Dysfunction In Rabbits Research Articles

Abstract P307: A Novel Protective Effect of the Antidiabetic Drug Voglibose via GLP-1 Receptor in the Infarcted Heart

Glucagon-like peptide 1 (GLP-1) reportedly exerts a protective effect against cardiac ischemia. We hypothesized that the α-glucosidase inhibitor voglibose, an unabsorbable antidiabetic drug with cardioprotective effects, may act via stimulation of GLP-1 receptors. The results of the present study suggest oral administration of voglibose reduces myocardial infarct size and mitigates cardiac dysfunction in rabbits following 30 min of coronary occlusion and 48 h of reperfusion. Voglibose increased basal and postprandial plasma GLP-1 levels and reduced postprandial plasma glucose levels. The infarct size-reducing effect of voglibose was abolished by treatment with exendin(9–39), wortmannin, L-NAME or 5-HD, which inhibit GLP-1 receptors, PI3K, NOS and K ATP channels, respectively. Western blot analysis showed that treatment with voglibose upregulated myocardial expression of phospho-Akt, phospho-eNOS, phospho-ERK and HSP27 following myocardial infarction. The upregulation of phospho-Akt was inhibited by exendin(9–39) and wortmannin, while the upregulation of phospho-ERK and HSP27 was inhibited by wortmannin but not by exendin(9–39). These findings suggest that voglibose reduces myocardial infarct size through stimulation of GLP-1 receptors, activation of PI3K-Akt-eNOS and ERK pathways, and the opening of mitochondrial K ATP channels. These findings may provide new insight into therapeutic strategies for the treatment of diabetic patients with coronary artery disease.

Effect of solifenacin plus and minus antioxidant supplements on the response to experimental outlet obstruction and overactive bladder dysfunction in rabbits—Part 2

ObjectiveOne of the most common forms of bladder dysfunction is related to the development of unstable bladder contractions (bladder overactivity). Solifenacin is a relatively new, selective, antimuscarinic agent that has been shown to be particularly useful in the treatment of overactive bladder (OAB) dysfunctions in both men and women. Experimentally, we have demonstrated that OAB and obstructive bladder dysfunction are associated with the generation of free radicals and oxidative damage to the bladder. The hypothesis tested was that solifenacin + coenzyme Q10 + α-lipoic acid (CoQ + LA) would be more effective in the treatment of OAB than either would be individually. Materials and methodsForty-eight male White New Zealand rabbits were separated into 8 groups of 6 rabbits each. The following oral treatments were given to each group: Groups 1 and 5, vehicle (saline); Groups 2 and 6, solifenacin; Groups 3 and 7, CoQ + LA; Groups 4 and 8, solifenacin + CoQ + LA. After three weeks of treatment (by oral gavage), the rabbits in Groups 1–4 received partial outlet obstruction as detailed above. The rabbits continued their treatments for four weeks following surgery. At the end of this four-week period, immediately following urodynamic and physiological studies, the bladder was excised and the muscle and mucosa were separated and frozen for biochemical research. ResultsThe following marker enzymes were quantitated: choline acetyltransferase, citrate synthase, catalase, superoxide dismutase, and malondialdehyde (MDA, marker for lipid peroxidation). Solifenacin had no effect on citrate synthase activity of the bladder smooth muscle. However, pretreatment with both the antioxidants or the combination of solifenacin + antioxidants protected the citrate synthase activity such that it remained at control values. Partial outlet obstruction (PBOO) resulted in a 60% decrease in choline acetyltransferase activity (ChAT) activity, while solifenacin had no effect on reduced ChAT activity. Both the antioxidant and combination therapy resulted in maintaining ChAT activity at control values. PBOO resulted in a significant increase in MDA of both the muscle and mucosa. For both tissues, all treatments resulted in a significantly lower MDA content. In general, the results demonstrate the combination of solifenacin + antioxidants was more effective than either solifenacin or antioxidants alone. ConclusionThe addition of the antioxidants CoQ + LA works synergistically with solifenacin in the treatment of obstructive bladder dysfunction and OAB.

