Lamellar events related to insulin-like growth factor-1 receptor signalling in two models relevant to endocrinopathic laminitis.

BACKGROUND: Insulin dysregulation, obesity, and exposure to high-nonstructural carbohydrate (NSC) forage are risk factors for equine metabolic syndrome-associated laminitis (EMSAL); high systemic insulin concentrations in EMSAL are proposed to induce cellular dysregulation in the digital lamellae through activation of the insulin-like growth factor-1 receptor. OBJECTIVES: To use a dietary challenge model (DCM) and a euglycaemic-hyperinsulinaemic clamp (EHC) model to assess lamellar growth factor-related signalling. STUDY DESIGN: Lamellar phospho (P)-protein concentrations of signalling proteins important in growth factor-related signalling were assessed in 2 models: 1) lean and obese ponies on a low- or high-NSC diet; and 2) EHC model using Standardbred horses. METHODS: Ponies stratified for body condition (lean [LN, n = 11] and obese [OB, n = 11]) were exposed to a low-NSC diet (LO, n = 5 per group for LN LO and OB LO) or a high NSC diet (HI, n = 6 per group for LN HI and OB HI groups) for 7 days. For the EHC model, horses were administered insulin (constant rate infusion [6 mIU/kg bwt/min] combined with 50% dextrose, EHC group, n = 8)] or saline (0.57 mL/kg bwt/h, CON group, n = 8) for 48 h. Immunoblotting was employed to assess concentrations of activated/phosphorylated and total protein for members of the PI3K/Akt/mTORC1 and Ras/ERK pathways in lamellar samples from both models. RESULTS: In the DCM, lamellar P-(Ser 240/244) RPS6 was increased in OB HI ponies (vs. OB LO, P<0.05); positive correlations existed (P<0.05; r>0.5) between Day 7 basal serum insulin concentrations and lamellar concentrations of P-p70S6K and P-(Ser 240/244) RPS6. In the EHC model, lamellar concentrations of P-Akt, P-p70S6K, P-ERK 1/2, P-p90RSK, and both P-(Ser 235/236) and P-(Ser 240/244) RPS6 were increased in the EHC group (vs. CON, P<0.05). MAIN LIMITATIONS: The primary limitations of this study are the small number of animals per group in the DCM study, and the fact that many animals did not develop laminitis as that was not the endpoint of either study. CONCLUSIONS: These results support further investigation of mTORC1/RPS6 signalling as a potential therapeutic target(s) in EMSAL. The Summary is available in Chinese - see Supporting Information.

Vasorelaxation responses to insulin in laminar vessel rings from healthy, lean horses.

Hyperinsulinemia causes laminitis experimentally and is a risk factor for naturally occurring laminitis. The aim of this study was to investigate the effects of insulin on laminar vascular relaxation and to induce insulin-associated vascular dysfunction in vitro. Relaxation responses of isolated laminar arterial and venous rings to acetylcholine and insulin were evaluated. To alter vascular function in response to insulin, all vessel rings were incubated with insulin or vehicle, submaximally contracted, administered insulin again and relaxation responses recorded. Laminar arteries were also incubated with the mitogen-activated protein kinase (MAPK) inhibitor, PD-98059. Relaxation in response to acetylcholine was not different between arteries and veins, but veins relaxed less in response to insulin than arteries. In arteries incubated with insulin, the subsequent relaxation response to insulin was blunted. Veins had minimal relaxation to insulin regardless of incubation. Arteries incubated with PD-98059 relaxed more in response to insulin than arteries not exposed to PD-98059, indicating that MAPK plays a role in maintenance of basal tone in laminar arteries. A differing response of laminar veins and arteries to insulin-induced relaxation may be important in understanding the link between hyperinsulinemia and laminitis. In vitro induction of vascular dysfunction in response to insulin in laminar arteries may be useful for testing therapeutic interventions and for understanding the pathophysiology of laminitis.

Plasma and pulmonary fluid endothelin in horses with seasonal recurrent airway obstruction.

