Correlation of Renal Tissue Oxygenation to Venous, Arterial, and Capillary Blood Gas Oxygen Saturation in Preterm Neonates.

OBJECTIVE: The aim of the study is to assess the correlation of renal regional tissue saturation of oxygen (RrSO2) measured by near-infrared spectroscopy (NIRS) in preterm neonates to venous oxygen saturation (SvO2) obtained from umbilical venous catheters (UVCs), arterial oxygen saturation (SaO2) obtained from umbilical artery catheters (UACs), and capillary oxygen saturation (ScO2) from capillary heel blood draws. STUDY DESIGN: A secondary analysis of a prospective RrSO2 monitoring study in preterm neonates born <32 weeks gestational age. Neonates with any blood gas obtained during RrSO2 monitoring were included. RrSO2 was compared with simultaneous O2 saturation using non-parametric Mann Whitney U-test and Spearman correlation coefficient. RESULTS: In 35 neonates, 25 UVC, 151 UAC, and 68 heel capillary specimens were obtained. RrSO2 was lower than the median SvO2 (58.8 vs. 78.9, p <0.01), SaO2 (51.0 vs. 93.2, p <0.01), and ScO2 (62.2 vs. 94.25, p <0.01). RrSO2 values correlated to both SaO2 and ScO2 (r = 0.32; p <0.01, r = 0.26; p = 0.03), but not SvO2 (r = 0.07; p = 0.74). CONCLUSION: In this secondary analysis, RrSO2 was consistently lower than blood gas O2 saturations and correlated with SaO2 and ScO2 but not SvO2. Lack of a correlation to SvO2 could be due to the small UVC sample size limiting statistical power. Future studies should prospectively evaluate if RrSO2 truly primarily reflects venous oxygenation in preterm neonates. KEY POINTS: · Renal oxygenation correlates with arterial and capillary oxygen saturation.. · Renal oxygenation did not correlate with venous oxygenation from umbilical venous catheters.. · Studies are needed to determine if renal oxygenation primarily reflects venous or arterial oxygen..

Characterization of Dual-Acting A3 Adenosine Receptor Positive Allosteric Modulators That Preferentially Enhance Adenosine-Induced Gαi3 and GαoA Isoprotein Activation.

The A3 adenosine receptor (A3AR) is a promising therapeutic target for inflammatory diseases, cancer, and chronic neuropathic pain, with agonists already in advanced clinical trials. Here we report an in-depth comparison of the pharmacological properties and structure-activity relationships of existing and expanded compound libraries of 2-substituted 1H-imidazo[4,5-c]quinolin-4-amine and 4-amino-substituted quinoline derivatives that function as A3AR positive allosteric modulators (PAMs). We also show that our lead compound from each series enhances adenosine-induced A3AR signaling preferentially toward activation of Gαi3 and GαoA isoproteins, which are coexpressed with the A3AR in immune cells and spinal cord neurons. Finally, utilizing an extracellular/intracellular chimeric A3AR approach composed of sequences from a responding (human) and a nonresponding (mouse) species, we provide evidence in support of the idea that the imidazoquinolin-4-amine class of PAMs variably interacts dually with the orthosteric ligand binding site as well as with a separate allosteric site located within the inner/intracellular regions of the receptor. This study has advanced both structural and pharmacological understanding of these two classes of A3AR PAMs, which includes leads for future pharmaceutical development.

Renal tissue oxygenation after caffeine administration in preterm neonates.

