Effect of gabapentin on ambulatory, direct, systemic arterial blood pressure in apparently healthy cats in the at-home and in-clinic environments.

OBJECTIVES: Situational increases in blood pressure (BP) frequently confound the accurate diagnosis of pathological systemic hypertension in cats. The objective of this study was to investigate the effect of gabapentin on direct, ambulatory systolic arterial BP (SBP) in cats in at-home and in-clinic environments. METHODS: Six adult purpose-bred cats with surgically implanted femoral artery telemetric BP-sensing catheters were administered 100 mg of gabapentin or a placebo orally in two randomized, masked, crossover study phases. In the first, direct BP was measured continuously in undisturbed cats for 24 h before (at-home baseline) and 4 h after administration of study drug. The mean SBP after administration of the drug was compared between treatments. In the second study period, cats were administered gabapentin or placebo 90 mins before transport to a clinic, where direct BP was measured continuously during a simulated veterinary visit that included an indirect BP measurement session. Changes in mean direct SBP relative to the 24-h at-home pre-treatment period were calculated for each of one waiting room and two examination-room periods, and compared between treatments. Concurrent in-clinic direct and indirect SBP measurements were compared within-cat. Data were compared using linear mixed models. RESULTS: Direct SBP data from one cat were excluded due to implant failure. There were no differences in at-home or in-clinic SBP between treatment groups, with large inter-individual variability. Cats in both treatment groups experienced in-clinic increases in direct SBP relative to at-home baseline (range 11-50 and 10-52 mmHg in placebo- and gabapentin-treated cats, respectively). Across all visits, direct SBP was 15.6 mmHg higher than indirect SBP (P <0.001). No effects of treatment on difference between direct and indirect SBP were identified. CONCLUSIONS AND RELEVANCE: Significant effects of gabapentin on direct SBP were not identified, though a type II error is possible. Situational increases cannot be excluded in gabapentin-treated cats with high SBP.

Lung megakaryocytes are immune modulatory cells.

Although platelets are the cellular mediators of thrombosis, they are also immune cells. Platelets interact both directly and indirectly with immune cells, impacting their activation and differentiation, as well as all phases of the immune response. Megakaryocytes (Mks) are the cell source of circulating platelets, and until recently Mks were typically only considered bone marrow-resident (BM-resident) cells. However, platelet-producing Mks also reside in the lung, and lung Mks express greater levels of immune molecules compared with BM Mks. We therefore sought to define the immune functions of lung Mks. Using single-cell RNA sequencing of BM and lung myeloid-enriched cells, we found that lung Mks, which we term MkL, had gene expression patterns that are similar to antigen-presenting cells. This was confirmed using imaging and conventional flow cytometry. The immune phenotype of Mks was plastic and driven by the tissue immune environment, as evidenced by BM Mks having an MkL-like phenotype under the influence of pathogen receptor challenge and lung-associated immune molecules, such as IL-33. Our in vitro and in vivo assays demonstrated that MkL internalized and processed both antigenic proteins and bacterial pathogens. Furthermore, MkL induced CD4+ T cell activation in an MHC II-dependent manner both in vitro and in vivo. These data indicated that MkL had key immune regulatory roles dictated in part by the tissue environment.

Platelet-derived ß2m regulates age related monocyte/macrophage functions.

Platelets have central roles in both immune responses and development. Stimulated platelets express leukocyte adhesion molecules and release numerous immune modulatory factors that recruit and activate leukocytes, both at the sites of activation and distantly. Monocytes are innate immune cells with dynamic immune modulatory functions that change during the aging process, a phenomenon termed "inflammaging". We have previously shown that platelets are a major source of plasma beta-2 microglobulin (ß2M) and that ß2M induced a monocyte pro-inflammatory phenotype. Plasma ß2M increases with age and is a pro-aging factor. We hypothesized that platelet derived ß2M regulates monocyte phenotypes in the context of aging. Using wild-type (WT) and platelet specific ß2M knockout mice (Plt-ß2M-/-) mice, we found that plasma ß2M increased with age and correlated with increased circulating Ly6CHi monocytes. However, aged Plt-ß2M-/- mice had significantly fewer Ly6CHi monocytes compared to WT mice. Quantitative real-time PCR of circulating monocytes showed that WT mouse monocytes were more "pro-inflammatory" with age, while Plt-ß2M-/- derived monocytes adopted a "pro-reparative" phenotype. Older Plt-ß2M-/- mice had a significant decline in heart function compared to age matched WT mice, as well as increased cardiac fibrosis and pro-fibrotic markers. These data suggest that platelet-derived ß2M regulates age associated monocyte polarization, and a loss of platelet derived ß2M shifted monocytes and macrophages to a pro-reparative phenotype and increased pro-fibrotic cardiac responses. Platelet regulation of monocyte phenotypes via ß2M may maintain a balance between inflammatory and reparative signals that affects age related physiologic outcomes.