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The long-term effect of elevated tail venous pressure (Pv) on interstitial fluid pressure (Pi) and colloid osmotic pressure (COPi) was studied in rats. Measurements were performed on different rats after 1–5 days of congestion, and on a sham operated control group. Two different degrees of venous stasis were obtained by means of graded ligation of tail veins and skin. Moderate degree of ligation (group 1) caused no visual oedema. More extensive ligation (group 2) gave marked oedema already on day 1 and further progression and exudation from the skin during the following 3 days. Tail venous pressure was measured by micropuncture and interstitial fluid pressure by the wick-in-needle technique. Interstitial fluid was sampled by a dry wick method, and colloid osmotic pressure was measured with a membrane osmometer. In group 1, Pv had increased from 6.5 to 21.5 mmHg on day 1, and thereafter remained unchanged. Interstitial fluid pressure increased from 3.4 to 16.9 mmHg after ligation and to 19.2 mmHg on day 1. Colloid osmotic pressure fell from 11.7 to 5.8 mmHg. From day 1, both interstitial fluid pressure and colloid osmotic pressure remained largely unchanged. In group 2 rats, tail venous pressure increased to 33.0 and 36.3 mmHg on day 1 and 2 and then fell towards control level during the following 3 days. Interstitial fluid pressure increased to 22.9 and 31.4 mmHg before a rapid decline towards control level. Colloid osmotic pressure was reduced from 11.7 to 5.6 mmHg. We conclude that hydrostatic counterpressure may provide an oedema-preventing effect of up to about 15 mmHg. Greater acute increase of interstitial fluid pressure lead to exudation and pressure fall. Reduction of colloid osmotic pressure contributed 6–7 mmHg already on day 1.

This study was performed to provide information on the determinants of lymph flow by comparing the effect of venous stasis and hypoproteinaemia in the rat tail. This low-compliant tissue was chosen in an attempt to induce preferential changes in interstitial pressure or volume. The removal rate (kAIb) of 1251-labelled human serum albumin (I-HSA) injected subcutaneously was monitored with external gamma-counting equipment and used as a measure of lymph flow. Interstitial fluid hydrostatic pressure (Pi) was measured with wick-in-needle technique, and interstitial fluid was collected post mortem by dry wicks. Colloid osmotic pressure of plasma (COPp) and wick fluid (COPi) was measured with a colloid osmometer. In a separate group of experiments, 51Cr-EDTA and [125I]HSA were used to measure the interstitial fluid volume. Venous stasis, induced by bilateral ligation of the external tail veins, increased interstitial fluid hydrostatic pressure from 1.7 to 16 mmHg and A/b from 0.030 to 0.063 h-1, whereas tail circumference was nearly constant. Interstitial volume averaged 1.17 ml/g dry weight in control animals and 1.27 ml/g during increased venous pressure. Daily injections of aminonucleoside in salt-loaded rats (0.3yo NaCl as drinking water) reduced colloid osmotic pressure of plasma from 19.1 to 8.5 mmHg and of wick fluid from 11.2 to 2.9 mmHg, while interstitial fluid hydrostatic pressure increased to 5.2 mmHg. The removal rate of 125 I-labelled human serum albumin increased to 0.113 h-1, compared to 0.051 h-1 in salt-loaded controls. The interstitial volume showed a marked increase in salt-loaded hypoproteinaemic rats, 1.75 ml/g dry weight, compared to 1.30 ml/g in salt-loaded controls. The results indicate that absolute interstitial fluid pressure is not the main determinant of lymph flow and rather support the hypothesis that an increase of interstitial volume promotes lymph formation by pulling open the initial lymphatics through their anchoring filaments.

The effect of local venous stasis upon blood flow in human subcutaneous adipose tissue on the distal part of the forearm was investigated in three healthy subjects and two chronically sympathectomized patients suffering from manual hyperhidrosis. The area under study was separated into two parts by means of a lead shield exerting a pressure of about 360 mmHg on the skin. The effect of venous stasis of about 40 mmHg on one side of the shield upon blood flow measured simultaneously on both sides of the shield by the local 133Xenon washout technique was investigated. During venous stasis on one side of the shield, blood flow decreased about 40% on both sides. The vasoconstrictor impulse could be transmitted over a distance of about 1-2 cm. The phenomenon was unaffected by nerve blockade induced 3 cm proximally, medially, and laterally to the area by infiltration the skin with lidocaine. Thus a vasoconstrictor impulse could be transmitted from the side of stasis to the non stasis side of the lead shield. The transmission was not affected by phentolamine but was blocked by lidocaine and chronic sympathetic denervation. The vasoconstrictor impulse elicited during venous stasis is therefore most likely transmitted by means of a local nervous mechanism involving sympathetic adrenergic vasoconstrictor fibres.

