Recent investigations by the Australian Department of Agriculture, Fisheries and Forestry into high mortalities on live export voyages from Australia to the Middle East during the Northern hemisphere summer suggest that animal welfare may be compromised by heat stress. The live export industry has generated a computer model that aims to assess the risk of heat stress and to contain mortality levels on live export ships below certain arbitrary limits. Although the model must be complied with under Australian law, it is not currently available for independent scientific scrutiny, and there is concern that model and the mandated space allowances are inadequate. This review appraises the relevant literature on heat stress in sheep and cattle, including laboratory studies aimed at mimicking the ambient temperatures and humidity levels likely to be encountered on live export voyages. Animal welfare is likely to be very poor as a result of heat stress in some shipments.

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The concentration-effect relationships of phenylbutazone, indomethacin, betamethasone, pentosan polysulphate (PPS) and polysulphated glycosaminoglycan (PSGAG), on proteoglycan synthesis by equine cultured chondrocytes grown in monolayers, and articular cartilage explants were measured. The effect of PSGAG on interleukin-1beta induced suppression of proteogycan synthesis was also investigated. Proteoglycan synthesis was measured by scintillation assay of radiolabelled sulphate (35SO4) incorporation. Polysulphated glycosaminoglycan and PPS stimulated proteoglycan synthesis in chondrocyte monolayers in a concentration-related manner with maximal effects being achieved at a concentration of 10 microg/mL. Polysulphated glycosaminoglycan reversed the concentration-related suppression of proteoglycan synthesis induced by interleukin-1beta. Neither PSGAG nor PPS exerted significant effects on radiolabel incorporation in cartilage explants. Betamethasone suppressed proteoglycan synthesis by both chondrocytes and explants at high concentrations (0.1-100 microg/mL), but the effect was not concentration-related. At low concentrations (0.001-0.05 microg/mL) betamethasone neither increased nor decreased proteoglycan synthesis. Phenylbutazone and indomethacin increased radiolabel incorporation in chondrocyte cultures but not in cartilage explants at low (0.1, 1 and 10 microg/mL), but not at high (20 and 100 microg/mL) concentrations. These findings may be relevant to the clinical use of these drugs in the treatment of equine disease.

Summary The antithrombotic effects of aspirin at two dose rates (4 mg/kg and 12 mg/kg bodyweight [bwt]) were evaluated in normal, healthy ponies by measuring template bleeding time. Inhibition of platelet aggregation in response to adenosine diphosphate (ADP) and collagen was evaluated and cyclo‐oxygenase activity was monitored by radioimmunoassay of thromboxane B2 (TXB2), the stable metabolite of thromboxane A2 (TXA2). TXB2 was measured in serum and platelet rich plasma. Bleeding time was prolonged significantly until 48 h after treatment at 12 mg/kg bwt and until 4 h at the lower dose rate. Synthesis of TXB2 and collagen induced aggregation were diminished for much greater periods with similar results at each of the dose rates. The prolonged effects of aspirin on platelet function occurred in spite of a very short plasma half‐life of aspirin, because of its irreversible action on platelet cyclo‐oxygenase. The results show that low dose aspirin has a potential role in antithrombotic therapy in horses although the relationship between skin bleeding time in normal horses and improvement of clinical conditions requires further research and evaluation in clinical trials. TXB2 measurement appears to overestimate the duration of antithrombotic effects of aspirin in vivo.

1 We have investigated the mechanism of bradykinin (BK)-induced plasma extravasation into the knee joint of the anaesthetized rat. Accumulation of ["25Il-human serum albumin within the synovial cavity was used as a marker of increased vascular permeability.2 Perfusion with BK (1 uM) produced significant plasma extravasation into the knee which was inhibited by co-perfusion of the selective bradykinin B2 receptor antagonist D-Arg-[Hyp3,Thi5,DTic7,Oicl-bradykinin (Hoe 140, 200 nM). 3 The bradykinin B, receptor agonist, [des-Argl-BK (up to 100 mM), did not induce plasma extravasation into the knee joint over this time period. 4 Chemical sympathectomy by chronically administered 6-hydroxydopamine (6-OHDA) did not inhibit bradykinin-induced plasma extravasation. Acute intra-articular perfusion with 6-OHDA (to stimulate transmitter release from sympathetic nerve terminals) at concentrations up to 50 mM did not induce significant plasma extravasation. Intra-articular perfusion of 100 mM 6-OHDA induced significant plasma extravasation but produced severe systemic toxicity.5 The selective neurokinin, (NK') receptor antagonist, RP67580 (230 nmol kg-'), or receptor antagonists for the mast cell products histamine and 5-hydroxytryptamine did not significantly inhibit BK-induced plasma extravasation. 6 Co-perfusion of the NO synthase inhibitor, N0-nitro-L-arginine methyl ester (L-NAME) (1 mM) did not significantly inhibit the response to BK. '3'Xe clearance from L-NAME (1 mM)-injected joints was significantly (P <0.05) reduced compared to D-NAME injected joints, suggesting a reduction in blood flow as a result of decreased basal NO production. Systemic administration of L-NAME at doses sufficient to produce significant and sustained elevation of blood pressure (5 or 30 mg kg-', i.v. 15 min prior to BK perfusion) also failed to significantly inhibit the BK-induced response. 7 We conclude that, in normal joints, BK induces plasma extravasation by acting on bradykinin B2 receptors and that this response is not dependent on secondary release of mediators from sympathetic nerve terminals, sensory nerves, mast cells or on generation of NO.