Effect of solifenacin with and without antioxidant supplements on the response to experimental outlet obstruction and overactive bladder dysfunction in rabbits: Part 1

ObjectiveOne of the most common forms of urinary dysfunction is related to the development of overactive bladder (OAB) dysfunction. Solifenacin is a relatively new selective antimuscarinic agent that has been shown to be particularly useful in treating OAB dysfunction in both men and women. Experimentally, we have previously demonstrated that OAB is associated with the generation of free radicals and oxidative damage to the bladder. We tested the hypothesis that the combination of solifenacin + coenzyme Q10 (CoQ10) + α-lipoic acid (α-LA) is more effective in treating OAB than the individual compounds. Materials and MethodsIn total, 48 male New Zealand White rabbits were separated into 8 groups of 6 rabbits each. The following oral treatments were given to each group: groups 1 and 5 received vehicle (saline); groups 2 and 6 received solifenacin; groups 3 and 7 received CoQ10 + α-LA; and groups 4 and 8 received solifenacin + CoQ10 + α-LA. After 3 weeks of treatment (by oral gavage), rabbits in groups 1 to 4 received partial outlet obstruction. The rabbits continued their treatments for 4 weeks following surgery. At the end of this 4-week period, each rabbit received cystometry and then underwent an in situ study for OAB. ResultsThe results clearly demonstrated that obstructive bladder dysfunction and the level of OAB were reduced in all three treatment groups, but the combination of solifenacin + antioxidants was significantly more effective than either solifenacin or antioxidants alone. ConclusionThe addition of the antioxidants CoQ10 + α-LA worked synergistically with solifenacin in the treatment of obstructive bladder dysfunction and OAB.

NADPH oxidase inhibition ameliorates cardiac dysfunction in rabbits with heart failure

Increased NADPH oxidase activity is found in both experimental and clinical HF. Here, we investigated the effects and mechanisms of NADPH oxidase inhibition on cardiac function in rabbits with HF. HF was induced by combined volume and pressure overload. Rabbits with HF or sham operation were randomized to orally receive apocynin, an inhibitor of NADPH oxidase (15 mg per day) or placebo for 8 weeks. Echocardiography was performed to examine the cardiac function and structure of the rabbits. Cardiac fibrosis was evaluated by masson's trichrome staining. The transforming growth factor-beta (TGF-β), connective tissue growth factor (CTGF), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) expression were measured by real-time PCR. The expression of SERCA2a and phospholamban (PLB) was detected by reverse transcription-polymerase chain reaction and Western Blot. SERCA2a activity was evaluated by measuring the Pi liberated from ATP hydrolysis. Rabbits with HF exhibited cardiac dysfunction and fibrosis. These changes were associated with significant increases in myocardial NADPH oxidase activity and oxidative stress. Compared with sham-operated rabbits, the TGF-β, CTGF, MMP-2, and MMP-9 mRNA expression significantly increased, the expression of SERCA2a and PLB dramatically decreased, and the SERCA2a activity was lower in HF rabbits. Apocynin reduced NADPH oxidase activity and oxidative stress, decreased TGF-β, CTGF, MMP-2, and MMP-9 expression, attenuated cardiac fibrosis, increased SERCA2a and PLB expression, restored SERCA2a activity, and thereby ameliorated cardiac dysfunction. Thus, chronic NADPH oxidase inhibition ameliorated cardiac dysfunction by decreasing cardiac fibrosis and preserving SERCA2a expression and activity.