The effect of increased tissue pressure on blood flow in subcutaneous and skeletal muscle tissue was studied in 8 healthy humans resting in horizontal position. Blood flow was measured by the local 133Xe washout technique in the mid-calf region. Tissue pressure in the depot area was increased by inflating a compression cuff, 50 cm wide (knee to ankle). Blood flow rates were obtained from compressed tissues with normal vasomotor tone, at papaverine-induced vasoparalysis and during distension of the compressed vessels. The latter was achieved by inflating a proximal (extra) compression cuff on the thigh 10 or 20 mmHg above the pressure level in the more distally placed compression cuff. Increased tissue pressure was a potent stimulus for arteriolar dilatation (autoregulation) in both tissues. The autoregulatory response was to some extent counteracted by an increase in local vascular resistance in the postcapillary section as evidenced by the results of simultaneous venous stasis. Blood flow ceased in vasoparalysed tissues as well as in tissues with normal vasomotor tone, when the compression cuff was inflated to the level of the local diastolic blood pressure. Maintaining external compression at the diastolic blood pressure level, blood flow reappeared in both tissues, when the compressed vessels were distended by adding the proximal (extra) compression. It is concluded, that blood flow cessation in compressed tissues is caused by a widespread arterial-arteriolar collapse in diastole, as the volume of blood injected during the systolic peak is too small to expand also the distal sections of the precapillary vessels.

Duration of increase in vascular volume in the crus following application of venous stasis was studied in 3 healthy subjects placed in a supine position. Changes in calf volume during venous stasis was measured by plethysmography. In one series of experiments changes in vascular volume were studied by measurements of accumulation of 133Xenon proximal to a depot located in the anterior tibial muscle. In another series of experiments changes in activity of 99mTc-labelled erythrocytes were used as indicator for changes in vascular volume. Following application of venous stasis in the horizontal position the rate of increase in calf volume declined to a steady level after about 5 min. Both the studies with 133Xenon and with 99mTc-erythrocytes indicate that vascular volume continued to increase for 3, 3.5 and 5 min following venous stasis of 20, 30 and 40 mmHg, respectively. When the crus was lowered 50 cm below heart level the duration of increase in vascular volume following an additional increase in venous pressure induced by venous stasis was shorter than in the horizontal position. When the calf is placed at heart level the results indicate that for up to 5 min after application of venous stasis of 40 mmHg both increase in vascular volume and transcapillary fluid filtration contribute to the observed increase in calf volume. Using the rate of increase in calf volume within 5 min after induction of venous stasis thus leads to overestimation of CFC. After 5 min vascular volume appears to remain constant and the observed increase in calf volume seems to be solely due to a net increase in interstitial fluid volume.

The effect of venous pressure elevation upon capillary filtration rate in the limb was studied in 6 chronically sympathectomized patients. Five healthy subjects served as controls. Volume changes of the forearm or calf were recorded by a strain-gauge plethysmograph. Relative blod flow in subcutaneous and muscle tissue during venous stasis was measured by the local 133Xe washout technique. In the denervated limbs there was a linear relationship between net capillary filtration rate and venous pressure elevation. In the controls a non-linear relationship was seen as venous pressure elevation of 40 mmHg only caused an increase in net filtration rate of about 66% of that expected from a linear relationship. In the denervated limbs blood flow in muscle and subcutaneous tissue remained constant during venous pressure elevation of more than 30 mmHg whereas in the non-denervated limbs blood flow decreased by about 50% in both tissues. The results suggest that a local sympathetic veno-arteriolar (axon) reflex plays a dominant role for the reduced increase in net capillary filtration rate during large increases in venous pressure. The local axon reflex may therefore act as an edema protecting factor.

