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PubMed1982

The ferret for non-rodent toxicity studies - a pathologist's view.

Ferrets have been used in our laboratories over the past 4 years in 12 small drug toxicity studies (14-28 days, 6-8 ferrets, usually male) and recently for a larger study (90 days, 54 ferrets). This has provided a basis for assessing the suitability of the ferret as an alternative species for non-rodent drug toxicity studies. It is amenable to daily dosing by gavage, and it shows gastric damage of a similar type and degree to the dog in response to oral non-steroidal anti-inflammatory drugs. Certain minor peculiarities of its background pathology are worth noting, but no major problems were seen in this area which would limit its usefulness for routine toxicity testing.

Animal Diseases↗
PubMed1989

Preponderance of beta- over alpha-adrenoceptors in mediating the positive inotropic effect of phenylephrine in the ferret ventricular myocardium.

[3H]prazosin bound to the membrane fraction derived from the ferret ventricular muscle with high affinity in a saturable manner (Kd = 0.25 nmol/l and Bmax = 27 fmol/mg protein in the right ventricle). [3H]CGP-12177, a beta-adrenoceptor ligand, bound to the membrane fraction with a Kd value of 0.29 nmol/l and a Bmax of 42 fmol/mg protein. In the isolated ferret papillary muscle driven at 1 Hz at 37 degrees C, phenylephrine elicited a concentration-dependent positive inotropic effect. The maximal effect of phenylephrine was comparable to that of isoprenaline. Prazosin (0.3 mumol/l) shifted the concentration-response curve for phenylephrine slightly but significantly to the right, the maximal response being unaffected. In contrast, bupranolol (0.3 mumol/l) shifted the curve for phenylephrine markedly downwards: the maximal response was depressed significantly to 40% and the curve became less steep. In the presence of prazosin and bupranolol the curve was shifted to the right, being essentially parallel to the control curve. These results indicate that in the ferret ventricular myocardium both alpha- and beta-adrenoceptors mediate the positive inotropic effect of phenylephrine. The extent of contribution of the two classes of adrenoceptor is quite different from that in other mammalian species. In the ferret heart, beta-adrenoceptors predominate over alpha-adrenoceptors in mediating the positive inotropic effect of phenylephrine, although the number of beta-adrenoceptors is not especially high when compared with other species.

Adrenergic beta-Antagonists↗
PubMed1989

Evidence for the delayed expression of a brainstem abnormality in albino ferrets.

Previous reports have suggested that neurons of the medial superior olivary nucleus in albino cats and rabbits are smaller than those in normally pigmented strains. In this investigation, the mean cross-sectional areas of neuronal perikarya in the medial superior olivary nucleus of pigmented and albino ferrets were compared at juvenile (14 weeks) and adult (greater than six months) ages. The mean cross-sectional area of the perikarya in adult albino ferrets was found to be 45% smaller than that of adult pigmented ferrets, confirming observations in cat and rabbit. The same comparison in juvenile ferrets, however, showed no significant differences. These results suggest that the mechanisms producing the abnormality of the auditory pathways differ from those responsible for the production of abnormal retinofugal pathways in albinos.

Albinism↗
PubMed1987

Food intake and struvite crystalluria in ferrets.

Four adult, castrated, male ferrets were studied in two similar trials for effects of food intake on variables hypothesized to promote struvite (ammonium, magnesium, phosphate hexahydrate) crystal formation in urine. Struvite crystalluria occurred in three of the four ferrets. Urine pH (UpH) averaged 6.6 for these ferrets. UpH in the ferret without crystalluria was 6.0. By simple linear regression analysis, no relationship was found between the amount of food ingested and the urinary concentration and excretion of magnesium and phosphorous. However, urine osmolality and excretion of both protein and ammonium were correlated to food intake (P less than .05). Ways in which these effects could promote struvite crystal formation are discussed.

Animals↗
PubMedDate not supplied

Cardioprotection associated with preconditioning in the anesthetized ferret.

