Effect of Chronic Sympathetic Denervation upon Local Regulation of Blood Flow in Human Subcutaneous Tissue

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.     

Local Reflex in Microcirculation in Human Cutaneous Tissue

Blood flow in cutaneous tissue measured by the local ¹³³Xenon washout technique decreased about 35 per cent during venous stasis of 40 mmHg in three normal subjects. The response was unaffected by block of the nerve three cm proximally to the labelled area. When the tissue was infiltrated with lidocaine or with phentolamine, blood flow remained constant, indicating that the decrease in blood flow is due to an arteriolar vasoconstrictor response to increase in venous transmural pressure. Local venous stasis elicited a vasoconstrictor response in an adjoining area not affected by the stasis. The response was blocked by lidocaine applied to the side of stasis. In 2 chronically sympathectomized patients, the vasoconstrictor response was abolished in the denervated limbs hut present on the non-operated side (1 patient with unilateral sympathectomy). The results indicate that the vasoconstrictor response to an increase in venous transmural pressure is due to a local nervous mechanism involving sympathetic adrenergic fibres, most likely a sympathetic axon reflex.     

Effect of “Vein Pump” Activation upon Venous Pressure and Blood Flow in Human Subcutaneous Tissue

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 subcutaneous 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-arteriolar reflex.     

Increased sympathetic tone in forearm subcutaneous tissue in primary hypothyroidism

Sympathetic reflex regulation of subcutaneous blood flow (SBF) in the forearm was studied in eight patients with primary hypothyroidism. Diastolic arterial pressure was greater than or equal to 95 mmHg in five patients. SBF was determined by local clearance of Na99mTcO4. Sympathetic vasoconstriction normally seen after lowering the forearm 40 cm below heart level was absent since SBF only decreased by 4% (+/- 7%, P greater than 0.1) during these conditions. In head-up vertical position we noticed a diminished baroreceptor response as SBF at heart level was reduced by 11% (+/- 7%, P greater than 0.1) compared to supine position. After proximal local anaesthesia SBF increased by 351% (+/- 81%, P less than 0.01) and disclosed a normal vasoconstrictor response as SBF was reduced by 53% (+/- 5%, P less than 0.01) during arm lowering. Five of the treated patients were restudied in the euthyroid state. Mean arterial pressure was reduced in mean by 20 mmHg (+/- 6 mmHg, P less than 0.02) during treatment and a significant vasoconstriction was observed both during arm lowering (SBF = -52% (+/- 6%, P less than 0.02)) and in head-up vertical position (SBF = -45% (+/- 11%, P less than 0.02)). In conclusion sympathetic vasoconstrictor activity in adipose tissue is markedly increased in primary hypothyroidism. Sympathetic tone and arterial pressure are reduced during treatment.     

Local Nervous Mechanism in Regulation of Blood Flow in Human Subcutaneous Tissue

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 per cent 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.     

Local regulation of subcutaneous blood flow and capillary filtration in limbs with occlusive arterial disease. Studies before and after arterial reconstruction

The aim of the study was to examine the local blood flow regulation and the capillary filtration rate in patients with occlusive arterial disease before and after arterial reconstructive surgery. Fourty-seven normal subjects and 99 patients were studied. Subcutaneous blood flow was measured on the forefoot by the local 133Xenon method. Forefoot arterial blood pressure was measured indirectly by cuff and strain-gauge technique. Capillary filtration rate was measured by strain-gauge plethysmography on the forefoot. The arterial and venous pressures of the forefoot were changed by elevating or lowering the foot in relation to heart level. In normal limbs autoregulation was demonstrated during elevation of the limb when blood flow remained almost constant despite the reduction in arterial and perfusion pressures. The local vasoconstrictor response to increased venous transmural pressure was demonstrated when the limb was lowered and blood flow decreased about 30% despite a constant perfusion pressure. In limbs with occlusive arterial disease both local blood flow regulation mechanisms became progressively more abnormal the severe the symptoms and the lower the distal blood pressure. Estimations of the changes in local vascular resistance suggested that the abnormalities in blood flow regulation in all but the severest cases are the result of changes in local perfusion pressure rather than the result of inability of the arteriolar smooth muscle to dilate and constrict in response to changes in arterial and venous pressures. After arterial reconstruction the two mechanisms generally normalized within about a week. However, disturbances occurred in some cases in the early postoperative period, possibly as the result of postoperative pain and stress. Postreconstructive hyperaemia developed in most limbs despite the early normalization of local blood flow regulation. Compared with normal limbs, the forefoot capillary filtration rate was reduced in limbs with occlusive arterial disease. In the early postoperative period the filtration rate remained reduced, but it increased to normal values within three months. Postreconstructive oedema developed independently of the normalization of blood flow regulation, and almost exclusively after femoro-distal by-pass surgery. The study supports the hypothesis that the postreconstructive oedema is a lymphoedema due to surgical trauma, rather than the result of microvascular derangement.     

