Radiotelemetry In Rats Research Articles

Stress Drivers of Glucose Dynamics during Ozone Exposure Measured Using Radiotelemetry in Rats.

Inhaled irritant air pollutants may trigger stress-related metabolic dysfunction associated with altered circulating adrenal-derived hormones. We used implantable telemetry in rats to assess real-time changes in circulating glucose during and after exposure to ozone and mechanistically linked responses to neuroendocrine stress hormones. First, using a cross-over design, we monitored glucose during ozone exposures (0.0, 0.2, 0.4, and ) and nonexposure periods in male Wistar Kyoto rats implanted with glucose telemeters. A second cohort of unimplanted rats was exposed to ozone (0.0, 0.4 or 0.8 ppm) for 30 min, 1 h, 2 h, or 4 h with hormones measured immediately post exposure. We assessed glucose metabolism in sham and adrenalectomized rats, with or without supplementation of adrenergic/glucocorticoid receptor agonists, and in a separate cohort, antagonists. Ozone () was associated with significantly higher blood glucose and lower core body temperature beginning 90 min into exposure, with reversal of effects 4-6 h post exposure. Glucose monitoring during four daily 4-h ozone exposures revealed duration of glucose increases, adaptation, and diurnal variations. Ozone-induced glucose changes were preceded by higher levels of adrenocorticotropic hormone, corticosterone, and epinephrine but lower levels of thyroid-stimulating hormone, prolactin, and luteinizing hormones. Higher glucose and glucose intolerance were inhibited in rats that were adrenalectomized or treated with adrenergic plus glucocorticoid receptor antagonists but exacerbated by agonists. We demonstrated the temporality of neuroendocrine-stress-mediated biological sequalae responsible for ozone-induced glucose metabolic dysfunction and mechanism in a rodent model. Stress hormones assessment with real-time glucose monitoring may be useful in identifying interactions among irritant pollutants and stress-related illnesses. https://doi.org/10.1289/EHP11088.

Renal oxygenation during the early stages of adenine-induced chronic kidney disease.

To assess whether renal hypoxia is an early event in adenine-induced chronic kidney disease, adenine (100 mg) or its vehicle was administered to male Sprague-Dawley rats by daily oral gavage for 7 days. Kidney oxygenation was assessed by 1) blood oximetry and Clark electrode in thiobutabarbital-anesthetized rats, 2) radiotelemetry in unanesthetized rats, and 3) expression of hypoxia-inducible factor (HIF)-1α and HIF-2α protein. After 7 days of treatment, under anesthesia, renal O2 delivery was 51% less, whereas renal O2 consumption was 65% less, in adenine-treated rats than in vehicle-treated rats. Tissue Po2 measured by Clark electrode was similar in the renal cortex but 44% less in the medulla of adenine-treated rats than in that of vehicle-treated rats. In contrast, in unanesthetized rats, both cortical and medullary tissue Po2 measured by radiotelemetry remained stable across 7 days of adenine treatment. Notably, anesthesia and laparotomy led to greater reductions in medullary tissue Po2 measured by radiotelemetry in rats treated with adenine (37%) than in vehicle-treated rats (16%), possibly explaining differences between our observations with Clark electrodes and radiotelemetry. Renal expression of HIF-1α was less after 7 days of adenine treatment than after vehicle treatment, whereas expression of HIF-2α did not differ significantly between the two groups. Renal dysfunction was evident after 7 days of adenine treatment, with glomerular filtration rate 65% less and serum creatinine concentration 183% greater in adenine-treated rats than in vehicle-treated rats. Renal cortical tissue hypoxia may not precede renal dysfunction in adenine-induced chronic kidney disease and so may not be an early pathological feature in this model.