Antidiabetic Drug Voglibose Is Protective Against Ischemia—Reperfusion Injury Through Glucagon-Like Peptide 1 Receptors and the Phosphoinositide 3-Kinase-Akt-Endothelial Nitric Oxide Synthase Pathway in Rabbits

Glucagon-like peptide 1 (GLP-1) reportedly exerts a protective effect against cardiac ischemia. We hypothesized that the alpha-glucosidase inhibitor voglibose, an unabsorbable antidiabetic drug with cardioprotective effects, may act through stimulation of GLP-1 receptors. The results of the present study suggest oral administration of voglibose reduces myocardial infarct size and mitigates cardiac dysfunction in rabbits after 30 minutes of coronary occlusion and 48 hours of reperfusion. Voglibose increased basal and postprandial plasma GLP-1 levels and reduced postprandial plasma glucose levels. The infarct size-reducing effect of voglibose was abolished by treatment with exendin(9-39), wortmannin, Nomega-nitro-L-arginine methylester, or 5-hydroxydecanoate), which inhibit GLP-1 receptors, phosphoinositide 3-kinase, nitric oxide synthase, and K(ATP) channels, respectively. Western blot analysis showed that treatment with voglibose upregulated myocardial levels of phospho-Akt, phosphoendothelial nitric oxide synthase after myocardial infarction. The upregulation of phospho-Akt was inhibited by exendin(9-39) and wortmannin. These findings suggest that voglibose reduces myocardial infarct size through stimulation of GLP-1 receptors, activation of the phosphoinositide 3-kinase-Akt-endothelial nitric oxide synthase pathways, and the opening of mitochondrial K(ATP) channels. These findings may provide new insight into therapeutic strategies for the treatment of patients with coronary artery disease.

Treatment of Obstructive Bladder Dysfunction in Rabbits with Coenzyme Q10 and Alpha Lipoic Acid

Objectives: Partial bladder outlet obstruction (PBOO) is one of the major pathological effects of benign prostatic hyperplasia in men. It is well demonstrated that ischemia followed by reperfusion and the resulting generation of free radicals and oxidative damage to proteins occur in our rabbit model of PBOO and are involved in the observed progressive obstructive bladder dysfunction. The aim of the current project was to determine if treatment of obstructed rabbits with alpha lipoic acid and coenzyme Q10 can reverse the urodynamic, biochemical, and physiological responses to PBOO.Methods: Twenty adult NZW male rabbits were divided into four groups (n = 5 per group): control (sham surgical) animals with no treatment (group 1); control animals treated with coenzyme Q10 + alpha lipoic acid for 3 weeks beginning 4 weeks after surgery (group 2); 7‐week obstructed rabbits (group 3); and 7‐week obstructed rabbits treated for the last 3 weeks with the combination of the two drugs (group 4).Results: Bladder weight, compliance, volume at micturition and contractile response to all forms of stimulation were reduced following obstruction, but significantly improved after treatment. In addition, the level of reactive oxygen species and reactive nitrogen species damage was significantly reduced by treatment.Conclusion: Our results provide additional support for the beneficial effects of treatment of PBOO with strong antioxidants.

Neurally adjusted ventilatory assist decreases ventilator-induced lung injury and non-pulmonary organ dysfunction in rabbits with acute lung injury