Sympathetic reflex-induced vasoconstriction during renal venous stasis elicited from the capsule in the dog kidney

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.     

A comparison between 133Xenon washout technique and Laser Doppler flowmetry in the measurement of local vasoconstrictor effects on the microcirculation in subcutaneous tissue and skin

Changes in skin blood flow measured by Laser Doppler flowmetry and changes in subcutaneous blood flow measured by 133Xenon washout technique were compared during activation of the local sympathetic mediated veno-arteriolar vasoconstrictor reflex by lowering the area of investigation below heart level. The measurements were performed in tissue with and without sympathetic innervation. In five subjects, who all had been cervically sympathectomized for manual hyperhidrosis, the Laser Doppler and 133Xenon blood flow measurements were performed simultaneously on the sympathetically denervated forearm, and on the calf with preserved sympathetic nerve supply. The Laser Doppler method registered a 23% reduction in skin blood flow during lowering of the extremities independently of the sympathetic nerve supply to the skin. The 133Xenon method recorded a 44% decrease in blood flow in innervated and unchanged blood flow in denervated subcutaneous tissue during lowering of the extremities. Our results indicate that the Laser Doppler method and 133Xenon method are not comparable, and that the Laser Doppler method is not useful in measuring local sympathetic mediated blood flow changes.     

Local Reflex in Microcirculation in Human Skeletal Muscle

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.     

Local Reflex in Microcirculation in Human Subcutaneous Tissue

The effect of changes in transmural pressure in the vessels of the extremities on blood flow in subcutaneous adipose tissue was investigated in three healthy subjects. Changes in transmural pressure were obtained either by postural changes of a limb, by locally induced subatmospheric pressure, or by 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 resistance, but remained constant in the contralateral side. This vasoconstrictor 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 vessels and thereby act as an edema protecting factor.     

Regional differences in the responsiveness of isolated arteries from cattle,dog and man

Changes in tension of spiral strips from basilar, external carotid, temporal and muscle arteries from cattle, dog and man were monitored isometrically. Dose-response curves for 5-HT, noradrenaline and ergotamine indicated a variation in responsiveness between different arteries of the same species as well as between the same arteries of different species. When tested against 5-HT ergotamine consistently acted as non-competitive dualist but it antagonized responses to noradrenaline only in peripheral arteries from dog and man. In all arteries from the carotid vasculature and in bovine muscle arteries the vasoconstrictor effects of ergotamine and noradrenaline were independent additive. It is suggested that the therapeutic value of ergotamine in the treatment of migraine headache is due to its selective vasoconstrictor activity in the external carotid vasculature mediated through independent additive vasoconstrictor effects of ergotamine and noradrenaline.Dedicated to K. Bucher on the occasion of his 65th birthday.     

Simultaneous application of differential servo-oscillometry and volume-clamp plethysmography for continuous non-invasive recording of the finger blood pressure response to a hand postural change

Continuous blood pressure recordings obtained by the volume-clamp method (Finapres 2300 BP monitor, Ohmeda, USA) were compared with measurements made by using the modified oscillometric method (UT9201 beat-to-beat monitor, University of Tartu, Estonia) in normal subjects during a hand postural change. Changes in the local blood pressure were induced in 11 healthy volunteers by passive elevation of the hand by 40 cm and lowering it again after one minute. We did not reveal a statistically significant difference between the group-averaged responses of the oscillometric finger mean blood pressure measurement device and those of Finapres during this test. The difference UT9201 minus Finapres equalled ?1.3 ± 3.1 mm Hg (p = 0.15). Blood pressure responses were similarly tracked by both beat-to-beat finger blood pressure monitors despite the considerable variability in the shape of the subjects' individual responses.     

