The metabotropic glutamate receptor subtype 5 (mGluR5) has been reported to be implicated in various neurological disorders in the central nervous system. To investigate physiological and pathological functions of mGluR5, noninvasive imaging in a living body with PET technology and an mGluR5-specific radiotracer is urgently needed. Here, we report the synthesis of 3-[(18)F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([(18)F]FPEB) through a convenient thermal reaction as a highly specific PET radiotracer for mGluR5. The precursor and standard compounds were prepared by a coupling reaction catalyzed by palladium. Radiosynthesis of [(18)F]FPEB was performed using nitro as a leaving group replaced by [(18)F]fluoride under conventional heating condition. Biodistribution, metabolite, and microPET studies were performed using Sprague-Dawley rats. Upto 30 mCi of [(18)F]FPEB was obtained with a radiochemical yield of 5% and a specific activity of 1900 +/- 200 mCi/mumol at the end of syntheses. Biodistribution showed rapid clearance from the blood pool and fast and steady accumulation of radioactivity into the brain. Metabolite studies indicated that only 22% of [(18)F]FPEB remained in the blood system 10 min after administration, and that a metabolite existed which was much more polar than the parent tracer. MicroPET studies demonstrated that [(18)F]FPEB accumulated specifically in mGluR5-rich regions of the brain such as striatum and hippocampus, and that blockade with 2-methyl-6-(2-phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) substantially reduced the activity uptake in these regions. Selectivity was investigated by blockage with 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-caroxamide (YM-298198), a specific antagonist for mGluR1. [(18)F]FPEB was prepared conveniently and showed high specificity and selectivity toward mGluR5. It possesses the potential to be used in human studies to evaluate mGluR5 functions in various neurological disorders.

The intracellular messenger cyclic GMP (cGMP) represents the key signal in several transduction pathways throughout the animal world. In the heart cGMP signaling contributes to functional interaction of different cell types. Nitric oxide (NO) and natriuretic peptides (NPs), major autocrine-paracrine cardiovascular regulators, increment intracellular cGMP through guanylate cyclases (GCs). NO and NPs interact with two GC types: cytosolic (soluble: sGC) and membrane bound [particulate: pGC (NP receptor types A and B)], respectively. Depending on sub-cellular localization and regulation of the enzymes, cGMP produced by either pGC or sGC exerts different complementary effects. The two pathways are reciprocally regulated. NPs-depending pGC is modulated by NO-cGMP signaling, and the activity of NO is influenced by cellular concentrations of both NO itself and NPs. This heterologous feedback regulates GCs, linking cardiovascular autocrine-paracrine activities of NPs and NO. Importance of these cGMP converging routes goes far beyond their role under normal conditions. They are of relevance especially in disease states when tissue and circulating levels of NPs, and local NO production are altered. An example is the endothelial dysfunction associated with deficient NO production and uncoupled endothelium-myocardium communications. In this case, NPs-pGC-cGMP could supplement the reduced activity of NO-scGC-cGMP pathway. In addition, these systems regulate cell growth and apoptosis, playing a role in myocardial pathological morpho-functional remodeling. Here we will review recent concepts on NO/NPs dependent control of heart function in vertebrates, also focusing on cGMP-activated downstream signaling and its role in health and disease conditions.

Although an increased oxidative stress has been associated with several pathologies, predictive value of circulating oxidative stress biomarkers remains poorly understood. It has been demonstrated that several pathologies underestimated in women, including cardiovascular diseases, develop differently by gender. In this study, conducted on 195 healthy volunteers, we assessed the putative gender difference in prooxidant and antioxidant status. Our results were successful in demonstrating a significant difference in oxidative stress between sexes, whereas no difference was found in the plasma antioxidant barrier efficiency. To assess whether this difference was due to hormonal status (i.e. estrogen levels), female samples were divided into pre-menopausal and post-menopausal groups. No significant difference emerged for both biomarkers. Despite the well-known antioxidant estrogen role, women in this study presented a higher oxidative status than males. This suggests that there is a difference in the production and metabolic deactivation of reactive oxygen metabolite.

Taken together, our findings provide functional evidence for beta3-AR modulation of ventricular relaxation in the rat heart which involves PTx-sensitive inhibitory Gi protein and occurs via an NO-cGMP-PKG cascade. Whether the effects of beta3-AR stimulation on lusitropism are beneficial or detrimental remains to be established.

ACh exerted a biphasic effect in the in vitro working heart of Rana esculenta. High concentrations (10−7 M) of ACh depressed stroke volume (SV) and stroke work (SW) by ∼30% with a shorter systolic phase and reduced peak pressure. Doses from 10−10 M induced a positive response peaking at 10−8 M (SV: +8.6%; SW: +6.5%) and a prolonged systolic phase without affecting peak pressure. Atropine and pirenzepine blocked both the positive and the negative effects of ACh. Pretreatment with Triton X-100 (0.1 ml, 0.05%) or with nitric oxide (NO)-cGMP pathway antagonists ( N G-nitro-l-arginine, N G-nitro-l-arginine methyl ester, N G-monomethyl-l-arginine, and 1 H-[1,2,4]oxadiazolo-[4,3- a]quinoxalin-1-one) abolished the positive and negative cholinergic effects. Infusion of 8-bromoguanosine 3′,5′-cyclic monophosphate reverted the positive effect of ACh to a negative effect. Milrinone blocked the positive inotropism but did not change the negative cholinergic response. The NO donor 3-morpholinosydnonimine generated a biphasic dose-response curve with a maximum positive effect at 10−8 M (SV: +8%; SW: +5.6%; systolic phase: +28 ms) and a negative effect at 5 × 10−8 M (SV and SW: about −12%; systolic phase: −70 ms; peak pressure: −1.50 mm). We conclude that in the avascular frog heart the endocardial endothelium mediates the inotropic effect of luminal cholinergic stimuli via a NO-cGMP pathway.