The cardioprotective effect of ischemic preconditioning (PC) was investigated in the anesthetized ferret model of myocardial ischemia followed by reperfusion. PC of 2, 5, or 10-min duration, followed by 10-min reflow, was studied in animals subjected to 60-min sustained LAD coronary artery ischemia followed by 5-h reperfusion. Infarct size was determined by tetrazolium staining. Sham PC ferrets had a mean infarct of 72% of risk zone. A 2-min or 5-min cycle of PC significantly reduced tissue damage to 54% (p < 0.05) and 44% (p < 0.01), respectively. Infarct reduction associated with 10-min ischemic PC was not significant (57% of AAR). The cardioprotective effects of 5-min PC were lost when sustained ischemia was prolonged to 75 or 90-min. Myocardial salvage afforded by 5-min PC was also abolished by both a) inhibition of ATP-sensitive potassium channels using either glyburide or 5-HD and b) blockade of adenosine receptors with the A1 selective agent DPCPX. In the absence of PC, activation of ATP-sensitive potassium channels with the cardiac-selective agonist BMS-180448 significantly (p < 0.01) reduced infarct size from 66% to 37% of the risk zone. Cardioprotection, or its loss, was not the result of hemodynamic alterations occurring during PC, drug administration, or the coronary occlusion and reperfusion phases. Based upon its body size and lack of extensive myocardial collateral circulation the ferret offers a usefull alternative small species for study of ischemia and reperfusion salvage. It is concluded in the ferret that: a) the threshold for PC is less than in either the rat, rabbit, or dog; unlike the dog and pig, the beneficial effects of PC are b) reduced when the ischemic PC interval is extended to 10-min or c) lost if sustained coronary occlusion is maintained for a period of 75-min or longer; and last, a role in PC for both d) ATP-sensitive potassium channels and e) adenosine A1 receptors can be demonstrated.

Animals↗
PubMed1984

EEG and seizure threshold in normal and lissencephalic ferrets.

Changes in EEG and susceptibility to electrically induced seizures were examined in the ferret with lissencephaly produced by exposure to a single injection of methylazoxymethanol acetate (MAM Ac) given to the pregnant jill on gestation day 32. Ten lissencephalic and 11 normal ferrets were chronically implanted with 14 cortical stainless steel electrodes. EEG records were sampled from various stages of the sleep/awake cycle. Six of each group were subjected to electrical stimulation for seizure threshold. Although the number of stimulations and the current intensity required to produce epileptiform afterdischarges (AD) and seizures were not different between the two groups, the lissencephalic ferrets had significantly longer AD and seizures, and a greater number of generalized seizures, indicating an enhanced seizure susceptibility. The EEG of the lissencephalic ferrets was characterized by increased slow wave activity within the low theta band range, extreme spindle activity, focal or multifocal slow and sharp waves, spikes, or spike and slow wave complexes. The differences in the EEG were more pronounced during drowsiness and sleep stages. The brains of all of the treated animals were lissencephalic and hydrocephalic, and weighed significantly less than those of the normals. The cerebral cortex was thin and flattened, with the parieto-occipital region most severely affected. Heterotopic foci were found in the cerebellum as well as in the cerebral cortex. Abnormalities in the configuration of the cerebellar folia were also seen. Comparison between the electrophysiological and neuropathological data suggests that the extent of the extreme spindle activity, and longer AD and seizure duration depended on the degree of cerebellar dysplasia, whereas the EEG focal abnormalities were related to lesions in the cerebral hemispheres.

Animals↗
PubMed1991

Organisation of the visceral solitary tract nucleus in the ferret as defined by the distribution of choline acetyltransferase and nerve growth factor receptor immunoreactivity.