Local interstitial fluid volume (IFV) and pressure (IFP) were used to estimate interstitial compliance (= delta IFV/delta IFP) in skin and skeletal muscle of normotensive (NT) and renal hypertensive rats (HT). The IFV was measured as the extravascular 51Cr-EDTA space, and IFP with micropipettes (tip diameter 2-4 microns) connected to a servocontrolled counter-pressure system. After control measurements, overhydration was induced by infusion of saline, 10% of body weight i.v. with or without venous stasis. Alternatively, dehydration was induced by peritoneal dialysis with 20% glucose or by furosemide infusion with or without 24 h fluid deprivation. Control ECV averaged 24.94 and 24.73 ml per 100 g in NT and HT, respectively (P greater than 0.05). Control PV averaged 2.81 and 3.28 ml per 100 g in NT and HT, respectively (P = 0.061), and control IFP was more positive in HT than in NT: 0.4 mmHg in skin (P less than 0.05) and 0.2 mmHg in skeletal muscle (P greater than 0.05). Dehydration changed PV significantly more in HT than in NT (P less than 0.05). The interstitial volume-pressure curve was linear in dehydration and the initial part of overhydration but gradually levelled off, and the maximal rise in IFP was 1-1.5 mmHg in skin and muscle. Interstitial compliance was calculated from the dehydration part of the volume-pressure curve and was in NT 14% per mmHg both in skin and skeletal muscle. In HT, compliance during dehydration was 10.2 and 20.7% reduction in IFV per mmHg fall in IFP in skin and muscle, respectively, not significantly different from corresponding values in NT (P greater than 0.05). We conclude that HT had unaltered ECV and a tendency to higher PV, and that interstitial compliance was not significantly different in normotensive and hypertensive rats.

The effect of 24 h caval/iliac venous obstruction on interstitial fluid volume (IFV), hydrostatic (Pi) and colloid osmotic (COPi) pressure in hindlimb skeletal muscle was studied in three groups of rats: Group I (G I), Intact innervation, unrestricted motor activity. Group II (G II), Sympathectomized, unrestricted. Group III (G III), Motoric and sympathetic denervation + immobilization of the hindlimbs. Subcutaneous edema was present in all groups at femoral venous pressure (Pv) exceeding 13 mmHg. Skeletal muscle edema was seen in G III at Pv above 12 mmHg, in two rats in G II at Pv of 18 and 23 mmHg, but in no rats in GI. Without venous obstruction, control COPi was 8-10 mmHg in all groups. With increasing Pv, COP fell moderately in G I and G II: delta COPi/delta Pv = 0.22. In G III, COPi fell from a control of 8.2 to 3.5 mmHg at a Pv of 12 mmHg (delta COPi/delta Pv = 0.52), but remained constant with further rise in Pv. Pi was about 0 mmHg in controls and 1-2 mmHg in rats with muscle edema. IFV rose by 6% per mmHg increase in Pv in G III, and 2% in G I and G II. This expansion of IFV may explain about 70% of the fall in COPi, the remaining being due to lymphatic washout of interstitial proteins. It is concluded that normal muscle activity together with dilution and washout of interstitial proteins constitute the main edema preventing mechanisms in skeletal muscle.

The effect of close intra-arterial administration of pentobarbital in the concentration of about 2 X 10(-4) mol/l on the venous stasis induced arteriolar constriction in the dog hindleg was studied in 6 neurolept anesthetized dogs. It was found that the blood flows and vascular resistances in the legs before pentobarbital infusion were equal and the vasoconstrictor responses to venous stasis were the same. Pentobarbital infusion into the femoral artery in one of the legs increased the total leg blood flow compared to the control leg and abolished the increase in vascular resistance during venous stasis. In another experimental series the effect of general pentobarbital anesthesia on the vasoconstrictor activity in response to venous stasis locally in subcutaneous and muscle tissue in the hind limb was examined in 6 dogs. It was found that during the first 2-3 h of anesthesia the vasoconstrictor response was present in both tissues although the response in muscle tissue exhibited a great variation between the dogs during this period. However, after 4-5 h of anesthesia the response was abolished in both tissues. During neurolept anesthesia with fentanyl/N2O the same vasoconstrictor response was demonstrated in the hindleg 1 h and 5 h after induction of the anesthesia. It is concluded that pentobarbital anesthesia abolishes the arteriolar constriction induced by venous stasis. The mechanism may be blockade of the local sympathetic vasoconstrictor fibres or interference with myogenic vasoconstrictor mechanism of the vascular smooth muscle cells or both. It is suggested that fentanyl/N2O anesthesia is better suited for this kind of studies.