Abstract B108: Assessment of the hyperglycemia profile of NVP-BYL719, a selective inhibitor of the class Ia PI3K isoform alpha using real-time continuous glucose monitoring via radio-telemetry in rats

Abstract The gene encoding for the catalytic subunit of the phosphatidylinositol-3-kinase (PI3K), p110a (PIK3CA) is the most frequently mutated kinase in cancer. This discovery triggered the development of small molecule anti-PI3K inhibitors, such as NVP-BYL719. However, the PI3K / Akt signaling pathway plays not only an important role in promoting cell growth, proliferation and survival but also in regulating glucose homeostasis by directly mediating insulin-stimulated glucose uptake into insulin sensitive tissues (adipocytes and muscles). Hyperglycemia has been reported to be one of the most frequent adverse events in clinical trials for PI3K inhibitors. Therefore, NVP-BYL719, a selective inhibitor of the class Ia PI3K isoform-alpha, can impair glucose metabolism. However until now, continuous glucose monitoring options have been very limited in biomedical research. Investigators have used periodic sampling of blood glucose using a glucometer and test strips approach to provide a snap-shot assessment of the effect of PI3K inhibitors to glucose metabolism. Thus, ‘around the clock’ real-time measurements of blood glucose in unstressed, freely moving animals are needed to better assess pharmacokinetic (PK: drug levels in plasma) and pharmacodynamics (PD: glucose levels in blood) relationship in pre-clinical models. The present study evaluates the use of a new radio-telemetry device (HD-XG, Data Sciences International) incorporating an implantable glucose sensor for chronic continuous (every minute) glucose measurements in the arterial blood of brown Norway (BN) rats. We evaluate the day-and-night profile of glucose blood levels as well as the PK/PD relationship of NVP-BYL719 following daily oral treatment at efficacious anti-tumor doses. In conclusion, our data suggest that the glucose telemetry implant offers a novel solution to obtain continuous, real-time, blood glucose measurements in rats while reducing animal stress and measurement variability commonly associated with glucose test-strips. For the first time, a continuous 24h data profile on blood glucose for NVP-BYL719 could be obtained. This profile is reproducible over time and a clear PK/PD relationship could be demonstrated. NVP-BYL719 treatment in BN rats induced a transient glucose level increase suggestive of glucose metabolism impairment consistent with insulin resistance/insensitivity. It can be emphasized that the use of such a novel technology will enable advances in the understanding of the physiology of glucose metabolism regulation following PI3K inhibition possibly leading to improved therapies in the clinic. Citation Format: CHRISTIAN R. SCHNELL, Thomas Ferrat, Christine Fritsch, Michael R. Jensen. Assessment of the hyperglycemia profile of NVP-BYL719, a selective inhibitor of the class Ia PI3K isoform alpha using real-time continuous glucose monitoring via radio-telemetry in rats. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B108.

The long-term effects of phase advance shifts of photoperiod on cardiovascular parameters as measured by radiotelemetry in rats

Cardiovascular parameters, such as blood pressure and heart rate, exhibit both circadian and ultradian rhythms which are important for the adequate functioning of the system. For a better understanding of possible negative effects of chronodisruption on the cardiovascular system we studied circadian and ultradian rhythms of blood pressure and heart rate in rats exposed to repeated 8 h phase advance shifts of photoperiod. The experiment lasted 12 weeks, with three shifts per week. Spectral power as a function of frequency for both circadian and harmonic ultradian rhythms was expressed as the circadian–ultradian power ratio. The circadian rhythms of blood pressure, heart rate and locomotor activity were recorded during the control light:dark (LD) regimen with higher values during the D in comparison with the L. Phase advance shifts resulted in a diminished circadian–ultradian power ratio for blood pressure, heart rate and locomotor activity indicating suppressed circadian control of these traits greater in heart rate than blood pressure. In conclusion, rats kept under irregular LD conditions have suppressed circadian control of heart rate, blood pressure and locomotor activity and rely more on an acute response to the LD regime. Their ability to anticipate regular loads can be weakened and in this way chronodisruption can contribute to the pathogenesis of cardiovascular diseases.