BACKGROUND: Summer pasture-associated recurrent airway obstruction (SPA-RAO), a seasonal airway obstructive disease of horses, is characterized by clinical exacerbation after exposure to pasture during warm months of the year. Endothelin (ET)-1, potent bronchoconstrictor, mitogen, secretagogue, and proinflammatory mediator, has been implicated in the pathogenesis of asthma and equine heaves. HYPOTHESIS: Immunoreactive ET-1 concentrations increase during clinical exacerbation and return to basal values during periods of disease remission. ANIMALS: Twelve horses, 6 affected with SPA-RAO and 6 nonaffected. METHODS: Prospective, observational study. Bronchoalveolar lavage fluid (BALF), arterial and venous plasma samples, and clinical variables were obtained from affected horses during clinical exacerbation and remission. Samples and data of nonaffected horses were collected during the summer and winter on dates similar to affected horses. Immunoreactive ET-1 was determined using a commercial ELISA. RESULTS: The median and range ET-1 concentrations (pg/ml) in arterial (1.3, 0.7-1.8) and venous (1.3, 1.2-1.7) plasma and in BALF (0.3, 0.2-0.4), and pulmonary epithelial lining fluid (PELF) (25.5, 21-50) were greater in affected horses during clinical exacerbation compared with remission (P < .01). The concentrations of immunoreactive ET-1 were greater in affected horses during clinical exacerbation compared with nonaffected horses (P < .05). CONCLUSIONS AND CLINICAL IMPORTANCE: During clinical exacerbation of SPA-RAO, ET-1 is increased in circulation and pulmonary secretions. Intervention with ET receptor antagonists should provide further information on the role of ET-1 in SPA-RAO.

Systemic AL amyloidosis associated with multiple myeloma in a horse.

AL amyloidosis is the most common type of systemic amyloidosis in humans, and it is frequently associated with multiple myeloma. But, AL amyloidosis is very rare in domestic animals. A 16-year-old Quarter horse gelding was diagnosed with systemic AL amyloidosis associated with multiple myeloma. Clinical problems were rapid weight loss, muscle atrophy, soft unformed stool, and ventral edema. Grossly, diffuse gastrointestinal hemorrhage, markedly thickened jejunal mucosa, and splenomegaly were present. Microscopically, diffuse severe amyloid deposits were present in the lamina propria of glandular stomach, duodenum, and jejunum. Much of the spleen and sternal bone marrow was replaced by neoplastic round cells, and multiple foci of amyloid were also present in the spleen and bone marrow. Electron microscopy revealed the neoplastic round cells to be of plasma cell origin, and the amyloid showed a strongly positive immunoreactivity with polyclonal anti-human immunoglobin lambda light-chain antisera. To our knowledge, this is the second report describing systemic AL amyloidosis in domestic animals-associated plasma cell neoplasia and the first associated with multiple myeloma, as is common in humans.

Evidence for vascular and enzymatic events in the pathophysiology of acute laminitis: which pathway is responsible for initiation of this process in horses?

To date, there is a substantial amount of data to support the hypotheses that vascular and enzymatic changes are ongoing in experimental laminitis. Furthermore, there is substantial in vitro evidence that the enzymatic changes weaken the dermo-epidermal attachments leading to mechanical failure of the hoof-bone interface of the equine digit. However, investigators of both the vascular and enzymatic theories have, to date, been unable to substantiate the effects of these pathophysiological changes in vivo on laminar tissues of horses afflicted with experimentally induced or naturally acquired laminitis. In addition, the effects of laminitis-inducing treatment have not been prevented or reversed by treatment with an MMP inhibitor or a vasoactive antagonist. It is possible that there is simultaneous activation of the vascular and enzymatic pathways and/or other inflammatory processes. Moreover, the third theory involving mechanical factors cannot be discounted simply because strong evidence for vascular and enzymatic changes exists. It is common for horses with severe musculoskeletal disease affecting weightbearing on a limb to develop laminitis in the contralateral limb. It remains to be determined what factors are responsible for initiation of laminitis in these individuals. Evidence has not been presented that precludes the possibility of coincident occurrence of vascular and enzymatic changes. In fact, many of the inflammatory mediators (e.g. interleukin-1beta) found in laminitic tissues can concurrently stimulate synthesis of vasoactive substances and activate MMPs. Because enzymatic action on proteins is largely dependent on the concentrations of proteins and enzyme, the enzymatic theory is not dependent upon increased delivery of enzymes via increased capillary flow. Likewise, because vascular changes can alter tissue function via increased capillary flow and oedema formation, the vascular theory is not dependent upon decreased capillary flow. It is true that naturally acquired laminitis is widely variable in severity and predisposing diseases. Therefore, most probably there are multiple mechanisms involved in the initiation and propagation of the pathophysiologic cascade(s) and, therefore, successful intervention will necessitate multiple treatment modalities.

