Evaluation of forearm vascular resistance during orthostatic stress: Velocity is proportional to flow and size doesn't matter.

BACKGROUND: The upright posture imposes a significant challenge to blood pressure regulation that is compensated through baroreflex-mediated increases in heart rate and vascular resistance. Orthostatic cardiac responses are easily inferred from heart rate, but vascular resistance responses are harder to elucidate. One approach is to determine vascular resistance as arterial pressure/blood flow, where blood flow is inferred from ultrasound-based measurements of brachial blood velocity. This relies on the as yet unvalidated assumption that brachial artery diameter does not change during orthostatic stress, and so velocity is proportional to flow. It is also unknown whether the orthostatic vascular resistance response is related to initial blood vessel diameter. METHODS: We determined beat-to-beat heart rate (ECG), blood pressure (Portapres) and vascular resistance (Doppler ultrasound) during a combined orthostatic stress test (head-upright tilting and lower body negative pressure) continued until presyncope. Participants were 16 men (aged 38.4±2.3 years) who lived permanently at high altitude (4450m). RESULTS: The supine brachial diameter ranged from 2.9-5.6mm. Brachial diameter did not change during orthostatic stress (supine: 4.19±0.2mm; tilt: 4.20±0.2mm; -20mmHg lower body negative pressure: 4.19±0.2mm, p = 0.811). There was no significant correlation between supine brachial artery diameter and the maximum vascular resistance response (r = 0.323; p = 0.29). Forearm vascular resistance responses evaluated using brachial arterial flow and velocity were strongly correlated (r = 0.989, p<0.00001) and demonstrated high equivalency with minimal bias (-6.34±24.4%). DISCUSSION: During severe orthostatic stress the diameter of the brachial artery remains constant, supporting use of brachial velocity for accurate continuous non-invasive orthostatic vascular resistance responses. The magnitude of the orthostatic forearm vascular resistance response was unrelated to the baseline brachial arterial diameter, suggesting that upstream vessel size does not matter in the ability to mount a vasoconstrictor response to orthostasis.

The coronary baroreflex in humans.

Previous studies have identified the presence of coronary baroreceptors in animal models. We set up a study to explore the presence of coronary baroreceptors in humans, which was performed with isolated, graded aortic root perfusion in patients during cardiopulmonary bypass. With ethical approval 12 patients with normal coronary arteries, aged 58-75 (mean 69) years undergoing mitral valve surgery were recruited to the study with informed consent. Those with aortic valve incompetence, coronary, or peripheral artery disease and diabetes mellitus were excluded. They were randomized to have their coronary perfusion pressure set low at 50 mmHg for 90 seconds and then adjusted high to 80 mmHg for 90 seconds (group L-H) or the reverse sequence (group H-L). Average arterial pressure and approximately constant systemic flow over 30-second periods were used to calculate vascular resistance (SVR). The first six experiments followed initiation of cardiopulmonary bypass and aortic clamping but before the delivery of cold blood cardioplegia; the blood temperature for these experiments was kept at 32 degrees C. The remaining six were conducted prior to removal of the aortic cross clamp at 37 degrees C. Coronary sinus blood samples were analyzed to exclude myocardial ischemia. Coronary sinus blood samples showed insignificant variation in oxygen saturation, lactate, and troponin T. Three patients were excluded because of unstable blood pressure. In the (L-H) group SVR reduced in 4 of 4 remaining patients (mean -9.4%, range -3.9 to -19.6%). In the (H-L) group SVR increased in three patients (mean +2.0%, range 1.1 to 3.7%) but decreased in two (-8.9% and -15.8%). These preliminary results, although not statistically different, suggest the presence of coronary baroreceptors in humans. The reflex vascular responses are similar to those previously reported in animal models.

Blockade of peripheral vascular responses to isoprenaline by three beta-adrenoceptor antagonists in the anaesthetized dog.

1 A dog's hind limb was vascularly isolated by strong nylon snares and its sympathetic nerve supply interrupted. Blood was perfused at constant flow into the femoral artery and drained from the femoral vein. In some dogs the cardiac nerves were cut.2 Isoprenaline infused intravenously caused an increase in heart rate and a decrease in arterial resistance.3 Practolol (2 mg/kg) effectively blocked heart rate responses to isoprenaline infused at up to 10 mug/min but was relatively ineffective in blocking arterial responses. ICI 66082 (2 mg/kg) reduced vasomotor responses and propranolol (0.5 mg/kg) abolished vasomotor responses.4 Small cumulative doses of beta-adrenoceptor antagonists were given to some dogs. Practolol blocked heart rate responses in lower doses than were required to block vasomotor responses. Propranolol preferentially blocked vasomotor responses and ICI 66082 was intermediate between the other two in its effects.

