Many common cardiovascular events (including myocardial infarction, cardiac death and stroke) have reproducible, daily fluctuations, which are almost certainly due in part to circadian rhythms. VPAC2 receptor null mice (Vipr2-/-) mice, lack a functional circadian “master clock” in the suprachiasmatic nuclei (SCN) of the hypothalamus, and do not exhibit robust circadian rhythms of wheel running behaviour and corticosterone secretion when given ad libitum access to food (Sheward et al. 2007). We have investigated rhythms of heart rate, blood pressure and locomotor activity in these mice using implanted radio-telemetry devices. Male Vipr2-/- and wildtype (WT) mice were anaesthetised with ketamine (50mgkg-1, i.p.) and medetomidine (0.75mgkg-1, i.p.). Radiotelemetric catheters (PA-C10, Data Sciences International, St Paul, MN) were inserted into the left common carotid artery with the transmitter implanted subcutaneously. Mice were housed individually at 22°C, initially with a 12:12 light:dark cycle (LD). After 5-7 days, mice had recovered from surgery and exhibited regular diurnal rhythms of activity. In LD, Vipr2-/- mice showed bouts of activity throughout the day and night whereas the WT mice were active predominantly during the night. In contrast to the WT, Vipr2-/- mice had absent or attenuated diurnal rhythms of heart rate and blood pressure and the predominant rhythms were ultradian with a period of about 2-3h. The ultradian component was also present in WT mice, but was less prominent and had the stronger circadian rhythm superimposed. Transfer into constant dark (DD) conditions increased the ultradian nature of rhythms of activity and the cardiovascular parameters in the Vipr2-/- mice. Mice were returned to LD conditions and allowed free access to running wheels. The presence of the running wheel imposed a strong diurnal rhythm of activity, blood pressure and heart rate in Vipr2-/- mice, which were replaced with a strong ultradian rhythm after transfer to DD conditions. We have shown that, unlike wheel running, general locomotor activity is not greatly suppressed by light in mice. Heart rate and mean arterial blood pressure showed a clear 24h rhythm in WT mice, whereas in Vipr2-/- mice the rhythm is predominantly ultradian in nature. Mice in which core clock genes, such as Bmal1 and Clock, are mutated in all tissues also display ultradian rhythms, suggesting that these are not driven by the circadian clock, (Curtis et al. 2007). The main function of the SCN clock is to impose a partitioning of the day into subjective night (largely active) and day (largely at rest); in the absence of SCN control an ultradian rhythm of rest/activity is the main determinant of heart rate and blood pressure.
University of Leeds (2008) Proc Physiol Soc 10, C7 and PC56
Oral Communications: The cardiovascular phenotype of VPAC2 receptor knockout mice lacking a functional suprachiasmatic nucleus clock
W. J. Sheward1, P. S. Hartley1, J. M. Horn1, G. Brooker1, M. H. Holmes1, A. J. Harmar1
1. Circadian Physiology Group, Centre for Cardiovascular Studies, QMRI, 47 Little France Crescent,, University of Edinburgh, Edinburgh, United Kingdom.
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