Cardiopulmonary, blood and peritoneal fluid alterations associated with abdominal insufflation of carbon dioxide in standing horses.

REASONS FOR PERFORMING STUDY: Abdominal insufflation is performed routinely during laparoscopy in horses to improve visualisation and facilitate instrument and visceral manipulations during surgery. It has been shown that high-pressure pneumoperitoneum with carbon dioxide (CO2) has deleterious cardiopulmonary effects in dorsally recumbent, mechanically ventilated, halothane-anaesthetised horses. There is no information on the effects of CO2 pneumoperitoneum on cardiopulmonary function and haematology, plasma chemistry and peritoneal fluid (PF) variables in standing sedated horses during laparoscopic surgery. OBJECTIVES: To determine the effects of high pressure CO2 pneumoperitoneum in standing sedated horses on cardiopulmonary function, blood gas, haematology, plasma chemistry and PF variables. METHODS: Six healthy, mature horses were sedated with an i.v. bolus of detomidine (0.02 mg/kg bwt) and butorphanol (0.02 mg/kg bwt) and instrumented to determine the changes in cardiopulmonary function, haematology, serum chemistry and PF values during and after pneumoperitoneum with CO2 to 15 mmHg pressure for standing laparoscopy. Each horse was assigned at random to either a standing left flank exploratory laparoscopy (LFL) with CO2 pneumoperitoneum or sham procedure (SLFL) without insufflation, and instrumented for measurement of cardiopulmonary variables. Each horse underwent a second procedure in crossover fashion one month later so that all 6 horses had both an LFL and SLFL performed. Cardiopulmonary variables and blood gas analyses were obtained 5 mins after sedation and every 15 mins during 60 mins baseline (BL), insufflation (15 mmHg) and desufflation. Haematology, serum chemistry analysis and PF analysis were performed at BL, insufflation and desufflation, and 24 h after the conclusion of each procedure. RESULTS: Significant decreases in heart rate, cardiac output and cardiac index and significant increases in mean right atrial pressure, systemic vascular resistance and pulmonary vascular resistance were recorded immediately after and during sedation in both groups of horses. Pneumoperitoneum with CO2 at 15 mmHg had no significant effect on cardiopulmonary function during surgery. There were no significant differences in blood gas, haematology or plasma chemistry values within or between groups at any time interval during the study. There was a significant increase in the PF total nucleated cell count 24 h following LFL compared to baseline values for LFL or SLFL at 24 h. There were no differences in PF protein concentrations within or between groups at any time interval. CONCLUSIONS: Pneumoperitoneum with CO2 during standing laparoscopy in healthy horses does not cause adverse alterations in cardiopulmonary, haematology or plasma chemistry variables, but does induce a mild inflammatory response within the peritoneal cavity. POTENTIAL RELEVANCE: High pressure (15 mmHg) pneumoperitoneum in standing sedated mature horses for laparoscopic surgery can be performed safely without any short-term or cumulative adverse effects on haemodynamic or cardiopulmonary function.

Alterations in systemic and local colonic hemodynamic variables associated with intravenous infusion of ATP-MgCl2 in healthy anesthetized horses.

