The effect of bethanechol, neostigmine, metoclopramide, and propranolol on myoelectric activity of the ileum, cecum, and proximal loop of the ascending colon was determined in 6 healthy Jersey cows implanted with 8 pairs of bipolar electrodes. Assigned at random, each cow received each of 5 treatments in 3-day intervals. The treatments included bethanechol (0.07 mg/kg of body weight, SC), neostigmine (0.02 mg/kg, SC), metoclopramide (0.15 mg/kg, IM), DL-propranolol (0.2 mg/kg, IM), and 0.9% sodium chloride (NaCl) solution (20 ml, SC). All drugs were administered during early phase I of the migrating myoelectric complex in the ileum. Myoelectric activity was recorded for 4 hours after treatment, and data were analyzed for each hour separately. Bethanechol and neostigmine significantly (P < 0.05) increased the number of cecocolic spikes per minute per electrode, duration of cecocolic spike activity (%), and number of cecocolic propagated spike sequences per 10 minutes, relative to NaCI, during 1 or more hours of the recording period. The effect of bethanechol was more pronounced on duration of spike activity and number of propagated spike sequences, whereas neostigmine mainly increased the number of (uncoordinated) spikes. Metoclopramide and propranolol had no significant effect on cecocolic myoelectric activity, relative to NaCl. It was concluded that bethanechol and, less likely, neostigmine at the dosage used in this study may be suitable for medical treatment of cecal dilatation in cattle in which hypomotility of the cecum and proximal loop of the ascending colon has to be reversed. The potential advantage of bethanechol vs neostigmine for medical treatment of cecal dilatation is worth further evaluation.

Efficacy of sulbactam, a beta-lactamase inhibitor, in combination with ampicillin, was evaluated for treatment of experimentally induced pneumonia caused by beta-lactam-resistant Klebsiella pneumoniae. Infection was experimentally induced in 18 healthy weanling foals that were randomly allocated to 3 treatment groups: sulbactam plus ampicillin (S/A, 3.3 and 6.6 mg/kg of body weight, respectively), ampicillin (6.6 mg/kg), or vehicle only. Foals were treated daily for 7 days; the observer was unaware of treatment status. Compared with ampicillin and vehicle, treatment with S/A resulted in a statistically significant (P < 0.05) decrease in severity of pneumonia, with regard to bronchoalveolar lavage cytologic findings (decreased total cell and neutrophil numbers, and increased lymphocyte numbers) and extent of macroscopic lesions in lung tissue of the noninoculated regions. Marked trends toward improvement of S/A-treated foals were observed for quantitative results of bacteriologic culture of bronchoalveolar lavage fluid samples (P < 0.07), macroscopic pathologic features of the whole lung (P < 0.1), and histopathologic variables (P < 0.07), compared with ampicillin- and vehicle-treated foals. Treatment effects were not observed for radiographic, hematologic, and blood gas abnormalities that resulted from infection. In conclusion, the combination of sulbactam plus ampicillin was found to have synergistic effects in vivo, to reduce the extent and severity of experimentally induced grain-negative lung infection in foals.

To determine the role of thromboxane A2 in the pathogenesis of experimentally induced immune complex glomerulonephritis, 12 concanavalin A-immunized Beagles were infused with 1 mg of concanavalin A via each renal artery and treated twice daily for 8 days with either 30 mg of CGS 12970/kg, PO, a specific thromboxane synthetase inhibitor, or placebo. The effect of treatment was assessed by measuring endogenous creatinine clearance and urine protein and eicosanoid excretion, and by evaluating changes in glomerular morphometric characteristics. On postinfusion day 8, urine protein, thromboxane B2, and 11-dehydro-thromboxane B2 excretion, glomerular epithelial crescent formation, and glomerular cell proliferation in the CGS 12970-treated dogs were significantly decreased when compared with values in the placebo-treated group. Differences were not observed in endogenous creatinine clearance, urine prostaglandin E2 and 6-keto-prostaglandin F1 alpha excretion, or glomerular polymorphonuclear leukocyte infiltration between groups in this study. These findings suggest thromboxane A2 has a role in the development of immune complex glomerulonephritis and that thromboxane synthetase inhibition may be beneficial in attenuating some of the functional and histologic changes associated with immune complex glomerulonephritis.

