Age-matched Hamsters Research Articles

ETBreceptor dependent alteration in aortic responses to ET-1 in the cardiomyopathic hamsterThis paper is one of a selection of papers published in this Special issue, entitled Second Messengers and Phosphoproteins—12th International Conference.

The aim of this study was to verify whether an alteration in the aortic endothelin-1 (ET-1) response takes place in UM-X7.1 cardiomyopathic hamsters. Our results showed that ET-1 (10(-12) - 10(-5) mol/L) induces dose-dependent sustained increases in tension in the intact and endothelium denuded aortas from both normal and cardiomyopathic hamsters. The EC50 values of ET-1 of both intact and endothelium denuded aortas of normal hamsters were similar (2.2 x 10(-9) mol/L and 1.8 x 10(-9) mol/L, respectively). However, in cardiomyopathic hamsters, the EC50 of ET-1 in intact aortas was higher (1.5 x 10(-8) mol/L) than that of the endothelium denuded preparations (2.7 x 10(-9) mol/L). The EC50 of ET-1 in normal and cardiomyopathic hamster denuded aortas were similar. However, the EC50 of ET-1 in intact aortas of cardiomyopathic hamster was higher (1.5 x 10(-8) mol/L) than that of normal hamsters (2.2 x 10(-9) mol/L). Pre-treatment with the ETA receptor antagonist ABT-627 (10(-5)mol/L) of intact and endothelium denuded aortas from both normal and cardiomyopathic hamsters significantly prevented ET-1 (10(-7) mol/L) from inducing an increase in tension. Pre-treatment with the ETB receptor antagonist A-192621 (10(-5) mol/L) had no effect on the ET-1-induced increase in tension in endothelium denuded aortas of both normal and cardiomyopathic hamsters, as well as in intact preparations of normal animals. However, blockade of the ETB receptors in intact aortas of cardiomyopathic hamsters significantly (p < 0.001) potentiated the ET-1-induced increase in tension. In summary, an attenuation of the contraction response to ET-1 was found in UM-X7.1 cardiomyopathic hamsters when compared with normal age-matched hamsters. This alteration of the ET-1 effect in the aortas of cardiomyopathic hamsters seems to be dependent on the presence of the endothelium and could be due, in part, to an increase in the contribution of endothelial ETB receptors to relaxation, which in turn acts as a physiological depressor of ET-1 vasoconstriction. Our results suggest that an increase in the endothelium ETB receptor density may play a role in the development of hypotension in UM-X7.1 cardiomyopathic hamsters.

Age, sex and co-exposure to N-ethyl-N-nitrosourea influence mutations in the Alu repeat sequences in diethylstilbestrol-induced kidney tumors in Syrian hamsters.

We report, for the first time, mutations in the Alu repeat regions in the genome of kidney tumors induced by diethylstilbestrol in Syrian hamsters. Among the 66 loci amplified by 11 random primers, 28 loci exhibited insertions, deletions or losses or gains in intensity in the genome of kidney tumor tissues compared with normal kidney tissues from age-matched hamsters. Higher numbers of mutated Alu loci were observed in the tumors of old hamsters compared with young hamsters. In N-ethyl-N-nitrosourea- and diethylstilbestrol-treated hamsters deletion of a 0.59 kb locus amplified with primer OPC03 was observed in most of the female hamsters, but not in male hamsters. An insertion mutation of a 0.498 kb locus amplified with primer OPC03 was observed in 12 of 36 diethylstilbestrol-induced kidney tumors. The cloning and sequencing of the 0.498 kb locus amplified with primer OPC03 revealed that it had significant sequence similarity to the mouse RIKEN cDNA clone. These findings indicate that age, sex and co-exposure to N-ethyl-N-nitrosourea influence mutations in the Alu repeat sequences in the genome of diethylstilbestrol-induced kidney tumors in Syrian hamsters. Structural alterations in Alu repeats in critical target genes may be involved in diethylstilbestrol-induced carcinogenesis.

Decrease of food intake by MC4-R agonist MTII in Siberian hamsters in long and short photoperiods.

We investigated the role of the hypothalamic melanocortin system in the regulation of food intake in the Siberian hamster, which shows a profound seasonal decrease in food intake and body weight in short photoperiod (SP). In male hamsters maintained in long photoperiod (LP), intracerebroventricular injection of melanotan II (MTII) just before lights off significantly decreased food intake relative to vehicle treatment over the 6-h observation period. Similar effects were observed in age-matched hamsters after exposure to a short daylength for 9 wk, when body weight had significantly decreased. There was no clear difference in either the magnitude of response or the dose required for half-maximal inhibition of food intake in hamsters in SP compared with those in LP. MTII significantly increased grooming in both LP and SP. Our results indicate that the melanocortin system is a potent short-term regulator of food intake. However, the lack of differential response or sensitivity to MTII treatment in the obese (LP) vs. lean (SP) states does not support the hypothesis that changes in this melanocortin pathway underlie the long-term decrease in food intake that occurs in this seasonal model.