The effect of changes in transmural pressure in the vessles of the extremities on blood flow in subcutaneous adipose tissue were investigated in three healthy subjects. Changes in transmural pressure were obtained either by postural changes of a limb, by locally induced subatmospheric pressure, or be venous stasis. Blood flow in subcutaneous tissue was measured 10 cm distal to the fibular head and at the lateral malleolus in the leg, or in the distal part of the forearm by the local 133Xenon washout technique. When transmural pressure increased 25 mmHg or more, blood flow decreased about 50 per cent due to an increase in vascular resconstrictor response to increase in transmural pressure could be blocked by infiltrating the area under study with phentolamine or lidocaine or by induced counterpressure. In these cases blood flow remained constant. The findings indicate that the vasoconstrictor response to increase in transmural pressure of 25 mmHg or more is due to a local nervous mechanism involving adrenergic nerves. The receptors are presumably stretch receptors placed in the small veins. The effector site is probably the arterioles. When the vasoconstrictor response is blocked, autoregulation of blood flow in subcutaneous tissue, i.e. maintenance of constant blood flow during changes in perfusion pressure head or during changes in transmural pressure, is revealed. The vasoconstrictor response to increase in transmural pressure will counteract an increase in transmural pressure in the exchange vessles and thereby act as an edema protecting factor.

The study was performed in order to determine the effect of venous pressure elevation induced by unilateral partial renal venous ligation upon total renal blood flow and filtration fraction in the dog kidney. An anaesthesia with no known inhibitory effect on sympathetically mediated vasoconstriction was used. During control conditions instantaneous increase in renal venous pressure to 60 mmHg induced a decrease in renal blood flow (66 +/- 4%) corresponding to an ipsilateral vasoconstriction which was completely abolished following (1) surgical denervation of the kidney, (2) local alpha-receptor blockade of the kidney, and (3) application of lidocaine on the kidney surface. The most striking feature during step increase in renal venous pressure to 40 mmHg was an increase in renal vascular conductance. Renal venous pressure elevation of more than 40 mmHg induced a vasoconstriction, but the vasoconstrictor response was less pronounced as compared with that observed during instantaneous increase in renal venous pressure to the same level. The results strongly suggest that venous stasis of more than 40 mmHg activates an adrenergic sympathetic vasoconstrictor reflex comprising the spinal cord. The reflex is probably elicited from stretch receptors located in the renal capsule. Changes in filtration fraction at venous stasis during the experimental conditions indicate that renal venous pressure elevation activates mechanisms other than neural ones accounting for the reduction in the filtration fraction.

The effect of "vein pump" activation upon superficial venous pressure and blood flow in human subcutaneous adipose tissue was studied in 6 normals and 2 patients with venous insufficiency. Blood flow in subcltaneous tissue was measured at the lateral malleolus by the local 133Xenon washout technique, with the subject placed in a supine position. During passive lowering of the leg blood flow decreased 50 per cent and total vascular resistance increased 136 per cent. Activation of the vein pump by continuously tipping the foot up and down caused a decrease in venous pressure of 5 mmHg in horizontal position. Venous pressure increased only by 8 mmHg when the leg was lowered during exercise. In this situation blood flow remained constant corresponding to an increase in vascular resistance of 42 per cent. However increasing venous pressure to 28 mmHg by venous stasis in the lowered leg during exercise caused an additional increase in vascular resistance of 82 per cent. In the patients with venous insufficiency exercise did not prevent the decrease in blood flow during lowering of the leg. Hence venous pressure elevation of 25 mmHg or more caused an additional increase in vascular resistance in subcutaneous tissue, "vasoconstrictor response". It is concluded that this "vasoconstrictor response" depends on a vasoconstrictor impulse transmission from veins to arterioles, veno-artertolar reflex.

The effect of venous stasis of 40 mmHg upon blood flow in human skeletal muscle was studied in four normal subjects and in two chronically sympathectomized patients. Blood flow in skeletal muscle was measured by the local 133Xenon washout technique. Blood flow decreased about 30 per cent during venous stasis of 40 mmHg. In a "passive vascular bed" induced by means of histamine, blood flow decreased only by 16 per cent, indicating that the decrease in blood flow is due to a vasoconstrictor response to increase in vascular transmural pressure. The vasoconstrictor response was unaffected by a spinal sympathetic blockade, but was blocked in areas infiltrated with lidocaine or with phentolamine. The vasoconstrictor response was present in the nonoperated limbs used as a control, but abolished in the denervated arms in the two chronically sympathectomized patients. The findings strongly suggest that the vasoconstrictor response in skeletal muscle is due to a local nervous mechanism involving adrenergic fibres. Thus a local reflex mechanism, most likely a sympathetic axon reflex, seems to be present in human skeletal muscle as in cutaneous and subcutaneous tissue. This indicates that about 45 per cent of the change in total vascular conductance, when a person changes from supine to upright position, is due to this local reflex mechanism operating independently of the central nervous system.

