Dysfunction In Guinea Pigs Research Articles

Dietary Long-Chain Fatty Acids Accelerate Metabolic Dysfunction in Guinea Pigs with Non-Alcoholic Steatohepatitis.

The composition of dietary fatty acids may be important for the development and progression of metabolic syndrome and non-alcoholic steatohepatitis (NASH). This study investigated the effect of two high-fat diets based on coconut oil, containing predominantly medium-chain fatty acids (MCFA), or cocoa butter, containing mainly long-chain fatty acids (LCFA), on glucose homeostasis and NASH in guinea pigs following 16 and 32 weeks of diet. At week 16, glucose intolerance was increased in the LCFA animals compared to the MCFA animals (p < 0.001), with both groups differing from the controls by week 32 (p < 0.0001), supported by increased hemoglobin A1c (p < 0.05). NASH was present in both high-fat groups from week 16, with advancing fibrosis appearing more progressive in the LCFA animals at week 16. In agreement, gene expression showed overall increased expression of NASH target genes in the LCFA animals compared to the MCFA animals at weeks 16 and 32 (p < 0.05 and p < 0.0001, respectively). The LCFA animals also displayed increased plasma uric acid at both time points (p < 0.05), a phenomenon linked to NASH in humans. In conclusion, this study reports that a diet high in LCFA promotes metabolic imbalance and may accelerate NASH-associated hepatic fibrosis. This highlights the importance of a critical evaluation of fatty acid composition when investigating NASH-associated endpoints.

Reversible renal glomerular dysfunction in guinea pigs exposed to glutaraldehyde-polymerized cell-free hemoglobin

Chemically modified hemoglobin (Hb)-based oxygen carriers are promising oxygen replacement therapeutics however their potential renal effects are not fully understood. Using a guinea pig exchange transfusion model, we examined the effects of glutaraldehyde-polymerized bovine hemoglobin (HbG) on the permeability and integrity of the glomerular filtration barrier (GFB), which is comprised of podocytes, fenestrated endothelium, and the glomerular basement membrane. HbG induced marked proteinuria characterized in part by the loss of high molecular weight proteins, including albumin, immunoglobulin, and transferrin, at 4 and 12 h post-infusion that resolved by 72 h. This correlated with HbG-induced GFB alterations based on the reduced expression of specific markers of podocytes (podocin, nephrin, podocalyxin, and Wilms Tumor 1 protein) and endothelial cells (ETS-related gene and claudin-5). Lectin binding studies also demonstrated marked but reversible alterations to the GFB glycocalyx accompanied by increased intraglomerular HbG deposition and 4-HNE protein adduct expression indicative of oxidative damage. Together, these findings indicate that HbG induces reversible glomerular barrier dysfunction in conjunction with transient GFB changes providing new insight into the renal response to chemically modified Hb therapeutics.

Vestibular Function Change in a Vasopressin-Induced Hydrops Model.

A vasopressin-induced endoymphatic hydrops model can represent an acute vertiginous attack in Menière's disease (MD). Previous animal models are not appropriate to evaluate the efficacy of new treatments for hydrops because they cannot represent an acute attack of MD. Recently, a new dynamic model was introduced for acute hydrops exacerbation using the vasopressin type 2 receptor agonist, desmopressin (1-deamino-8-D-Arginine vasopressin, VP); however, resulting changes in vestibular function have not been investigated. A total of 37 guinea pigs were used. Two to 4 weeks after surgical ablation of endolymphatic sacs in 33 guinea pigs, acute exacerbation of hydrops was induced by a single VP injection in 18 animals (group A). Next, two VP injections at 1 hour interval were administered to investigate the effect of multiple VP doses on vestibular function in the other 15 animals (group B). In the remaining four animals, VP was injected without surgery for the control group (control). Bidirectional sinusoidal harmonic acceleration (SHA) tests of vestibular function were performed. "Type I response" was defined as when the maximum slow-phase velocity (SPV) during left rotation (toward the operated ear) was lower than that during right rotation (toward the normal ear). In contrast, "Type II response" was defined as when maximum SPV at the left rotation was higher than that at the right rotation. Vestibular symmetry scores were analyzed at baseline and after each of two VP injections given 1 hour apart. Vestibular symmetry scores increased at 1 hour after VP injection in all 18 animals in group A (p < 0.001). Two hours after VP injection, symmetry score decreased to the initial score. Two different types of vestibular response were observed after VP. However, the symmetry scores between type I and II responses were not significantly different (p = 0.173). In all 15 animals of Group B, vestibular asymmetry was sustained over 3 hours when two VP injections were given 1 hour apart. In three of Group B, the type of vestibular response changed from type II response to type I response after the 2nd VP injection; however, no animal demonstrated a shift from type I to type II response. VP can transiently induce an acute exacerbation of hydrops and asymmetric vestibular dysfunction in guinea pigs. This model could help in studying new treatments for acute hydrops and in explaining the mechanism of bidirectional nystagmus in MD.

