2014 Aug 6. pii: jpet.114.216036. [Epub ahead of print]
Neuronal Nitric Oxide Synthase Dependent Elevation in Adiponectin in the Rostral Ventrolateral Medulla Underlies GPR18-mediated Hypotension in Conscious Rats.
Abstract
Direct activation (abnormal cannabidiol; Abn CBD) of the endocannabinoid receptor GPR18 in the rostral ventrolateral medulla (RVLM) of conscious rats elevates local nitric oxide (NO) and adiponectin (ADN) levels and reduces oxidative stress and blood pressure (BP). However, the molecular mechanisms for GPR18-mediated neurochemical responses, including the NOS isoform that generates NO, and their potential causal link to the BP reduction are not known. We hypothesized that GPR18-mediated enhancement of Akt-ERK1/2-nNOS phosphorylation, triggered by a reduction in cAMP, accounts for the NO/ADN-dependent reductions in RVLM oxidative stress and BP. Intra-RVLM GPR18 activation (Abn CBD; 0.4 μg) enhanced RVLM Akt, ERK1/2 and nNOS phosphorylation and ADN level, during the hypotensive response, and prior GPR18 blockade (O-1918) produced the opposite effects, and abrogated Abn CBD-evoked neurochemical and BP responses. Pharmacological inhibition of RVLM PI3K/Akt (wortmannin), ERK1/2 (PD98059) or nNOS (Nω-propyl-L-arginine, NPLA) or activation of adenylyl cyclase (forskolin) virtually abolished the intra-RVLM Abn CBD-evoked hypotension, and the increases in Akt, ERK1/2 and nNOS phosphorylation, and in ADN levels in the RVLM. Our pharmacological and neurochemical findings support pivotal role for the PI3K/Akt-ERK1/2-nNOS and adenylyl cyclase, via modulation of NO, ADN and cAMP levels, in GPR18 regulation of RVLM redox state and BP in conscious rats.
The American Society for Pharmacology and Experimental Therapeutics.
The American Society for Pharmacology and Experimental Therapeutics.
KEYWORDS:
ERK; MAP kinases; blood pressure; cAMP; cannabinoid receptors; nitric oxide; nitric oxide synthase; oxidative stress
- PMID:
25100751
[PubMed – as supplied by publisher]