To determine if neurally adjusted ventilatory assist (NAVA) that delivers pressure in proportion to diaphragm electrical activity is as protective to acutely injured lungs (ALI) and non-pulmonary organs as volume controlled (VC), low tidal volume (Vt), high positive end-expiratory pressure (PEEP) ventilation. Prospective, randomized, laboratory animal study. Twenty-seven male New Zealand white rabbits. Anesthetized rabbits with hydrochloric acid-induced ALI were randomized (n = 9 per group) to 5.5 h NAVA (non-paralyzed), VC (paralyzed; Vt 6-ml/kg), or VC (paralyzed; Vt 15-ml/kg). PEEP was adjusted to hemodynamic goals in NAVA and VC6-ml/kg, and was 1 cmH2O in VC15-ml/kg. PaO2/FiO2; lung wet-to-dry ratio; lung histology; interleukin-8 (IL-8) concentrations in broncho-alveolar-lavage (BAL) fluid, plasma, and non-pulmonary organs; plasminogen activator inhibitor type-1 and tissue factor in BAL fluid and plasma; non-pulmonary organ apoptosis rate; creatinine clearance; echocardiography. PEEP was similar in NAVA and VC6-ml/kg. During NAVA, Vt was lower (3.1 +/- 0.9 ml/kg), whereas PaO2/ FiO2, respiratory rate, and PaCO2 were higher compared to VC6-ml/kg (p<0.05 for all). Variables assessing ventilator-induced lung injury (VILI), IL-8 levels, non-pulmonary organ apoptosis rate, and kidney as well as cardiac performance were similar in NAVA compared to VC6-ml/kg. VILI and non-pulmonary organ dysfunction was attenuated in both groups compared to VC15-ml/kg. In anesthetized rabbits with early experimental ALI, NAVA is as effective as VC6-ml/kg in preventing VILI, in attenuating excessive systemic and remote organ inflammation, and in preserving cardiac and kidney function.

Adventitial application of the NADPH oxidase inhibitor apocynin in vivo reduces neointima formation and endothelial dysfunction in rabbits

Reactive oxygen species including superoxide have been shown to promote atherogenesis. We previously showed that a major source of superoxide, the NADPH oxidase system, is upregulated in the intima and adventitia during remodelling induced by periarterial collars in rabbits. We have now examined the action of the NADPH oxidase inhibitor apocynin, given via the adventitia, on the neointima formation and endothelial function in this model. Perivascular collars were implanted around the common carotid arteries of male NZW rabbits for 14 days to induce intimal thickening. The periarterial space of one collar was filled with apocynin (1 mM) while the contralateral collar with the vehicle (0.1% DMSO). After 14 days, local treatment with apocynin via the adventitia, reduced superoxide generation. In addition, apocynin significantly reduced neointima formation and proliferation of cells in both the neointima and adventitia. Moreover, NO-dependent vasorelaxation to acetylcholine, which is normally impaired in collared arteries, was improved, and apocynin suppressed the endothelial expression of intracellular adhesion molecule-1 and vascular cell adhesion molecule-1. NADPH oxidase is implicated in vascular remodelling and superoxide-stimulated cell proliferation in the neointima contributes to intimal hyperplasia in this collar model. Targeting NADPH oxidase via adventitial drug delivery not only reduces superoxide generation, but also normalises endothelial cell function. Targeting the primary source of NADPH oxidase-derived superoxide is an effective approach to prevent deleterious arterial remodelling, providing a rationale for designing more efficacious and selective inhibitors of vascular NADPH oxidase as potential therapeutics for human vascular disease.

Chlorpyrifos induces cardiac dysfunction in rabbits

This study was carried out to evaluate the effects of organophosphate (OP) insecticide chlorpyrifos on cardiac morphology and function in rabbits using echocardiography. Twenty New Zealand male rabbits were divided equally into four groups. Rabbits were exposed to chlorpyrifos in drinking water at concentrations of 0, 125, 250 or 375 ppm for 90 days. The comparison among the groups indicated that 375 ppm chlorpyrifos resulted in significant decrease ( p < 0.05) in heart rate (HR), cardiac output (CO), left ventricular fractional shortening (FS), left ventricular ejection fraction (EF), percentage thickening of left ventricle posterior wall (PWT), and significant increase ( p < 0.05) in left atrial diameter (LA), left ventricular internal diameter in end diastole (LVIDD), left ventricular end diastolic (EDV) and end systolic volumes (ESV) compared to those of the control group. These results showed that chlorpyrifos induces cardiac dysfunction in rabbits.

Mechanisms of endothelial dysfunction after ionized radiation: selective impairment of the nitric oxide component of endothelium-dependent vasodilation.

