Search results
Found 12031 matches for
Exaggerated pulmonary vascular response to acute hypoxia in older men.
What is the central question of this study? Pulmonary arterial pressure is higher in older than younger humans and predicts mortality. It is also increased by acute hypoxia, which causes constriction of the pulmonary vasculature. We asked whether this pulmonary vascular response to hypoxia is greater in older humans. What is the main finding and its importance? Using Doppler echocardiography in 12 younger (∼ 20 years old) and nine older men (∼ 55 years old) exposed to 20 min of moderate isocapnic hypoxia, we demonstrated that older men showed a significantly greater rise in pulmonary arterial pressure during alveolar hypoxia than younger men. Future studies should examine the pathophysiological importance of increased hypoxic pulmonary vasoconstriction with age. Resting pulmonary arterial pressure increases with age in humans. In the general population, higher values are associated with increased mortality, and in common cardiopulmonary diseases, such as congestive heart failure and chronic obstructive pulmonary disease, the presence of pulmonary arterial hypertension portends a worse outcome. Pulmonary arterial pressure increases during alveolar hypoxia, as a consequence of constriction in the pulmonary vasculature. We hypothesized that older men have more vigorous hypoxic pulmonary vasoconstriction than younger men. Twelve younger (20.5 ± 0.5 years old) and nine older men (55.8 ± 2.1 years old) were exposed for 20 min on different days to isocapnic hypoxia (end-tidal PO2 = 50 mmHg) and isocapnic euoxia (end-tidal PO2 = 100 mmHg); each was preceded (baseline) and followed by 5 min of isocapnic euoxia. Systolic pulmonary arterial pressure and cardiac output were measured continuously using Doppler echocardiography. Systolic pulmonary arterial pressure was greater during baseline euoxic measurements in older participants (27.8 ± 0.8 versus 24.1 ± 0.7 mmHg, P = 0.001) and also increased more during hypoxia in older participants (15.2 ± 1.3 versus 9.6 ± 0.9 mmHg, P = 0.011). Cardiac output did not differ between the two groups during baseline measurements (P = 0.60) or hypoxia (P = 0.49). All data are means ± SEM. The increased magnitude of hypoxic pulmonary vasoconstriction demonstrated with age has implications for individuals wishing to ascend to high altitude or travel by air, for those suffering from conditions in which global alveolar hypoxia is a feature and for patients requiring general anaesthesia.
Cognitive decline in the elderly after surgery and anaesthesia: results from the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort.
Concerns have been raised about the effects on cognition of anaesthesia for surgery, especially in elderly people. We recorded cognitive decline in a cohort of 394 people (198 women) with median (IQR) age at recruitment of 72.6 (66.6-77.8) years, of whom 109 had moderate or major surgery during a median (IQR) follow-up of 4.1 (2.0-7.6) years. Cognitive decline was more rapid in people who on recruitment were: older, p = 0.0003; male, p = 0.027; had worse cognition, p < 0.0001; or carried the ε4 allele of apoliprotein E (APOEε4), p = 0.008; and after an operation if cognitive impairment was already diagnosed, p = 0.0001. Cognitive decline appears to accelerate after surgery in elderly patients diagnosed with cognitive impairment, but not other elderly patients.
How Do Antihypertensive Drugs Work? Insights from Studies of the Renal Regulation of Arterial Blood Pressure.
Though antihypertensive drugs have been in use for many decades, the mechanisms by which they act chronically to reduce blood pressure remain unclear. Over long periods, mean arterial blood pressure must match the perfusion pressure necessary for the kidney to achieve its role in eliminating the daily intake of salt and water. It follows that the kidney is the most likely target for the action of most effective antihypertensive agents used chronically in clinical practice today. Here we review the long-term renal actions of antihypertensive agents in human studies and find three different mechanisms of action for the drugs investigated. (i) Selective vasodilatation of the renal afferent arteriole (prazosin, indoramin, clonidine, moxonidine, α-methyldopa, some Ca(++)-channel blockers, angiotensin-receptor blockers, atenolol, metoprolol, bisoprolol, labetolol, hydrochlorothiazide, and furosemide). (ii) Inhibition of tubular solute reabsorption (propranolol, nadolol, oxprenolol, and indapamide). (iii) A combination of these first two mechanisms (amlodipine, nifedipine and ACE-inhibitors). These findings provide insights into the actions of antihypertensive drugs, and challenge misconceptions about the mechanisms underlying the therapeutic efficacy of many of the agents.
