Cerebral blood flow and blood viscosity in patients with polycythaemia secondary to hypoxic lung disease.

Blood viscosity, cerebral blood flow (CBF) and cerebral oxygen carriage (CBF X arterial oxygen content) were measured in 12 patients with polycythaemia secondary to hypoxic lung disease. CBF and cerebral oxygen carriage were both significantly higher than in a comparative group of 20 patients with raised packed cell volumes and normal lung function. The patients with secondary polycythaemia then underwent venesection and their mean packed cell volume fell from 0.613 to 0.495. This led to a consistent reduction in blood viscosity, which fell by 44% at a low shear rate (0.67/s) and 33% at a high shear rate (0.91/s). CBF rose by 21% (p less than 0.01), but cerebral oxygen carriage did not significantly increase in the group as a whole. Four of the patients with secondary polycythaemia had complained of episodes of confusion before venesection, which improved considerably once the packed cell volume had been lowered. Headache was relieved in a further two patients and none of the subjects was adversely affected by venesection. It was not possible, however, to show a correlation between symptomatic improvement and an increase in cerebral oxygen carriage.     

The age factor in blood flow in the calf and in vascular resistance at rest and in reactive hyperaemia.

The blood flow and vascular resistance in the calf were studied in two groups of healthy subjects (mean ages 22 and 49 years) at rest and in reactive hyperaemia produced by five minutes' ischaemia of the lower limb. The blood flow was determined by venous occlusive plethysmography and vascular resistance was computed from the mean blood pressure measured by auscultation on the arm and from the blood flow in the calf, at rest and during reactive hyperaemia. The resting flow and blood flows throughout practically the whole time of hyperaemia were found to be significantly smaller in young individuals. The maximal flow was significantly lower, the maximal flow time was significantly prolonged in young subjects. The recovery time and repayment of the flow debt in the two groups were the same. Vascular resistance in the calf was significantly greater in young subjects, both at rest and during dilatation. We assume from the results that the capacity of the arterial system in the lower limbs is significantly smaller in young individuals.     

Brain oxygen transport related to levels of fetal haemoglobin in stable preterm infants.

The relative amount of regional cerebral oxygen transport was compared between different preterm infants by performing measurements of cerebral blood flow velocity, mean arterial blood pressure, whole blood viscosity and haemoglobin content for each individual. In addition the percentage of fetal haemoglobin was determined. On 25 occasions measurements of fetal haemoglobin and cerebral oxygen transport have been performed prior to and following a blood transfusion with adult red blood cells. Comparison of the data for cerebral oxygen transport suggests that the actual amount of cerebral oxygen transport is lowest at fetal haemoglobin levels below 30% and will increase progressively as soon as the percentage of fetal haemoglobin rises about 30%. Thus, at increasing fetal haemoglobin levels, cerebral haemodynamic mechanisms in the human neonate cause elevations of regional cerebral blood flow and oxygen transport. The found increase of cerebral blood flow and oxygen transport at high fetal haemoglobin levels will minimize the impeded dissociation and delivery of oxygen to brain tissues.     

Haemoglobin Rahere (beta Lys-Thr): A new high affinity haemoglobin associated with decreased 2, 3-diphosphoglycerate binding and relative polycythaemia.

A new haemoglobin with increased oxygen affinity, beta82 (EF6) lysine leads to threonine (Hb Rahere), was found during the investigation of a patient who was found to have a raised haemoglobin concentration after a routine blood count. The substitution affects one of the 2, 3-diphosphoglycerate binding sites, resulting in an increased affinity for oxygen, but both the haem-haem interaction and the alkaline Bohr effect are normal in the haemolysate. This variant had the same mobility as haemoglobin A on electrophoresis at alkaline pH but was detected by measuring the whole blood oxygen affinity; it could be separated from haemoglobin A, however, by electrophoresis in agar at acid pH. The raised haemoglobin concentration was mainly due to a reduction in plasma volume (a relative polycythaemia) and was associated with a persistently raised white blood count. This case emphasises the need to measure the oxygen affinity of haemoglobin in all patients with absolute or relative polycythaemia when some obvious cause is not evident.     