OBJECTIVE: To characterize alterations in systemic and local colonic hemodynamic variables associated with IV infusion of ATP-MgCl2 in healthy anesthetized horses. ANIMALS: 12 adult horses. PROCEDURE: Six horses were given ATP-MgCl2, IV, beginning at a rate of 0.1 mg of ATP/kg of body weight/min with incremental increases until a rate of 1.0 mg/kg/min was achieved. The remaining 6 horses were given an equivalent volume of saline (0.9% NaCl) solution over the same time period. Colonic and systemic hemodynamic variables and colonic plasma nitric oxide (NO) concentrations were determined before, during, and after infusion. RESULTS: Infusion of ATP-MgCl2 caused a rate-dependent decrease in systemic and colonic vascular resistance, principally via its vasodilatory effects. A rate of 0.3 mg of ATP/kg/min caused a significant decrease in systemic and colonic arterial pressure and colonic vascular resistance without a significant corresponding decrease in colonic arterial blood flow. Consistent alterations in NO concentrations of plasma obtained from colonic vasculature were not detected, despite profound vasodilatation of the colonic arterial vasculature. CONCLUSIONS AND CLINICAL RELEVANCE: Results revealed that IV infusion of ATP-MgCl2 may be beneficial in maintaining colonic perfusion in horses with ischemia of the gastrointestinal tract, provided a sufficient pressure gradient exists to maintain blood flow.

Hemodynamic and metabolic alterations associated with intravenous infusion of a combination of adenosine triphosphate and magnesium chloride in conscious horses.

OBJECTIVE: To determine hemodynamic and metabolic effects of IV infusion of ATP-MgCl2 combination and maximal safe IV infusion rate in conscious horses. ANIMALS: 6 adult female horses. PROCEDURE: All horses received an IV infusion of ATP-MgCl2 combination, beginning at a rate of 0.05 mg of ATP/kg of body weight/min, which was increased by 0.05 mg/kg/min increments at 10-minute intervals until a rate of 1.0 mg/kg/min was achieved. Data were collected prior to the start of the infusion, at the end of each infusion rate, and at 15-minute intervals for the next hour after discontinuation of the infusion. Measured or calculated hemodynamic variables included cardiac output, cardiac index, heart rate, stroke volume, systemic and pulmonary arterial pressures, and systemic and pulmonary vascular resistances. Arterial blood gas tensions, CBC, plasma biochemical profiles, urine volume and specific gravity, and selected clinical signs of disease also were evaluated. RESULTS: Intravenous infusion of ATP-MgCl2 significantly increased cardiac output, decreased systemic vascular resistance, and caused mild pulmonary hypertension. Magnitude of the hemodynamic alterations was dependent on rate of infusion. Maximal safe infusion rate for these horses was 0.3 mg/kg/min. All horses became lethargic, and their appetites diminished during the infusion; 5 horses had mild signs of abdominal discomfort. Flank sweating was observed in all horses as infusion rate increased. Urine volume and specific gravity and hematologic, biochemical, and arterial blood gas alterations were detected during and after infusion. CONCLUSIONS AND CLINICAL RELEVANCE: Intravenous administration of ATP-MgCl2 in healthy, conscious, adult horses caused various metabolic and hemodynamic alterations that were without appreciable detrimental effects.

Palmar digital vessel relaxation in healthy horses and in horses given carbohydrate.

OBJECTIVE: To compare in vitro smooth muscle relaxation of palmar digital vessels from healthy horses with those from horses in the prodromal stage of experimentally (carbohydrate) induced laminitis. ANIMALS: 16 adult horses. PROCEDURE: Segments of palmar digital vessels were obtained from 5 healthy horses and 6 horses given carbohydrate. Vascular rings from the palmar digital artery and vein were suspended in individual organ baths containing buffer solution and indomethacin; isometric tension was recorded, and contraction and relaxation were compared. Smooth muscle contraction in response to cumulative addition of phenylephrine was recorded in the absence and presence of 1 microM NG-nitro-L-arginine methyl ester (L -NAME). After wash out, vascular rings were preconstricted with phenylephrine (0.3 microM), and cumulative endothelium-dependent (acetylcholine-induced) and independent (nitroprusside-induced) smooth muscle relaxations were recorded in the absence or presence of L -NAME. RESULTS: Phenylephrine increased vascular smooth muscle tone in ring preparations of palmar digital arteries and veins. Addition of acetylcholine or nitroprusside induced relaxation of palmar digital artery and vein ring preparations. Use of L-NAME (1 microM) significantly reduced maximal relaxation induced by acetylcholine, but not by nitroprusside. Maximal relaxation induced by acetylcholine, but not by nitroprusside, was reduced in vascular rings prepared from carbohydrate-overloaded horses. CONCLUSION AND CLINICAL RELEVANCE: Reduced endothelium-dependent relaxation of palmar digital vessels may have a role in the pathophysiology of acute laminitis after carbohydrate overload in horses.