Release by hypoxia of a soluble vasoconstrictor from rabbit small pulmonary arteries.
BACKGROUND: Soluble pulmonary vasoconstrictors released in response to hypoxia have been reported in pig and rat preparations, but not in rabbit preparations. METHODS: We used myography to evaluate the contribution of a soluble factor to constriction in rabbit small pulmonary arteries (external diameter 300-475 microm) exposed to 45 min hypoxia (PO(2)=9 mm Hg). RESULTS: Hypoxia produced gradually intensifying constriction. Return to euoxia (PO(2)=145 mm Hg) for 30 min relaxed only approximately 30% of the constriction, whereas elution of the myograph bath yielded full relaxation. Reapplication of the eluent gradually restored the constriction to its pre-elution level over a 30-min period. CONCLUSIONS: In this closed system, a soluble factor contributes substantially to hypoxic pulmonary vasoconstriction.
Effects of haloperidol on ventilation during isocapnic hypoxia in humans.
Exposure to isocapnic hypoxia produces an abrupt increase in ventilation [acute hypoxic ventilatory response (AHVR)], which is followed by a subsequent decline [hypoxic ventilatory depression or decline (HVD)]. In cats, both anesthetized and awake, haloperidol has been reported to increase AHVR and almost entirely abolish HVD. To investigate whether this occurs in humans, the ventilatory responses of 15 healthy young volunteers to 20 min of isocapnic hypoxia (end-tidal PO2 = 50 Torr) were assessed at 1, 2, and 4.5 h after placebo (control) and after oral haloperidol (Seranace, 0.05 mg/kg) on different days. Three subjects were unable to complete the study because of akathisia. AHVR was significantly greater with haloperidol compared with control (P < 0.01, analysis of variance). However, no significant change in HVD was found [control HVD = 9.3 +/- 1.6 (SD) l/min, haloperidol HVD = 9.9 +/- 2.1 l/min; P = not significant, analysis of variance]. We conclude that combined central and peripheral dopamine-receptor antagonism in humans with haloperidol produces a similar pattern of change to that reported previously with the peripheral antagonist domperidone. We have been unable to show in humans a decrease in HVD by the centrally acting drug as observed in cats.
Effects of midazolam and flumazenil on ventilation during sustained hypoxia in humans.
The purpose of this study was to investigate whether increases in gamma-aminobutyric acid (GABA) in the brain stem underlie the ventilatory decline observed during hypoxia in man. The ventilatory responses to sustained isocapnic hypoxia were studied in six adult male subjects on three separate days in three pharmacological conditions: (1) without any drug administration; (2) during infusion of midazolam (a drug which potentiates the effect of GABA); and (3) during infusion of flumazenil (a benzodiazepine antagonist). On each experimental day, the following protocol was repeated three times: end-tidal PO2 was held at 100 Torr for 10 min, then at 50 Torr for 20 min and finally at 100 Torr for 5 min. End-tidal PCO2 was held constant throughout. Responses in the three pharmacological conditions were similar. We conclude that neither potentiation of GABA transmission (midazolam) nor antagonism of this potentiation (flumazenil) greatly affect the decline in ventilation which occurs during extended exposure to hypoxia.
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.
Time course of the human pulmonary vascular response to 8 hours of isocapnic hypoxia.