(1) Gamma radiation impairs vascular function, leading to the depression of endothelium-dependent vasodilatation. Loss of the nitric oxide (NO) pathway has been implicated, but little is known about radiation effects on other endothelial mediators. (2) This study investigated the mechanisms of endothelial dysfunction in rabbits subjected to whole-body irradiation from a cobalt(60) source. (3) The endothelium-dependent relaxation of rabbit aorta evoked by acetylcholine (ACh) or A23187 was impaired in a dose-dependent manner by irradiation at 2 Gy or above. Inhibition was evident 9 days post-irradiation and persisted over the 30 day experimental period. (4) Endothelium-independent responses to glyceryl trinitrate (GTN), sodium nitroprusside (SNP) and 3-morpholino-sydnonimine (SIN-1) were suppressed over a similar dose range at 7-9 days post-irradiation, but recovered fully by 30 days post-irradiation. (5) In healthy vessels, ACh-induced relaxation was inhibited by L-N(omega)-nitroarginine (L-NA; 3 x 10(-4) M) and charybdotoxin (10(-8) M) plus apamin (10(-6) M) but resistant to indomethacin, indicating the involvement of NO and endothelium-derived hyperpolarizing factor (EDHF). Supporting this, ACh caused smooth muscle hyperpolarization that was reduced by L-NA and charybdotoxin plus apamin. (6) In irradiated vessels, responses to ACh were insensitive to L-NA but abolished by charybdotoxin plus apamin, indicating selective loss of NO-mediated relaxation. (7) In animals treated shortly after irradiation with the antioxidant, alpha-tocopherol acetate, the NO-dependent relaxation was restored without effect on the EDHF-dependent component. (8) The results imply that radiation selectively impairs the NO pathway as a consequence of oxidative stress, while EDHF is able to maintain endothelium-dependent relaxation at a reduced level.

Distinct mechanisms implicated in atherosclerosis-induced erectile dysfunction in rabbits

Ageing and atherosclerosis (ATH) are well-known risk factors for erectile dysfunction (ED). To identify the mechanisms implicated in ATH-induced ED, independently of its ageing-associated component, we studied (i) erectile responses in vivo, and, (ii) endothelium-dependent and independent relaxations of corporal strips from young adult (YAD, n=6), adult (AD, n=6), and cholesterol-fed (ATH, n=8) New-Zealand white rabbits. Measurement of Intima/Media (I/M) ratio on iliac arteries from ATH rabbits determined those with moderate (Mod ATH, 0.5±0.3) or severe (Sev ATH, 1.5±0.4, P<0.05 Mann–Whitney) atherosclerotic lesions. Erectile responses were reduced in AD compared with YAD rabbits (at 6 V to 10 Hz: 51.6±4.6% vs. 57.5±1.4%); they were similar in AD and mod ATH rabbits (48.1±4.6%) but drastically impaired in Sev ATH rabbits (34.8±5.4%, P<0.05, two-way analysis of variance (ANOVA)). Corporal endothelium-dependent and -independent relaxations were comparable in YAD and AD rabbits (maximal relaxation to acetylcholine: 51.3±9.5 vs. 56.1±9.3%) but decreased in ATH rabbits (37.1±1.6%, P<0.001, two-way ANOVA). These results suggest that the mechanisms implicated in ATH-induced ED are distinct from the ageing-related process in rabbits. Thus, future therapeutic targets to treat or prevent ATH-induced ED may include the reduction of the atherosclerotic plaque size or progression, as well as an improvement of the smooth muscle and endothelial reactivity of the corpus cavernosum.

Mechanisms of cholinergic dysfunction in rabbits following recurrent aspiration of cow's milk.