Increased orthostatic tolerance following moderate exercise training in patients with unexplained syncope.

OBJECTIVE: To determine whether a programme of simple, moderate exercise training increases blood volume and improves orthostatic tolerance in patients with attacks of syncope or near syncope related to orthostatic stress. DESIGN: An open study in 14 patients referred with unexplained attacks of syncope, who were shown to have a low tolerance to an orthostatic stress test. Measurements were made of plasma and blood volumes, orthostatic tolerance to a test of combined head up tilt and lower body suction, and baroreceptor sensitivity by applying subatmospheric pressures to a chamber over the neck. Cardiorespiratory fitness was assessed from the relation between heart rate and oxygen uptake during a graded treadmill exercise test. Assessments were made before and after undertaking an exercise training programme (Canadian Air Force 5BX/XBX). RESULTS: After the training period, 12 of the 14 patients showed evidence of improved cardiorespiratory fitness. All 12 patients were symptomatically improved; they showed increases in plasma and blood volumes and in orthostatic tolerance, and decreases in baroreceptor sensitivity. Despite the improved orthostatic tolerance, values of blood pressure both while supine and initially following tilting were lower than before training. CONCLUSIONS: Exercise training has a role in the management of patients with syncope and poor orthostatic tolerance. It improves symptoms and increases orthostatic tolerance without increasing resting blood pressure.

Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.

OBJECTIVE: To determine whether in patients presenting with posturally related syncope administration of salt increases plasma volume and improves orthostatic tolerance. Patients with poor tolerance of orthostatic stress tend to have lower than average plasma and blood volumes. DESIGN: A double blind placebo controlled study in 20 patients and an open study in 11 of the effects of giving 120 mmol/day of sodium chloride. PATIENTS: 31 patients presenting with episodes of syncope who had no apparent cardiac or neurological disease. Plasma volume was determined by Evans blue dye dilution, orthostatic tolerance by time to presyncope in a test of combined head-up tilt and lower body suction, and baroreceptor sensitivity by the effect of neck suction on pulse interval. RESULTS: 8 weeks after treatment, 15 (70%) of the 21 patients given salt and three (30%) of the placebo group showed increases in plasma and blood volumes and in orthostatic tolerance, and decreases in baroreceptor sensitivity. Improvement was related to initial salt excretion in that patients who responded to salt had a daily excretion below 170 mmol. The patients in the placebo group who improved also showed increases in salt excretion. CONCLUSIONS: In patients with unexplained syncope who had a relatively low salt intake administration of salt increased plasma volume and orthostatic tolerance, and in the absence of contraindications, salt is suggested as a first line of treatment.

Physiological cardiac reserve: development of a non-invasive method and first estimates in man.

OBJECTIVE: To investigate whether physiological cardiac reserve can be measured in man without invasive procedures and whether it is a major determinant of exercise capacity. DESIGN: Development of method of measurement and an observational study. SETTING: A regional cardiothoracic centre. SUBJECTS: 70 subjects with a wide range of cardiac function, from heart failure patients to athletes. METHODS: Subjects underwent treadmill, symptom limited cardiopulmonary exercise tests to measure aerobic exercise capacity (represented by VO2max) and cardiac reserve. Cardiac output was measured non-invasively using the CO2 rebreathing technique. RESULTS: Cardiac power output (CPOmax) at peak exercise was found to be significantly related to aerobic capacity: CPOmax (W) = 0.35 + 1.5 VO2max (1/min), r = 0.87, p < 0.001. It also correlated well with exercise duration (r = 0.62, p < 0.001), suggesting that cardiac reserve is a major determinant of exercise capacity. In the study, cardiac reserve ranged from 0.27 to 5.65 W, indicating a 20-fold difference between the most impaired cardiac function and that of the fittest subject. CONCLUSIONS: A non-invasive method of estimating physiological cardiac reserve was developed. The reserve was found to be a major determinant of exercise capacity in a population of normal subjects and patients with heart disease. This method may thus be used to provide a clearer definition of the extent of cardiac impairment in patients with heart failure.

Cardiovascular reflexes from ventricular and coronary receptors.