To examine the hypothesis that the human pulmonary vascular response to hypoxia has a component with a slow time course, we measured pulmonary vascular resistance (PVR) in six healthy adult males during 8 h of isocapnic hypoxia. A balloon-tipped pulmonary artery catheter with thermistor was introduced via a forearm vein and used to derive PVR. The subjects were seated in a chamber in which the oxygen and carbon dioxide concentrations were adjusted to maintain an end-tidal Po2 of 50 Torr and an end-tidal Pco2 equal to the subject's normal prehypoxic value. PVR was measured before and at 0.5-h intervals during 8 h of hypoxia, the following 3 h of isocapnic euoxia (end-tidal Po2 100 Torr), and a subsequent 1-h reexposure to hypoxia. PVR rose from 1.23 +/- 0.26 (SE) Torr-min.1(-1) under euoxia [time (t) = 0] to 1.77 +/- 0.21 Torr.min.1(-1) at t = 0.5 h, reached a maximum at 2 h (2.91 +/- 0.33 Torr.min.1(-1)), and remained fairly constant between 2 and 8 h. Restoration of euoxia at 8 h led to a reduction in PVR with a slow component. Reexposure to hypoxia at 11 h resulted in a greater increase in PVR than at 1 h. Systemic vascular resistance had a similar slow component to its response, falling from 18.6 +/- 1.3 Torr.min.1(-1) at t = 0 to 17.3 +/- 1.4 Torr.min.1(-1) at t = 0.5 h, 14.4 +/- 0.6 Torr.min.1(-1) at t = 4 h, and 13.8 +/- 0.8 Torr.min.1(-1) at t = 8 h. The human pulmonary and systemic vascular responses to hypoxia extend over at least several hours.
Effects of dopamine and domperidone on ventilation during isocapnic hypoxia in humans.
In order to investigate the role of dopamine in the ventilatory response to sustained, isocapnic hypoxia six subjects were studied three times in each of three pharmacological conditions: (1) in the absence of any drug administration, (2) during i.v. infusion of dopamine (3 micrograms.kg-1.min-1), and (3) after pretreatment with domperidone. Otherwise the experimental protocol was identical on each day and consisted of holding the subjects' end-tidal PO2 at 100 Torr for 10 min, then 50 Torr for 20 min and finally at 100 Torr again for 5 min. End-tidal PCO2 was held constant 2-3 Torr above normal throughout the experiment. Domperidone increased, and dopamine decreased the magnitudes of both the fast on- and off-responses, but neither drug affected the magnitude of the hypoxic ventilatory decline (HVD). The results of this study suggests: (1) that a peripheral dopaminergic mechanism is not involved in the genesis of HVD, and (2) the peripheral chemoreflex may be modulated peripherally to produce HVD.
Effects of desferrioxamine on serum erythropoietin and ventilatory sensitivity to hypoxia in humans.
In cell culture, hypoxia stabilizes a transcriptional complex called hypoxia-inducible factor-1 (HIF-1) that increases erythropoietin (Epo) formation. One hallmark of HIF-1 responses is that they can be induced by iron chelation. The first aim of this study was to examine whether an infusion of desferrioxamine (DFO) increased serum Epo in humans. If so, this might provide a paradigm for identifying other HIF-1 responses in humans. Consequently a second aim was to determine whether an infusion of DFO would mimic prolonged hypoxia and increase the acute hypoxic ventilatory response (AHVR). Sixteen volunteers undertook two protocols: 1) continuous infusion of DFO over 8 h and 2) control. Epo and AHVR were measured at fixed times during and after the protocols. The results show that 1) compared with control, Epo increased in most subjects at 8 h [52.8 +/- 57.7 vs. 6.9 +/- 2.5 (SD) mIU/ml, for DFO = 4 g/70 kg body wt, P < 0.05] and 12 h (63.7 +/- 76.3 vs. 7.3 +/- 2.5 mIU/ml, P < 0.001) after the start of DFO administration and 2) DFO had no significant effect on AHVR. We conclude that, whereas infusions of DFO mimic hypoxia by increasing Epo, they do not mimic prolonged hypoxia by augmenting AHVR.
Effects of 8 h of isocapnic hypoxia with and without muscarinic blockade on ventilation and heart rate in humans.
