We have described a rat model that responds to repetitive episodic hypoxia (12-s infusions of nitrogen into daytime sleeping chambers every 30 s, 7 h/day for 35 days) with an increase in diurnal systemic blood pressure. We hypothesized that afferent information from the peripheral chemoreceptors may be necessary to produce diurnal blood pressure elevation in this hypoxia model. Carotid body denervation (CBD) was accomplished by severing both carotid sinus nerves in two groups of male Wistar rats (250-375 g). Group 4 CBD rats were subjected to intermittent hypoxia for 35 days (3-5% nadir ambient O2) as described above, whereas group 5 CBD rats remained unhandled in their usual cages. Additional sham-operated controls included group 2 sham-"hypoxia" rats, which were housed in chambers identical to the hypoxia rats but supplied with compressed air instead of nitrogen, group 1 (not denervated) rats, which remained unhandled in their usual cages, and group 3 sham-operated rats, which were subjected to 35 days of intermittent hypoxia identical to group 4 CBD rats. Femoral arterial baseline and end-of-study blood pressures were measured in conscious rats. The group 3 rats exposed to episodic hypoxia displayed a 13-mmHg increase in mean blood pressure, whereas the other groups showed no significant change from baseline. Left ventricular hypertrophy was evident in all rats exposed to episodic hypoxia, but right ventricular hypertrophy was evident only in the group 4 rats. All CBD rats developed increased hematocrit and hemoglobin, while the group 3 rats (non-CBD, episodic hypoxia) did not. The baroreceptor reflex at baseline was not depressed in the CBD rats.(ABSTRACT TRUNCATED AT 250 WORDS)

An association between chronic high blood pressure and obstructive sleep apnea has been described. We hypothesized that repetitive episodic hypoxia patterned after the hypoxia seen in sleep apnea could contribute to diurnal elevation of blood pressure. Using 12-second infusions of nitrogen into daytime sleeping chambers, four groups of male rats (250-375 g) were subjected to intermittent hypoxia (3-5% nadir ambient oxygen) every 30 seconds, 7 hours per day for up to 35 days. In one group, blood pressure was measured weekly by the tail-cuff method in conscious animals during 5 weeks of episodic hypoxia. In the other three groups, blood pressure was measured in conscious animals via femoral artery catheters at baseline and after 20, 30, or 35 days of exposure. Additional groups served as controls: two sham groups housed in identical "hypoxia" chambers received compressed air instead of nitrogen (35 days) while two other groups remained unhandled in their usual cages (35 days). Both groups challenged with 35 days episodic hypoxia showed significant increases in blood pressure compared with controls: the tail-cuff rats showed a 21 mm Hg increase in systolic pressure (/?<0.05) and the intra-arterially measured rats a 13.7 mm Hg increase in mean arterial pressure (p<0.05). The 30-day exposed rats also showed a 5.7 mm Hg increase in mean pressure over baseline (p<0.05). Blood pressure did not change significantly from baseline in the control groups. Left ventricle-to-body weight ratio was higher in both 35-day exposed groups than in unhandled or sham controls. This duration-of-exposure-related blood pressure response to hypoxia along with increased left ventricular size after 35 days indicates that chronic intermittent hypoxia could be a mechanism directly contributing to diurnal arterial blood pressure elevation. 1 Chronic hypertension seen in OSA patients may be reversed by treatment of the apnea.2 -4 Other reports show an increased prevalence of sleep apnea in populations of middle-aged men with primary hypertension, 5 -8 but this association has been challenged by more recent epidemiological studies.910 Possible mechanisms for the development of long-term diurnal blood pressure (BP) elevation in this setting are stress related to episodic repetitive hypoxia, disruption of sleep architecture, and modification of the cardiovascular system (including fluid balance) in response to marked fluctuations in intrathoracic pressure. There have been no studies to date examining the effect of any of these individual mechanisms on long-term diurnal BP. It would be quite difficult to prospectively examine factors effecting diurnal BP in humans since such changes may take many years to manifest in the face of progressively more severe, recurrent OSA. One approach is to develop an animal model with a sufficiently short life span in which some conditions of OSA can be duplicated. We chose the rat as a suitable animal in which to examine the effects of hypoxia on BP because of extensive knowledge about mechanisms of systemic hyperte...

No abstract

No abstract

We have previously described a rat model that responds to repetitive episodic hypoxia (FiO 2 nadir 3-5% for 12 seconds every 30 seconds for 7 hr/day for 35 days) with chronic increase in arterial blood pressure. The purpose of the current study was to determine if peripheral sympathetic nervous system denervation blocks this persistent blood pressure elevation. Chemical sympathetic denervation was achieved and maintained by three intraperitoneal injections (100 mg/kg 6-hydroxydopamine) on days 1, 3, and 27 of a 47-day experiment in two groups of rats. One denervated group was subjected to episodic hypoxia for 40 consecutive days beginning on day 7 and the other remained unhandled in their usual cages. A third group was injected with vehicle only and subjected to the same episodic hypoxia while a fourth group remained unhandled for 40 days. The vehicle-treated, episodic hypoxia-exposed group showed a 7.7 mm Hg increase in mean arterial blood pressure (conscious, unrestrained) over the 40-day period, whereas all other groups showed a decrease in mean arterial pressure. The left ventricle and septum/whole body weight ratio was higher in both episodic hypoxia-exposed groups at the end of the study. Plasma epinephrine in both groups administered 6-hydroxydopamine was higher on day 6 than in the vehicle-injected rats. Measurement of catecholamines in cardiac muscle homogenate confirmed denervation in 6-hydroxydopamine animals. These results indicate that the peripheral sympathetic nervous system is necessary for the persistent increase in blood pressure in response to repetitive episodic hypoxia. emia is associated with acute elevation of blood pressure, and in up to 50% of patients with chronic apnea, persistent elevation of daytime blood pressure is seen. '-3 Repetitive acute hypoxia with heightened sympathetic nerve activity could play an important role in the persistent elevation of blood pressure seen in some patients.With some species variability, acute hypoxemia causes increased heart rate, variable changes in arterial pressure, and increased cardiac contractility and output through stimulation of central and peripheral chemoreceptors and perhaps other local effects.4 -6 The effector arm of this reflex involves increased sympathetic discharge. Plasma norepinephrine is elevated in acute hypoxia, 7 -8 and urinary catecholamine elevation in patients with severe sleep apnea is reversed by tracheostomy.9 Acute hypoxia induces elevated blood pressure and increased microneurographic amplitude, implying increased postganglionic sympathetic activity. 1011 In spontaneously hypertensive rats (SHR) 12 and in humans with borderline hypertension, the sympathetic response to acute hypoxia is exaggerated. 13 The response is further exaggerated in borderline hypertensive humans when apnea is added to acute hypoxia.14 Finally, muscle nerve sympathetic activity recorded during apnea in humans shows a progressive increase throughout the apnea followed by an abrupt reduction at apnea termination. 15A key concept in the above hy...