The cholinergic innervation of the visceral component of the nucleus of the solitary tract in the ferret was investigated by using choline acetyltransferase immunocytochemistry. The subdivisions of the ferret solitary tract nucleus as defined by Nissl architectonics were found to correspond to most of those previously assigned to the cat solitary tract nucleus. The subnuclei of the ferret solitary tract nucleus were also outlined by using immunohistochemical and histochemical methods to stain for nerve growth factor (NGF) receptor and acetylcholinesterase, respectively. In particular, the gelatinosus and interstitial subnuclei stain intensely for NGF receptor immunoreactivity and for acetylcholinesterase activity. Since abundant NGF receptor immunoreactivity is observed also in the nodose ganglion and in the solitary tract, it was assumed that the gelatinosus and the interstitial subnuclei represent the principal sites of termination of primary visceral afferents. A rich choline acetyltransferase-positive terminal axonal arborization was located in all of the subdivisions of the solitary tract nucleus but was found to be lacking in the gelatinosus and interstitial subnuclei. A small number of giant choline acetyltransferase-positive axon terminals was seen in the subnucleus gelatinosus but was assumed to be of doubtful functional significance because these terminals derive from only one or two large axons on each side of the brain. The weak cholinergic innervation of the gelatinosus and interstitial subnuclei and the stronger innervation of the other subnuclei suggest that acetylcholine has a more important role in the secondary rather than the primary processing of afferent visceral information. Because the distribution of acetylcholinesterase activity in the nucleus of the solitary tract matches that of the NGF receptor immunoreactivity rather than that of the cholinergic acetyltransferase immunoreactivity, a non-cholinergic function for acetylcholinesterase may dominate in the solitary tract nucleus of the ferret.

Animals↗
PubMed1993

Characterisation of the peptido-leukotriene receptor PL2 on the ferret spleen strip.

The peptido-leukotriene receptor(s) (PL) on the ferret isolated spleen strip have been characterised by functional studies using the naturally occurring leukotrienes (LTs), a range of structurally distinct PL antagonists, and by ligand binding studies. LTB4 (0.01-10 microM) was inactive on ferret spleen whereas LTC4, LTD4 and LTE4 produced concentration-related contractions with maximal responses, relative to noradrenaline, of 57% (EC50 0.28 microM), 60% (EC50 0.5 microM) and 7% respectively. The leukotriene responses were unaltered by L-serine borate, L-cysteine, indomethacin, phentolamine, propranolol, mepyramine, methysergide or atropine, suggesting that the peptido-leukotrienes were acting through distinct PL receptors. The PL1 antagonists, FPL 55712 (0.01-10 microM), ICI 198615 (10 microM), SK&F 104353 (10 microM) and MK541 (10 microM) were all inactive against LTC4- or LTD4-induced contractile responses. LTE4 was a partial agonist with respect to LTC4 and LTD4 with pKB values of 5.8 and 5.5 respectively. Nifedipine (0.1 microM) produced a rightward shift of the concentration-response curves to both LTC4 and LTD4 and depressed their maximal responses. An unacceptably high level of non-specific binding of [3H]LTD4 to membrane preparations of ferret spleen prevented characterisation of this receptor by ligand binding. These results suggest that the ferret spleen has a homogeneous population of a PL receptor type which is insensitive to existing PL1 receptor antagonists. The functional characteristics of this PL receptor type are similar to those of the PL2 receptor on other tissues. The absence of PL1 receptors on this tissue makes it particularly useful in identifying new and selective drug tools for the PL2 receptor.

Animals↗
PubMed1990

Effects of substance P and vasoactive intestinal polypeptide on contractile activity and epithelial transport in the ferret jejunum.

Previous studies in the ferret demonstrated that vagal nerve stimulation induced an atropine-resistant water secretion. Substance P and vasoactive intestinal polypeptide are possible mediators of this secretory response. The objectives of this study were to investigate the in vivo effects of substance P and vasoactive intestinal polypeptide on the jejunal musculature and epithelium. Substance P caused an increase in jejunal motility, water secretion, and transmural potential difference. Cholinergic blockade did not affect the substance P-induced contractions, but did reduce the increase in transmural potential difference, suggesting an inhibition of water secretion. Vasoactive intestinal polypeptide abolished motor activity; however, it induced an increase in transmural potential difference that was atropine and tetrodotoxin resistant. By immunohistochemical methods, immunoreactive vasoactive intestinal polypeptide and immunoreactive substance P were localized to both nerve cell bodies and nerve fibers in the ferret intestine. Determination of intestinal concentrations of vasoactive intestinal polypeptide and substance P in the ferret showed concentrations of these two neuropeptides that were similar to those in human intestine and demonstrated much higher concentrations of these substances in the muscular layer than in the epithelial layer. Our data demonstrate that in the ferret substance P excites and vasoactive intestinal polypeptide inhibits jejunal motor activity. However, both peptides increase water secretion. Our results suggest that in response to vagal stimulation, neuronally released substance P or vasoactive intestinal polypeptide may participate in the atropine-resistant water secretion.

