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.

MicroRNAs are differentially expressed in the serum and renal tissues of cats with experimentally induced chronic kidney disease: a preliminary study.

OBJECTIVE: To identify differentially expressed microRNA in the serum and renal tissues of cats with experimentally induced chronic kidney disease (CKD). SAMPLE: Banked renal tissues and serum from 4 cats. PROCEDURES: Cats previously underwent 90-minute unilateral ischemia with delayed contralateral nephrectomy 3 months after ischemia. Tissues were collected from the contralateral kidney at the time of nephrectomy and from the ischemic kidney 6 months after nephrectomy (study end). Serum was collected prior to ischemia (baseline serum) and at study end (end point serum). Total RNA was isolated from tissues and serum, and microRNA sequencing was performed with differential expression analysis between the contralateral and ischemic kidney and baseline and end point serum. RESULTS: 20 microRNAs were differentially expressed between ischemic and contralateral kidneys, and 52 microRNAs were differentially expressed between end point and baseline serum. Five microRNAs were mutually differentially expressed between ischemic and contralateral kidneys and baseline and end point serum, with 4 (mir-21, mir-146, mir-199, and mir-235) having increased expression in both the ischemic kidney and end point serum and 1 (mir-382) having increased expression in the ischemic kidney and decreased expression in end point serum. Predicted target search for these microRNA revealed multiple genes previously shown to be involved in the pathogenesis of feline CKD, including hypoxia-inducible factor-1α, transforming growth factor-ß, hepatocyte growth factor, fibronectin, and vascular endothelial growth factor A. CLINICAL RELEVANCE: MicroRNAs were differentially expressed after CKD induction in this preliminary study. Regulation of renal fibrosis in feline CKD may occur through microRNA regulation of mRNAs of pro- and anti-fibrotic genes.

Evaluation of profibrotic gene transcription in renal tissues from cats with naturally occurring chronic kidney disease.

BACKGROUND: Increased gene transcription of hypoxia-induced mediators of fibrosis in renal tissue has been identified in experimentally induced, ischemic chronic kidney disease (CKD). OBJECTIVE: To characterize hypoxia-induced profibrotic pathways in naturally occurring CKD in cats. ANIMALS: Twelve client-owned cats with CKD and 8 healthy control cats. METHODS: In this prospective, cross-sectional study, bilateral renal tissue samples were assessed histologically for inflammation, tubular atrophy, and fibrosis, and by reverse transcription-quantitative PCR for characterization of transcript levels of hypoxia-inducible factor-1α (HIF1A), matrix metalloproteinases-2 (MMP2), -7 (MMP7), and -9 (MMP9), tissue inhibitor of metalloproteinase-1 (TIMP1), transforming growth factor-ß1 (TGFB1), and vascular endothelial growth factor-A (VEGFA). Linear mixed models were used to compare gene transcription between diseased and healthy kidneys, and to examine the association between transcript levels and serum creatinine concentration for all cats, and between transcript levels and histologic scores of diseased kidneys. RESULTS: Kidneys from cats with CKD had significantly higher transcript levels of HIF1A, MMP2, MMP7, MMP9, TIMP1, and TGFB1 (all P < .001), and lower levels of VEGFA (P = .006) than those from control cats. Transcript levels of MMP7 (P = .05) and TIMP1 (P = .005) were positively associated with serum creatinine in cats with CKD, but not in control cats. In diseased kidneys, transcript levels of MMP2 (P = .002), MMP7 (P = .02), and TIMP1 (P = .02) were positively, whereas those of VEGFA (P = .003) were negatively, associated with histologic score severity. CONCLUSION AND CLINICAL SIGNIFICANCE: Evaluation of the expression of the corresponding proteins in larger populations could identify therapeutic targets and/or biomarkers of tubulointerstitial fibrosis in cats.

Profibrotic gene transcription in renal tissues from cats with ischemia-induced chronic kidney disease.