Changes in haemorheology in the racing greyhound as related to oxygen delivery

Arterial blood samples were obtained from six greyhounds during rest, immediately before, and after a 704-m (7/16th mile) race. Measurements were made of various haematological (red cell count, haemoglobin, packed cell volume, white cell count, plasma proteins) and haemorheological variables. Blood and plasma viscosity were determined at high wall shear stresses (67-200 dynes.cm-2, 670-2000 microN.cm-2) in a 20-microns glass capillary device which was designed to take the diameter dependence of blood viscosity (Fahraeus-Lindqvist effect) into account. Compared to values at rest, substantial haemoconcentration occurred before the race, mainly due to splenic discharge of red cells. Additional haemoconcentration was found after the race. The increase of effective blood viscosity caused by elevation of packed cell volume was greater than the increase in O2 binding capacity resulting from the elevated haemoglobin concentration, suggesting that the haemoconcentration observed in the exercising greyhound does not enhance O2 delivery to skeletal muscle. The main physiological effect of red cell discharge from the contracting spleen appeared to be a consequence of the volume rather than the composition of the circulating blood.     

Effect of sildenafil on coronary active and reactive hyperemia

Sildenafil, a selective inhibitor of phosphodiesterase type 5, produces relaxation of isolated epicardial coronary artery segments by causing accumulation of cGMP. Because shear-induced nitric oxide-dependent vasodilation is mediated by cGMP, this study was performed to determine whether sildenafil would augment the coronary resistance vessel dilation that occurs during the high-flow states of exercise or reactive hyperemia. In chronically instrumented dogs, sildenafil (2 mg/kg per os) augmented the vasodilator response to acetylcholine, with a leftward shift of the dose-response curve relating coronary flow to acetylcholine dose. Sildenafil caused a 6. 7 +/- 2.1 mmHg decrease of mean aortic pressure, which was similar at rest and during treadmill exercise (P < 0.05), with no change of heart rate, left ventricular (LV) systolic pressure, or LV maximal first time derivative of LV pressure. Sildenafil tended to increase myocardial blood flow at rest and during exercise (mean increase = 14 +/- 3%; P < 0.05 by ANOVA), but this was associated with a significant decrease in hemoglobin, so that the relationship between myocardial oxygen consumption and oxygen delivery to the myocardium (myocardial blood flow x arterial O(2) content) was unchanged. Furthermore, sildenafil did not alter coronary venous PO(2), indicating that the coupling between myocardial blood flow and myocardial oxygen demands was not altered. In addition, sildenafil did not alter the peak coronary flow rate, debt repayment, or duration of reactive hyperemia that followed a 10-s coronary occlusion. The findings suggest that cGMP-mediated resistance vessel dilation contributes little to the increase in myocardial flow that occurs during exercise or reactive hyperemia.     

Changes of regional myocardial blood flow during and after acute focal experimental ischaemia.

The regional blood flow through the myocardium of the left ventricle was measured in 11 dogs after ligation of the left anterior descending coronary artery, by means of a local injection of 133Xe depot and precordial detection of its washout 2 hours after ligation. Immediately after ligation the blood flow in the ischaemic area declined considerably but at the same time there was a significant increase of blood flow in the non-ischaemic left ventricular myocardium. The regional flow in the ischaemic and non-ischaemic area increased insignificantly for 2 hrs. These changes were not due to alterations in coronary artery pressure, as the mean arterial pressure declined significantly during the first hour. After temporary ischaemia by ligation of the left anterior descending coronary artery for 2--4 minutes, an intensive reactive hyperaemia developed in the ischaemic region (the blood flow reached 221% of control values on the average) which was the more intensive, the greater the drop of blood flow in the ischaemic area after ligation.     

Metabolic vasodilatation in skeletal muscle and the problem of the direct or indirect action of oxygen on resistant blood vessels.