The effect of chronic sympathetic denervation upon the vasoconstrictor response to an increase of vascular transmural pressure in human subcutaneous adipose tissue was investigated in 6 patients suffering from manual hyperhidrosis. Changes in transmural pressure were obtained either by postural changes of a forearm or by venous stasis of 30 mmHg. Blood flow was measured in the distal part of the forearm or crus by means of the local 133Xenon washout technique. 2 patients were studied before and after sympathectomy. When the area under study was lowered about 40 cm below the jugular notch, blood flow decreased about 50 per cent preoperatively, about 30 per cent 24 h after the operation, but remained constant 4 days after or later. Similar results were obtained during venous stasis. Hence about 4 days after sympathectomy, the vasoconstrictor response to an increase in vascular transmural pressure was abolished. In 3 chronically sympathectomized patients blood flow remained constant in the denervated limb, but decreased significantly in the control limb. In another patient studied 580 days after surgery blood flow remained constant during lowering of the denervated forearm as well as during venous stasis. These findings might indicate that the vasoconstrictor response to an increase in vascular transmural pressure in human subcutaneous adipose tissue is due to a local nervous mechanism involving symphathetic adrenergic nerves, but a myogenic mechanism cannot be definitively excluded.

The influence of renal interstitial pressure on the resistance pattern within the superficial cortical vasculature has been investigated from determinations of I) the glomerular blood flow with a modified microsphere technique and 2) the intravascular hydrostatic pressures. Interstitial pressure was monitored via a 50 μm PVC-catheter placed into the subcapsular interstitial space. Two conditions were analyzed viz. a) elevation of iiretheral pressure to 20 mm Hg and b) venous stasis to 10–15 mm Hg. Both conditions produced an increase in the interstitial pressure from 1–2 mm Hg to about 5 mm Hg as well as an increased hilar lymph flow and protein flow of about the Same size. The vascular reactions were different, however. Urethcral stasis (but not the stasis of a single nephron) produced a decreased resistance in the afferent arteriolae with a concomitant increase in the pressures in the glomerular capillaries, and the peritubular capillary network. In contrast, venous stasis produced only small changes in the parameters studied but for the obvious rise in the peritubular capillary pressure. The results suggest that factors other than the interstitial pressure are governing the afferent vascular tone; the tubular wall tension might he one of these factors.

The effect of vein pump activation upon superficial venous pressure and blood flow in human skeletal muscle tissue was studied in 7 healthy subjects. Blood flow was measured in the anterior tibial muscle by the local 133Xe washout technique. The subjects were placed on a steeply tilted couch in nearly erect position. The vein pump in gastrocnemius-soleus muscles was activated by heel-raisings, and the anterior tibial muscle remained relaxed during this procedure. Blood flow in the resting anterior tibial muscle was constant before, during and after 20 heel-raisings per min. A more heavy exercise with 40 heel-raisings per min increased blood flow about 100%. This increase in blood flow was absent during venous stasis (40 mmHg), and in areas infiltrated with lidocaine. It is concluded, that intense dynamic exercise in gastrocnemius-soleus muscles, in erect humans, increased blood flow considerably in another crural muscle remaining in the resting state. The present study strongly suggests, that the observed increase in blood flow, was associated with a decrease in regional subfascial venous pressure to below the threshold level of the local sympathetic veno-arteriolar reflex.

Changes in normal human leg lymph protein concentration, output, and lymph flow/lymph protein concentration relationship, as well as lactate dehydrogenase and alkaline phosphatase activity were followed during procedures known to increase capillary filtration as venous stasis, muscular exercise and warming of tissues. Lymph flow increased by 83% during two hour ergometer cycling, and by 117% during two hour warm water foot bath. During a two hour period of venous stasis lymph flow dropped by 50%. There was an increase in lymph flow during the rest period following all three types of experiment, most pronounced after foot warming. An inverse relationship between the lymph flow rate and lymph protein concentration was found. Lymph enzymes followed the same pattern of changes as total protein.