Antagonist of nitric oxide synthesis inhibits nerve-mediated relaxation of isolated strips of rumen and reticulum.

The present study investigated the possibility that nitric oxide is a nonadrenergic, noncholinergic neurotransmitter of nerves that are intrinsic to the forestomach. Tunica muscularis, myenteric plexus preparations of bovine reticulum and rumen were maintained in vitro in a physiological solution of buffer that contained scopolamine. Trains of electric field stimulation transiently reduced (relaxed) the tone induced by BaCl2. NG-Nitro-L-arginine methyl ester, a nitric oxide synthase competitive antagonist, inhibited relaxation of the rumen and reticulum preparations that had been induced by the electrical field. The actions of NG-nitro-L-arginine methyl ester were partially reversed by L-arginine. These data suggest that nitric oxide, or a related substance, is an inhibitory neurotransmitter of nerves that are intrinsic to tunica muscularis, myenteric plexus preparations of the bovine forestomach.

Endotoxaemia in dairy cattle: mechanism of reticulorumen stasis.

The objective of this study was to determine whether blockade of alpha(-2) adrenergic receptors would restore reticulorumen motility during toxaemia in cows. Reticulorumen contractions were measured via a water-filled balloon connected to a pressure transducer. Intravenous infusion of endotoxin (100 ng kg-1 over 30 min) significantly decreased the number of reticulorumen contractions. Intravenous infusion of yohimbine (125 micrograms kg-1 over 30 min) alone did not affect reticulorumen contractions. However, when yohimbine (125 micrograms kg-1 over 30 min) was infused concurrently with endotoxin (100 ng kg-1 over 30 min), the effects of endotoxin on reticulorumen contraction frequency decreased, suggesting that endotoxaemia causes reticulorumen stasis via a mechanism that involves alpha(-2) adrenergic receptors.

Digital Starling forces and hemodynamics during early laminitis induced by an aqueous extract of black walnut (Juglans nigra) in horses.

Starling forces and hemodynamics in the digits of 5 horses were studied during early laminitis induced by oral administration of an aqueous extract of black walnut (Juglans nigra). The black walnut extract was prepared from heartwood shavings and was administered by nasogastric tube. Heart and respiratory rates, rectal temperature, central venous and arterial pressures, digital pulses, and signs of lameness were monitored. Blood samples were collected for determination of WBC count, hemoglobin concentration, and PCV and for endotoxin and tumor necrosis factor assays. Total WBC count and central venous pressure were monitored until they decreased by 30 or 20%, respectively. These decreases in WBC count and central venous pressure were observed 2 to 3 hours after dosing with black walnut extract. Respiratory and heart rates, body temperature, systolic and diastolic blood pressures, PCV, and hemoglobin concentration did not change significantly. Anesthesia was induced, heparin (500 IU/kg of body weight) was administered IV, and a pump-perfused extracorporeal digital preparation was established. Digital arterial and venous pressures were maintained at 100 and 30 mm of Hg, respectively. Blood flow, capillary pressure, lymph and plasma protein concentrations, and weight of the isolated digit during rapid increase in venous pressure were measured. Isogravimetric capillary filtration coefficient, vascular compliance, vascular and tissue oncotic pressures, tissue pressure, osmotic reflection coefficient, and precapillary and postcapillary resistances were calculated. Mean digital blood flow was 14 ml/min/100 capillary pressure was 52 mm of Hg, and vascular compliance was 0.06 ml/mm of Hg. The vascular and tissue oncotic pressures were 21.49 and 4.93 mm of Hg, respectively. The osmotic reflection coefficient was 0.71, and tissue pressure was 41 mm of Hg. The precapillary and postcapillary resistances were 7 and 2 mm of Hg/ml, respectively. Capillary permeability to proteins was not significantly different from that previously measured in healthy horses, suggesting that the increased capillary filtration coefficient reflected increased capillary hydrostatic pressure and perfusion of previously nonperfused capillaries. Neither endotoxin nor serum tumor necrosis factor activity was detected in any samples. The hemodynamic and Starling forces observed in this study were similar to those observed after laminitis was induced by administration of a carbohydrate gruel. Significant differences between the 2 models were detected for total vascular resistance, postcapillary resistance, and capillary filtration coefficient. It is likely that these differences were identified because the horses administered the black walnut extract were at an earlier stage in the disease process. The findings of this study suggest that the increase in capillary pressure causes transvascular fluid movement, resulting in increased tissue pressure and edema. We hypothesize that further increases in tissue pressure may collapse capillary beds and lead to tissue ischemia.