Bilirubin Attenuates Bufadienolide-Induced Ventricular Arrhythmias and Cardiac Dysfunction in Guinea-Pigs by Reducing Elevated Intracellular Na+ Levels

Bufadienolides, known ligands of the sodium pump, have been shown to inhibit the proliferation of several cancer cell types. However, their development to date as anticancer agents has been impaired by a narrow therapeutic margin resulting from their potential to induce cardiotoxicity. In the present study, we examined the effects of bilirubin, an endogenous antioxidant, on the cardiotoxicity of bufadienolides (derived from toad venom) in guinea-pigs. The results showed that bufadienolides (8mg/kg) caused ventricular arrhythmias, conduction block, cardiac dysfunction and death in guinea-pigs. Pretreatment with bilirubin (75 and 150mg/kg) significantly prevented bufadienolide-induced premature ventricular complexes, ventricular tachycardia, ventricular fibrillation and death. Bilirubin also markedly improved the inhibition of cardiac contraction in bufadienolide-treated guinea-pigs as evidenced by increases in left ventricular systolic pressure and decreases in left ventricular diastolic pressure in vivo. Furthermore, bilirubin significantly reduced the intracellular sodium content ([Na(+)]( i )) in ex vivo bufadienolide-stimulated guinea-pig ventricular myocytes loaded with the sodium indicator Sodium Green. An antitumor study showed that bilirubin did not compromise the ability of bufadienolides to inhibit gastric cancer cell MGC-803 proliferation. These results suggested that bilirubin can attenuate bufadienolide-induced arrhythmias and cardiac dysfunction in guinea-pigs by reducing elevated [Na(+)]( i ) and may improve bufadienolide therapeutic index in cancer treatment.

A Combined Deficiency of Vitamins E and C Causes Severe Central Nervous System Damage in Guinea Pigs

A short period of combined deficiency of vitamins E and C causes profound central nervous system (CNS) dysfunction in guinea pigs. For this report, CNS histopathology was studied to define the nature and extent of injury caused by this double deficiency. Weanling guinea pigs were fed a vitamin E-deficient or -replete diet for 14 d. Then vitamin C was withdrawn from the diet of some guinea pigs. Four diet groups were thus formed: replete, vitamin E deficient, vitamin C deficient, and both vitamin E and C deficient. From 5 to 11 d after institution of the doubly deficient diet, 9 of 12 guinea pigs developed paralysis, and 2 more were found dead. The remaining guinea pig in the doubly deficient group and all animals in the other 3 groups survived without clinical impairment until the experiment was terminated at 13-15 d. Brains and spinal cords were serially sectioned and stained for examination. Only the combined deficiency produced damage in the CNS. The damage consisted mainly of nerve cell death, axonal degeneration, vascular injury, and associated glial cell responses. The spinal cord and the ventral pons in the brainstem were most severely affected, often exhibiting asymmetric cystic lesions. Several features of the lesions suggest that the primary damage was to blood vessels. These results indicate that the paralysis and death caused by combined deficiency of vitamins E and C in guinea pigs is caused by severe damage in the brainstem and spinal cord.

