Victoria Louise Cooper

Interaction of chemoreceptor and baroreceptor reflexes by hypoxia and hypercapnia – a mechanism for promoting hypertension in obstructive sleep apnoea

Asphyxia, which occurs during obstructive sleep apnoeic events, alters the baroreceptor reflex and this may lead to hypertension. We have recently reported that breathing an asphyxic gas resets the baroreceptor–vascular resistance reflex towards higher pressures. The present study was designed to determine whether this effect was caused by the reduced oxygen tension, which affects mainly peripheral chemoreceptors, or by the increased carbon dioxide, which acts mainly on central chemoreceptors. We studied 11 healthy volunteer subjects aged between 20 and 55 years old (6 male). The stimulus to the carotid baroreceptors was changed using graded pressures of −40 to +60 mmHg applied to a neck chamber. Responses of vascular resistance were assessed in the forearm from changes in blood pressure (Finapres) divided by brachial blood flow velocity (Doppler) and cardiac responses from the changes in RR interval and heart rate. Stimulus–response curves were defined during (i) air breathing, (ii) hypoxia (12% O2 in N2), and (iii) hypercapnia (5% CO2 in 95% O2). Responses during air breathing were assessed both prior to and after either hypoxia or hypercapnia. We applied a sigmoid function or third order polynomial to the curves and determined the maximal differential (equivalent to peak sensitivity) and the corresponding carotid sinus pressure (equivalent to ‘set point’). Hypoxia resulted in an increase in heart rate but no significant change in mean blood pressure or vascular resistance. However, there was an increase in vascular resistance in the post‐stimulus period. Hypoxia had no significant effect on baroreflex sensitivity or ‘set point’ for the control of RR interval, heart rate or mean arterial pressure. Peak sensitivity of the vascular resistance response to baroreceptor stimulation was significantly reduced from −2.5 ± 0.4 units to −1.4 ± 0.1 units (P < 0.05) and this was restored in the post‐stimulus period to −2.6 ± 0.5 units. There was no effect on ‘set point’. Hypercapnia, on the other hand, resulted in a decrease in heart rate, which remained reduced in the post‐stimulus period and significantly increased mean blood pressure. Baseline vascular resistance was significantly increased and then further increased in the post‐control period. Like hypoxia, hypercapnia had no effect on baroreflex control of RR interval, heart rate or mean arterial pressure. There was, also no significant change in the sensitivity of the vascular resistance responses, however, ‘set point’ was significantly increased from 74.7 ± 4 to 87.0 ± 2 mmHg (P < 0.02). This was not completely restored to pre‐stimulus control levels in the post‐stimulus control period (82.2 ± 3 mmHg). These results suggest that the hypoxic component of asphyxia reduces baroreceptor–vascular resistance reflex sensitivity, whilst the hypercapnic component is responsible for increasing blood pressure and reflex ‘set point’. Hypercapnia appears to have a lasting effect after the removal of the stimulus. Thus the effect of both peripheral and central chemoreceptors on baroreflex function may contribute to promoting hypertension in patients with obstructive sleep apnoea.

Carotid baroreceptor reflexes in humans during orthostatic stress

Orthostatic stress, including standing, head‐up tilting and lower body suction, results in increases in peripheral vascular resistance but little or no change in mean arterial pressure. This study was undertaken to determine whether the sensitivity of the carotid baroreceptor reflex was enhanced during conditions of decreased venous return. We studied eight healthy subjects and determined responses of pulse interval (ECG) and forearm vascular resistance (mean finger blood pressure divided by Doppler estimate of brachial artery blood velocity) to graded increases and decreases in carotid transmural pressure, effected by a neck suction/pressure device. Responses were determined with and without the application of lower body negative pressure (LBNP) at ‐40 mmHg. Stimulus‐response curves were determined as the responses to graded neck pressure changes and the differential of this provided estimates of reflex sensitivity. Changes in carotid transmural pressure caused graded changes in R‐R interval and vascular resistance. The cardiac responses were unaffected by LBNP. Vascular resistance responses, however, were significantly enhanced during LBNP and the peak gain of the reflex was increased from 1.2 ± 0.3 (mean ± S.E.M.) to 2.2 ± 0.3 units (P < 0.05). The increased baroreflex gain may contribute to maintenance of blood pressure during orthostatic stress and limit the pressure decreases during prolonged periods of such stress.

Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.