1. Vasodilatation induced by venous blood infusion and reactive hyperaemia following the reduction of perfusion pressure for different lengths of time (1 to 128 sec) were studied in the haemodynamically isolated and denervated vascular bed of the dog gracilis muscle. The two local regulatory situations differed chiefly in respect to the oxygen concentration in the precapillary part of the blood bed (51.4% and 97.6% respectively) and in the size of the blood flow (100% and 48.5% of the resting value). 2. The interval between the time when venous blood entered the resistant precapillary vessels and the onset of the local regulatory response was 25.1 +/- 1.9 seconds. In prolongation of the duration of reduced perfusion pressure, the continuous increase in the maximum reactive hyperaemia value was interrupted, on reducing it for 16-32 seconds, by a significant (P less than 0.001) abrupt increase in this value. 3. We conclude from the good agreement of these two time values that: 1. reduction of the blood oxygen concentration to 51.4% does not directly affect the smooth muscle cells in the wall of resistant vessels; 2. an interval of 25.1 +/- 1.9 sec (16-32 seconds) is needed for interference with the metabolism of skeletal muscle to attain a critical value and for the relevant chemical signal to produce a dilatation response in the arterioles.     

VO(2) on-kinetics in isolated canine muscle in situ during slowed convective O(2) delivery

The purpose of this study was to examine O(2) uptake (Vo(2)) on-kinetics when the spontaneous blood flow (and therefore O(2) delivery) on-response was slowed by 25 and 50 s. The isolated gastrocnemius muscle complex (GS) in situ was studied in six anesthetized dogs during transitions from rest to a submaximal metabolic rate (≈50-70% of peak Vo(2)). Four trials were performed: 1) a pretrial in which resting and steady-state blood flows were established, 2) a control trial in which the blood flow on-kinetics mean response time (MRT) was set at 20 s (CT20), 3) an experimental trial in which the blood flow on-kinetics MRT was set at 45 s (EX45), and 4) an experimental trial in which the blood flow on-kinetics MRT was set at 70 s (EX70). Slowing O(2) delivery via slowing blood flow on-kinetics resulted in a linear slowing of the Vo(2) on-kinetics response (R = 0.96). Average MRT values for CT20, EX45, and EX70 Vo(2) on-kinetics were (means ± SD) 17 ± 2, 23 ± 4, and 26 ± 3 s, respectively (P < 0.05 among all). During these transitions, slowing blood flow resulted in greater muscle deoxygenation (as indicated by near-infrared spectroscopy), suggesting that lower intracellular Po(2) values were reached. In this oxidative muscle, Vo(2) and O(2) delivery were closely matched during the transition period from rest to steady-state contractions. In conjunction with our previous work showing that speeding O(2) delivery did not alter Vo(2) on-kinetics under similar conditions, it appears that spontaneously perfused skeletal muscle operates at the nexus of sufficient and insufficient O(2) delivery in the transition from rest to contractions.     

A 31P-NMR study of tissue respiration in working dog muscle during reduced O2 delivery conditions.

To investigate the role of tissue oxygenation as one of the control factors regulating tissue respiration, 31P-nuclear magnetic resonance spectroscopy (31P-NMR) was used to estimate muscle metabolites in isolated working muscle during varied tissue oxygenation conditions. O2 delivery (muscle blood flow x arterial O2 content) was varied to isolated in situ working dog gastrocnemius (n = 6) by decreases in arterial PO2 (hypoxemia; H) and by decreases in muscle blood flow (ischemia; I). O2 uptake (VO2) was measured at rest and during work at two or three stimulation intensities (isometric twitch contractions at 3, 5, and occasionally 7 Hz) during three separate conditions: normal O2 delivery (C) and reduced O2 delivery during H and I, with blood flow controlled by pump perfusion. Biochemical metabolites were measured during the last 2 min of each 3-min work period by use of 31P-NMR, and arterial and venous blood samples were drawn and muscle blood flow measured during the last 30 s of each work period. Muscle [ATP] did not fall below resting values at any work intensity, even during O2-limited highly fatiguing work, and was never different among the three conditions. Muscle O2 delivery and VO2 were significantly less (P < 0.05) at the highest work intensities for both I and H than for C but were not different between H and I. As VO2 increased with stimulation intensity, a larger change in any of the proposed regulators of tissue respiration (ADP, P(i), ATP/ADP.P(i), and phosphocreatine) was required during H and I than during C to elicit a given VO2, but requirements were similar for H and I.(ABSTRACT TRUNCATED AT 250 WORDS)     

