Capillary hypertension and abnormal pressure dynamics in patients with essential hypertension.

1. Pressure was measured within 28 capillaries of the nailfolds of nine patients with essential hypertension and in 33 capillaries of nine age- and sex-matched normotensive control subjects, using direct micropuncture, a dynamic servo-nulling system and computerized analysis. 2. Average pressure at the apex of the capillary was found to be elevated in the patients with hypertension (21.1 +/- 4.9 mmHg compared with 13.0 +/- 2.0 mmHg in the control subjects; mean +/- SD, P less than 0.01). If the two groups were combined, there was an overall correlation between average capillary pressure and mean blood pressure (r = 0.68, P less than 0.01, n = 18), but within each group separately there was no significant relation between these parameters. 3. There were also abnormalities in the waveforms of pulsations in capillary pressure in the group with hypertension, with an increased attenuation of high-frequency harmonics. Pulses appeared to be conducted more rapidly along the vascular tree in the patients with hypertension. 4. The elevation of capillary pressure in essential hypertension demonstrated in this study is in agreement with indirect evidence of capillary hyperfiltration provided by other studies which showed a reduced plasma volume and increased transcapillary escape rate of plasma proteins. 5. The finding of elevated capillary pressure demands the inclusion of the postcapillary segment (and possibly vascular density) in the resistance equation in essential hypertension.

Dynamic compliance of single perfused frog mesenteric capillaries and rat venules: a filtration coefficient correction.

The compliance of microvessels produces a potential source of error in the measurement of hydraulic conductance, regardless of which method is used. The compliance characteristics of rat and frog microvessels, in vivo, was studied using a two oil technique capable of measuring changes in radius of 0.01 micron at intervals of 0.02 seconds. Two water insoluble immiscible oils were micro-injected into occluded segments of the vessel. Since the volume of the oil remained constant the position of the interface at different times, following a sudden change in applied pressure, could be used to determine the time course of changes in vessel diameter. It was found that approximately 90% of the compliance response had occurred within 0.4 seconds of applying a step change in pressure. This compliance response coincides with the initial change in fluorescence used in the measurement of fluid with the initial change in fluorescence used in the measurement of fluid filtration by the densitometric technique.

Distensibility of single capillaries and venules in the rat and frog mesentery.

The distensibility characteristics of single microvessels in the mesentery of frogs and rats has been determined by a new technique capable of resolving a change in radius of about 0.01 micron in vivo. Two water insoluble immiscible oils were micro-injected into occluded segments of the vessels. Since the volume of the oil remained constant, the position of the interface at different applied pressures could be used to determine changes in vessel diameter. The stress/strain relationship of capillaries and venules in the frog mesentery and venules in the rat mesentery were determined and found to be similar to each other. Vessel diameters increased by up to 15% over the whole pressure range used but in a markedly non-linear manner, stiffening at higher strains. It is suggested that the basement membrane has the appropriate properties to explain this behaviour.

Dynamic measurement of human capillary blood pressure.

1. Capillary blood pressure was measured in man using a dynamic servo-nulling system and direct micropuncture. This enabled assessments of the normal variations in pressure which influence fluid filtration and reabsorption. 2. Seventy-eight capillaries in 19 subjects were punctured in one of three positions around the capillary loop with the hand at the level of the sternal angle. Mean pressure around the loop fell from 37.7 +/- 3.7 mmHg (arteriolar limb, mean +/- SEM, n = 12) to 19.4 +/- 1.0 mmHg (apex, n = 25) to 14.6 +/- 0.5 mmHg (venular limb, n = 41) at skin temperatures of 18.7-33.1 degrees C. These values agree closely with Landis' original studies in 1930 [E. Landis (1930) Heart, 15, 209-228]. 3. The mean filtration/reabsorption state of any particular capillary limb was not static because of cardiac, vasomotor and respiratory fluctuations in capillary pressure. From a total of 38 capillaries in which recordings were analysed for 30 s, the fluctuations in pressure were such that 27 capillaries probably had periods of both filtration and reabsorption. 4. Computerized superimposition and coherent averaging of trains of capillary pulses enabled an accurate description of the pulse waveform to be made in three capillaries. This was remarkably similar to waveforms from the radial artery, albeit at reduced amplitude (average 3.6 +/- 3.4 mmHg, mean +/- SD overall). The time for the pulse to travel between the radial artery and the finger capillary was approximately 10 ms, which implies a propagation velocity of several metres per second.(ABSTRACT TRUNCATED AT 250 WORDS)

Filtration coefficient and osmotic reflection coefficient to albumin in rabbit submandibular gland capillaries.