OBJECTIVE: To characterize transcription of profibrotic mediators in renal tissues of cats with ischemia-induced chronic kidney disease (CKD). SAMPLE: Banked renal tissues from 6 cats with experimentally induced CKD (RI group) and 8 healthy control cats. PROCEDURES: For cats of the RI group, both kidneys were harvested 6 months after ischemia was induced for 90 minutes in 1 kidney. For control cats, the right kidney was evaluated. All kidney specimens were histologically examined for fibrosis, inflammation, and tubular atrophy. Renal tissue homogenates underwent reverse transcription quantitative PCR assay evaluation to characterize gene transcription of hypoxia-inducible factor-1α (HIF-1α), matrix metalloproteinase (MMP)-2, MMP-7, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), transforming growth factor-ß1, and vascular endothelial growth factor A. Gene transcription and histologic lesions were compared among ischemic and contralateral kidneys of the RI group and control kidneys. RESULTS: Ischemic kidneys had greater transcript levels of MMP-7, MMP-9, and transforming growth factor-ß1 relative to control kidneys and of MMP-2 relative to contralateral kidneys. Transcription of TIMP-1 was upregulated and that of vascular endothelial growth factor A was downregulated in ischemic and contralateral kidneys relative to control kidneys. Transcription of HIF-1α did not differ among kidney groups. For ischemic kidneys, there were strong positive correlations between transcription of HIF-1α, MMP-2, MMP-7, and TIMP-1 and severity of fibrosis. CONCLUSIONS AND CLINICAL RELEVANCE: Transcription of genes involved in profibrotic pathways remained altered in both kidneys 6 months after transient renal ischemia. This suggested that a single unilateral renal insult can have lasting effects on both kidneys.

Evaluation of orally administered telmisartan for the reduction of indirect systolic arterial blood pressure in awake, clinically normal cats.

OBJECTIVES: The aim of this study was to compare the effects of multiple once- or twice-daily oral dosage rates of the angiotensin II, type-1 receptor blocker, telmisartan (TEL), or placebo (PLA) on indirect systolic arterial blood pressure (SBP) in awake, clinically normal cats. METHODS: Utilizing an incomplete crossover design and following a 14 day acclimation period, 28 healthy laboratory cats were randomized to undergo treatment with three of the following 14 day treatment protocols, each separated by a 1 week washout period: oral PLA q24h, oral TEL at a dosage of 1, 1.5, 2 or 3 mg/kg q24h, or oral TEL at a dosage of 1 or 1.5 mg/kg q12h. Using the Doppler ultrasound method, indirect SBP was measured daily during each treatment period, and daily during the first 5 days of each washout period, approximately 3 h after administration of the morning treatment. RESULTS: Each treatment protocol was administered to a total of 12 cats. A statistically significant effect of treatment period was identified for the entire study; therefore, only data from the first treatment period (four cats per treatment group) were used for further analysis. Compared with PLA, during the first treatment period, SBP values were significantly lower in cats treated with TEL at all tested dosages by the second week of treatment. SBP remained significantly lower than in PLA-treated animals for 2 days following administration of the last dose in all TEL treatment groups. No clinical signs of hypotension were noted in any group. CONCLUSIONS AND RELEVANCE: These results suggest that treatment with TEL at a total daily dose of 1-3 mg/kg - administered as a single dose, or split into two equal doses administered 12 h apart - results in a significant, relatively long-lasting reduction of SBP in clinically normal cats. TEL appears to be well tolerated by normal cats at the dosages tested.

Learning confounds algometric assessment of mechanical thresholds in normal dogs.

OBJECTIVE: To perform algometric readings in normal dogs in a design that would assess possible confounding factors. STUDY DESIGN: Prospective study. ANIMALS: Skeletally mature spayed female, intact male and castrated male retriever or retriever mix dogs without orthopedic or neurologic disease (n = 19). METHODS: Twelve common surgical sites were selected for algometric pressure testing. Threshold response was defined as a conscious recognition of the stimulus, and recorded in Newtons. Sites were tested in the same order, and the testing sequence repeated 3 times on each side of the dog. Dogs were tested in the morning and evening of the same day and was repeated 10-14 days later, allowing 4 separate data collections for each dog. RESULTS: Data were analyzed using ANOVA or ANCOVA. When all the data were included in the analysis, dog (P < .0001), order (P < .0001), site (P < .0001), site order (P = .0217), time (P < .0001), day (P < .0001) and repetition (P < .0001) all significantly affected the algometer readings. When only the first reading for each site was included in the analysis, dog (P < .0001), site (P < .0001) and sex (P < .0001) all significantly affected algometer readings. CONCLUSION: These results suggest that learning occurred over repeated collection time points, with dogs anticipating the stimulus and reacting at lower thresholds.