo neurochemical studies.
Key results: The hypotensive response produced by intra-RVLM Abn CBD (-19± 4 mmHg) was virtually abolished following pretreatment with wortmannin (3± 3 mmHg), PD98059 (-2± 2 mmHg), forskolin (-2± 1 mmHg) or NPLA (-1± 1 mmHg) but not following L-NIO (-14± 1 mmHg). Molecular and neurochemical studies on RVLM tissues collected from treated and control animals are underway.
Conclusions: Our integrative pharmacological studies suggest a pivotal role for the activation of the RVLM PI3K/AKT-ERK1/2-nNOS and inhibition of cAMP signaling in GPR18-mediated sympathoinhibition/hypotension in conscious rats.
- © 2013 by American Heart Association, Inc.