Ventricular receptors are distributed throughout the left ventricle and most, if not all, are attached to nonmyelinated nerve fibers. The receptors may be chemosensitive, mechanosensitive or both. Chemosensitive afferents are classically excited by exogenous chemicals such as veratridine, although endogenous chemicals such as bradykinin and prostaglandins, which are released during ischemia, also excite these nerves. The reflex responses can be very powerful, resulting in profound bradycardia and hypotension. A normal physiological role for these receptors seems unlikely although it is probable that they contribute to the changes occuring in some pathological states. Ventricular mechanoreceptors, some of which may also exhibit chemosensitivity, are excited by increases in ventricular systolic pressure, but only when the pressure increases to extreme levels. They also appear to react to increases in inotropic state and increases, and possibly also to decreases, in ventricular filling. It seems that ventricular mechanoreceptors do not show the same intense response as is seen in the chemosensitive afferents following chemical stimulation and probably as a consequence of this their reflex responses are also weak and probably of little importance. Previous assertions that they are involved in the vasovagal reaction can probably now be discounted. The existence of coronary arterial baroreceptors has been suspected for about 30 years. This has now been confirmed and they have been shown to respond to pressure changes in much the same way as the well known carotid and aortic baroreceptors. There are, however, some interesting differences. Coronary baroreceptors, at least in the dog, do not control the heart rate, although they do influence respiratory activity. Another intriguing difference is that when vascular resistance has been inhibited reflexly by perfusing coronary receptors at a high pressure, it takes several minutes for the vascular resistance to increase when coronary pressure is again lowered. The implications of this are uncertain, but it is conceivable that, whereas carotid baroreceptors are involved in the responses to rapid changes in pressure, coronary baroreceptors may be more concerned with the regulation of the long-term level of arterial blood pressure.

The use of a microcomputer to automate measurement of action potential duration for both transmembrane and monophasic action potentials.

Measurement of action potential duration is made more valuable if it can be made simultaneously with other variables, to which it may be related. We have developed a microcomputer-based system which allows measurement of action potential duration, both for transmembrane action potentials and for monophasic action potentials. The system allows simultaneous recording and analysis of action potentials and intraventricular pressures. Both end-diastolic and maximum systolic pressures have been analysed. Action potential duration was assessed at four different levels of the repolarization curve. We have analysed the consistency of measurements made by the computer, and compared them to measurements made manually, using results from six dog experiments. For action potential duration, there was no systematic difference between the manual and the computer methods, but the computer was significantly more consistent. In the case of the pressure measurements, the two methods were approximately the same in their consistency, and again there was no systematic difference. We have demonstrated that potential errors in determination of the average diastolic potential did not significantly affect the results obtained by our method. The variances of action potential duration measurements made at different levels of repolarization were equal. We demonstrated that there was no effect of amplitude on the action potential duration of potentials recorded under steady-state conditions.

An acute animal model that simulates the hemodynamic situations present during +Gz acceleration.

Air combat maneuver acceleration (G) profiles with onset/offset patterns that occur faster than the response characteristics of the human cardiovascular system may lead to regulatory instability and, ultimately, acceleration-induced loss of consciousness (G-LOC) incidents. We have developed an acute animal model that simulates the hemodynamic situations seen under acceleration to study the effects of complex G environments on individual reflexogenic areas. This preparation allowed us to individually isolate the effects of high gravity on venous return and cardiac preload, arterial baroreflexes and splanchnic capacity. This report describes the preparation and presents examples of the types of +Gz simulations possible and recordings of the responses of the animals. Further, we tested the hypothesis that the volume of blood displaced from the cephalic regions of the circulation and the rate of displacement into the splanchnic capacitance with G onset is affected by distending pressure at the carotid/aortic baroreceptor sites. Early results from 7 dogs show that resistance to flow into the splanchnic beds is affected by changes in distending pressure occurring at arterial baroreceptor sites. When pressure distending the carotid/aortic baroreceptors was increased, resistance to flow into the abdominal vascular beds was decreased. This result suggests that sudden increases in +Gz loads occurring during the overshoot phase from a previous G-peak may result in reduced tolerance.

Differences between syncope resulting from rapid onset acceleration and orthostatic stress.