Cochlear damage due to germanium-induced mitochondrial dysfunction in guinea pigs

This investigation addressed the effect of germanium dioxide (GeO 2)-induced mitochondrial dysfunction on hearing acuity. Guinea pigs were fed chow that contained 0%, 0.15%, or 0.5% GeO 2. The animals that were fed 0.5% GeO 2 for 2 months developed hearing impairment chiefly due to degeneration of stria vascularis and cochlear supporting cells, which exhibited electron-dense mitochondrial inclusions. Cytochrome c oxidase activity was decreased in the skeletal muscles and kidney, which also exhibited electron-dense mitochondrial inclusions. No apparent pathological changes were observed in the utricle, semicircular canal, or among the vestibular nerve fibers, or in the liver or heart. The untreated animals and those treated with 0.15% GeO 2 did not exhibit hearing impairment or pathological changes in any organs. These findings suggest that administration of 0.5% GeO 2 induces mitochondrial dysfunction in the stria vascularis and supporting cells in the cochlea, as in the skeletal muscles and kidney, thereby causing hearing impairment in the guinea pigs.

High cholesterol diet induces baroreceptor dysfunction in guinea pigs

OR-28 Key Words: Baroreflex, Cholesterol, Autonomic Nervous System

Dexamethasone prevents virus-induced hyperresponsiveness via multiple mechanisms.

In the lungs, neuronal M2 muscarinic receptors inhibit acetylcholine release from the parasympathetic nerves. Parainfluenza virus infection causes loss of M2 receptor function, which increases acetylcholine release and vagally mediated bronchoconstriction. Because glucocorticoids are known to inhibit airway hyperresponsiveness, we tested whether dexamethasone (6.5 or 65 microg/kg i.p.) prevents virus-induced hyperresponsiveness and M2 receptor dysfunction in guinea pigs. In controls, pilocarpine, a muscarinic agonist, inhibited vagally induced bronchoconstriction, demonstrating functional M2 receptors. However, in virus-infected animals, pilocarpine failed to inhibit vagally induced bronchoconstriction, demonstrating M2 receptor dysfunction. Frequency-dependent bronchoconstriction was greater in virus-infected animals than in controls, indicating airway hyperresponsiveness. Low-dose dexamethasone (6.5 microg/kg i.p.) treatment prevented virus-induced airway hyperresponsiveness, ameliorated M2 receptor dysfunction, and decreased viral content in the lungs without inhibiting virus induced inflammation. High-dose dexamethasone (65 microg/kg i.p.) prevented virus-induced hyperresponsiveness, completely reversed M2 receptor dysfunction, decreased viral titers, and decreased virus-induced inflammation. This high-dose dexamethasone also increased M2 receptor function in uninfected animals. In conclusion, dexamethasone prevented virus-induced hyperresponsiveness and M2 receptor dysfunction via multiple mechanisms.

No evidence of auditory dysfunction in guinea pigs immunized with myelin P0 protein

Recent data have focused on the peripheral nerve myelin glycoprotein P0 as a putative autoantigen involved in the autoimmune etiology of some cases of Meniere’s disease, idiopathic sensorineural hearing loss and sudden deafness. To determine whether antibodies to myelin P0 can alter cochlear function, 13 healthy guinea pigs were immunized with purified porcine myelin P0 while 10 controls were injected with saline water. The animals were then evaluated for evidence of evolving inner ear disease using immunological, electrophysiological and morphological methods. Twenty-six experimental ears were tested weekly with a brainstem auditory evoked potential technique for a period of 4 months and were compared to 20 control ears. Uniformly, all P0-sensitized guinea pigs showed antibodies to myelin protein P0 as evidenced by ELISA. Clinical signs of inflammatory demyelination were not discernible in P0-sensitized guinea pigs and all the animals were qualitatively normal. No significant increase of evoked potential thresholds was found in the P0-sensitized animals when compared to controls ( P>0.05). Peak latencies of waves I, II, III, IV and V and inter-peak latencies in P0-sensitized guinea pigs did not significantly differ from those of controls ( P>0.05). Histological sections of inner ear and peripheral nerves were free of disease in both groups. These findings indicate that the sole presence of antibodies to myelin P0 in the sera of guinea pigs or patients suspected of having autoimmune inner ear diseases is unlikely to elicit auditory abnormalities and that additional factors are necessary for the pathogenic development of these disorders.