Simultaneous application of differential servo-oscillometry and volume-clamp plethysmography for continuous non-invasive recording of the finger blood pressure response to a hand postural change

Continuous blood pressure recordings obtained by the volume-clamp method (Finapres 2300 BP monitor, Ohmeda, USA) were compared with measurements made by using the modified oscillometric method (UT9201 beat-to-beat monitor, University of Tartu, Estonia) in normal subjects during a hand postural change. Changes in the local blood pressure were induced in 11 healthy volunteers by passive elevation of the hand by 40 cm and lowering it again after one minute. We did not reveal a statistically significant difference between the group-averaged responses of the oscillometric finger mean blood pressure measurement device and those of Finapres during this test. The difference UT9201 minus Finapres equalled -1.3 +/- 3.1 mm Hg (p = 0.15). Blood pressure responses were similarly tracked by both beat-to-beat finger blood pressure monitors despite the considerable variability in the shape of the subjects' individual responses.     

Effect of lower body negative pressure upon local regulation of blood flow in human subcutaneous tissue

Local regulation of subcutaneous blood flow in the forearm was studied during lower body negative pressure (LBNP) in 7 young healthy male subjects in supine position. Blood flow was measured on the forearm by the local ¹³³Xe washout technique. LBNP of -40 and -60 mmHg induced a decrease in the ¹³³Xe washout rate of 34 and 50% respectively. This response to LBNP could be blocked by proximal nervous blockade indicating that the vasoconstriction observed was due to a central sympathetic reflex mechanism. The vasoconstrictor response to increase in venous transmural pressure induced by lowering the arm (veno-arteriolar reflex mechanism) could not be demonstrated during 40 mmHg LBNP. The abolishment of this reflex is most likely due to centrally elicited increase in sympathetic activity as a normal veno-arteriolar reflex was elicited following proximal nervous blockade.     

Hemodynamic and functional changes during renal venous stasis in dog kidneys

The effect of renal venous pressure (RVP) elevation on renal hemodynamics and tubular function was studied in neurolept anaesthetized dogs. Renal blood flow (RBF) was measured electromagnetically. Clearance of 51Cr-EDTA was used as a measure of the rate of glomerular filtration (GFR). GFR, urinary excretion rates of sodium and water, and lithium clearance (CLi) were used for assessing the absolute and fractional reabsorption rates of sodium and water in the proximal as well as in more distal segments of the nephron. The vasoconstrictor response to RVP elevation was partly abolished by acute surgical denervation or by local application of lidocain on the renal capsule, suggesting that RVP elevation activates an adrenergic vasoconstrictor reflex comprising the spinal cord, and elicited from stretch receptors located in the renal capsule. Further studies in alpha-adrenoceptor blocked or chronic denervated kidneys and in decapsulated kidneys favour the view, that neurogenic and myogenic mechanisms significantly influence the vasoconstrictor response to RVP elevation: The neurogenic contribution to the vasoconstrictor response comprising intrarenal and extrarenal vasoconstrictor mechanisms evoked reflexly by RVP elevation; the myogenic contribution to the vasoconstrictor response comprising opposing vasodilator mechanisms due to increase in renal interstitial tissue pressure during RVP elevation. Studies carried out in intact kidneys, acutely surgically or chronically denervated kidneys or alpha-adrenoceptor blocked kidneys indicate that the increase in proximal reabsorption rates during moderate RVP elevation is due mainly to local intrarenal alpha-adrenergic reflex mechanisms, since the decrease in CLi (during constant filtered load) induced by RVP elevation was unaffected by acute surgical denervation, but completely abolished by chronic denervation of the kidney, or by local alpha-adrenoceptor blockade of the kidney.     

