Cyclic AMP (cAMP) is well known to enhance tyrosine hydroxylase activity in PC12 cells. We were able to demonstrate, however, that the cellular dopamine level in PC12 was lowered by dibutyryl cAMP. Furthermore, the decrease in the cellular level of dopamine was accompanied by about a 10‐fold increase in the medium. The aim of this work was to elucidate the effect of cAMP on catecholamine transport. Dibutyryl cAMP did not induce exocytotic release of norepinephrine but rather inhibited its uptake. As with forskolin and cholera toxin, physiological signaling molecules such as vasoactive intestinal polypeptide (VIP) and AMP, for which PC12 cells are known to have receptors linked to activation of adenylate cyclase, also inhibited norepinephrine uptake. The inhibitory effects of dibutyryl cAMP, VIP, and AMP were dose dependent, and EC50 values were estimated to be 100 µM, 10 nM, and 1.0 µM, respectively. The inhibition profile of dibutyryl cAMP over the time course of norepinephrine uptake was biphasic: Inhibition became clearly detectable after the cytosolic pool of norepinephrine had been saturated. This profile is similar to that of reserpine. Nomifensine, however, inhibited uptake at a rather constant rate throughout the entire time course. The ATP‐dependent serotonin uptake by digitonin‐permeabilized cells was lowered to ∼50% that of the control by dibutyryl cAMP treatment before permeabilization, indicating inhibition of vesicular monoamine transport. This effect was also dependent on a dibutyryl cAMP concentration with an EC50 of ≤100 µM. These results suggest that cAMP may be capable of elevating extracellular dopamine levels in the nervous system by inhibiting its translocation into storage vesicles while enhancing its synthesis in the cytosol. Moreover, endogenous neurotransmitters such as VIP, AMP, and adenosine may act as intrinsic antidepressants via the cAMP pathway.

Aims/Introduction To evaluate the benefit of sodium–glucose cotransporter 2 inhibitors (SGLT2i) versus dipeptidyl peptidase‐4 inhibitors (DPP4i) in reducing cardiovascular disease (CVD) events in patients with type 2 diabetes mellitus with and without a CVD history. Materials and Methods This retrospective cohort study used Japanese hospital administrative data from the Medical Data Vision database (January 2015 to April 2020). Patients with type 2 diabetes mellitus ( n = 625,739) who were new users of an SGLT2i ( n = 57,070; 9.1%) or DPP4i ( n = 568,669; 90.9%) were included. Outcomes included hospitalization for heart failure (hHF), all‐cause death (ACD) and the composite of hHF or ACD. Hazard ratios (HR) were calculated using the inverse probability weighting Cox proportional hazards model to compare CVD event risks between treatment groups. Results Compared with DPP4i, SGLT2i was associated with a significant reduction in hHF risk among patients without a CVD history (HR 0.507, 95% confidence interval 0.283–0.907), but not in the full cohort or those with a CVD history. SGLT2i was associated with a significant risk reduction of ACD (HR 0.592, 95% confidence interval 0.481–0.729) and the composite of hHF or ACD (HR 0.712, 95% confidence interval 0.613–0.826), compared with DPP4i in the full cohort; similar results were observed among patients with and without a CVD history. Conclusions In this real‐world study, SGLT2i versus DPP4i was associated with a significant reduction in hHF, ACD and hHF or ACD events in patients with type 2 diabetes mellitus without a CVD history.

Background Anemia status may be transient. Causal associations between changes in anemia status over time and adverse outcome development are not well characterized in community-dwelling subjects at the beginning of impaired kidney function. Methods This retrospective cohort study used annual health checkup and medical and pharmacy claims data from the JMDC between January 2005 and June 2019. Community-dwelling subjects in Japan with a pre-index estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 followed by a subsequent eGFR < 60 mL/min/1.73 m2 (index) were included. The composite renal outcome was ≥ 30% eGFR reduction over 3 years from baseline, serum creatinine doubling, progression to chronic dialysis, kidney transplantation, or eGFR < 15 mL/min/1.73 m2. The composite cardiovascular outcome was fatal and non-fatal unstable angina, myocardial infarction, heart failure, or cerebrovascular event. Time-dependent anemia risk was evaluated using Breslow’s estimator and marginal structural Cox models (MSM). Results In 32,870 included subjects, 1,396 had anemia at baseline. Adverse outcome incidence was higher in the baseline anemic group, but absolute differences in renal and cardiovascular outcomes between groups were diminished after adjusting for baseline characteristics. In MSM, time-dependent anemia status was associated with higher risk of renal (hazard ratio [95% confidence interval]; 2.6 [1.7–3.8]) and cardiovascular (1.6 [1.2–2.2]) outcomes and mortality (2.8 [1.8–4.3]). Absolute differences in survival probabilities were retained over time but were clinically marginal (1.1–2.7% over 6 years). Conclusions Even in subjects at the very early stage of impaired kidney function, early detection and treatment of anemia may help reduce the development of negative sequelae.

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