1. The isolated perfused submandibular salivary gland of the rabbit has been used in order to make estimates of the filtration coefficient (Kf) and reflection coefficient (sigma d) of the capillary wall to albumin. 2. An isogravimetric preparation was used and in paired experiments the value for Kf obtained in glands perfused with albumin-Krebs solution, 0.96 +/- 0.086 (mean +/- S.E. of mean) ml min-1 mmHg-1 100 g-1, was not significantly different from that in blood-perfused glands, 0.90 +/- 0.15. 3. On analysing the data for reflection coefficient, it was concluded that the above values underestimated Kf by about 30%; using corrected values for Kf, osmotic reflection coefficients were determined from the weight changes following a sudden change in the oncotic pressure of the perfusate. The value for sigma d to albumin lay between 0.79 and 1.0, the lower value being obtained after the Kf correction. 4. The high hydraulic conductivity, combined with sieving properties comparable to those in continuous capillaries, is consistent with other data on fenestrated capillaries. 5. Finally, it was observed that, while the Kf value calculated from the initial flux rate was similar whether measured during fluid efflux from or influx into the microvasculature, on returning to the initial conditions after raising osmotic pressure, efflux was now more rapid than influx. This phenomenon is discussed in relation to readjustment of Starling forces and the possible existence of an asymmetric double membrane in the capillary, interstitium system and cells of the salivary gland.

Changing sensitivity to H1 and H2 receptor antagonists in the growing vasculature.

1. Resting albumin efflux is greater from immature vessels than from mature and this is associated with a greater blood flow in immature vessels. 2. Both resting blood flow and albumin efflux in immature vessels are reduced by an H2 antagonist. 3. Histamine produces a greater albumin efflux from mature vessels than from immature and the associated increase in blood flow in response to histamine was also greater in mature vessels. 4. Blood flow and permeability increase produced by histamine are separately mediated via H2 and H1 receptors respectively in mature vessels. 5. In immature vessels, H2 receptors appear to mediate both responses.

An analysis of the permeability of a fenestra.

In this analysis of published data we evaluate the permeabilities of unit area of fenestral pathway to water and small solutes. These properties are then used to assess the functional significance of the fenestral diaphragm which, along with the glycocalyx and basement membrane, makes up the fenestral pathway. Endothelial hydraulic conductance and permeability to small lipophobic solutes increase with fenestral density in a variety of mammalian tissue. The increase in conductance per unit increment in fenestral area (Kfen) averages 0.38 micron X s-1 X mm Hg-1 (regression analysis). This value means that a single fenestra (diam 0.06 micron, area 0.003 micron2) has a greater conductance than 1 micron2 of continuous (skeletal muscle) endothelium. Similarly the diffusional permeability of unit fenestral area (Pfen) to B12 and inulin is high. But neither Kfen nor Pfen is as great as might be expected from the extreme thinness of the diaphragm (less than or equal to 5 nm). Pfen depends on diffusivity (D) and pathlength (delta chi): Pfen = D'/delta chi. D' depends on the fraction of the fenestral surface available for exchange and on restriction to diffusion. These relations were applied to test the view that the diaphragm, rather than the glycocalyx or basement membrane, is the major barrier to fluid and small solutes in the fenestral pathway. If this were turn, over 98 1/2% of the diaphragm's area would have to be totally impermeable in order to yield the observed values of Pfen--a result consequent upon the extreme thinness of the diaphragm. In this event there would be less than one equivalent pore (radius 5-11 nm) per diaphragm on average-which is incompatible with ultrastructural evidence. The resistance of a 5-nm-thick diaphragm containing one or more pores is not high enough to account for fenestral resistance. It is concluded that much thicker structures, such as the glycocalyx and/or basement membrane, and not the diaphragm, account for fenestral resistance to small-solute and water transport.

Transcapillary transport during secretion by the rabbit submandibular salivary gland.

Fluid exchange in the rabbit submandibular gland has been studied with a view to improving understanding of the mechanisms underlying transcapillary transport during salivation. Using maximally vasodilated glands perfused in vitro, we found that acetylcholine had no significant effect on either hydraulic conductance (filtration coefficient, Lp) or reflection coefficient to albumin (sigma alb) of the gland microvessels. In vivo, parasympathetic nerve stimulation increased blood flow 20-fold, interstitial fluid production (total fluid efflux - saliva flow) increased approximately 10-fold, while filtration fraction remained constant. At the same time, isogravimetric capillary pressure increased about six-fold. There are several possible explanations for these findings, and it is argued that they are likely to include capillary recruitment. Thus, during salivation, parasympathetic nerve stimulation does not lead to a change in capillary permeability as such, but rather produces a relaxation of resistance vessels and a fall in precapillary resistance, accompanied by an increase in available capillary surface area. This leads to a rise in capillary blood flow and pressure, which in turn increase fluid filtration. These changes are self-limiting due to the resulting dilution of interstitial protein and rise in interstitial pressure, but during salivation, since the secretion is pumped out of the interstitium, this fluid transport has no net effect on transcapillary gradients.

