Ventilatory responses to isocapnic and poikilocapnic hypoxia in humans

We examined the hypoxic ventilatory response (HVR) including breathing frequency (f(R)) and tidal volume (V(T)) responses during 20 min of step isocapnic (IH) and poikilocapnic (PH) hypoxia (45 Torr). We hypothesized an index related to [Formula: see text] (pHPR) may be more robust during PH. Peak HVR was suppressed during PH (P<0.001), and mediated by V(T) during PH and both V(T) and f(R) during IH. The relative magnitude of HVD remained similar between conditions indicating a suppressive role of hypocapnia in development of the HVR unrelated to the degree of subsequent HVD, implying a primarily O(2) dependant mechanism. Post-hypoxic frequency decline was observed following both IH (3.4+/-3.7 bpm, P<0.05) and PH (3.6+/-3.1 bpm, P<0.01), despite no f(R) response during exposure to PH. Use of pHPR improved the signal to noise ratio during PH, though failed to detect the peak ventilatory response, and therefore may not be appropriate when describing peak responses.     

Protocol to measure acute cerebrovascular and ventilatory responses to isocapnic hypoxia in humans

This study describes a protocol to determine acute cerebrovascular and ventilatory (AHVR) responses to hypoxia. Thirteen subjects undertook a protocol twice, 5 days apart. The protocol started with 8 min of eucapnic euoxia (end-tidal P(CO2) (PET(CO2)= 1.5 Torr) above rest; end-tidal P(O2) (PET(O2)) = 88 Torr) followed by six descending 90 s hypoxic steps (PET(O2) = 75.2, 64.0, 57.0, 52.0, 48.2, 45.0 Torr). Then, PET(O2) was elevated to 300 Torr for 10 min while PET(O2) remained at eucapnia (5 min) then raised by 7.5 Torr (5 min). Peak blood flow velocity in the middle cerebral artery (MCA) and regional cerebral oxygen saturation (Sr(O2)) were measured with transcranial Doppler ultrasound and near-infrared spectroscopy, respectively, and indices of acute hypoxic sensitivity were calculated (AHR(CBF) and AHRSr(O2)). Values for AHR(CBF), AHRSr(O2) and AHVR were 0.43 cm s(-1) % desaturation(-1), 0.80% % desaturation(-1) and 1.24l min(-1) % desaturation(-1), respectively. Coefficients of variation for AHR(CBF), AHRSr(O2) and AHVR were small (range = 8.0-15.2%). This protocol appears suitable to quantify cerebrovascular and ventilatory responses to acute isocapnic hypoxia.     

Dynamics of swallowing-induced cardiac chronotropic responses in healthy subjects

Simultaneous recording of ECG and swallowing movements in healthy humans (n=23, age 20-57 years) showed that each swallow is accompanied by transient tachycardia with initial abrupt and pronounced heart rate increase. These rapid changes in heart rate (evaluation by maximum increment of heart rate over two successive heartbeats, HR_2bt) are typical of vagal chronotropic responses. The amplitude of tachycardia induced by a single swallow was significantly higher in the supine position (13.1±5.6 bpm) compared to the standing position (8.5±3.8 bpm; p<0.0001). Chronotropic responses to a series of three or more successive swallows consisted of two phases, the initial abrupt acceleration and subsequent slower growth of heart rate. In the standing position, the portion of the first rapid phase significantly decreased, while the portion of the slower phase increased compared to the supine position. The amplitude of tachycardia induced by a single swallow and parameter HR_2bt can serve as indices of the strength of parasympathetic modulation of the heart. By contrast, further slow increase in the heart rate determined by summation of responses to a series of successive swallows can result from not only inhibition of the parasympathetic influences, but also enhancement of sympathetic activity during swallowing.     