Regulation of subcutaneous blood flow during head-up tilt (45°) in normals

Local and remote regulation of subcutaneous blood flow in the forearm and leg was studied during head-up tilt (45°) in 6 young healthy male subjects. Relative blood flow was estimated by the local ¹³³Xe washout technique. Lowering of a leg lead to a 51 % decrease in its subcutaneous blood flow due to a veno-arteriolar reflex elicited by the increase in venous transmural pressure. During head-up tilt subcutaneous blood flow in the arm remaining at heart level decreased by 27%, in the leg blood flow decreased by 50%. Following proximal nervous blockade, head-up tilt did not induce vasoconstriction in forearm at heart level, but blood flow in distal leg decreased by 45%. Thus there was no difference in the vasoconstrictor response in the leg to head-up tilt or lowering of the labelled area by 40 crn. Since head-up tilt caused neurogenically mediated vasoconstriction in subcutaneous tissue, subcutaneous blood flow in the extremities seems to be regulated by remote (baroreceptor) as well as local sympathetic reflex mechanisms (veno-arteriolar reflex).     

Effect of chronic sympathetic denervation upon the transcapillary filtration rate induced by venous stasis

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.     

Augmented vasoconstrictor response to changes in vascular transmural pressure in patients with essential arterial hypertension

The vasoconstrictor response to increase in venous transmural pressure in subcutaneous tissue was studied in 9 patients with essential arterial hypertension. Subcutaneous blood flow was measured on the distal part of the forearm and at the lateral malleolus by the local ¹³³Xe washout technique. Increase in venous transmural pressure was obtained by lowering the area under study 40cm below midaxillary line in the recumbent subject. Average mean arterial pressure ± 1 S.E. was 133 ± 6 mmHg. The fractional increase in vascular resistance induced by arteriolar constriction was more pronounced in the hypertensive patients than in a normotensive control group. “Minimal vascular resistance” in the papaverine relaxed vascular bed was higher in the hypertensive patients than in the controls. Distensibility of the papaverine relaxed resistance vessels was diminished in the patients. Follow-up studies after 6–18 months of anti-hypertensive treatment indicate that the vasoconstrictor response as well as “minimal vascular resistance” are normalized, whereas the distensibility of the papaverine relaxed arterioles remained unaltered in the hypertensive patients. The results indicate that the arteriolar smooth muscle cells of hypertensive patients are subjected to reversible hypertrophy whereas the reduced distensibility of the resistance vessels is due to irreversible structural changes.     

Local and central sympathetic reflex control of blood flow in skeletal muscle and subcutaneous tissue in normal man

The effect of age and sex on relative changes in blood flow and vascular resistance in skeletal muscle and subcutaneous tissue during postural changes and during local increase in transmural pressure was studied in 33 healthy subjects. The intra-individual variation was studied in five subjects. Blood flow was measured by the local 133Xenon wash-out method. No relation to age or sex was seen in the centrally elicited sympathetic vasoconstrictor responses in subcutaneous tissue and skeletal muscle and in the locally elicited vasoconstriction in subcutaneous tissue. A small, but statistically significant, correlation to sex and age was found in the local sympathetic vasoconstrictor response in skeletal muscle. The age correlation was caused only by an attenuated response in the young subjects below 40 years of age and may be fortuitous. The intra-individual variation was acceptably small. Based on the present results, a reduction in blood flow in skeletal muscle and subcutaneous tissue during centrally or locally elicited sympathetic vasoconstriction of 10% or less should be considered abnormal. The local 133Xenon wash-out method is of value in examining patients suspected of dysfunction in the sympathetic part of the autonomic nervous system.     

Effect of Spinal Sympathetic Blockade upon Local Regulation of Blood Flow in Subcutaneous Tissue

The influence of spinal sympathetic blockade upon local regulation of blood flow in subcutaneous adipose tissue was investigated in six subjects. The effect of changes in orthostatic pressure on blood flow in subcutaneous tissue in the crus and distal forearm was measured before and after sympathetic blockade obtained by epidural anesthesia in 4 subjects and by a bilateral sympathectomy in 2 patients suffering from manual hyperhidrosis. Blood flow in subcutaneous tissue measured by ¹³³Xe washout technique decreased by about 40 per cent when the limb was lowered, and remained constant during 30 cm elevation. This was found both before and after the blockade, though in one of the patients, the orthostatic decrease in blood flow was less pronounced 24 h after sympathectomy. Hence central sympathetic reflexes do not alter local orthostatic changes of blood flow in subcutaneous tissue. These changes therefore are most likely due to local mechanisms.