Impaired microvascular hyperaemic response to minor skin trauma in type I diabetes.

The microvascular response of foot skin to minor thermal injury and the skin of the anterior abdominal wall to injury from a needle was assessed by laser Doppler flowmetry in 23 patients with type I diabetes and 21 healthy control subjects. After minor thermal injury mean (SD) maximum skin blood flow was significantly lower in the diabetic group than the control group (0.53 (0.11) v 0.72 (0.10) V, in arbitrary units of flow, respectively, p less than 0.001) and was negatively correlated with the duration of diabetes (r = -0.60; p less than 0.01). After needle injury a similar pattern of impairment was seen, the peak flow value recorded being significantly lower in the diabetic group than the control group (0.28 (0.10) v 0.41 (0.09) V, respectively; p less than 0.001) and also negatively correlated with the duration of diabetes (r = -0.61; p less than 0.01). There was a significant relation between the response obtained at the two sites of injury in the diabetic group (r = +0.72, p less than 0.001) but not in the control group. The impairment in response was not related to diabetic control and was not explicable in terms of a reduction in superficial skin capillary density. The inability of the diabetic skin microvasculature to respond normally to injury may be an important factor in the development of foot ulceration that often follows minor trauma.

Evidence from O2 uptake measurements for Na+ -K+ -2 Cl- co-transport in the rabbit submandibular gland.

There is evidence that the production of primary saliva by acinar cells is a consequence of Na+ -Cl- co-transport but more recently it has been proposed that in fact Na+ -K+ -2 Cl- co-transport is responsible. The latter would be energetically more efficient and the present experiments were designed to measure the stoichiometry of acinar secretion in order to distinguish between these two mechanisms. Submandibular salivary glands from anaesthetised rabbits were isolated vascularly and oxygen consumption measured from the oxygen content of arterial inflow and venous effluent blood and the total flow through the gland. Measurements were made in the steady-state at rest and during different secretion rates induced by parasympathetic nerve stimulation. The rate of sodium transport across the acinar and ductal epithelium was determined from plasma and salivary sodium concentration and salivary flow rate. Multiple regression analysis of this data showed that 22.1 mol Na+ was secreted per mol O2 consumed while 11.9 mol Na+ was reabsorbed per mol O2 consumed. Since acinar secretion is energetically about twice as efficient as ductal absorption, a mechanism for Na+ transport other than that for tight epithelia must be involved. Na+ -K+ -2 Cl- co-transport is thus more likely than Na+ -Cl- and it is suggested that Na+ -K+ -2 Cl- co-transport is the main mechanism involved in salivary acinar secretion.

Exchange area and surface properties of the microvasculature of the rabbit submandibular gland following duct ligation.

The exchange area of the submandibular salivary gland microvasculature has been measured to allow the value of microvascular permeability (P) to hydrophilic solutes to be calculated from previous measurements of permeability-surface area (PS) products. Glands whose ducts had been ligated for 2 weeks and the contralateral control glands were perfusion-fixed with a modified Karnovsky's fixative after perfusion with a solution containing cationized ferritin, and examined with transmission electron microscopy. Stereological techniques were used to estimate the surface area of the exchange vessels on random thin sections from four control and four duct-ligated glands. The mean exchange surface area in control glands was 512 cm2 g-1 and 336 cm2 g-1 in duct-ligated glands. The fenestral density was calculated to be 0.57% of the exchange surface in control glands and 0.30% in duct-ligated tissue. Molecules of cationized ferritin appeared bound to the luminal surface of the microvascular endothelium, including the surface of the fenestrae to a depth of about 25 nm in both control and ligated glands. These experiments have shown that the exchange surface area of the fenestrated endothelium of the submandibular salivary gland is comparable to that in cardiac muscle but the permeability (P) to small solutes is about 10 times greater. Following ligation of the salivary gland duct, solute permeability falls and an explanation of this, based on the reduced surface area and the nature of the permeability-flow relationship for small solutes is offered.

The effects of compliance on measurement of hydraulic conductivity in microvessels.

A method for the measurement of compliance in mesenteric frog capillaries and rat venules is described briefly. The error introduced by capillary compliance in the measurement of hydraulic conductivity is then discussed in the light of these measurements and some of the recent literature on hydraulic conductivity are reassessed.

The role of cyclic nucleotides and related compounds in nerve-mediated vasodilatation in the cat submandibular gland.