Beneficial Effects of Angiotensin-Converting Enzyme Inhibition in Adriamycin-Induced Cardiomyopathy in Hamsters

This study was performed to determine whether angiotensin (Ang) II-forming enzymes, angiotensin converting enzyme (ACE) and chymase might contribute to the development of adriamycin-induced cardiomyopathy in hamsters. Hamsters were administered adriamycin (2.0 mg/kg per day, i.p.) three times weekly for 2 weeks. In the ACE inhibitor-treated group, the hamsters received lisinopril (20 mg/kg per day, p.o.) for 2 weeks after the last injection of adriamycin. The 4-week mortality rates of the vehicle- and ACE inhibitor-treated hamsters were 44% and 12%, respectively. In comparison to the age-matched hamsters used as the control hamsters, a significant decrease in cardiac function and a significant increase in the ratio of the heart weight to the body weight were observed in the vehicle hamsters. Cardiac ACE activity, but not the chymase activity, in the vehicle hamsters was significantly increased in comparison to that in the control hamsters. In the ACE inhibitor-treated group, the increased ACE activity was reduced significantly, and the cardiac hypertrophy and dysfunction were improved significantly. In adriamycin-induced cardiomyopathic hamsters, cardiac ACE activity was increased and ACE inhibition significantly improved cardiac function and survival rate, indicating that cardiac ACE, but not the chymase, plays the pivotal role in the development of the adriamycin-induced cardiomyopathy.

Circadian rhythms, aging and memory

In human beings and animal models, cognitive performance is often impaired in natural and experimental situations where circadian rhythms are disrupted. This includes a general decline in cognitive ability and fragmentation of behavioural rhythms in the aging population of numerous species. There is some evidence that rhythm disruption may lead directly to cognitive impairment; however, this causal link has not been made for effects due to aging. We have tested this link by examining rhythms and performance on contextual conditioning with the conditioned place preference task, in elderly, age-matched hamsters. Young healthy hamsters developed a preference for a context that is paired with the opportunity to engage in wheel-running (experiment 1). Aged animals with consolidated locomotor rhythms developed similar degrees of preference, whereas the age-matched hamsters with fragmented rhythms did not (experiment 2). The degree of preference was also correlated with activity amplitude. These results support the notion that age-related rhythm fragmentation contributes to the age-related memory decline.

Circadian rhythms, aging and memory

In human beings and animal models, cognitive performance is often impaired in natural and experimental situations where circadian rhythms are disrupted. This includes a general decline in cognitive ability and fragmentation of behavioural rhythms in the aging population of numerous species. There is some evidence that rhythm disruption may lead directly to cognitive impairment; however, this causal link has not been made for effects due to aging. We have tested this link by examining rhythms and performance on contextual conditioning with the conditioned place preference task, in elderly, age-matched hamsters. Young healthy hamsters developed a preference for a context that is paired with the opportunity to engage in wheel-running (experiment 1). Aged animals with consolidated locomotor rhythms developed similar degrees of preference, whereas the age-matched hamsters with fragmented rhythms did not (experiment 2). The degree of preference was also correlated with activity amplitude. These results support the notion that age-related rhythm fragmentation contributes to the age-related memory decline.

The effects of hibernation on the myenteric plexus of the golden hamster small and large intestine.

We have examined the effects of hibernation on the neurochemical composition of myenteric neurones in the small and large intestine of the golden hamster using immunohistochemical and histochemical techniques. Hibernation was induced in golden hamsters by altering the photoperiod and external ambient temperature. Age-matched hamsters kept at room temperature and those kept at 5 degrees C but which failed to hibernate were used as controls. Cell counts were carried out to examine possible changes in the numbers of cell bodies immunoreactive to all of the markers examined. The results demonstrated a significant increase during hibernation in the number of neurones immunoreactive to vasoactive intestinal polypeptide, substance P and calcitonin gene-related peptide; cell bodies positive for tyrosine hydroxylase, which were largely absent in the control animals, were prominent in the hibernating animals. There was a significant decrease in the number of neurones immunoreactive to 5-hydroxytryptamine, and no significant changes in the numbers of neurones immunoreactive to protein gene-product and nitric oxide synthase. It is suggested that selective upregulation and downregulation of myenteric neurones containing certain neurotransmitters may occur as a protective mechanism during hibernation to maintain the integrity of the muscular and mucosal layers of the intestine in the absence of luminal contents.

Effect of U-50,488H on the contractile response of cardiomyopathic hamster ventricular myocytes

We examined the effects of a selective κ opioid receptor agonist (U-50,488H) on the contractile properties of single ventricular myocytes from 127 day old control (F1B) and cardiomyopathic (BIO 14.6) hamsters. Myocytes in bicarbonate buffered solution with 1.5 mM [Ca 2+] were electrically stimulated with field electrodes in the bath. Length changes were monitored via myocyte edge tracking. Twitch amplitude and the velocity of cell shortening were less in the cardiomyopathic hamster myocytes than in age-matched hamsters (P≤0.05). There was a concentration-dependent effect of U-50,488H (0.1–20 μM) to decrease twitch amplitude and shortening velocity in both control and cardiomyopathic myocytes (P≤0.001). In cells loaded with the Ca 2+ indicator indo-1 the negative inotropic action of U-50,488H was associated with a decreased indo-1 fluorescence transient amplitude. There was no difference in the negative inotropic effect of U-50,488H on control and cardiomyopathic cells. Thus, the CM hamster does not demonstrate a different contractile response to U-50,488H.