Acute neurohormonal responses to hypoxaemia in man

We have studied the integrated neuroendocrine and haemodynamic effects of acute hypoxaemia in ten healthy volunteers studied on two separate occasions. After reaching a resting haemodynamic state, subjects breathed either room air or a nitrogen/oxygen mixture which rendered arterial oxygen saturation between 75% and 80%. Measurements of pulmonary and systemic haemodynamics were made and blood samples taken at baseline and after 30 min breathing air or the hypoxic gas. Blood was assayed for plasma sodium and potassium, renin-angiotensin-aldosterone system activity, natriuretic peptides, cortisol and catecholamines. Hypoxaemia significantly increased heart rate, cardiac output and mean pulmonary artery pressure (P _pa), but not mean arterial pressure compared with normoxaemia. Although plasma renin activity, angiotensin II and cortisol were unaffected by hypoxaemia, plasma aldosterone fell significantly in comparison with normoxaemia. This was associated with an increase in plasma atrial natriuretic peptide (ANP) but not b-type natriuretic peptide (BNP) during hypoxaemia whilst no changes were observed during normoxaemia. The increase in plasma ANP correlated positively with the increase inP _pa. During hypoxaemia there is therefore dissociation of the renin-angiotensin-aldosterone system where plasma aldosterone decreased, despite there being no effects on plasma renin activity and angiotensin II or on plasma cortisol. This dissociation may be due to increased levels of ANP but not BNP having specific inhibitory effects on aldosterone biosynthesis. ANP increased in proportion to the degree of pulmonary vasoconstriction induced by hypoxaemia which may indicate a counter-regulatory role.     

Respiratory and cardiac responses to dynamic exercise in man

Ventilation (VE), cardiac output (Q), oxygen consumption (VO2), carbon dioxide production (VCO2), and end tidal gas tensions (PETO2 and PETCO2) were measured in four healthy men during stepwise, steady state increases in work rate on a bicycle ergometer (25, 50, 75, 100, 125, and 150 W). Both the ventilation equivalent (VE/VCO2) and the cardiac equivalent (Q/VCO2) for carbon dioxide, fell during a steady state exercise at 150 W to 2/3 and to 1/3 of the initial levels, respectively. This stepwise reduction in the carbon dioxide production with increasing work rate was compatible with a non-chemical stimulus increasing in proportion to work rate, and governing both ventilation and circulation. These observations do not support the cardio-dynamic hypothesis.     

Intermittent hypoxia reduces cerebrovascular sensitivity to isocapnic hypoxia in humans

The purpose of this study was to determine the changes in human cerebrovascular function associated with intermittent poikilocapnic hypoxia (IH). Healthy men (n=8; 24+/-1 years) were exposed to IH for 10 days (12% O(2) for 5min followed by 5min of normoxia for 1h). During the hypoxic exposures, oxyhemoglobin saturation (SaO(2)) was 85% and the end-tidal partial pressure of CO(2) was permitted to fall as a result of hypoxic hyperventilation. Pre- and post-IH intervention subjects underwent a progressive isocapnic hypoxic test where ventilation, blood pressure, heart rate, and cerebral blood flow velocity (middle cerebral artery, transcranial Doppler) were measured to determine the ventilatory, cardiovascular and cerebrovascular sensitivities to isocapnic hypoxia. When compared to the pre-IH trial, cerebrovascular sensitivity to hypoxia significantly decreased (pre-IH=0.28+/-0.15; post-IH=0.16+/-0.14cms(-1)%SaO(2)(-1); P<0.05). No changes in ventilatory, blood pressure or heart rate sensitivity were observed (P>0.05). We have previously shown that the ability to oxygenate cerebral tissue measured using spatially resolved near infrared spectroscopy is significantly reduced following IH in healthy humans. Our collective findings indicate that intermittent hypoxia can blunt cerebrovascular regulation. Thus, it appears that intermittent hypoxia has direct cerebrovascular effects that can occur in the absence of changes to the ventilatory and neurovascular control systems.     