Abstract. This study had three main objectives: to examine in patients presenting with unexplained syncope the relationship between orthostatic tolerance and dietary salt intake; to examine in patients with relative low baseline salt excretion the effect of salt loading on both orthostatic tolerance and blood pressure; and to examine the relationship between dietary salt intake and the sensitivity of the baroreceptor reflex. In 178 patients with unexplained syncope we determined 24-hour urinary sodium excretion, supine arterial blood pressure, carotid cardiac baroreceptor sensitivity (neck suction) and tolerance to orthostatic stress (head-up tilt and lower body suction). Those with low salt excretions and poor orthostatic tolerance were given salt supplements and reassessed after three months. Baseline studies revealed that patients with sodium excretions < 170 mmol/day had significantly lower orthostatic tolerance than those with higher excretions. Salt loading caused a small but significant increase in mean pressure and significant increases in orthostatic tolerance and baroreceptor sensitivity. Improved orthostatic tolerance was seen in 68 of 98 (69 %) patients in whom salt was given. These patients had significantly greater changes in baroreceptor sensitivity than those failing to improve. These results confirm the benefits of salt loading patients with posturally-related syncope. Incidence of hypertension following salt in these patients is relatively uncommon but it is advisable to monitor the effects on blood pressure.

Effects of simulated obstructive sleep apnoea on the human carotid baroreceptor–vascular resistance reflex

Obstructive sleep apnoea (OSA), which is characterized by periodic inspiratory obstruction, is associated with hypertension and possibly with changes in the baroreceptor reflex. In this investigation we induced changes in inspiratory resistance and in inspiratory oxygen and carbon dioxide content, which simulate some of the changes in OSA, to determine whether this caused changes in the gain or setting of the carotid baroreflex. In eight healthy subjects (aged 21–62 years) we changed the stimulus to carotid baroreceptors, using neck chambers and graded pressures of −40 to +60 mmHg, and assessed vascular resistance responses in the brachial artery from changes in blood pressure (Finapres) divided by brachial artery blood flow velocity (Doppler ultrasound). Stimulus–response curves were defined during (a) sham (no additional stimulus), (b) addition of an inspiratory resistance (inspiratory pressure −10 mmHg), (c) breathing asphyxic gas (12% O2, 5% CO2), and (d) combined resistance and asphyxia. Sigmoid or polynomial functions were applied to the curves and maximum differentials (equivalent to peak gain) and the corresponding carotid pressures (equivalent to ‘set point’) were determined. The sham test had no effect on either gain or ‘set point’. Inspiratory resistance alone had no effect on blood pressure and did not displace the curve. However, it reduced gain from −3.0 ± 0.6 to −2.1 ± 0.4 units (P < 0.05). Asphyxia alone did increase blood pressure (+7.0 ± 1.1 mmHg, P < 0.0005) and displaced the curve to higher pressures by +16.8 ± 2.1 mmHg (P < 0.0005). However, it did not affect gain. The combination of resistance and asphyxia both reduced gain and displaced the curve to higher pressures. These results suggest that inspiratory resistance and asphyxia cause changes in the baroreceptor reflex which could lead to an increase in blood pressure. These changes, if sustained, could provide a mechanism linking hypertension to obstructive sleep apnoea.

Cross-spectral analysis of cardiovascular parameters whilst supine may identify subjects with poor orthostatic tolerance.

An easy and low-cost method for identification of subjects prone to orthostatic vasovagal syncope would be of clinical benefit. An orthostatic test with 60 degrees head-up tilt and progressive lower-body negative pressure was performed on 79 patients with histories of unexplained syncope and 26 control subjects. The test was stopped at the onset of presyncope and time to presyncope was taken as a measure of orthostatic tolerance. Spectral and cross-spectral analysis was performed on the supine time series of the R-R interval (ECG) and systolic pressure (Finapres) recorded before the beginning of the test. According to reference values, 38 patients and 11 controls were classified as having poor orthostatic tolerance (PPT and CPT respectively), whereas 41 patients and 15 controls displayed normal orthostatic tolerance (PNT and CNT respectively). The central frequency of the low-frequency (LF approximately equal to 0.1 Hz.) oscillations in PNT and CNT was significantly higher than that in PPT and CPT. In addition, it was significantly linearly correlated with the time of presyncope. Using our test of orthostatic tolerance as a comparison, the LF central frequency allows the classification of subjects with poor or normal tolerance with 80% sensitivity and 82% specificity. These results suggest that the LF central frequency in the supine position may provide a useful index in the diagnosis of orthostatic intolerance.