Elevated plasma vasopressin in cardiomyopathic hamsters

Hamsters of the BIO 14.6 strain characteristically develop cardiomyopathy as they age, and hamsters of this strain have overt signs of heart failure by 11 months of age. Plasma levels of the posterior pituitary hormone arginine-vasopressin (AVP) were found to be elevated (approximately 2-fold) in 11 month old BIO 14.6 hamsters, compared to age-matched hamsters of a control strain. AVP appeared inappropriately elevated in these animals, since they were neither hyperosmotic nor markedly hypotensive. The elevated levels of AVP observed in these animals appears to contribute to vasomotor tone, since intravenous adminstration of a specific antagonist of the vasoconstrictor action of AVP [d(CH 2) 5Ome(TYR)AVP] elicited a fall in arterial pressure (9±2 mm Hg, n=6, p<0.05). The AVP antagonist had no effect on arterial pressure in hamsters of a control strain, and vehicle administration had no effect on arterial pressure in either strain. These data indicate that inappropriately elevated levels of AVP contribute to the cardiovascular state of myopathic hamsters. Since elevated plasma AVP has been noted in human congestive heart failure, these results suggest that AVP may contribute to the cardiovascular status during congestive heart failure.

Microvascular alterations develop in Syrian hamsters after the induction of diabetes mellitus by streptozotocin.

Microvessels in the cheek pouch of the hamster were investigated to determine their structural, reactivity, and permeability characteristics after the induction of diabetes. To induce diabetes, hamsters were injected with streptozotocin (50 mg/kg body wt./day, i.p., for 3 days). Vehicle-injected, age-matched hamsters were the controls. Diabetic hamsters were characterized by elevated serum glucose (greater than 300 mg/dl) and triglycerides and decreased serum insulin (50%). Microvascular studies were completed on cheek pouch microvessels suffused with Ringer's solution (37 degrees C, pH 7.4) bubbled with 95% N2-5% CO2. Vascular dimensions and reactivity of selected arterioles and venules to microapplications of norepinephrine were determined with a video micrometer using intravital microscopy. Restrictiveness of the microvascular membranes to fluorescein-labeled dextran fractions (mol wt: 150,000; 40,000; 20,000 daltons) was measured by determining the number of leaky sites. Stimulation of membrane permeability by histamine was investigated. There were no major alterations in arteriolar lumen and wall diameters, whereas venular lumen diameters were increased in hamsters diabetic for two months. Likewise, arteriolar responses to norepinephrine were not altered by diabetes; however, venular responses were decreased at two months. The restrictiveness of the vascular membrane to various dextran fractions was dramatically decreased in the diabetic animals at two months. Histamine did not alter microvascular leakage in the diabetic as it did in the normal hamsters. These studies indicate that microvascular alterations, venular dilation, and increased permeability to large molecules occur in the diabetic hamster within two months after the induction of diabetes.

Norepinephrine turnover in the heart and spleen of the cardiomyopathic Syrian hamster.

Although a reduction in myocardial norepinephrine stores in cardiac hypertrophy and congestive failure is well documented, norepinephrine turnover has been inadequately studied in such hearts. We compared norepinephrine turnover in control and cardiomyopathic hamsters by following the decline in specific activity of myocardial norepinephrine after labelling with an intraperitoneal tracer dose of 3H-norepinephrine. Adult myocardial norepinephrine concentrations were not attained until 4 weeks of age in both strains. There was no difference in the rate of constant (K) for myocardial norepinephrine turnover (0.107+/-0.004 hours-1 vs. 0.100+/-0.005 hours-1) in the two strains of hamsters during the neonatal period. In young control hamsters, K fell to 0.064+/-0.004 hours-1, but that for age-matched hamsters with mild cardiac hypertrophy was 0.102+/-0.001 hours-1 (P less than 0.001). There was little change in K as control hamsters aged. With the development of more severe hypertrophy in cardiomyopathic hamsters, cardiac norepinephrine decreased and resting K rapidly increased to approach the value obtained when hamsters were subjected to immobilization stress (0.302+/-0.013 hours-1). The maximum achievable K remained the same for both control and dystrophic hamsters even during terminal disease. Prolonged immobilization led to a reduction in cardiac norepinephrine in both strains. Ganglionic blockade of failing hamsters completely restored the levels of both cardiac norepinephrine and K to control values. Splenic noradrenergic nerves showed no change in K, norepinephrine content, or maximum K during cardiac decompensation. We conclude that, in the late stages of hamster cardiomyopathy, there is a progressive and possibly specific increase in cardiac sympathetic tone which leads to a concomitant decrease in cardiac norepinephrine. With the loss of sympathetic reserve, congestive failure supervenes.