Differential chronotropic and dromotropic responses to focal stimulation of cardiac vagal ganglia in the rat

Vagal cardioinhibition is exerted through a reduction not only in the heart rate but also in the rate of propagation of the cardiac action potential and in myocardial contractility. In several species, such effects can be produced independently by selective activation of ganglia in identified 'fat pads'. In this study we investigate differential control of heart rate and atrioventricular conduction by two ganglionic clusters in the rat, a species increasingly important in studies of cardiovascular control. Epicardial sites producing low-threshold changes in P-P and P-R interval of the ECG in an arterially perfused preparation were explored with concentric bipolar stimulating electrodes. Stimulation sites centred on two principal ganglia, the sinoatrial (SA) ganglion at the junction of the right superior vena cava and right atrium, and the atrioventricular (AV) ganglion at the junction of the inferior pulmonary veins and left atrium. Stimulation of the SA ganglion decreased heart rate in all preparations, with little or no effect on AV conduction in one-third. Stimulation of the AV ganglion consistently slowed conduction without eliciting a comparable bradycardia. Responses survived blockade of ganglionic transmission by trimetaphan, with an enhanced chronotropic selectivity to SA ganglion stimulation, suggesting that co-excitation of preganglionic elements en passant may have contributed to the earlier mixed responses. Effective stimulation sites were precisely circumscribed and corresponded to principal ganglionic clusters confirmed histologically. We conclude that cardiac vagal ganglia in the rat show a topographical functional organisation and are amenable to investigation using the arterially perfused preparation.     

Effect of maternal nutrient restriction in early gestation on responses of the hypothalamic-pituitary-adrenal axis to acute isocapnic hypoxaemia in late gestation fetal sheep

Epidemiological and experimental evidence suggests that maternal undernutrition during pregnancy may alter development of fetal organ systems. We have demonstrated previously that fetal hypothalamic-pituitary-adrenal (HPA) axis responses to exogenous corticotropin-releasing hormone (CRH) + arginine vasopressin (AVP), or adrenocorticotrophin hormone (ACTH), are reduced in fetuses of mildly undernourished ewes. To examine these effects further we tested HPA axis responses to acute isocapnic hypoxaemia in fetal sheep at 114-129 days gestation (dGA), following 15% reduction in maternal nutritional intake between 0 and 70 dGA. Fetuses from control (C) and nutrient-restricted (R) ewes were chronically catheterised and plasma ACTH and cortisol responses were determined at 114-115, 120-123 and 126-129 dGA during hypoxaemia (1 h) induced by lowering the maternal inspired O2 fraction (FI,O2). Basal plasma cortisol concentrations and HPA axis responses at 114-115 and 120-123 dGA did not differ between C and R fetuses. At 126-129 dGA, both plasma ACTH (P < 0.01) and cortisol (P < 0.05) responses were smaller in R fetuses compared to C fetuses. Fetal blood gas status, fetal body weight, body proportions and organ weights did not differ between the groups. We conclude that mild maternal undernutrition alters development of the fetal HPA axis producing a reduction in pituitary and adrenal responsiveness to endogenous stimuli.     

Respiratory, cerebrovascular and cardiovascular responses to isocapnic hypoxia

We simultaneously measured respiratory, cerebrovascular and cardiovascular responses to 10-min of isoxic hypoxia at three constant CO(2) tensions in 15 subjects. We observed four response patterns, some novel, for ventilation, middle cerebral artery blood flow velocity, heart rate and mean arterial blood pressure. The occurrence of the response patterns was correlated between some measures. Isoxic hyperoxic and hypoxic ventilatory sensitivities to CO(2) derived from these responses were equivalent to those measured with modified (Duffin) rebreathing tests, but cerebrovascular sensitivities were not. We suggest the different ventilatory response patterns reflect the time course of carotid body afferent activity; in some individuals, carotid body function changes during hypoxia in more complex ways than previously thought. We concluded that isoxic hyperoxic and hypoxic ventilatory sensitivities to CO(2) can be measured using multiple hypoxic ventilatory response tests only if care is taken choosing the isocapnic CO(2) levels used, but a similar approach to measuring the cerebrovascular response to isocapnic hyperoxia and hypoxia is unfeasible.     