1 Intra-arterial administration of a number of purine compounds to the cat submandibular salivary gland led to an increased blood flow. The threshold concentration of the most potent vasodilators, adenosine 5'-triphosphate (ATP) and adenosine 5'-diphosphate (ADP) was about 2 mumol/l. Adenosine and guanosine 5'-triphosphate (GTP) required about 25 mumol/l, adenosine 3',5'-cyclic monophosphate (cyclic AMP) 40 mumol/l, guanosine 5'-diphosphate (GDP) 125 mumol/l and dibutyryl guanosine 3',5' cyclic monophosphate (db cyclic GMP) 400 mumol/l. Dibutyryl cyclic AMP and cyclic GMP were ineffective. 2 The cyclic nucleotide phosphodiesterase inhibitors, theophylline, papaverine, quinine and 3-isobutyl-1-methylxanthine (IBMX), all acted as vasodilators. 3 When intra-arterial infusion of theophylline or IBMX was combined with sympathetic nerve stimulation, the vasodilatation observed after the stimulus ceased was significantly potentiated. 4 Theophylline and IBMX also potentiated the vasodilatation accompanying parasympathetic nerve stimulation and this response persisted after atropine. 5 These results are discussed in relation to the possible mediators of sympathetic and parasympathetic vasodilatation in the gland.

Transcapillary exchange in the cat salivary gland during secretion, bradykinin infusion and after chronic duct ligation.

1. Capillary permeability-surface area products for 86Rb, [51Cr]EDTA (mol. wt. 357), [57Co]cyanocobalamin (mol. wt. 1353) and [125I]insulin (approximate mol. wt. 6000) have been measured using the single-circulation, multiple-tracer dilution technique in the in situ perfused submandibular salivary gland during parasympathetic nerve stimulation, close-arterial bradykinin infusion and following chronic duct ligation. 2. In glands with a natural blood supply, permeability-surface area for 86Rb and [51Cr]EDTA increased during parasympathetic stimulation, but this was shown to be related to the concomitant increase in blood flow rather than to a change in capillary permeability or in surface area. 3. In glands perfused at constant flow, parasympathetic stimulation led to a decrease in permeability-surface area for EDTA (-19.1 +/- 5.2%, mean +/- S.E., n = 5, P less than 0.05) cyanocobalamin (-12.3 +/- 6.0, n = 12, P less than 0.05), and insulin (-15.3 +/- 4.8, n = 11, P less than 0.02). It is suggested that this may be the result of a redistribution of flow from the acinar microcirculation to a less permeable ductal vasculature. 4. Bradykinin infusion had no significant effect on permeability-surface area for EDTA and cyanocobalamin in perfused glands. 5. In perfused glands, ligation of the submandibular duct for 3--12 days reduced permeability-surface area (ml.min-1.g-1) for [51Cr]EDTA from 5.26 +/- 0.60 (mean +/- S.E., n = 9) to 4.20 +/- 0.12 (n = 4, P less than 0.30), [57Co]cyanocobalamin from 3.22 +/- 0.12 (n = 48) to 2.02 +/- 0.08 (n = 15, P less than 0.001) and [125I]insulin from 1.52 +/- 0.07 (n = 39) to 0.72 +/- 0.23 (n = 11, P less than 0.001).

Permeability of the fenestrated capillaries in the cat submandibular gland to lipid-insoluble molecules.

1. Permeability-surface area products for the fenestrated capillaries in the perfused cat submandibular gland have been measured for graded lipid-insoluble molecules using the single-passage, multiple-tracer dilution technique. 2. The permeability-surface area for [57Co]cyanocobalamin (mol. wt. 1353) increased as the perfusion flow was increased, but reached a constant value of 4.11 +/- 0.25 ml.min-1.g-1 (mean +/- S.E., n = 9) at flows above 8 ml. min-1.g-1. For [125I]insulin (approximate mol. wt. 6000) it was 1.80 +/- 0.13 ml.min-1.g-1 (mean +/- S.E., n = 9) and apparently diffusion-limited at all the high flow rates studied. A similar permeability-surface area product was measured for [14C]inulin (mol. wt. 5500): 1.76 +/- 0.10 (mean +/- S.E., n = 4). 3. Permeability-surface area values for cyanocobalamin and insulin in the salivary gland are respectively about 20 and 200 times larger than the estimates reported for the continuous capillaries of cardiac and skeletal muscle. 4. The permeability-surface area (PS) ratio [57Co]cyanocobalamin/[125I]insulin (2.33 +/- 0.15, mean +/- S.E., n = 9) was significantly greater than the apparent ratio of their free diffusion coefficients (1.76), suggesting restricted diffusion of insulin relative to cyanocobalamin across the capillary endothelium. 5. Permeability-surface area products for the smaller molecular weight tracers (22Na, 86Rb and 51Cr-EDTA (mol. wt. 357)) increased continuously with perfusion rate, indicating flow-limited solute exchange. The PS ratio of Rb/EDTA was close to unity whereas the corresponding free diffusion ratio is 3.85. 6. The high permeability-surface area values measured were thought to be associated with the fenestrae which appeared to act as high concentrations of 'small pores' rather than as 'large pores'.