Flow-induced dilation of the dog gracilis muscle artery

The external diameter of the artery (1.08 +/- 0.04 mm) predominantly supplying the gracilis muscle was monitored in situ in 12 dogs under thiopental anaesthesia using a contact inductive transformer. The blood flow in the artery could be controlled by an arteriovenous shunt. After a latency of 10.6 +/- 0.7 s, an increase of blood flow through the artery from 4.0 +/- 0.3 to 45.0 +/- 3.4 ml.min-1 induced an increase in its diameter by 44.9 +/- 3.6% of the resting value (p less than 0.001). When the blood flow-rate was reduced to the initial level, the artery constricted with a half-recovery time of 307.2 +/- 30.7 s. The amplitude and the time course of the arterial dilation were identical when the blood pressure at the site of diameter measurement decreased or remained unchanged. The dilation became maximal at blood flows corresponding to the peak of reactive hyperaemia in the gracilis muscle after 2 min arterial occlusion. It is being suggested that the blood flow-induced dilation ensures autostabilization of conduit artery function.     

Calf blood flow and vascular resistance during reactive hyperaemia in young athletes and trained middle-aged subjects

The effect of training on dilatation capacity in the lower limbs was evaluated by studying the blood flow and vascular resistance in the calf in 10 young athletes aged 19-29 years and 15 trained middle-aged subjects aged 52-58 years during post-ischaemic reactive hyperaemia. The control groups comprised untrained subjects of approximately the same ages, i.e. 16 men aged 18-29 and 37 aged 40-60. The calf blood flow as determined plethysmographically and the blood pressure was measured on the arm by auscultation. Vascular resistance was calculated from the mean blood pressure and from the maximal calf blood flow measured during hyperaemia. A significantly higher maximal blood flow and significantly lower resistance in the calf were found in young athletes than in untrained subjects. In athletes, the flow debt was significantly overpaid. In middle-aged subjects, the effect of training was manifested only in significant overpayment of the flow debt, while vascular resistance and the maximal blood flow were the same as in the controls. It can be concluded from these findings that significant improvement of vasodilatation ability in association with training occurs primarily in young subjects. The findings also correspond to the known ability of young athletes to give a higher maximal performance than veteran athletes.     

Oxygen delivery at high blood viscosity and decreased arterial oxygen content to brains of conscious rats

We addressed the question to which extent cerebral blood flow (CBF) is maintained when, in addition to a high blood viscosity (Bvis) arterial oxygen content (CaO2) is gradually decreased. CaO2) was decreased by hemodilution to hematocrits (Hct) of 30, 22, 19, and 15% in two groups. One group received blood replacement (BR) only and served as the control. The second group received an additional high viscosity solution of polyvinylpyrrolidone (BR/PVP). Bvis was reduced in the BR group and was doubled in the BR/PVP. Despite different Bvis, CBF did not differ between BR and BR/PVP rats at Hct values of 30 and 22%, indicating a complete vascular compensation of the increased Bvis at decreased CaO2. At an Hct of 19%, local cerebral blood flow (LCBF) in some brain structures was lower in BR/PVP rats than in BR rats. At the lowest Hct of 15%, LCBF of 15 brain structures and mean CBF were reduced in BR/PVP. The resulting decrease in cerebral oxygen delivery in the BR/PVP group indicates a global loss of vascular compensation. We concluded that vasodilating mechanisms compensated for Bvis increases thereby maintaining constant cerebral oxygen delivery. Compensatory mechanisms were exhausted at a Hct of 19% and lower as indicated by the reduction of CBF and cerebral oxygen delivery.     