Increased Cardiomyocyte Intracellular Calcium during Endotoxin-Induced Cardiac Dysfunction in Guinea Pigs

Septic shock is a complex pathophysiologic state characterized by circulatory insufficiency, multiple system organ dysfunction, and frequent mortality. Although profound cardiac dysfunction occurs during sepsis, the pathogenesis of this dysfunction remains poorly understood. To determine whether abnormalities in intramyocyte calcium accumulation might contribute to the development of cardiac dysfunction, we measured myocyte intracellular calcium during peak cardiac dysfunction after an endotoxin challenge. Intraperitoneal administration of Escherichia coli lipopolysaccharide 4 mg/kg to adult guinea pigs resulted in significantly impaired cardiac performance (Langendorff preparation) 18 h after challenge compared with control. This included diminished left ventricular pressure development (56 +/- 7 versus 95 +/- 4 mm Hg, p < 0.05), maximal rate of left ventricular pressure rise (998 +/- 171 versus 1784 +/- 94 mm Hg/s, p < 0.05) and left ventricular pressure fall (1014 +/- 189 versus 1621 +/- 138 mm Hg/s, p < 0.05). Assay of intracellular calcium in fura-2AM-loaded cardiac myocytes demonstrated increased intracellular calcium concentration in myocytes obtained from lipopolysaccharide-challenged animals compared with controls (234 +/- 18 versus 151 +/- 6 nM, p < 0.05). Inhibition of calcium-release channel (ryanodine receptor) opening by administration of dantrolene prevented the increase in intracytoplasmic calcium (159 +/- 8 versus 234 +/- 18 nM, p < 0.05) and partially ameliorated systolic and diastolic ventricular dysfunction. These data indicate that abnormalities of intracellular calcium contribute to the development of endotoxin-induced myocardial dysfunction.

P1-144 - Role of histamine H3 receptor on hypoxiareoxygenation-induccd cardiac dysfunction in guinea-pigs

P1-144 - Role of histamine H3 receptor on hypoxiareoxygenation-induccd cardiac dysfunction in guinea-pigs

Swimming test for evaluating vestibular function in guinea pigs.

A swimming test was used to evaluate vestibular function in guinea pigs. We first observed tracings of the swimming patterns of 20 healthy guinea pigs to establish the normal range. Then the same test was used in a group of 49 guinea pigs with endolymphatic hydrops induced by immunologic techniques. They did not show spontaneous nystagmus or body deviation while walking, but a total of 20 out of 49 animals displayed abnormal swimming patterns, with 8 swimming clockwise and 4 counterclockwise. This swimming test is easily able to detect mild vestibular dysfunction in guinea pigs, and can be repeated, so that we consider it useful for examining vestibular function in these animals.

Cellular immune reactions and blood cerebrospinal fluid barrier dysfunction in guinea pigs.

Both young and adult strain 13 guinea pigs have been treated with complete Freund's adjuvant (CFA). In young animals CFA induced an increase in the lymphocyte cell count in blood and a reversible blood CSF barrier impairment. Both these effects could be suppressed by the immunosuppressant drug Cyclosporin A. In contrast to the young animals treatment with CFA in adult strain 13 guinea pigs influenced neither the lymphocyte cell count nor blood CSF barrier function. In young and adult CFA-treated animals the number of polymorphonuclear cells in blood were increased and this increase was not reversed by Cyclosporin A. We discuss the influence of a systemic immune stimulation and suppression on blood CSF barrier function for proteins and its relevance to the pathogenesis of inflammatory diseases of the central nervous system.

Computer-averaged input-output curves and visual detection levels in methylmercury-poisoned guinea pigs

The present electrophysiological study was done to confirm an expected low-tone dysfunction in guinea pigs poisoned with cumulated doses of methylmercury. Forty young-adult Hartley strain guinea pigs were fitted stereotaxically with permanent recording electrodes having tips in the auditory tubercle and on the dural surface of the cerebrum. Twenty animals were injected subcutaneously with cumulated doses (2 mg/kg/day) of methylmercury chloride solution five times per week for periods ranging from 10 to 38 days. Twenty control subjects were injected with comparable volumes of sterile water. Click- and pure-tone-evoked responses were recorded during the waking state using a summing computer. Neither input-output functions nor visual detection levels for tones from 0.125 through 16 kHz provided any evidence for low-tone dysfunction in methylmercury-treated subjects. Supranormal evoked response amplitudes were seen at 8 and 16 kHz. Contrary to earlier conclusions based only on morphological data, the guinea pig as a species appears to be an inappropriate model for methylmercury-induced deafness reported in human victims.