Recurrent aspiration of cow's milk has been shown to alter neural control of airways in young rabbits (Gelfand et al., 1997). The purpose of this study was to define the mechanisms responsible for in vitro cholinergic hyperresponsiveness in this model. Beginning at 1 week of age, rabbits received either 0.5 mL/kg whole cow's milk or sterile saline intranasally while under light anesthesia. This was repeated each weekday for 2 weeks. At 8 weeks of age, rabbits were sacrificed. Portions of lungs underwent lavage with sterile saline. Tracheal smooth muscle (TSM) segments were also removed. Segments were assessed for acetylcholine (ACh) release by high-performance liquid chromatography ( HPLC) with electrochemical detection or acetylcholinesterase (AChE) kinetic activity by spectrophotometry. Substance P (SP), a neuropeptide that can increase ACh release from nerves, was also assessed using an enzyme immunoassay to define the content in lavage and TSM segments. Immunohistochemistry for SP within airways was also assessed. We found that recurrent aspiration of milk led to statistically significant alterations in many parameters. Acetylcholine release was significantly greater in segments of airways from rabbits that had aspirated cow's milk (27.5 +/- 1.7 vs. 20.1 +/- 1.6 pmol/min/g tissue) than saline. At the same time, AChE activity was less in the group that aspirated milk (8.7 +/- 0.4 vs. 10.2 +/- 0.5 nmol/min/mg protein) compared to saline. The amount of SP within both lavage as well as tissue homogenates was greater in the group that had aspirated the foreign protein (159.1 +/- 28.9 vs. 41.9 +/- 5.2 pmol/mg protein in lavage; 158.7 +/- 31.9 vs. 80.5 +/- 7.8 pmol/mg protein in tissues) than saline controls. While total cholinergic nerve density as assessed by choline acetyltransferase was not significantly different between groups, SP-positive immunoreactive nerves were easily identified in the group that aspirated cow's milk. This study suggests that cholinergic hyperresponsiveness caused by repeated aspiration of milk is due to several abnormalities, including prejunctional (increase in ACh release) as well as junctional (decrease in AChE) mechanisms within the airways. In addition, an upregulation of SP within airways is part of this process.

Dexamethasone Prevents Acute Cadmium-Induced Hepatic Injury but Exacerbates Kidney Dysfunction in Rabbits

Cadmium is a potent hepatotoxicant for which neither effective preventive methods nor the mechanism of toxicity has been established. We investigated the preventive effect of dexamethasone against cadmium toxicity on cadmium-induced liver injury in rabbits. Pretreatment with dexamethasone at 1 mg/kg increased the rate of survival in rabbits administered 2.5 mg/kg iv cadmium. Cadmium induced acute severe liver injury characterized by hepatocellular necrosis, infiltration by inflammatory cells, and increases of plasma GOT, GPT, LDH, and LDH5. Dexamethasone mitigated the acute hepatotoxic effect of cadmium, but exacerbated cadmium-induced kidney dysfunction, with destruction of renal tubular cells and increases in excretion of protein, glucose, and amino acids into urine. The cadmium concentration in liver and kidney of rabbits administered cadmium was not changed by dexamethasone pretreatment. Although metallothionein mRNA expression induced by cadmium was not affected by dexamethasone in liver or kidney, cadmium-induced metallothionein protein production was augmented at the early phase in liver and decreased at the later phase in kidney. Neutrophilia observed after cadmium administration was enhanced initially by dexamethasone pretreatment. These results indicate that dexamethasone pretreatment potently prevented cadmium-induced liver injury, but exacerbated renal tubular dysfunction.

Effect of atorvastatin on endothelium-dependent constrictor factors in dyslipidemic rabbits