Cardiovascular function and circadian patterns in rats after area postrema lesions or prolonged food restriction

The role of the area postrema (AP) in baseline cardiovascular function was evaluated by radio telemetry in rats with lesions of AP (APX), along with the effect of APX on circadian patterns of cardiovascular function and ingestive behavior. Despite lesion-induced hypophagia and body weight loss, APX did not affect circadian patterns of mean arterial pressure (MAP), heart rate (HR), or ingestion but did cause a substantial decrease (−60 bpm) in resting HR. The bradycardia was not attributable to weight loss, as resting HR in weight-matched controls, though decreased from baseline, was significantly greater than that in rats with APX. In weight-matched controls, HR increased slightly when weight returned to baseline; however, the bradycardia persisted in rats with APX. These results suggest that AP contributes to resting HR, independent of weight loss or changes in circadian patterns of HR or MAP.

Effects of exercise conditioning on thermoregulatory responses to repeated administration of chlorpyrifos

Little is known about the effects of physical activity (i.e., exercise training) on susceptibility to environmental toxicants. Chlorpyrifos (CHP), an organophosphate (OP) insecticide, affects thermoregulation, causing an acute period of hypothermia followed by a delayed fever. Since exercise conditioning alters the thermoregulatory responses of rodents, this study examined whether exercise training would alter the thermoregulatory response to repeated CHP administration in the female Sprague–Dawley rat. Core temperature ( T c) and motor activity (MA) were monitored by radiotelemetry in rats housed at an ambient temperature ( T a) of 22°C. The rats either were provided with continuous access to running wheels (exercise group) or were housed in standard cages without wheels (sedentary group). The exercise group rats ran predominately at night with an average of 7.6 km/24 h. After 8 weeks the rats in both groups were gavaged daily with corn oil or 10 mg/kg CHP (dissolved in corn oil) for 4 days. CHP induced an immediate hypothermic response followed by a delayed fever throughout the next day in the sedentary group rats after the first three doses of CHP. The exercise group rats showed no hypothermia after the first dose of CHP. However, they became hypothermic after the second and third doses of CHP. The exercise group rats developed a smaller daytime fever after each dose of CHP compared to the sedentary group rats. Overall, exercise training attenuated the hypothermic and febrile effects of repeated CHP. Thus, the data suggest that a sedentary lifestyle may increase the sensitivity to OP insecticides. Exercise training was also associated with a more rapid recovery of plasma cholinesterase activity.

Seizures induce phase shifts of rat circadian rhythms

Rationale: Epileptic seizures may alter neuroendocrinological cycles. Light pulses induce phase shifts in circadian rhythms. Using hippocampal-kindled rats to ensure maximal clinical expression, we determined if seizures likewise induce phase shifts. Methods: We monitored the circadian rhythm of temperature (CRT) with intraperitoneal radiotelemetry in rats ( n=21) isolated from time cues and light for 3-week trials. Seizures were triggered with hippocampal electrical stimulation at different circadian phases. Optimized, least-error phase shifts were calculated from preictal and postictal CRTs. Induced seizures were referenced to CRT ( t max=00:00, 24-h circadian cycle). Results: Phase shifts (individual responses=57) differed across the circadian cycle. Rather than forming a clear phase–response curve, phase shifts were especially variable between 00:00 and 06:00 h. Conclusions: This study demonstrates that electrically-induced seizures induce advances and delays in CRT in a phase-dependent fashion but in a pattern different from typical light-induced phase shifts. Disorders of circadian regulation may contribute to some of the altered endogenous cycles associated with epilepsy.

The neuronal selective nitric oxide inhibitor AR-R 17477, blocks some effects of phencyclidine, while having no observable behavioural effects when given alone.