Subtype-selective blockade of cardiac muscarinic receptors inhibits vagal chronotropic responses in cats

This study was designed to determine if chronotropic responses induced by neurally released acetylcholine are modified by subtype-selective blockade of cardiac muscarinic cholinoreceptors. In anesthetized cats, a single burst of vagal stimulation was generated with an incremental time delay after the P wave of the atrial electrogram (P-Stimulus interval). The slope of the relationships between P-Stimulus and P–P intervals was used to assess changes in responsiveness of cardiac pacemaker to vagal effects throughout the cardiac cycle. An increase in P-Stimulus interval over the initial portion (∼120 ms) of the cardiac cycle produced a significant increment in lengthening of the P–P interval. Once the maximal negative chronotropic response was achieved, a further increase in P-Stimulus interval by only ∼25 ms resulted in profound (by 80–90%) reductions in vagal effects, thus yielding a bimodal vagal phase response curve. Antagonists of M₁ (pirenzepine), M₂ (methoctramine and gallamine), and M₃ (4-DAMP) muscarinic cholinoreceptors produced a reduction in the magnitude of maximal lengthening of cardiac cycle as well as an increase in latency of vagal effects. However, the increment in prolongation of P–P interval induced by a given change in timing of vagal stimulation during cardiac cycle was reduced by M₁ and M₂ muscarinic receptor blockers, but was unaffected by 4-DAMP. None of the antagonists modified the range of P-Stimulus intervals over which the maximum-to-minimum change of vagal responses occurred. Taken together, these data suggest different contribution of various subtypes of cardiac muscarinic receptors into the negative chronotropic responses induced by brief bursts of vagal stimulation.     

Muscle sympathetic nerve activity responses to dynamic passive muscle stretch in humans

It is suggested that mechanoreceptors in muscle play an important role in the exercise pressor reflex. However, it has not been verified whether isolated stimulation of the mechanoreceptors can induce responses in muscle sympathetic nerve activity (MSNA) in young healthy individuals. We tested the hypothesis that passive stretch of muscle can evoke an increase in MSNA in healthy individuals. In 12 young subjects, leg calf muscles were passively stretched, or actively contracted for 5 s followed by a 15–25 s (random length) relaxation period. Stretch and contraction were each repeated 25 times. MSNA, heart rate and blood pressure were analysed, and averaged according to the onset of the force on a beat-by-beat basis. At the 1st to the 3rd heart beat from the onset of stretch, MSNA (199 ± 30%, P < 0.05) as well as heart rate (102.5 ± 0.7%, P < 0.05) increased transiently but significantly from the prior stretch baseline (100%), followed (from 3rd to 7th beat from the onset of stretch) by a transient increase in mean blood pressure (101.9 ± 0.3%, P < 0.05) from the baseline. Similar response patterns were observed during active muscle contractions. The present data show that MSNA responses to isolated stimulation of mechanoreceptors are measurable. Because of baroreflex engagement, the magnitude of the response is small and transient, and the haemodynamic consequences using this protocol may be limited.     

Vasomotor responses to decreased venous return: effects of cardiac deafferentation in humans

We compared haemodynamic and peripheral vasomotor responses to lower body negative pressure (LBNP) in cardiac transplant recipients who had undergone bicaval anastomoses, involving right atrial deafferentation (−RA), and the conventional procedure in which some atrial baroreceptor afferents remain intact (+RA). We measured mean forearm blood flow (FBF) responses using Doppler/ultrasound during three randomised trials involving 0 (baseline), −20 and −40 mmHg LBNP in 15 transplant recipients (9 −RA, 6 +RA) and in eight healthy matched controls. A significant effect of LBNP on FBF existed between control and transplant groups ( P < 0.05; two-way ANOVA). Mild LBNP (−20 mmHg), significantly decreased FBF by 29.7 ± 10.0% relative to baseline in +RA subjects ( P < 0.05), whereas the 17.7 ± 10.3% decrease in −RA subjects was not significant. In response to −40 mmHg LBNP, FBF significantly decreased in control (42.4 ± 4.6%, P < 0.05) and +RA subjects (33.3 ± 11.4%, P < 0.05) with no significant change in the −RA group. The response of systolic blood pressure (SBP) to −40 mmHg significantly differed between groups ( P < 0.05): −RA subjects decreased significantly ( P < 0.05) whilst the decrease in SBP in +RA subjects did not achieve significance and control subjects exhibited an increase. The heart rate increase from baseline to −40 mmHg was significantly attenuated in −RA relative to controls and the +RA group ( P < 0.05). The present study demonstrates that atrial deafferentation impairs reflex vasomotor control of the circulation in response to low- and high-level LBNP, indicating that atrial deafferentation may contribute to abnormal arterial pressure regulation.     