Relaxations to acetylcholine and contractions to acetylcholine in the presence of the nitric oxide (NO) synthesis inhibitor ( l- N G-nitroarginine methyl ester, l-NAME) were studied in aortic rings from rabbits fed either a control or a diet containing 0.5% cholesterol+14% coconut oil for 14 weeks and treated or not with atorvastatin (2.5 mg kg −1 day −1). Rings were incubated with the endothelin (ET A) receptor antagonist BQ123, and/or the thromboxane A 2 (TXA 2)/prostaglandin H 2 (PGH 2) receptor antagonist ifetroban. In rabbits, high cholesterol and triglyceride plasma levels were associated with intimal thickening and blunted acetylcholine-relaxation as compared with controls. By contrast, acetylcholine+ l-NAME response was higher. Incubation with either ifetroban or BQ123 increased acetylcholine-relaxation in both diet groups and it reduced the constrictor response only in dyslipidemic rabbits. Removal of endothelium reduced acetylcholine+ l-NAME contraction in dyslipidemic rabbits, although increased it in control animals. Atorvastatin treatment reduced plasma lipid levels and lesion size in dyslipidemic animals. Likewise, it prevented acetylcholine-relaxation reduction. In addition, atorvastatin reduced constrictor response in dyslipidemic rabbits but only in rings with endothelium. Incubation with either ifetroban or BQ123 did not further modify these responses in atorvastatin-treated animals in any group. These data suggest that ET and TXA 2 availabilities seem to participate in the endothelial dysfunction associated with dyslipidemia. Atorvastatin treatment reduces intimal thickening and improves endothelial dysfunction in rabbits. This effect seems to be a consequence of its ability to act on ET and TXA 2 systems.

家兎におけるバンコマイシンの腎機能障害に及ぼす併用薬の影響 （４）

家兎におけるバンコマイシンの腎機能障害に及ぼす併用薬の影響 （４）

Long-term total parenteral nutrition-induced hepatobiliary dysfunction in a rabbit model

Background/Purpose: Currently, the reason for hepatobiliary dysfunction associated with long-term total parenteral nutrition (TPN) is much debated and still unclear. No agreement can be achieved about whether bacteriotoxins and sepsis, enteral starvation, consequences of abdominal operations, or the TPN solution itself is the real cause for the disease. Animal models were criticized for their short period of TPN and their failure to demonstrate cholestasis and bile duct proliferation. The aim of this study was to establish an animal model for long-term TPN in which the same alterations of the hepatobiliary system as observed in humans could be produced. Methods: In this model, rabbits could be kept for the first time under continuous TPN for 4 weeks. Three serial liver biopsy sections were taken operatively from each animal and biochemical analyses were performed four times. A control group of enterally fed rabbits underwent exactly the same procedure in respect to operations and handling, so that differences in macroscopical, biochemical, and histological changes between both groups could be attributed exclusively to TPN. Results: Only in the TPN group gallbladder distension developed in all animals after 1 week. After 3 and 4 weeks, viscous dark bile, sludge and stones, a slight rise in direct bilirubin, and a decline in plasma albumin and alkaline phosphatase was noted. In both groups liver biopsy results showed a similar degree of mild portal inflammation and single-cell necrosis at equivalent time points. These changes could be caused by antiseptics, antibiotics, anesthesia, and operations. Although mild to moderate proliferative changes and no hydropic degeneration developed in the control group during the same time, the TPN group generated marked proliferative and degenerative changes. We noted as early as 1 week after starting TPN a severe hydropic degeneration in 90% of the animals. Fibrosis and bile duct proliferation increased from a slight degree after 1 week up to a moderate to severe degree after 3 and 4 weeks, respectively. Conclusions: The hepatobiliary alterations associated with TPN in children, which cannot be separated clinically from consequences of multiple other factors, can almost identically be reproduced in our rabbit model as a clear consequence of TPN. Furthermore, the hydropic degeneration of the liver cells begins in zone 3 and is an early predominant feature of hepatobiliary dysfunction in rabbits and infants. It must be rated as a response to a direct cytotoxic effect on the liver cell.

Effect of the beta-agonist clenbuterol on dexamethasone-induced diaphragm dysfunction in rabbits.