Action Potentials↗
PubMed1995

The effects of compensated cardiac hypertrophy on dihydropyridine and ryanodine receptors in rat, ferret and guinea-pig hearts.

The number of dihydropyridine and ryanodine receptors (DHP-R and RyR) has been measured in control and hypertrophied ventricles from rats, guinea pigs and ferrets to determine whether these two channels contribute to the alterations in excitation-contraction coupling (ECC), and in Ca2+ transient during compensated cardiac hypertrophy. We found that ventricular hypertrophy did not change the density of DHP-R. Mild hypertrophy did not alter the density of RyR in the rat but decreased it in the guinea-pig and in the ferret (30% and 36%, respectively). Severe hypertrophy decreased the density of RyR by 20% in the rat and by 34% in the guinea-pig. Therefore, the decrease is greater in ferret and guinea-pig hearts than in rat heart. We conclude that the sarcoplasmic reticulum (SR) Ca2+ release channels but not the L-type Ca2+ channels could contribute to the slowing of intracellular Ca2+ movements and to the reduced velocity of shortening of the hypertrophied hearts. We suggest that, in the guinea pig and ferret hearts which express only the beta myosin heavy chain (MHC) isoform, the reduced velocity of shortening during hypertrophy is related to the decrease in RyR density, whereas in the rat, it is regulated primarily via a shift in the MHC isoform, except in severe hypertrophy in which the moderate decrease in RyR would also be involved.

Adaptation, Physiological↗
PubMed1985

Effects of neonatal castration and testosterone treatment on sexual partner preference in the ferret.

Groups of male and female ferrets were tested in a T maze to determine whether they preferred to approach and interact with a sexually active male or an estrous female. Control male and female ferrets gonadectomized (GX) on postnatal Day 35 and tested in adulthood while receiving no hormone or testosterone (T) displayed no significant preference. When given estradiol benzoate (EB), however, control males preferred stimulus females whereas control females preferred stimulus males. When tested in adulthood with EB treatment, males GX on postnatal Day 5 showed a significant reduction in their approach to stimulus females, although they did not switch their preference to stimulus males and thereby resemble control females. Female ferrets GX on postnatal Day 5 and given a high dosage of T over postnatal Days 5-20 showed a significant reduction in their approach to stimulus males, although they did not switch their preference to stimulus females, and thereby resemble control males. The results suggest that extended perinatal exposure of male ferrets to T is required for the development of a sociosexual preference for females.

Animals↗
PubMed1986

Pharmacology of peptide leukotrienes on ferret isolated airway smooth muscle.

The contractile activities of peptide leukotrienes (LT) on isolated spiral strips of ferret trachea were characterized pharmacologically. LTC4 and LTD4 contracted ferret tracheal strips in a concentration-related manner and were 3- to 8-fold more potent than carbachol. In contrast, high concentrations of LTE4 evoked either weak contractions or none at all, whereas LTC4 and D4 were partial agonists compared to carbachol. In tissues which were unresponsive to LTE4, this compound antagonized contractile responses to LTC4 and D4 in an apparently competitive manner: Carbachol-induced contractions were not altered by LTE4. The cyclooxygenase inhibitor, indomethacin (5 microM), LT antagonist, FPL55712 (10 microM), atropine (1 microM), phenoxybenzamine (10 microM), and LTB4 (10 microM) failed to alter LTC4 and D4 concentration-response curves. The results indicate that ferret trachea is sensitive to the contractile activity of LTC4 and LTD4 but not LTE4. The LT-induced contractions appear to be mediated by a direct action of the LT rather than indirectly through release of secondary mediators such as thromboxane, prostaglandin, or acetylcholine. LT receptors in ferret trachea are insensitive to FPL55712 but are antagonized by LTE4.

