Disturbance of Circadian Rhythm in Heart Rate, Blood Pressure and Locomotive Activity at the Stroke-Onset in Malignant Stroke-Prone Spontaneously Hypertensive Rats

Abstract

ABSTRACT-Malignant stroke-prone spontaneously hypertensive rats (M-SHRSP), separated from SHRSP, develop severe hypertension and spontaneously develop stroke at early ages. Using this model of cerebrovascular stroke, influence of stroke-onset on the autonomic nervous system was investigated. Heart rate (HR), systolic and diastolic blood pressures (SBP and DBP) and locomotive activity were monitored during development of stroke using a telemetry system. Stroke-onset was assessed by neurologic symptoms, changes in body weight, fluid intake and serum NO x level. The rat displayed a nocturnal pattern of circadian rhythms. At stroke-onset, mean HR over 24 h increased by 20 to 30 bpm and rapidly increased at post stroke, approximately 100 bpm higher than that at pre stroke. Circadian variation in HR, which was normally 50 bpm higher during night than during day, attenuated at stroke-onset, and it was blunted or reversed at post stroke. BP variation, which was approximately 7 mmHg higher at night than at day, decreased one or two days before stroke-onset and reversed at post stroke, especially in DBP. Insufficient falls in HR and BP during the day mainly accounted for the disturbed circadian variations. Variation of locomotive activity also decreased. These changes serve as reliable and accurate markers for stroke-onset in evaluation of drugs for the prevention and outcome predictions of stroke.Keywords: Malignant stroke-prone spontaneously hypertensive rats (M-SHRSP), Stroke, Circadian rhythm, Heart rate, Blood pressure Stroke-prone spontaneously hypertensive rats (SHRSP), a model of genetic hypertension established by Okamoto and colleagues (1), have a high incidence of spontaneous stroke. Salt-loading accelerates this occurrence. Malignant SHRSP (M-SHRSP) were separated through selective brother-sister breeding between precociously and severely hypertensive SHRSP siblings by Okamoto et al. (2) in 1986. These rats develop extremely severe hypertension at an early age, have a higher incidence of cerebrovascular lesions and a shorter life span (approximately 90 days in males) than do SHRSP. Because M-SHRSP spontaneously develop stroke at comparatively early ages (approximately 80 days) without additional salt-loading, this strain serves as a suitable model of hypertension-induced cerebrovascular stroke.Nagaoka and colleagues (3) reported that 80% of SHRSP subjected to salt-loading at 8 weeks of age developed stroke. Rats showed neurologic signs, body weight loss and a marked increase in water intake at stroke-onset, and there were brain lesions in these rats at autopsy. Using this temporal definition of stroke, we demonstrated that the serum level of lipid peroxides increased immediately after strokeonset following a gradual increase preceding the stroke in salt-loaded male SHRSP (4). In addition, there is a significant decrease in glutathione peroxidase (GSH-Px) activity and superoxide dismutase activity in erythrocytes in rats that developed stroke. Murakami et al. (5) later confirmed this finding, reporting that the...

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