Effects of vatinoxan on cardiorespiratory function, fecal output and plasma drug concentrations in horses anesthetized with isoflurane and infusion of medetomidine

A constant rate infusion (CRI) of medetomidine is used to balance equine inhalation anesthesia, but its cardiovascular side effects are a concern. This experimental crossover study aimed to evaluate the effects of vatinoxan (a peripheral α2-adrenoceptor antagonist) on cardiorespiratory and gastrointestinal function in anesthetized healthy horses. Six horses received medetomidine hydrochloride 7 μg/kg IV alone (MED) or with vatinoxan hydrochloride 140 μg/kg IV (MED + V). Anesthesia was induced with midazolam and ketamine and maintained with isoflurane and medetomidine CRI for 60 min. Heart rate, carotid and pulmonary arterial pressures, central venous pressure, cardiac output and arterial and mixed venous blood gases were measured. Selected cardiopulmonary parameters were calculated. Plasma drug concentrations were determined. Fecal output was measured over 24 h. For statistical comparisons, repeated measures analysis of covariance and paired t-tests were applied.Heart rate decreased slightly from baseline in the MED group. Arterial blood pressures decreased with both treatments, but significantly more dobutamine was needed to maintain normotension with MED + V (P = 0.018). Cardiac index (CI) and oxygen delivery index (DO2I) decreased significantly more with MED, with the largest difference observed at 20 min: CI was 39 ± 2 and 73 ± 18 (P = 0.009) and DO2I 7.4 ± 1.2 and 15.3 ± 4.8 (P = 0.014) mL/min/kg with MED and MED + V, respectively. Fecal output or plasma concentrations of dexmedetomidine did not differ between the treatments. In conclusion, premedication with vatinoxan induced hypotension, thus its use in anesthetized horses warrants further studies. Even though heart rate and arterial blood pressures remained clinically acceptable with MED, cardiac performance and oxygen delivery were lower than with MED + V.</p

Muscle-lactate and its transport across membranes in horses: A review

Horses have high oxidative capacity, but during maximal effort a considerable percentage of energy is produced by anaerobic glycolysis as indicated by the production of lactate and protons. To maintain intracellular pH, efflux of lactate and protons is facilitated by monocarboxylate transporters (MCT), which cotransport these two ions. Mainly two MCT isoforms, MCT1 and MCT4, are expressed in equine muscles. Both of these need an ancillary protein, CD147, for full activity and their proper orientation on membranes. Lactate efflux depends also on the proton gradient between muscle and blood plasma, and to keep up this gradient lactate and protons are taken up by tissues that rely on oxidative metabolism, but also by red blood cells (RBC), which during exercise act as a lactate sink. In equine skeletal muscle and RBC the expression of CD147 is bimodally distributed with 25% of standardbred horses showing low expression in comparison to the rest 75%. The lactate transport activity is autosomally inherited with the high activity being the dominant form. Equine MCT1, MCT4 and CD147 have been sequenced, but the polymorphisms in the coding region of MCT1 and CD147 or the promoter region of CD147 cannot explain the differences in the lactate transport activity leaving the reason for differences in lactate transport activity to be solved.vo

Immunohistochemical analysis of MCT1 and CD147 in equine skeletal muscle fibres

v2010o

Role of Type 1 diabetes associated SNPs on risk of autoantibody positivity in the TEDDY study.

The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,677 children enrolled from birth, who carry HLA-susceptibility genotypes for development of islet autoantibodies (IA) and type 1 diabetes (T1D). During the median follow-up time of 57 months, 350 children developed at least one persistent IA (GADA, IA-2A or mIAA) and 84 of them progressed to T1D. We genotyped 5,164 Caucasian children for 41 non-HLA SNPs that achieved genome-wide significance for association with T1D in the GWAS meta-analysis conducted by the Type 1 Diabetes Genetics Consortium. In TEDDY-participants carrying high-risk HLA-genotypes, eight SNPs achieved significant association to development of IA using time-to-event analysis (p&lt;0.05), whereof four were significant after adjustment for multiple testing (p&lt;0.0012): rs2476601 in PTPN22 (hazard ratio [HR] 1.54 [95% CI 1.27-1.88]), rs2292239 in ERBB3 (HR 1.33 [95% CI 1.14-1.55]), rs3184504 in SH2B3 (HR 1.38 [95% CI 1.19-1.61]) and rs1004446 in INS (HR 0.77 [0.66-0.90]). These SNPs were also significantly associated with T1D in particular: rs2476601 (HR 2.42 [95% CI 1.70-3.44]). Although genes in the HLA-region remain the most important genetic risk factors for T1D, other non-HLA genetic factors contribute to IA, a first step in the pathogenesis of T1D, and the progression of the disease