R–R interval–blood pressure interaction in subjects with different tolerances to orthostatic stress

In addition to the gain, the time delay in the input–output response in a feedback system is crucial for the maintenance of its stability. Patients with posturally related (vasovagal) syncope have inadequate control of blood pressure and one possible explanation for this could be prolonged latency of the baroreflex. We studied 14 patients with histories of syncope and poor orthostatic tolerance (assessed by a progressive orthostatic stress test) and 16 healthy controls. We performed spontaneous sequence analysis of the fluctuations of R–R period (ECG) and systolic arterial pressure (SAP, Finapres) recorded during a 20 min supine period and during 20 min 60 deg head‐up tilt (HUT). The baroreflex latency was determined by identifying the lag between the changes in SAP and in R–R interval from which the highest correlation coefficient was obtained. During the supine period, 74% of sequences in control subjects and 54% in patients occurred with zero beats of delay (i.e. R–R interval changed within the same R–R interval). The remaining sequences occurred with delays of up to four beats. HUT shifted the baroreflex delay to be approximately one heartbeat slower and again patients showed more sequences with prolonged response. The delay in heartbeats was transformed into delay in time. In control subjects, 75% of baroreflex responses occurred within 1 s. In patients, 75% of baroreflex responses took more than 2 s to occur. The results showed that syncopal patients with poor orthostatic tolerance have increased baroreflex latency. This may lead to instability and inadequate blood pressure control and may predispose to vasovagal syncope.

Prolonged latency in the baroreflex mediated vascular resistance response in subjects with postural related syncope

In addition to the gain, the delay of the baroreflex response plays an important role in the maintenance of cardiovascular system stability. Additionally when postural changes induce sudden drops in blood pressure, a delayed response may fail to maintain sufficient cerebral perfusion pressure. We tested the hypothesis that the delay of the carotid baroreceptor reflex is impaired in subjects with poor orthostatic tolerance. An orthostatic test with 60° head-up tilt, and progressive lower-body negative pressure was performed on 27 patients with histories of unexplained syncope and 13 control subjects. The test was stopped at the onset of presyncope and time to presyncope was taken as a measure of orthostatic tolerance. Twelve patients had normal tolerance and thirteen patients had low tolerance. We measured beat-to-beat blood pressure (Finapres) and brachial artery blood flow velocity (Doppler ultrasonography). Before the test, we determined the response of forearm vascular resistance (mean arterial pressure/mean brachial artery velocity) to loading/unloading of carotid baroreceptors by the application of neck suction/pressure (–/+30 mmHg) to a chamber fitted overlying the carotid sinus. We measured the gain in the response (maximum percentage change from baseline value in vascular resistance divided by the neck collar pressure) and the latency in the response (delay of the maximum change in vascular resistance after neck-collar stimulation). Results are reported as means ± SEM. In the three groups, there were no differences in the sensitivity of the vascular resistance response after baroreceptor loading/unloading. Following baroreceptor unloading, the latency of the response was 14.0±1.3 seconds in early fainters, 9.3±0.7 seconds in normal patients and 10.1±1.2 seconds in controls. The latency in blood pressure rise was 11.1±1.3 seconds in early fainters, 7.9±0.9 seconds in normal patients and 7.2±1.0 seconds in controls. The results following baroreceptor loading were more scattered. The early fainters still had a tendency to show prolonged latency. These results suggest that the delay in the baroreflex response plays an important role in postural related syncope.

Daytime variability of baroreflex function in patients with obstructive sleep apnoea: implications for hypertension.

Obstructive events during sleep in patients with obstructive sleep apnoea (OSA) cause large alterations in blood pressure, and this may lead to changes in baroreflex function with implications for long‐term blood pressure control. This study examined the daytime variations in the responses to carotid baroreceptor stimulation in OSA patients. We determined the cardiac and vascular responses every 3 h between 09.00 and 21.00 h in 20 patients with OSA, using graded suctions and pressures applied to a neck collar. These responses were plotted against estimated carotid sinus pressures and, from these plots, baroreflex sensitivities and operating points were taken as the maximal slopes and the corresponding carotid sinus pressures, respectively. We found that at 09.00 h, sensitivity for the control of vascular resistance was at its lowest (−1.2 ± 0.2% mmHg−1, compared with −1.9 ± 0.3% mmHg−1 at 12.00 h, P < 0.02) and operating point for control of mean arterial pressure was at its highest (101.1 ± 5.8 mmHg, compared with 94.1 ± 5.8 mmHg at 12.00 h, P < 0.05). This is in contrast to previous data from normal subjects, in whom sensitivity was highest and operating point lowest at 09.00 h. We suggest that the higher baroreflex sensitivity and lower operating point seen in the mornings in normal subjects may provide a protective mechanism against hypertension and that this protection is absent in patients with OSA. It is possible that the reduced reflex sensitivity and increased operating point in the mornings may actually promote hypertension.