Animals↗
PubMed1993

The central localization of the vagus nerve in the ferret (Mustela putorius furo) and the mink (Mustela vison).

The location of vagal preganglionic neurones (VPN) has been determined in nine ferrets (Mustela putorius furo) and seven mink (M. vison) using neuronal tract-tracing techniques employing horseradish peroxidase (HRP) and wheat-germ agglutinin conjugated HRP (WGA-HRP) mixtures injected into the nodose ganglion of the vagus nerve. Labelled VPN were located ipsilaterally in the dorsal motor nucleus of the vagus (DmnX), nucleus ambiguus (nA), and reticular formation (rf) of the medulla oblongata. In four of the ferrets, labelled VPN were also identified in the nucleus dorsomedialis (ndm) and the nucleus of the spinal accessory nerve (nspa). In a single mink a few labelled cells were observed in the ndm but no labelled VPN were found in the nspa. Labelling of afferent components of the vagus nerve was seen in two ferrets and two mink with the best labelling obtained following an injection of an HRP/WGA-HRP mixture into the nodose ganglion. Labelled afferents were observed to cross the ipsilateral spinal trigeminal tract (SpV) before entering the tractus solitarius (TS) in regions separate from the motor axons which exit the medulla in separate fasicles. Sensory terminal fields were identified bilaterally in the nucleus of the tractus solitarius (nTS) in both species and bilaterally in the area postrema (ap) of the ferret; however, the contralateral labelling was sparse in comparison to the densely labelled ipsilateral nTS/ap. Maximal terminal labelling was seen in regions just rostral and caudal to obex in both species.

Animals↗
PubMed1990

Auditory brainstem of the ferret: maturation of the brainstem auditory evoked response.

A longitudinal study of developmental changes in the brainstem auditory evoked response (BAER) was made on 19 ferrets between postnatal days 25 (P25) and 50. Responses to free-field click stimuli were recorded from anaesthetized animals, and compared with data obtained from 8 adult ferrets. A reproducible BAER was first recordable on P27, although the response onset was generally later in smaller animals. BAER onset preceded eye opening, which started on P32. Adult-like thresholds were observed in all animals by P40, but the age at which they were attained was also dependent on size. The BAER in the adult ferret consists of 4 main vertex-positive peaks occurring in the first 5 ms following transient acoustic stimulation. In the youngest animals the presence of an additional peak (between II and III) and the slurring of peaks III and IV were consistent features. The individual peaks undergo an asymmetrical pattern of development, with mean peak I latency attaining an adult value at P40, while mean peak IV latency is still 115% of the mean adult value at that age. BAERs could routinely be recorded using high stimulus presentation rates (greater than 40/s), though an increase in absolute and interpeak latencies occurred, the extent of which decreased with age. The pattern of BAER development in the ferret is compared with that in other species, and the concept of the 'silent period' (period between conception and onset of hearing) as a standard unit of auditory development is introduced.

Acoustic Stimulation↗
PubMed1989

The constitution and properties of phosphorylated and unphosphorylated C-terminal fragments of progastrin from dog and ferret antrum.