The alpha 1-proteinase inhibitors of trypsin, Spi1, Spi3A, and Spi3B, in bronchoalveolar lavage fluid (BALF) and serum of horses were separated by electrophoresis, and their proportions were quantified in 12 control horses and 12 with chronic obstructive pulmonary disease (COPD). A significantly lower proportion of Spi3B (P < 0.05) and higher proportion of Spi1 (P < 0.02 to P < 0.01) were detected in BALF, compared with serum, in control and COPD-affected horses and appeared to be attributable to reduced Spi3 activity in BALF. There was no significant difference between the control and COPD groups in this respect, indicating that the decrease in Spi3 may be a physiologic phenomenon. The differences observed may be associated with proteolytic damage to or preferential complex formation by Spi3.

Serum alpha-mannosidase activity and swainsonine concentration were determined in 4 cattle and 15 sheep (3 groups of 5 each) that were administered ground locoweed (Oxytropis sericea or Astragalus lentiginosus) containing swainsonine at dosages of approximately 0.8 mg/kg of body weight/d (cows, 30 days each) and 0, 1.0, and 1.5 mg/kg/d (sheep, 11 days each). The cattle developed mild clinical signs of locoism, including signs of depression, lethargy, and slight intention tremors. Clinical signs of toxicosis were not observed in the sheep. Within 24 hours of initial treatment, serum alpha-mannosidase activity in cows and sheep, measured by the release of 4-methylumbelliferone from an artificial substrate, was markedly decreased to 28 and 40 micromoles of 4-methylumbelliferone/L, respectively. Mean serum alpha-mannosidase activity of control cows and sheep was 400 +/- 94 and 422 +/- 42 (mean +/- SD), respectively. In the treated animals, decreased serum alpha-mannosidase activities returned to normal or higher activities within 6 days after treatment was discontinued. Using a jack bean alpha-mannosidase assay, increased swainsonine activity (153, 209, and 381 ng/ml, respectively) was detected in the serum of cattle and of sheep in the high- and low-dose groups within 24 hours after treatment with locoweed. Swainsonine concentration remained high, with mean concentrations of 204, 432, and 395 ng/ml (cows and 2 sheep groups, respectively) during the treatment period. After treatment, swainsonine was rapidly cleared, with estimated serum half-life of 16.4, 17.6, and 20.3 hours (cows, and high- and low-dose sheep groups, respectively). Significant differences in either alpha-mannosidase activity or swainsonine concentration were not detected between the 2 groups of treated sheep. These results suggest that serum alpha-mannosidase and swainsonine values are sensitive indicators of locoweed intoxication in cattle and sheep. Furthermore, it suggests that swainsonine is rapidly absorbed, resulting in rapid inhibition of serum alpha-mannosidase activity, leading to high serum swainsonine concentration. After exposure is eliminated, swainsonine is rapidly cleared from the serum, with serum alpha-mannosidase activity returning to normal values shortly thereafter.

A repeated-measures study was conducted on 5 dogs to clinically, radiographically, and echocardiographically characterize the actions of the angiotensin-converting enzyme inhibitor, enalapril, before and after development of experimentally induced heart failure. Heart failure was artificially induced, using a surgically implanted programmable ventricular pacemaker, which stimulated the heart at a rate of 245 beats/min until a low-output cardiomyopathic a state developed. This condition was then stabilized by decreasing the pacing rate to 190 beats/min. Pacing-induced heart failure was successfully induced in a mean +/- SD 4.2 +/- 1.95 weeks. The condition closely resembled the clinical, radiographic, and echocardiographic features of naturally acquired idiopathic dilated cardiomyopathy in dogs. Enalapril was well tolerated by dogs, and clinical adverse reactions did not develop. Results of echocardiographic studies indicated that enalapril treatment during the control period resulted in a significant (P < 0.05) increase in velocity of circumferential fiber shortening and a significant (P < 0.05) decrease in left ventricular ejection time. Therapeutic responses to enalapril were evident after development of heart failure. These included reduced severity of clinical signs of disease, evidence of decreased radiographically determined cardiac size (2 of 5 dogs), radiographic evidence of a reduction in pulmonary edema and congestion (4 of 5 dogs), significant (P < 0.05) reductions in left atrial and ventricular chamber dimensions (left atrial dimension, diastolic left ventricular internal dimension as determined echocardiographically), and improvement in some echocardiographic indices of left ventricular performance (velocity of circumferential fiber shortening and left ventricular ejection time).

