Study On The Mechanism Of Chronic Intermittent Hypoxia-Induced Hypertension In Rats

Obstructive sleep apnea syndrome(OSAS) is a chronic sleep-related respiratory disease and is common in clinical practice. Epidemiological and clinical studies in recent years confirmed that OSAS is an independent risk factor for hypertension, but the underlying mechanism remains unclear. The hypertension in patients with OSAS is difficult to control and standard pharmacological interventions are often ineffective, so it is very important to understand the pathogenesis. OSAS is characterised by recurrent upper airways obstruction which results in repetitive episodic hypoxia during sleep. Animal studies have verified that chronic intermittent hypoxia(CIHO) mimicking episodic hypoxia seen in humans with OSAS could lead to hypertension. Clinical studies showed recently that the plasma levels of endothelin(ET) and angiotensin II (AT II ) were elevated and nitric oxide(NO) levels were declined in patients with OSAS, which suggested that the abnormalities of these vasoactive substances might be related to OSAS-associated hypertension. So we observed the dynamic changes of the NO system, ET system and renin-angiotensin(R-A) system during the development of CIHO-induced hypertension in rats, and evaluated their role in the mechanism of CIHO-induced hypertension. Methods:72 male Wistar rats were divided randomly and equally into three groups as follows: intermittent hypoxia group(IH), Sham control group (SC) and unhandled control group(UC). Using 30-second infusions of nitrogen and followed by 30-second infusions of compressed air into exposure chambers (4%~6% nadir ambient oxygen with return to 21%), IH rats were subjected to intermittent hypoxia every 60 seconds for 8h/day during the diurnal sleep period; SC ratswere similarly handled but received compressed air instead of nitrogen and UC rats remained unhandled. The rats were killed on day 7,21and 42 after experiment respectively, and 8 rats were killed each time in each group.The dynamic changes of the following indexes were observed: (1) blood pressure (catheter method and tail-cuff method) and the pathological changes of vascular tissue; (2) The levels of NO ( nitrate reductase method) and the NO synthase(NOS) activity (chemical colorimetric analysis) in plasma and tissue, the expression of endothelial NOS (eNOS) mRNA in tissue (RT-PCR); (3) The levels of ET-1 in plasma and tissue (radioimmunoassay), the expression of ET-1 and ET receptor (ETAR) mRNA in tissue (RT-PCR); (4) The levels of AT II and the renin activity(RA) in plasma and tissue (radioimmunoassay), the expression of angiotensin-converting enzyme (ACE) and AT II receptor(AT)R) mRNA in tissue (RT-PCR). Results:1. Establishment of the model of CIHO-induced hypertension in rats(1) IH rats showed significant increases in blood pressure on day 42 compared with controls: mean arterial pressure(MAP) and diastolic pressure (DBP) measured by the catheter method increased by 8.1mmHg and 8.8 mmHg respectively; systolic pressure(SBP) measured by the tail-cuff method increased by llmmHg, (all P<0.01). Blood pressure did not change from that before experiment in two control groups.(2) Renal arterioles and abdominal aorta in SC and UC rats showed no pathological changes, so did the abdominal aorta in IH rats, but the wall of renal arterioles in IH rats were thicker than that in SC and UC rats.2. The dynamic changes of NO and NOS during the development of CIHO-induced hypertension in rats(1) Plasma NO levels and NOS activity in IH rats showed a time-dependent decrease, and began to decrease significantly on day 21 compared with that in two control groups (P<0.05 or P<0.01); Compared with that of SC and UC rats onday 42, plasma NO levels decreased by 50% and 54% respectively (both P<0.01), plasma NOS activity decreased by 43% and 41% respectively (both P<0.01).(2) Renal cortex NO levels and NOS activity as well as heart NOS activity in IH rats began to decrease significantly on day 21 compared with that in two control groups (all P<0.05); Compared with that of...