We have previously shown that the non-specific nitric oxide synthase inhibitor L-NAME blocks the behavioural effects of phencyclidine, but not d-amphetamine. To characterise the specificity of these effects, we used the specific neuronal nitric oxide synthase inhibitor AR-R 17477 in two rat models of psychosis: the prepulse inhibition of the acoustic startle response and locomotor activity. In biochemical assays, AR-R 17477 was shown to be selective for the neuronal nitric oxide synthase isoform. Test drugs were given subcutaneously. AR-R 17477 (0.5, 1 and 5 mg/kg) antagonised phencyclidine-induced hyperlocomotion, while higher doses (10 and 20 mg/kg) were less efficaceous. AR-R 17477 (1 mg/kg) antagonised phencyclidine-induced deficit in prepulse inhibition of the acoustic startle response, while a higher dose (15 mg/kg) was less active. AR-R 17477 did not affect startle amplitude or prepulse inhibition of the acoustic startle response, did not affect locomotion and did not induce any changes in gross behaviour (sniffing, rearing, etc.) as determined in a subjective observation study. AR-R 17477 (1 mg/kg) did not alter the effect of d-amphetamine in prepulse inhibition of the acoustic startle response. Using radiotelemetry in rats, L-NAME (10 mg/kg subcutaneously) increased blood pressure and decreased heart rate while AR-R 17477 (10 mg/kg) did not have any significant effect on these parameters. The results show that a neuronal nitric oxide synthase inhibitor antagonises the effects of phencyclidine on prepulse inhibition of the acoustic startle response and locomotor activity, without exhibiting significant behavioural effects of its own and suggest that our earlier results with L-NAME depended upon an inhibition of neuronal nitric oxide synthase and not on an inhibition of endothelial nitric oxide synthase or inducible nitric oxide synthase. The observed effects are unlikely to be related to an effect on cardiovascular function.

Tobacco smoke influence on heart rate, body temperature, and locomotor activity daily rhythms as assessed by radiotelemetry in rats

Using radiotelemetry, this study aimed to evaluate the influence of tobacco smoke on heart rate (H), body temperature (T) and locomotor activity (A) daily rhythms in rats. The tobacco smoke intoxication was produced with a smoking apparatus. H, T, and A data were captured by radiotelemetry. The study was divided into three periods: a 1-week control period (P1), a 1-week stress period (P2), in order to evaluate the stress induced by the animals' restraint in the smoking apparatus, and a 1-week daily tobacco smoke intoxication period (P3). For P1, P2, and P3, a power spectrum analysis was applied in order to determine the dominant period of rhythmicity. Then, characteristics of the rhythms were determined by cosinor analysis. Statistical comparisons were done by ANOVA. Power spectrum analysis showed that neither stress nor tobacco suppressed the daily rhythmicity. Cosinor revealed some modifications: H amplitude was decreased during P2 and P3 with a greater reduction during P3, while T and A amplitudes were decreased during P2 and P3 without difference between P2 and P3. T acrophase was delayed during P2, while A acrophase was delayed during P2 and P3 without any difference between P2 and P3. These perturbations may reflect the effects of stress and tobacco on the suprachiasmatic nucleus by a dopaminergic mechanism.

The role of behavioral thermoregulation as a thermoeffector during prolonged hypoxia in the rat

Exposing rodents to insults such as hypoxia and chemical toxicants induces regulated hypothermia, characterized by a preference for cooler ambient temperatures ( T a) and reduced core temperature ( T c). This study clarified the efficacy of behavioral thermoregulation to regulate T c when subjected to a steady-state hypoxic insult. T c, selected T a ( ST a), heart rate (HR), and motor activity (MA) were monitored by radiotelemetry in rats housed in a temperature gradient. A 6 to 6.5 h period of hypoxia (6.9% O 2)was induced by diluting the air entering the gradient with nitrogen. During the first hour of hypoxia T c decreased by 2.5°C while ST a decreased from 30 to 24.5°C. As hypoxia progressed, ST a rebounded slightly to 26–27°C while T c remained between 34–35°C. HR increased gradually from 300 to 375 beats min −1 during hypoxia. MA increased transiently but then remained near baseline throughout the remainder of the exposure period. Exposure to hypoxia in a gradient maintained at 31.5°C blocked the hypothermic response, showing that preference for cooler T aS during hypoxia is critical for regulating T c. Calorimetric measurements showed that exposure to hypoxia at a T a of 22°C led to a transient rise in dry heat loss, suppression in metabolic rate, and reduction in T c. At a warmer T a of 32°C, hypoxia led to a suppression in heat loss along with an elevation in CO 2 production and T c. Overall, the data show that behavioral and autonomic thermoeffectors serve to regulate T c at a hypothermic level throughout a prolonged period of hypoxic stress.