**7. General conclusion**

136 Modern Telemetry

have yielded such results. We think that telemetry is the most appropriate mean for measuring blood pressure in this kind of work involving the modulation of blood pressure by environmental stressors. We also want to underline the fact that stress is always present when dealing with blood pressure measurements in rodents. Given its impact on blood pressure, it has to be taken into consideration even when it is not specifically under study. This example is a good illustration of the study of the gene × environment interactions: We had to increase the genetic variance in order to be able to monitor changes that would not be visible otherwise. The first challenge was the use of an obesity-inducing diet that revealed differences in blood pressure response to stress and in the night period of the circadian pattern. The second challenge was the stress test where we could observe a delay in the return to the baseline in the high-fat diet treated rats. This is very interesting in the light of another finding: an augmentation of the cardiac mass in the rats fed a high fat diet. With the telemetric data, we can hypothesize that the increase in cardiovascular reactivity observed in the night (active period of the rats) and following a stress could explain an increased workload for the heart and the hypertrophy after only 12 weeks of high-fat diet. The effect of the diet would thus be more important when the animals are awake, active and experiencing daily stressors. This interpretation would be impossible without the telemetric

**6.2 Genetic determinants of emotionality and stress response in mice** 

Some strains of mice such as the A/J strain display high anxiety levels. The A/J and C57Bl6 strains are the progenitors of the recombinant congenic strains AcB/BcA. With the help of this recombinant congenic strains panel, Thifault et al. (2008) unveiled quantitative trait loci of the stress response and of emotionality in mice. For the stress response, a 30-minute immobilisation stress was carried out. In these mice, it is characterized by two phases: initial hypothermia followed by thermogenesis. For emotionality, open-field test (number of fecal boli) and elevated plus maze (enclosed arm duration and emergence latencies) were employed. The results unveiled several genomic loci associated with the differential response in the recombinant congenic strains panel. Of major interest, stress loci overlapped with candidate loci for cardiovascular diseases. For instance, the BcA70 strain showed a down regulation of the *Atp1a2* gene in the heart and brain as compared with the parental C57Bl6 strain (p<0,001 and p<0,05, respectively), and this is in accordance with the high emotionality of the knock-outs for that gene and its involvement in salt-sensitive

These remarkable data, resulting from complex analysis of genomic and phenotypic results would not have been possible without telemetry. The body temperature recordings from the stress test were performed with the telemetry implants and a strain distribution pattern over 2,5°C was obtained and could be used to unveil significant loci associated. This temperature difference could not have been monitored with precision with any other means. As for blood pressure, telemetry allowed the monitoring of body temperature continuously and the circadian pattern was obtained. It showed a significant strain x diet effect with the AcB strains (mostly A/J background) displaying a lower body temperature under high-salt diet, and the strain differences were steeper during the dark phase of the circadian cycle. Again, these subtle observations would not have been possible without continuous monitoring by

This study unveiled genetic loci responsible for the differential responses to many of the stressors and tests performed. Since it is easy to get spurious association with genetic

data.

hypertension.

telemetry.

In this review, we have tried to demonstrate the importance of the environmental component of hypertension. When recognizing this importance, we think that it becomes easier to select the right tools to measure blood pressure in animal models as well as in humans. Human studies tend to indicate a decrease of the prevalence of hypertension whereas it may only be the reflection of the new standardized methods for the measurement of blood pressure devoid of stress. We have shown that rodents used for hypertension research are also stress sensitive and that the most commonly used method for blood pressure determination exacerbates the stress perceived by the animals: it increases blood pressure and body temperature. Since we have presented evidences indicating that stress and temperature can in turn be involved in the development of hypertension, it seems essential to subtract their influence when studying hypertension. Therefore, we think that telemetry is the sole method to perform blood pressure measurement in animal models of hypertension because it enables to subtract the stress artefacts or, conversely, to study them. Furthermore, no genetic studies should be performed in animals if telemetry is not used to characterize the blood pressure levels. Some differences are small and inadequate phenotyping could ruin a GWAS by revealing spurious statistical associations and diverting researchers to wrong candidate genes. On the other side, in an effort to standardize the techniques and eliminating human interference and bias, human epidemiological and genetic studies tend to eliminate the stress component from the measurement of blood pressure. As we have shown, this approach is desired in animal studies especially because we are dealing with inbred strains and can test our hypothesis is several backgrounds. Small effect blood pressure loci have more chance of being 'true' and can be verified in congenics

Radio-Telemetry in Biomedical Research - Radio-Telemetry Blood Pressure

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#### **8. References**


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**7** 

*Japan* 

Masayoshi Kuwahara *The University of Tokyo,* 

**Recent Advances in Telemetry** 

**Monitoring and Analysis for Laboratory Animals** 

Measurement of physiological parameters in laboratory animals plays an important role in evaluating the biomedical applications. It has been widely known that a telemetry system is useful for these studies, because the telemetry system can obtain physiological measurements from conscious and unrestrained laboratory animals. Maurey was the first to report on a telemetry experiment in the scientific literature (see Mackay, 1970). Mackay wrote the experiment as follows: *"A rubber bulb detects the shortening of the pectoral muscle of a pigeon by its thickening the pneumatic signal traveling a rubber tube to a bulb pushing a stylus on a smoked arum. A flapping vane at the wingtip opens and closes an electric contact to indicate the relative duration of the period of elevation and depression of the wing."* One of the first telemetry experiments with the use of a radio signal is reported by Barr (1954). From the late 1950's, several research groups have developed radio-telemetry devices for laboratory animals (Gold & Malcolm, 1957; Essler & Folk, 1961; Franklin, et al., 1964). Although telemetry technology for monitoring laboratory animals have already existed since the early 1950's as described above, fully implantable and reliable telemetry devices for monitoring physiological functions in laboratory animals have been made commercially available since the late 1980's. Advances and further miniaturization of the implantable devices in the beginning of 1990's have provided to measure electrocardiogram (ECG), electromyogram (EMG), electroencephalogram (EEG), blood pressure (BP), body temperature (BT), and locomotor activity (LA). Therefore, the number of publications in which radio-telemetric results in laboratory animals has been tremendously increased for 2 decade. In these days, many companies commercially supply the radio-telemetry implants for monitoring

In this report, I would like to introduce a newly developed telemetry system in Japanese company and some useful software to analyze ECG data in the fields of cardiology and pathophysiology as well as pharmacology and toxicology. Further, I describe some

The telemetry system for rat and mouse consists of an implantable transmitter (ATE-01S) with a pair of flexible leads, a telemetry receiver (ATR-1001) and connected acquisition

experimental studies using a telemetry system and applications.

system (Softron ECG Processor; EP95) to personal computer (Fig. 1).

**2. Newly developed telemetry system** 

**1. Introduction** 

physiological parameters.

congenic mice and *in silico* evidence of convergence with cardiovascular candidate genes. *Hum Mol Genet*;17:331-344.