Objective--To test the hypothesis that endothelium-derived nitric oxide modulates vasomotor reactivity in equine digital arteries. Design--Digital arteries were isolated from adult horses, and their vasodilator properties were examined in an in vitro controlled environment. Animals--Five adult horses (1 gelding, 4 mares) without evidence of hoof or vascular disease were studied. Procedure--Arterial rings with or without endothelium were exposed to endothelium-dependent vasodilator drugs in the presence or absence of a pharmacologic inhibitor of the enzyme nitric oxide synthase. Results--Vasodilator effects of 3 endothelium-dependent vasorelaxant agents were significantly greater in endothelium-intact vessels than in endothelium-denuded vessels. Moreover a nitric oxide synthase inhibitor reduced vasodilator responses to endothelium-dependent vasodilators in endothelium-intact arteries, but had no discernable effects in endothelium-denuded arteries. Conclusions--These findings indicate the presence of endothelium-derived relaxing factor/nitric oxide in blood vessels of horses, and identify vascular endothelium as an endogenous modulator of vasomotor tone in the digital arteries of this species.

The lipoxygenase metabolites of arachidonic acid have an important role in lymphocyte activation. We used a specific 5-lipoxygenase inhibitor, A-63162, to examine the role of 5-lipoxygenase (5-LO) in equine blood mononuclear cell (BMC) proliferation and leukotriene B4 (LTB4) synthesis after stimulation with mitogen (phytohemagglutinin, PHA) or calcium ionophore (A23187). The A-63162 inhibited PHA-induced equine BMC proliferation and, at the same concentration, also inhibited A23187-induced LTB4 synthesis. The presence of exogenous interleukin 2 (IL-2) or the cyclooxygenase inhibitor indomethacin, failed to reverse the immunosuppression caused by A-63162. Further, we found that A-63162, at the concentration that inhibited BMC proliferation and LTB4 synthesis, had no effect on BMC viability. The addition of the specific protein kinase C inhibitor, H-7, did not inhibit A23187-induced LTB4 synthesis. Results indicate that 5-lipoxygenase metabolites may have an important role in equine lymphocyte activation and that protein kinase C has no role in regulating LTB4 production after A23187 stimulation.

A selected group of pharmaceutical compounds were evaluated for the ability to inhibit the biochemical activity of fibrinoligase (coagulation factor XIIIa) in pooled equine plasma. Criteria for the pharmaceuticals selected were based on the mechanism of the transglutamination biochemical reaction mediated by coagulation factor XIIa . These criteria were complemented by recognition of the molecular configuration and chemical composition of amino acid residue side chains involved in the process of covalent fibrin monomer polymerization (cross-linking, transglutamination) mediated by this enzyme. Each pharmaceutical was evaluated individually and in combination with other potential coagulation factor XIIIa inhibitors in an effort to detect additive and synergistic phenomenon. In this context, pharmaceuticals with a carbonylamide (eg, cefuroxime, Girard's reagent-P, prolinamide) were applied in concert with compounds with a terminal amine (eg, D-arginine, L-lysine) functional group. In concept, this method theoretically served to competitively simulate glutamine and lysine amino acid residues within strands of fibrin monomer substrate involved in phase I (carbonylamide) and phase II (terminal amine) of the transglutamination reaction (covalent fibrin monomer cross-linking). Halogen-dinitro and ethylene compounds were also evaluated because of their reported ability to inactivate enzyme systems dependent on an intact sulfhydryl group located at their biochemically active site (eg, cystine amino acid residue). This group of pharmaceutical compounds failed to inhibit the biochemical activity mediated by coagulation factor XIIIa in equine plasma.

A specific thromboxane synthetase inhibitor, 3-methyl-2 (3-pyridyl)-1-indoleoctanoic acid (CGS 12970) was administered orally to 6 healthy adult Beagles at a dosage of 30 mg/kg of body weight. Blood generation of thromboxane B2 and urinary excretion of thromboxane B2 were measured before and after administration of CGS 12970. Although 97 +/- 0.4% inhibition of thromboxane B2 generation was observed within 2 hours after a single dose of CGS 12970 was administered orally, an effect on urinary excretion of thromboxane B2 was not observed. Additionally, oral administration of 30 mg/kg every 12 hours resulted in 80 +/- 14% inhibition of thromboxane B2 generation but had no effect on urinary thromboxane B2 excretion.