This study examined the role of muscarinic parasympathetic mechanisms in generating the progressive increases in ventilation (V(E)) and heart rate previously reported with 8 h exposures to hypoxia. The sensitivities of V(E) (G(p)) and heart rate (G(HR)) to acute variations in hypoxia, and V(E) and heart rate during acute hyperoxia were assessed in 10 subjects before and after two 8 h exposures to isocapnic hypoxia (end-tidal P(O2) = 50 mmHg). The responses were measured during muscarinic blockade with glycopyrrolate (0.015 mg kg(-1)) and without glycopyrrolate, as a control. There were significant increases in G(p) (P < 0.01) and V(E) during hyperoxia (P < 0.01) following hypoxic exposure, but these were unaffected by glycopyrrolate. G(HR) increased significantly by 0.29 +/- 0.08 beats min(-1) %(-1) (mean +/- S.E.M.) following exposure to hypoxia under control conditions, but only non-significantly by 0.10 +/- 0.08 beats min(-1) %(-1) with glycopyrrolate. This difference was significant. Changes in heart rate during hyperoxia were slight and inconclusive. We conclude that muscarinic mechanisms play little role in the progressive ventilatory changes that occur over 8 h of hypoxia, but that they do mediate much of the progressive increase in heart rate. Experimental Physiology (2001) 86.4, 529-538.
Desferrioxamine elevates pulmonary vascular resistance in humans: potential for involvement of HIF-1.
Hypoxia-inducible factor (HIF)-1 is stabilized by hypoxia and iron chelation. We hypothesized that HIF-1 might be involved in pulmonary vascular regulation and that infusion of desferrioxamine over 8 h would consequently mimic hypoxia and elevate pulmonary vascular resistance. In study A, we characterized the pulmonary vascular response to 4 h of isocapnic hypoxia; in study B, we measured the pulmonary vascular response to 8 h of desferrioxamine infusion. For study A, 11 volunteers undertook two protocols: 1) 4 h of isocapnic hypoxia (end-tidal PO(2) = 50 Torr), followed by 2 h of recovery with isocapnic euoxia (end-tidal PO(2) = 100 Torr), and 2) 6 h of air breathing (control). For study B, nine volunteers undertook two protocols while breathing air: 1) continuous infusion of desferrioxamine (4 g/70 kg) over 8 h and 2) continuous infusion of saline over 8 h (control). In both studies, pulmonary vascular resistance was assessed at 0.5- to 1-h intervals by Doppler echocardiography via the maximum pressure gradient during systole across the tricuspid valve. Results show a progressive rise in pressure gradient over the first 3-4 h with both isocapnic hypoxia (P < 0.001) and desferrioxamine infusion (P < 0.005) to increases of ~16 and 4 Torr, respectively. These results support a role for HIF-regulated gene activation in human hypoxic pulmonary vasoconstriction.
Ventilatory effects of 8 h of isocapnic hypoxia with and without beta-blockade in humans.
This study investigated whether changing sympathetic activity, acting via beta-receptors, might induce the progressive ventilatory changes observed in response to prolonged hypoxia. The responses of 10 human subjects to four 8-h protocols were compared: 1) isocapnic hypoxia (end-tidal PO2 = 50 Torr) plus 80-mg doses of oral propranolol; 2) isocapnic hypoxia, as in protocol 1, with oral placebo; 3) air breathing with propranolol; and 4) air breathing with placebo. Exposures were conducted in a chamber designed to maintain end-tidal gases constant by computer control. Ventilation (VE) was measured at regular intervals throughout. Additionally, the subjects' ventilatory hypoxic sensitivity and their residual VE during hyperoxia (5 min) were assessed at 0, 4, and 8 h by using a dynamic end-tidal forcing technique. beta-Blockade did not significantly alter either the rise in VE seen during 8 h of isocapnic hypoxia or the changes observed in the acute hypoxic ventilatory response and residual VE in hyperoxia over that period. The results do not provide evidence that changes in sympathetic activity acting via beta-receptors play a role in the mediation of ventilatory changes observed during 8 h of isocapnic hypoxia.