Enhanced Diurnal Variations Of The Cardiac Renin-Angiotensin System In Hypertensive Rats

Hypertension is one of the most prevalent cardiovascular disorders, It is not only manifested by an increased arterial pressure; it also involves complex structural and functional alterations of its target organs. Hypertension-induced left ventricular hypertrophy (LVH), which initially serves as an adaptive ventricular response to pressure overload; but, eventually, is a major independent risk factor associated with increased cardiovascular morbidity and mortality. Moreover, LVH is also associated with an increased risk of cardiac failure, sudden death, ventricular dysrhythmias and coronary heart disease. The etiology of LVH is multifactorial, Factors known to affect the myocardium include nerrohumoral factors, mechanical stress. The activation of RAS can increase the blood pressure and induce LVH. Angiotensin II is the major effector. Angiotensin II mediates its effects by binding to specific AT1 and AT2 receptors. Angiotensin II, apart from its indirect effect of elevating arterial pressure, exerts mitogenic and growth promoting effects on cardiac myocytes and non-myocytic elements; both of these effects significantly contribute to the development and progression of myocardial hypertrophy.Circadian rhythms describe biological phenomena that oscillate with a 24-hour cycle. These rhythms include blood pressure, body temperature, hormone levels and the number of immune cells in blood. The generation and maintenance of circadian rhythm in mammalian is related to the periodcity of clock genes. In mammals, a master clock generating circadian rhythms is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Peripheral cells also contain a circadian clock which is similar to the one present in SCN neurons. SCN clocks can be defined as pacemakers which are able to independently generate and maintain their circadian oscillations whereas peripheral clocks are oscillators which require external signals to sustain and synchronise their circadian rhythms. The circadian rhythm make the tissue anticipate the changes of environment. The circadian rhythm of the molecular clock presumably enables the heart to adapt to various physiological stimuli. It is generally accepted that the heart has its own cardiac RAS which is independent of systemic RAS. Hypertension can make RAS activated. Angiotensin II may acts as a Zeitgeber changing the expression of clock gene, making the heart anticipate and adapt less well to external environment.To investigate whether clock gene is correlated with the expression of RAS in the myocardiums from three kinds of rats (SHR, RHR, CON) respectively and elucidate the role which clock genes play in the process of cardiac hypertrophy. Part one Construction of the model of hypertensive ratAim: To establish the model of hypertensive ratMethods: The model of RHR was established, four weeks after surgery, the blood pressure of RHR was measured. The blood pressure greater than 50mmHg (6.7kPa) in RHR was viewed successful. SHR, RHR, and normotensive control rats (CON) were housed in a separate environment-controlled room for two weeks. On day 15, rats were killed every four hours from 9:00am (ZTO) to 5:00 pm (ZT20). The heart weight was measured quickly. The left ventricle was isolated from other parts of the heart, weight and snap-frozen in liquid nitrogen, and stored at -80℃.Results: The blood pressure was significantly higher in the SHR and RHR compared with the CON rats. Heart weight to body weight ratios and left ventricle weight to heart weight ratios were increased in the SHR and RHR compared with normotensive rats.Conclusion: The hypertension induced left ventricular hypertrophy Part two Enhanced Diurnal Variations of the Cardiac Renin-Angiotensin System components in Hypertensive RatsAim: To investigate whether the circadian mRNA expression of therenin-angiotensin system (RAS) components (ATNG, AT1R, AT2R) inmyocardium is correlated with left ventricular hypertrophy in bothspontaneously hypertensive rats (SHR) and renal hypertensive rats (RHR).Methods: The circadian mRNA expression of ATNG,AT1R,AT2R in thehearts of SHR,RHR and CON rats were examined using ReverseTranscriptase-Polymerase Chain Reaction (RT-PCR).Results: The cardiac mRNA expression of the RAS components showedcircadian oscillations in SHR, RHR and CON rats. The amplitudes of thesecircadian fluctuations were greater in the SHR and RHR than in the CON rats.The mRNA levels of the RAS components were increased in the SHR and RHRcompared with the CON rats at many time points.Conclusion: Overexpression and enhanced amplitudes of circadian fluctuationsof RAS components in SHR and RHR may play a role in the development ofhypertrophy.