Changes in muscle oxygenation during weight-lifting exercise

The quantitative analysis of haemoglobin oxygenation of contracting human muscle during weight-lifting exercise was studied noninvasively and directly using near-infrared spectroscopy. This method was developed as a three-wavelength method which confirmed the volume changes in oxygenated haemoglobin (oxy-Hb), deoxygenated haemoglobin (deoxy-Hb) and blood volume (total-Hb; Oxy-Hb + deoxy-Hb). Nine healthy adult men with various levels of training experience took part in the study. Ten repetition maximum (10 RM) one-arm curl exercise was performed by all the subjects. Results showed that at the beginning of the 10-RM exercise, rapid increases of deoxy-Hb and decreases of oxy-Hb were observed. In addition, total-Hb gradually increased during exercise. These results corresponded to the condition of arm blood flow experimentally restricted using a tourniquet in contact with the shoulder joint, and they showed the restriction of venous blood flow and an anoxic state occurring in the dynamically contracted muscle. In three sets of lifting exercise with short rest periods, these tendencies were accelerated in each set, while total-Hb volume did not return to the resting state after the third set for more than 90 s. These results would suggest that a training regimen emphasizing a moderately high load and a high number of repetitions, and a serial set with short rest periods such as usually performed by bodybuilders, caused a relatively long-term anoxic state in the muscle.     

Effects of transfusion-induced polycythemia on O2 transport during exercise in the dog

An increased hematocrit could enhance peripheral O2 transport during exercise by improving arterial O2 content. Conversely, it could reduce maximal delivery of O2 by limiting cardiac output during exercise or by limiting the distribution of blood flow to peripheral capillaries with high O2 extractions. We studied O2 transport at rest and during graded treadmill exercise in splenectomized tracheostomized dogs at normal hematocrit (38 +/- 3%), and 48 h after transfusion of type-matched donor cells. This procedure increased hematocrit (60 +/- 3%) but also increased blood volume (P less than 0.05). Following transfusion, resting cardiac output (QT) and heart rate were not different. During exercise, QT was significantly lower at each level of O2 consumption (VO2) at high hematocrit (P less than 0.01). A reduction in QT was also seen during polycythemic exercise with hypoxemia produced by breathing 12 or 10% O2 in N2. Despite the reduction in QT, mixed venous PO2 was not lower at high hematocrit, and the increase in base deficit with VO2 was not different from control measurements. O2 delivery (QT X arterial content) was similar at each level of VO2 at both levels of hematocrit, during both normoxic and hypoxic studies. Both systemic and pulmonary arterial pressures were increased at rest after transfusion (P less than 0.05). However, pulmonary and systemic pressures were not higher than control during exercise at high hematocrit. We conclude that a hematocrit of 60% with increased blood volume is not associated with a cardiac limitation of O2 delivery, nor does it interfere with peripheral O2 extraction during exercise in the dog.     

Microvascular flow and tissue PO(2) in skeletal muscle of chronic reduced renal mass hypertensive rats

This study determined whether arteriolar blood flow, capillary red blood cell (RBC) velocity, capillary hematocrit (Hct(cap)), and tissue PO(2) are altered in cremaster muscles of rats with chronic reduced renal mass hypertension (RRM-HT) relative to normotensive rats on high- or low-salt (NT-HS vs. NT-LS) diet. The blood flow in first- through third-order arterioles was not different between NT and HT rats, either at rest or during maximal relaxation of the vessels with 10(-4) M adenosine. Capillary RBC velocity was similar between the groups at rest but was elevated in RRM-HT and NT-HS rats during adenosine superfusion. Hct(cap) was reduced at rest in RRM-HT and NT-HS rats compared with NT-LS and was reduced in RRM-HT rats during adenosine-induced dilation. Tissue PO(2) was reduced in RRM-HT and NT-HS rats compared with NT-LS rats during control conditions and was lower in RRM-HT than in NT-LS rats during adenosine-induced dilation. These results indicate that both RRM-HT and chronic exposure of normotensive rats to a high-salt diet lead to reduced tissue oxygenation, despite the maintenance of normal arteriolar blood flow.     