BACKGROUND: Caffeine has been associated with reduced rates of acute kidney injury (AKI) in preterm neonates. The effect of caffeine on preterm neonatal renal regional saturation of oxygen (RrSO2) is unknown. METHODS: RrSO2 was recorded continuously in neonates < 32 weeks' gestation until 7 days of age with INVOS™ neonatal near-infrared spectroscopy (NIRS) sensors. Baseline RrSO2 values were established by averaging the saturations in the 20 min prior to caffeine administration. Subgroup analysis was performed based on pre-caffeine RrSO2 averages. Change in RrSO2 was recorded at 0.5, 1, 2, 3, 4, 6, and 12 h after maintenance caffeine administration. RESULTS: Of 35 eligible neonates, 31 (median gestational age 28.4 weeks) received 156 caffeine doses (median 8 mg/kg). Analysis of combined doses showed no significant changes in RrSO2 after caffeine administration at any time. However, neonates with baseline 20-29.9% had significant increases from 1 to 12 h (range of increase 5.9-13.9%), and those with baseline 30-39.9 had significant increases at 1 h (8.06%, p < 0.05). CONCLUSIONS: Maintenance caffeine dosing increased RrSO2 in neonates with low RrSO2 in the first week. Further research is needed to determine the effect of loading doses of caffeine and if increases in RrSO2 correlate with improved clinical kidney outcomes. IMPACT: Caffeine administration is associated with increased renal tissue oxygenation in preterm neonates with low baseline values under 40%. The most significant renal tissue oxygenation changes occur in the first 3 h after IV caffeine administration. With recent studies suggesting low RrSO2 values in preterm neonates are associated with AKI, caffeine should be studied as a potential therapeutic for this common and complex morbidity in preterm neonates.

Design and in Vivo Characterization of A1 Adenosine Receptor Agonists in the Native Ribose and Conformationally Constrained (N)-Methanocarba Series.

(N)-Methanocarba ([3.1.0]bicyclohexyl) adenosines and corresponding ribosides were synthesized to identify novel A1 adenosine receptor (A1AR) agonists for CNS or peripheral applications. Human and mouse AR binding was determined to assess the constrained ring system's A1AR compatibility. N6-Dicyclobutylmethyl ribose agonist (9, MRS7469, >2000-fold selective for A1AR) and known truncated N6-dicyclopropylmethyl methanocarba 7 (MRS5474) were drug-like. The pure diastereoisomer of known riboside 4 displayed high hA1AR selectivity. Methanocarba modification reduced A1AR selectivity of N6-dicyclopropylmethyl and endo-norbornyladenosines but increased ribavirin selectivity. Most analogues tested (ip) were inactive or weak in inducing mouse hypothermia, despite mA1AR full agonism and variable mA3AR efficacy, but strong hypothermia by 9 depended on A1AR, which reflects CNS activity (determined using A1AR or A3AR null mice). Conserved hA1AR interactions were preserved in modeling of 9 and methanocarba equivalent 24 (∼400-fold A1AR-selective). Thus, we identified, and characterized in vivo, ribose and methanocarba nucleosides, including with A1AR-enhancing N6-dicyclobutylmethyl-adenine and 1,2,4-triazole-3-carboxamide (40, MRS7451) nucleobases.

Pituitary adenylate cyclase-activating polypeptide (PACAP) signaling in the prefrontal cortex modulates cued fear learning, but not spatial working memory, in female rats.

A genetic polymorphism within the gene encoding the pituitary adenylate cyclase- activating polypeptide (PACAP) receptor type I (PAC1R) has recently been associated with hyper-reactivity to threat-related cues in women, but not men, with post-traumatic stress disorder (PTSD). PACAP is a highly conserved peptide, whose role in mediating adaptive physiological stress responses is well established. Far less is understood about the contribution of PACAP signaling in emotional learning and memory, particularly the encoding of fear to discrete cues. Moreover, a neurobiological substrate that may account for the observed link between PAC1R and PTSD in women, but not men, has yet to be identified. Sex differences in PACAP signaling during emotional learning could provide novel targets for the treatment of PTSD. Here we investigated the contribution of PAC1R signaling within the prefrontal cortex to the acquisition of cued fear in female and male rats. We used a variant of fear conditioning called trace fear conditioning, which requires sustained attention to fear cues and depends on working-memory like neuronal activity within the prefrontal cortex. We found that cued fear learning, but not spatial working memory, was impaired by administration of a PAC1R antagonist directly into the prelimbic area of the prefrontal cortex. This effect was specific to females. We also found that levels of mRNA for the PAC1R receptor in the prelimbic cortex were greater in females compared with males, and were highest during and immediately following the proestrus stage of the estrous cycle. Together, these results demonstrate a sex-specific role of PAC1R signaling in learning about threat-related cues.