The present study was designed to examine whether clenbuterol (CLEN) could reduce dexamethasone (DEX)-induced diaphragm dysfunction. We studied four groups of New Zealand white (NZW) rabbits, each receiving one of the following daily injections subcutaneously for 2 wk: saline (control), DEX 3 mg/kg, DEX 3 mg/kg + CLEN 2 mg/kg, and CLEN 2 mg/kg. Diaphragm fiber cross-sectional areas (CSA) were measured. Twitch transdiaphragmatic pressure (Pdi) and tetanic Pdi were measured during bilateral phrenic stimulation both before and after 60 min of inspiratory resistive loading (IRL). DEX produced a marked atrophy of type IIa and type IIb diaphragm fibers. This diaphragm atrophy was prevented by CLEN in the DEX plus CLEN group. CLEN alone increased CSAs of all three types of diaphragm fibers. Significant reductions in twitch Pdi and tetanic Pdi at all stimulation frequencies both before and after IRL were observed similarly in the DEX group as well as in the DEX plus CLEN group compared with the control animals. We conclude that DEX produces significant diaphragm atrophy and decreases diaphragmatic contractility. CLEN produces hypertrophy of the diaphragm and minimizes diaphragm atrophy induced by DEX, but it has no demonstrable protective effect on DEX-induced diaphragm dysfunction.

Complement-induced endothelial dysfunction in rabbits: mechanisms, recovery, and gender differences.

Activation of complement and attenuation of endothelium-dependent relaxation occur in a number of pathophysiological conditions. The aim of this study was to investigate the mechanisms of human complement activation and loss of endothelium-dependent relaxation in rabbit tissue, the duration of this loss, and the effects of gender and serum concentration. In rabbit thoracic aortic rings precontracted with phenylephrine, human serum (HS) concentration dependently induced a loss of endothelium-dependent relaxation to the receptor-dependent vasodilator acetylcholine (ACh) and receptor-independent vasodilator calcium ionophore A23187. Serum-induced loss of ACh-dependent relaxation was decreased when rings were bathed in 1) HS depleted of factor B, C2, or C8, 2) heat-inactivated HS, or 3) HS with complement inhibitor sCR1 or sCR1[desLHR-A]. Superoxide dismutase had no effect on serum-induced loss of ACh-dependent relaxation. Serum-induced loss of ACh-dependent relaxation returned to control values after removal of HS. Serum-induced loss of ACh-dependent relaxation was greater in male than in female aortic rings. These results suggest that 1) complement activation directly attenuates endothelium-dependent relaxation via the classical and alternative pathways independent of superoxide anion formation, 2) this attenuation is concentration dependent, reversible, and dependent on formation of C5b-9, and 3) endothelial tissue from males is more susceptible than that from females to the acute effects of complement activation.

Acquired immune dysfunction in rabbits experimentally infected with an infectious molecular clone of the bovine immunodeficiency virus (BIV127).

To investigate the effect of bovine immunodeficiency virus (BIV) infection on the rabbit immune system, we studied the proliferative responses of peripheral blood lymphocytes (PBLs) of rabbits experimentally inoculated with BIV. All BIV127-inoculated rabbits seroconverted after 6 weeks and remained seropositive over a prolonged period of time. Assays for specific lymphocyte reactivity to concanavalin A (Con A) were performed monthly for over 1 year. One-hundred percent of infected rabbits developed abnormally low T cell responses, as measured by Con A stimulation. By 3 months postinoculation, the PBL response to Con A was diminished and remained depressed for 6 months. All animals were clinically asymptomatic within 14 months of BIV inoculation. By 15 and 16 months postinoculation, two of three infected rabbits exhibited recurrent lowering of the T cell responsiveness including a decrease in absolute PBL counts. One of these animals died unexpectedly. Our results further confirmed that a functional impairment of lymphocytes was induced early in the course of BIV infection, prior to clinical disease. These findings suggested that BIV infection may mimic asymptomatic infection of human immunodeficiency virus (HIV) and provided further evidence of the importance of BIV-induced disease in rabbits as a relevant model for the study of AIDS.

Vitamin E Protects against Cholesterol-Induced Endothelial Dysfunction in Rabbit

Vitamin E Protects against Cholesterol-Induced Endothelial Dysfunction in Rabbit