BACKGROUND AND HYPOTHESIS: Orthostatically-induced syncope is accompanied by venous pooling and vasodilatation. Loss of consciousness during head-to-foot acceleration (G-LOC) in aviators may be caused by a different mechanism, as venous pooling should be prevented through the use of an anti-G suit. This research was conducted to test the hypothesis that in individuals wearing a well-fitted anti-G garment, no important changes occur in the volume of dependent regions during loss of consciousness resulting from rapid onset acceleration stress. Further, this work compares venous pooling patterns in G-LOC subjects to patterns seen during syncope in volunteers and patients subjected to orthostatic stress. We conducted the tilt/LBNP tests to establish what level of venous pooling was required to induce syncope in the absence of a hydrostatic component (other than 1 G) and to confirm that our equipment was sensitive enough to detect volume changes large enough to cause syncope. METHODS: Shifts in blood volume to the calf, thigh and abdominal segments were compared in subjects with G-LOC to those in subjects taken to presyncope with orthostatic stress created by upright tilt and lower body negative pressure (LBNP). Centrifuge subjects were exposed to a 15 s rapid onset (6 G.s-1) + 5 Gz exposure on the centrifuge while remaining relaxed and wearing a well-fitting anti-G suit, but with the anti-G suit pressure inactivated. RESULTS: Blood volume decreased an average of 14.9 +/- 22.1 ml in the calf segment; increased an average of 64.1 +/- 7.9 ml in the thigh segment, and decreased an average of 80.1 +/- 29.7 ml in the abdominal segment. The mean net change in volume of the three combined regions was not significantly different from zero. Presyncope was induced in subjects by a progressive exposure to upright tilt, and then addition of LBNP at -20 mm Hg and -40 mm Hg. In the tilt/LBNP group, there was a net increase of 1022 +/- 269.8 ml for the combined segments. Changes in all three segments were significantly different than the mean segmental volume changes seen in centrifuge subjects at G-LOC endpoints. Significant changes from baseline mean arterial pressure, but not heart rate were also seen within, but not between the 2 groups, with mean eye level blood pressures (ELBP) falling an average of 45.6 +/- 7.7 mm Hg in the tilt/LBNP group at syncope and 105.1 +/- 15.5 mm Hg in the centrifuge subjects at G-LOC. CONCLUSIONS: These differences suggest that G-LOC may be due entirely to hydrostatic effects, with venous pooling being prevented by the wearing of an ant-G garment, even when it remains uninflated.

Sensory functions of the heart.

Stretch receptors are situated in the walls of the atria, left ventricle and coronary arteries. Atrial receptors are stimulated by atrial distension due to increased filling as the result, amongst other things, of an increased blood volume. Their reflex responses are increases in heart rate and in urine flow. Ventricular receptors may be stimulated by chemical agents, mechanical stimuli, or both. They are responsible for the Bezold-Jarisch reflex of bradycardia and hypotension, but their normal physiological role, if any, is uncertain. The proximal part of the left coronary artery contains baroreceptors which are excited by increases in blood pressure. Their role, like other baroreceptors, is to control blood pressure by regulation of the diameter of the peripheral blood vessels.

Vasodilator effects of leptin on canine isolated mesenteric arteries and veins.

1. Although leptin increases sympathetic nerve activity and blood pressure, its direct action on large arterial rings is to cause relaxation. However, it is the small resistance arteries and veins that are important in blood pressure control. The effects of leptin on these small vessels has not been reported previously in the canine and the effect of leptin on the capacitance vessels is not known. 2. In the present study, third- or fourth-order canine mesenteric arteries and veins were isolated and placed in a perfusion myograph and preconstricted with noradrenaline. The responses to graded concentrations of leptin were determined and the role of nitric oxide was assessed by administration of N(G)-nitro-l-arginine methyl ester (l-NAME), a blocker of nitric oxide synthase. 3. Leptin induced dose-related dilatations in both arterial and venous segments. The mean (+/-SEM) maximum increases in the diameter of the arteries and veins were 25.0 +/- 4.8 and 29.9 +/- 2.0% of the initial preconstriction, respectively. Relaxations of both arteries and veins were abolished by l-NAME or by endothelium denudation, although dilatations were still obtained to sodium nitroprusside, a nitric oxide donor. 4. These results indicate that leptin dilates canine small mesenteric arteries and veins by a mechanism involving endothelial release of nitric oxide. This observation may result in a decrease of peripheral resistance and venous return and, hence, counteract the leptin-induced neurally mediated vasoconstriction that has been reported previously.

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.

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% O(2) in N(2)), and (iii) hypercapnia (5% CO(2) in 95% O(2)). 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.