The effects of calcitonin gene-related peptide (CGRP) and other vasoactive mediators of inflammation on blood flow in the synovial vessels and plasma protein extravasation into the knee (femoro-tibial) joint of the pentobarbitone-anaesthetized rat were measured. 2 Changes in synovial blood flow were estimated by '33xenon clearance from the synovial cavity. CGRP (O.1 pmol and 1O pmol) and prostaglandin El (PGE,; 3 pmol and 300 pmol) significantly increased clearance from the knee joint measured 5 min after intra-articular injection. Substance P (1O pmol) had no effect on synovial blood flow. 3 Intra-articular perfusion of the rat knee with CGRP at concentrations up to 0.1 mM, or PGE, at concentrations up to 10 #LM, did not increase plasma extravasation into the synovial cavity measured by accumulation of intravenously injected '25I-albumin in the perfusate. 4 Plasma extravasation into the knee was significantly increased by infusion of bradykinin (0.1 0LM), 5-hydroxytryptamine (1 jiM) and histamine (0.1 mM), compared with the contralateral joints in the same animals which were perfused with Tyrode solution. 5 Perfusion of the knee joint with substance P did not specifically induce '251-labelled albumin accumulation in the synovial cavity even at doses that had systemic effects as observed by marked plasma extravasation into other tissues. 6 The increase in plasma extravasation induced by histamine (0.1 mM) was potentiated by co-infusion with CGRP (0.1 jIM) and PGEI (3 gM). However the response to a submaximal dose (0.1 jIm) of bradykinin, which induced similar plasma extravasation to histamine (0.1 mM), was not increased by co-infusion with CGRP or PGEI.7 These results show that CGRP is a potent vasodilator in the rat knee. CGRP released from sensory nerves may act synergistically with mediators of increased vascular permeability to modify the inflammatory response in this site.

The neuropeptide calcitonin gene-related peptide (CGRP) is a potent vasodilator in the microcirculation of many tissues including the skin and joint. In order to elucidate the mechanism of endogenous CGRP release, we have used a multiple site 133Xe clearance technique to measure local blood flow changes in response to agents injected intradermally in the rabbit. Capsaicin (100 nmol/site) and human alpha CGRP (3 pmol/site) stimulated similar increases in blood flow and, in both cases, the effect was totally abolished by the CGRP antagonist, CGRP8-37 (1 nmol/site). By contrast, the nitric oxide synthase inhibitor L-nitro arginine methyl ester (L-NAME, 30 nmol/site) had little effect on human alpha CGRP-induced vasodilation, but caused significant inhibition of the response to capsaicin (p < 0.05). These results show that increased blood flow in rabbit skin caused by exogenous CGRP is independent of nitric oxide. In addition, however, they suggest that nitric oxide is required for either the release of endogenous CGRP from capsaicin-sensitive nerves or its subsequent activity.

Summary The effects of access to hay and of restricted feeding on the pharmacokinetics of flunixin administered orally to six healthy ponies were compared in a cross‐over study. No access to feed for a few hours before and after flunixin administration resulted in rapid absorption with a mean peak plasma concentration of 2.84 ± 0.28 μg/ml attained in an average time of 0.76 ± 0.18 h, followed by an exponential decline in plasma concentration. A lower peak plasma concentration was obtained when ponies had free access to hay before and after drug dosing. The mean maximum concentration (Cmax) was 1.30 ± 0.23 μug/ml and maximum time (tmax) was prolonged to a mean time of 7.66 ± 1.74 h. Free access to hay reduced and delayed the peak plasma concentration resulting in two or three separate concentration peaks in some ponies. The mean area under the plasma concentration‐time curve was not significantly different for the two feeding regimens.