Foetal respiratory movements, electrocortical and cardiovascular responses to hypoxaemia and hypercapnia in sheep

1. Foetal breathing movements, electrocortical activity, arterial pressure and heart rate were recorded continuously in chronically catheterized sheep, 97-145 days pregnant.2. With increasing gestational age there was a fall in heart rate of 0.67 beats/day and a rise in arterial pressure of 0.46 mmHg/day.3. Hypoxaemia in the foetus was induced by allowing the ewe to breathe low oxygen mixtures, 9% O(2) with 3% CO(2) in N(2). In the younger foetuses there was an initial rise in heart rate whereas in the older foetuses there was a fall. After the end of hypoxia there was a persistent tachycardia in both groups. In the older foetuses there was a rise of arterial pressure.4. Two vagotomized older foetuses showed cardiovascular responses similar to those of the younger foetuses.5. Foetal breathing movements were abolished by hypoxaemia in twenty-two of twenty-five experiments. In the three exceptional experiments there was a small rise in P(a, CO2).6. The proportion of time occupied by low voltage electrocortical activity in the foetus was reduced by hypoxaemia.7. Hypercapnia was induced by giving the ewe 4-6% CO(2) with 18% O(2) in N(2) to breathe. After an initial slight fall the foetal heart rate increased and there was a small rise in foetal arterial pressure.8. The proportion of time occupied by low voltage electrocortical activity and breathing movements was increased by hypercapnia.9. Maternal hyperoxia, induced by giving 50% O(2) in N(2), did not significantly increase foetal breathing movements unless the ewe was in labour. In labour the foetuses had lower P(a, O2) values initially and a reduced incidence of foetal breathing, both of which were increased by maternal hyperoxia.     

Phase-dependent chronotropic response of the heart during running in humans

Heartbeat modulation by muscle contraction during rhythmic exercise involving a small muscle mass is phase-dependent, reflecting the timing of the muscle contraction within the cardiac cycle, but it remains unclear whether such modulation occurs during whole body exercise. To determine whether phase-dependent chronotropic changes in the heart would occur during running, we investigated the relationship between R–R interval (RRI) and the timing of vastus lateralis muscle contractions within the cardiac cycle. Seven healthy subjects were examined during high intensity running where the target heart rate was 160 beats · min⁻¹. The running pitch was made to wax and wane periodically in the neighborhood of the target heart rate to scan the effect of footfall timing within the cardiac cycle on heart period. We found that when muscle contraction occurred early in the cardiac cycle, RRI was reduced from the mean RRI (P<0.05). Conversely, when muscle contraction occurred in the latter half of the cardiac cycle, RRI tended to increase (P>0.05). Thus, the curve reflecting this phase-dependent relationship between heart period and timing of muscle contraction showed a positive slope within the first one-quarter to three-quarters of the cardiac cycle. Our results suggest the existence of a mechanism that provides beat-by-beat regulation of RRI even when it is very short (∼ 375 ms), i.e., a cardio-locomotor synchronization develops during running, when the frequencies of the two rhythms approach one another.An erratum to this article can be found at     

Protective effect of prone posture against hypergravity-induced arterial hypoxaemia in humans