Failure of calcium channel blockade to prevent intra-abdominal adhesions in ponies.

Intra-abdominal adhesions were created by localized serosal trauma in 11 adult ponies at three locations on the small intestine. Six ponies received verapamil hydrochloride (0.2 mg/kg) subcutaneously every eight hours for three days, and five ponies received an equal volume of saline solution at the same intervals. The investigators were not informed which treatments the ponies received. Systolic, diastolic, and mean carotid arterial pressures and heart rates were measured six hours before surgery, and then 0.5, 1, 1.5, and 8 hours after the first treatment on each day for three days. One pony was euthanatized on day 13 because of colic, and the other 10 ponies were euthanatized 14 days after surgery. Scoring methods were used to assess the severity of adhesion formation and to grade the histologic appearance of the abraded sites. No significant differences were found for rectal temperature, packed cell volume, total plasma proteins, heart rate, and systolic, diastolic, or mean arterial pressures between control and verapamil-treated ponies. No significant differences were detected between the treatment groups for adhesion scores per abraded site, total adhesion scores per pony, the total number of adhesions per pony, or in the histologic scores.

Blockade of endotoxin-induced cecal hypoperfusion and ileus with an alpha 2 antagonist in horses.

Stimulation of alpha 2 adrenergic receptors inhibits colonic motility and may constrict some peripheral vascular beds. Endotoxemia elicits release of sympathetic neurotransmitters and increases sympathetic nerve activity, which may result in stimulation of alpha 2 adrenergic receptors. The objective of this study was to determine whether blockade of alpha 2 adrenergic receptors would restore cecal motility and blood flow during endotoxemia in horses. Strain-gauge force transducers and ultrasonic flow probes were used to measure cecal and colonic mechanical activity and lateral cecal arterial blood flow. Intravenous infusion of endotoxin (cumulative dose of 0.03 mg/kg) significantly decreased cecal and right ventral colon contractile activity and lateral cecal arterial blood flow. Slow IV infusion of yohimbine (cumulative dose of 75 micrograms/kg) significantly attenuated those effects of endotoxin. On the basis of our findings, we concluded that endotoxemia causes cecal and proximal colonic ileus and cecal hypoperfusion via a mechanism that involves alpha 2 adrenergic receptors.

Endotoxemia in dairy cattle: role of eicosanoids in reticulorumen stasis.

The role of arachidonic acid metabolites in the forestomach stasis induced by Escherichia coli endotoxin was evaluated. Six adult Holstein cows received saline solution; endotoxin at 1, 10, and 100 ng/kg of body weight; flunixin meglumine at 1.1 mg/kg of body weight; and flunixin meglumine at 1.1 mg/kg plus endotoxin at 100 ng/kg. The frequency of reticulorumen contractions, mental attitude, body temperature, respiratory rate, heart rate, and plasma concentration of prostaglandin E2, prostacyclin, and thromboxane were evaluated. Administration of saline solution and endotoxin at 1 ng/kg had no significant effects. Administration of endotoxin at 10 ng/kg did not cause significant clinical effects or alter reticulorumen contractions but enhanced synthesis of thromboxane. Administration of endotoxin at 100 ng/kg caused mild clinical signs of stasis, reduced the frequency of reticulorumen contractions, and enhanced synthesis of thromboxane and prostacyclin. Reticulorumen stasis was not accompanied by an increase in the plasma concentration of prostaglandin E2. Flunixin meglumine abolished endotoxin-induced reticulorumen stasis, tachycardia, and synthesis of arachidonic acid metabolites. Reticulorumen stasis during bovine endotoxemia is caused either by enhanced synthesis of an arachidonic acid metabolite other than prostaglandin E2 or by local synthesis of prostaglandin E2.