After effects of chronic hypoxia on cardiac output and muscle blood flow at rest and exercise

Cardiac output (Q, by N2-CO2 rebreathing) and limb muscle blood flow (qm, from 133Xe clearance) were determined in eight male subjects at rest and during cycloergometric loads immediately before and 12 days after return from the 1981 Swiss Lhotse Shar (8,398 m) Expedition. Compared to control conditions, after exposure to hypoxia: 1) Q was unchanged at rest and at 75 watts (W) but was 18% less (P less than 0.01) at 150 W with constant heart rate (approximately 140 beats X min-1); 2) qm in the vastus lateralis was identical at rest but 26% and 39% less (P less than 0.05 and P less than 0.001, respectively) at two submaximal leg work loads (75 and 125 W); 3) qm in the biceps at 50 W was 34% less (P less than 0.01); 4) hemoglobin flow (QHb and qmHb), similarly to blood flow (Q and qm), was significantly reduced; 5) the qm adjustment rate, measured from the time required to attain a new steady state upon a square wave change of work load starting from rest, was slower, particularly at the lower work loads. From the above results as well as from corresponding morphometric findings showing in the same subjects: 1) a decrease of the ratio between fiber section and number of capillaries and 2) a rise of the mitochondrial to fiber volume ratio, it is concluded that during altitude acclimatization peripheral O2 delivery becomes more efficient.     

Erythrapheresis in patients with polycythaemia secondary to hypoxic lung disease.

Erythrapheresis was performed in 10 patients with polycythaemia secondary to hypoxic lung disease (mean PaO2, 6.8 kPa (51 mm Hg)). The mean packed cell volume decreased from 0.64 to 0.48 in men and from 0.56 to 0.42 in women, with significant decreases in blood viscosity at both high and low shear rates (p less than 0.001). Patients showed significant improvement in six-minute walking distances (p less than 0.001) and in tests of mental alertness (p less than 0.01) compared to control subjects. Visual analogue scales confirmed symptomatic improvement after erythrapheresis. Erythrapheresis significantly improved symptoms, mental function, and work performance in patients with polycythaemia secondary to hypoxic lung disease. The procedure was well tolerated by all patients and no complications occurred.     

Effects of propranolol and metoprolol on the peripheral circulation.

The effects of single doses of propranolol and metoprolol on skin temperature and skin and muscle blood flow were compared in 10 normal subjects and four patients with essential hypertension. In normal subjects the mean skin temperature fell by 1.30 +/- 0.62 degrees C 90 minutes after 80 mg propranolol and 0.15 +/- 0.05 degrees C after 100 mg metoprolol. Skin blood flow and resting muscle blood flow were not affected by metoprolol but fell significantly after propranolol. Both drugs reduced post-exercise muscle hyperaemia, propranolol by more than metoprolol. Similar changes were seen in the hypertensive patients. Propranolol should be used with care in patients with known vascular disease.     

Coronary reactive hyperaemia after two periods of coronary occlusion in the anaesthetized goat.

In the coronary circulation an ischaemic preconditioning obtained with two periods of 2.5 min each of occlusion of the left circumflex coronary artery alters the pattern of a coronary reactive hyperaemia which follows 15 s only of occlusion of the studied artery. The most remarkable change consists of a reduction of 40-45% of the time required by the flow to reach the maximum hyperaemic peak (time to peak) after the brief occlusion. The present investigation was planned to study whether the time to peak of the hyperaemia following the second 2.5 min preconditioning occlusion was shorter than the hyperaemia following the first occlusion. Experiments performed in the anaesthetized goat, in which coronary flow was measured with an electromagnetic flow-probe placed around the left circumflex coronary artery showed that in the hyperaemia occurring after the second preconditioning occlusion the time to peak was reduced by 18% only. The moderate effect of the second preconditioning occlusion in reducing the time to peak is attributed to the fact that the heart was already partially preconditioned after the first occlusion and that after relatively long periods (2.5 min) of occlusion the metabolic component of the hyperaemic response was so predominant to partially mask the role of the vascular mechanisms presumably responsible for the reduction of the time to peak.