Patients with acute respiratory distress syndrome have increased lung tissue weight and therefore an increased hydrostatic pressure gradient down the lung. Also, they have a better arterial oxygenation in prone (face down) than in supine (face up) posture. We hypothesized that this effect of the direction of gravity also existed in healthy humans, when increased hydrostatic gradients were induced by hypergravity. Ten healthy subjects were studied in a human centrifuge while exposed to 1 or 5 G in anterio-posterior (supine) or posterio-anterior (prone) direction. We measured blood gases using remote-controlled sampling and gas exchange by mass spectrometry. Hypergravity led to marked impairments of arterial oxygenation in both postures and more so in supine posture. At 5 G , the arterial oxygen saturation was 84.6 ± 1.2 % (mean ± s.e.m. ) in supine and 89.7 ± 1.4 % in prone posture ( P < 0.001 for supine vs. prone). Ventilation and alveolar P _O2 were increased at 5 G and did not differ between postures. The alveolar-to-arterial P _O2 difference increased at 5 G to 8.0 ± 0.2 kPa and 6.6 ± 0.3 kPa in supine and prone postures ( P = 0.003). Arterial oxygenation was less impaired in prone during hypergravity due to a better-preserved alveolo-arterial oxygen transport. We speculate that mammals have developed a cardiopulmonary structure that favours function with the gravitational vector in the posterio-anterior direction.     

Cardiovascular effects of 8 h of isocapnic hypoxia with and without beta-blockade in humans

This study seeks to confirm the progressive changes in cardiac output and heart rate previously reported with 8 h exposures to constant hypoxia, and to examine the role of sympathetic mechanisms in generating these changes. Responses of ten subjects to four 8 h protocols were compared: (1) air breathing with placebo; (2) isocapnic hypoxia (end-tidal PO2 = 50 mm Hg) with placebo; (3) isocapnic hypoxia with beta-blockade; and (4) air breathing with beta -blockade. Regular measurements of heart rate and cardiac output (using ultrasonography and N2O rebreathing techniques) were made with subjects seated in the upright position. The sensitivity of heart rate to rapid variations in hypoxia (GHR) and heart rate in the absence of hypoxia were measured at times 0, 4 and 8 h. No significant progressive effect of hypoxia on cardiac output was detected. There was a gradual rise in heart rate with hypoxia of 11+/-2 beats min(-1) in the placebo protocol and of 10+/-2 beats min(-1) in the beta-blockade protocol over 8 h, compared to the air breathing protocols. The rise in heart rate was progressive (P<0.001) and accompanied by progressive increases in both GHR (P<0.001) and heart rate measured in the absence of hypoxia (P<0.05). No significant effect of beta-blockade was detected on any of these progressive changes. We conclude that sympathetic mechanisms that act via beta -receptors play little role in the progressive changes in heart rate observed over 8 h of moderate hypoxia.     

Vascular responses to fear-induced stress in humans

The information about the effect of mental activities on detailed cardiovascular responses is limited, though strong and chronic psychological stressors are risk factors of cardiovascular morbidity and mortality in humans. The responses of vascular resistance (VR) during fear-induced stress was studied by measuring the mean arterial pressure (MAP), heart rate (HR), skin blood flow in the index finger and forehead, limb blood flow in the calf and forearm, and blood flow in the renal and superior mesenteric arteries before, during, and after a period of induced fear. After 2 min of rest, baseline data were acquired from eight subjects, after which they watched a 3-min video that was considered to be frightening. Minute-by-minute data were calculated. The MAP was divided by the blood flow to attain the VR. While a clear steady state was not evident in the stress-induced vascular response, stress significantly increased the MAP and HR (e.g., by 10 ± 3 mm Hg and 8 ± 3 bpm, respectively, at the 2nd min; mean ± SEM), and the VR of the forearm and finger skin (e.g., by 80 ± 26% and 79 ± 28%, respectively, at the 2nd min). The VR increased slightly in the calf and visceral arteries but not in the forehead throughout the stimulation. The variables returned to baseline levels by the 1st min after cessation of the fearful stimulation. These results suggest that fear-induced stress causes vasoconstriction in the forearm and finger.