Antibodies to the extreme C-terminal tryptic (nona-) peptide fragment of porcine progastrin have been used in radioimmunoassay to identify progastrin fragments in dog, ferret and pig antral mucosa extracts and to monitor their purification. In addition to previously characterised phosphorylated and unphosphorylated C-terminal tryptic peptides of porcine progastrin a minor form corresponding to the C-terminal octapeptide (i.e. des-Ser C-terminal nonapeptide) was isolated and characterised. The latter form together with phosphorylated and unphosphorylated forms of the nonapeptides were also isolated and chemically characterised from dog antrum, and the unphosphorylated nonapeptide was characterised from ferret antrum. The primary amino acid sequences of the dog, ferret and pig nonapeptides were identical. In ferret the unphosphorylated nonapeptide predominated, and in dog the phosphorylated form predominated; in pig both forms of the nonapeptide were well represented. Intact progastrin was identified in gel filtration eluates of extracts of all 3 species, but occurred only in relatively low concentrations. The nonapeptides did not stimulate acid secretion in the conscious gastric fistula rat and they did not modify the acid response to G17. Phosphorylation of progastrin-derived peptides is evidently well conserved across a range of species even though there appear to be differences in the relative proportions of phosphorylated and unphosphorylated forms.

Animals↗
PubMed1984

Coronary microangiography in the guinea pig, rabbit and ferret.

Using improved methods, we have developed a microangiographic technique for studying the coronary circulation in Langendorff perfused guinea pig, rabbit and ferret hearts. Striking anatomical differences were observed between these species. In the guinea pig, the interventricular septum was supplied by a large septal artery which always arose from the right coronary artery, whereas in the rabbit and ferret, the septal artery was smaller and originated from the left coronary artery. The circumflex artery was more prominent than the right coronary artery in the ferret and guinea pig, whereas the reverse pertained in the rabbit. Extensive apical collateral connections were observed between terminal branches of the left anterior descending, left ventricular branches and the septal artery in the guinea pig, while collaterals were usually absent in the rabbit and ferret. These species differences in the myocardial blood supply have wide ranging implications regarding the choice of small animals for cardiac research.

Angiography↗
PubMedDate not supplied

LHRH in the ferret: pubertal decrease in the number of immunopositive arcuate neurons.

This study correlated a region-specific change in the number of luteinizing hormone-releasing hormone-immunopositive (LHRH+) neurons with pubertal development in male ferrets. There were 50% fewer LHRH+ cell bodies in the arcuate nucleus of peri- and postpubertal ferrets than in prepubertal ferrets; this significant decrease represented a 15% reduction in the overall number of LHRH+ neurons. Intracerebroventricular colchicine did not reveal additional numbers of LHRH+ neurons in the arcuate nucleus, indicating that the pubertal decrease in arcuate LHRH+ cell bodies was not due to rapid transport of peptide. These results suggest that LHRH of arcuate origin may inhibit release of LHRH via ultrashortloop negative feedback in prepubertal ferrets. Cessation of peptide production in half of the arcuate LHRH neurons at puberty could result in a reduction in this inhibitory signal that permits the pubertal increase in LHRH/LH release. Alternatively, LHRH of arcuate origin may have a nonpituitary role. In either case, these data provide evidence for heterogeneity of function among LHRH+ neurons.

Animals↗
PubMed1994

Efficacy of adenovirus-vectored respiratory syncytial virus vaccines in a new ferret model.

In the absence of an adequate small animal model for testing the efficacy of adenovirus-vectored respiratory syncytial virus (RSV) vaccines, a ferret model was established for this purpose. Recombinant adenovirus types 4, 5 and 7 expressing the RSV fusion glycoprotein (F), the attachment glycoprotein (G) or both F and G were constructed previously. These recombinants contain a deletion of a large portion of the E3 region of the respective adenovirus vector. In addition, an Ad7(E3+)F recombinant virus which contains an intact E3 region was constructed to assess whether E3 region functions might enhance vaccine immunogenicity. Evaluation of these viruses in the ferret model demonstrated that Ad4 and Ad5 recombinants, administered intranasally to ferrets, induce stronger seroresponses to RSV than do Ad7 recombinant viruses. Ad7(E3+)F did not show enhanced immunogenicity relative to E3-deleted recombinant viruses. However, measurement of RSV infectivity in nasal washes, following intranasal RSV challenge, showed that five different vaccination regimens, Ad7F/Ad4F, Ad7G/Ad4G, Ad7FG/Ad4FG, Ad4F/Ad7(E3+)F and Ad5F/Ad4F, protected ferrets from RSV infection in a dose-dependent manner.

Animals↗