Antagonism of a specific dopaminergic receptor agonist with metoclopramide in horses.

Changes in lateral cecal arterial blood flow, mean internal carotid arterial pressure, and heart rate caused by nasogastric administration of fenoldopam (3, 6, and 9 mg/kg of body weight), a selective agonist of dopaminergic receptors, were recorded in 7 healthy horses. Cecal arterial blood flow was significantly increased within 30 minutes after administration of fenoldopam at all 3 dosages, with the peak increases from baseline (67.8 +/- 17.5 ml/min) being 125 +/- 28, 120 +/- 22, and 153 +/- 32 ml/min for 3, 6, and 9 mg/kg, respectively. Although carotid arterial pressure did not change significantly after administration of fenoldopam at the dosage of 3 mg/kg, administration of fenoldopam at the dosages of 6 and 9 mg/kg significantly reduced carotid arterial pressure from 113 +/- 10 to 88 +/- 3 and 81 +/- 5 mm of Hg, respectively. Intravenous infusion of metoclopramide, a dopaminergic receptor antagonist, at the rate of 0.125 mg/kg/h, blocked the effect of fenoldopam on cecal arterial blood flow and carotid arterial pressure. It was concluded that dopaminergic receptors mediate alterations in local blood flow and systemic pressure in horses.

Effects of xylazine butorphanol on cecal arterial blood flow, cecal mechanical activity, and systemic hemodynamics in horses.

A chronic model with an ultrasonic transit time blood flow probe and strain gauge force transducers implanted on the cecum was used to evaluate cecal mechanical activity and cecal arterial blood flow in 4 conscious adult horses. Intravenous administration of xylazine (1.1 mg/kg of body weight) significantly decreased heart rate and cardiac output, but significantly increased diastolic pulmonary arterial pressure, mean pulmonary arterial pressure, carotid arterial pressure, and central venous pressure. Lateral cecal arterial blood flow after xylazine administration was decreased substantially more than was cardiac output, suggesting that xylazine caused constriction of the cecal vasculature. This effect of xylazine may have resulted from either a direct effect of xylazine on the cecal vasculature or from reflex vasoconstriction attributable to reduced cardiac output. Intravenous administration of butorphanol tartrate (0.1 mg/kg) did not significantly alter the hemodynamic responses to xylazine. Cecal mechanical activity, as measured by the motility index, was decreased for 120 minutes after administration of xylazine and for 150 minutes after administration of xylazine/butorphanol.

Evaluation of cefotaxime alone and in combination with desacetylcefotaxime against strains of Staphylococcus aureus that produce variants of staphylococcal beta-lactamase.

We evaluated cefotaxime (CTX) alone and in combination with its metabolite, desacetylcefotaxime (dCTX) against strains of Staphylococcus aureus that produce the four recognized variants of staphylococcal beta-lactamase and a beta-lactamase-producing isolate characterized by the expression of borderline resistance to methicillin. Although macrodilution MICs revealed that dCTX was less active than CTX against these strains (geometric means of 16 micrograms/ml and 4 micrograms/ml, respectively), the addition of clinically achievable concentrations of dCTX to CTX resulted in a reduction in the observed CTX MICs. This effect was similar to although less pronounced than that obtained by combining clavulanic acid with cefazolin. The increased antistaphylococcal activity noted by MIC determinations was confirmed with kill-kinetic studies. Determination of the relative rates of hydrolysis of selected cephalosporins showed that neither CTX nor dCTX were appreciably hydrolyzed by the variant staphylococcal enzymes. Evaluation of the effect of CTX and dCTX upon the staphylococcal beta-lactamases demonstrated that neither agent inhibited the destruction of a 100 microM solution of nitrocefin, although the reduction of CTX and cefazolin MICs by low concentrations of dCTX suggests that the dCTX metabolite may act as a competitive inhibitor of beta-lactamase. These observations may explain the previously demonstrated clinical efficacy of CTX used alone for the treatment of serious infections caused by S. aureus.