© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Microvascular effects of atrial natriuretic peptide (ANP) in man: studies during high and low salt diet
Department of Internal Medicine, University Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands
* Corresponding author. Tel.: +31-43-3877005; Fax: +31-43-3875006; E-mail: bho@sint.azm.nl
Received 5 August 1997; accepted 5 February 1998
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Abstract |
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 Top Abstract 1 Introduction2 Subjects and methods3 Results4 DiscussionReferences |
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Objective: Infusion of ANP in anephric dogs causes a decrease in cardiac output and a rise in peripheral vascular resistance. This reduced cardiac output is possibly related to increased resistance to venous return generated in the microcirculation by venular constriction. The aim of the present study was to evaluate in healthy volunteers the effects of low-dose ANP infusion on both conjunctival and skin microcirculation during high or low salt diet. Methods: ANP (7.5 ng/kg/min) and placebo were infused (i.v.) for 4 h, in random order on two separate days, in two groups of 10 healthy male volunteers each. One group was studied during high salt (ad libitum), and one group during low salt (55 mmol Na+/24 h) diet. Microvascular density and diameters of both conjunctiva and nailfold were studied using intravital videomicroscopy. Nailfold capillary red blood cell velocity (CBV) was studied using intravital videomicroscopy, and skin (thermoregulatory) blood flow (SBF) was studied using laser-Doppler fluximetry. Results: In the high salt group ANP induced a 43% reduction in basal SBF as compared to an 18% reduction by placebo (P<0.01). Parallel to SBF, ANP significantly reduced CBV (P<0.02). Conjunctival capillary density decreased by 5% during ANP, while it increased by 28% during placebo (P<0.05). No such effects of ANP were observed in the low salt group. Blood pressure and heart rate were not influenced by ANP infusion in either group. Conclusion: Infusion of low doses of ANP into humans on an ad libitum salt diet results in vasoconstriction of the microcirculation, probably on the venular side. The lack of effect of ANP on the microcirculation during low salt diet may be related to a higher vascular tone prior to infusion.
KEYWORDS ANP; Microvascular morphometry; Blood flow, skin; Blood flow, renal; Nailfold; Conjunctiva; Human
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1 Introduction |
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TopAbstract1 Introduction2 Subjects and methods3 Results4 DiscussionReferences |
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Besides its renal effects, ANP has a direct action on the vascular wall which contributes to its hemodynamic effects. Infusion of ANP in anephric dogs results in a decrease in cardiac output and a rise in peripheral vascular resistance [1]. It is unlikely that the decline in cardiac output is related to a fall in heart rate or cardiac contractility [1, 2]. On the contrary, several studies suggest that the ANP-induced reduction in cardiac output is related to a diminished venous return [1, 3, 4]. Among the mechanisms that could cause a decrease in venous return are venous dilatation with pooling of venous blood, a fall in blood volume, and an increased resistance to venous return [5]. So far, animal experiments have failed to find evidence for venous dilatation [3, 4]. Although a decreased blood volume during ANP infusion has been found in several studies [3, 6, 7], Mizelle et al [1]demonstrated that the ANP-induced decrease in cardiac output is not related to a reduced circulating volume. These observations suggest that ANP may enhance resistance to venous return. The major determinant of resistance to venous return, i.e. venular resistance, was indeed found to be increased during ANP infusion in rats [8]. Unfortunately, no information is available with respect to the effects of ANP on the microcirculation in man. Based on the aforementioned studies we hypothesized that also in man ANP induces a fall in cardiac output and venous return through an action on the microcirculation, in particular by raising venular resistance.
The renal effects of ANP are largely influenced by changes in sodium intake [9]. Furthermore, it has been shown that in the kidney ANP may interfere with the renin–angiotensin–aldosterone system [10]. Both systems play an important role in blood pressure homeostasis and sodium/volume regulation. ANP antagonizes the sodium retaining effects of angiotensin II and aldosterone [11, 12]. On the other hand, ACE-inhibition (which lowers plasma angiotensin II levels) prevents ANP-induced plasma extravasation [13]but not ANP-induced natriuresis [14]. It is unknown whether interactions between ANP and angiotensin II also take place at the site of the peripheral vasculature. Parallel to its effects in the kidney, ANP could have different effects on the (micro)vasculature in the face of a suppressed (high salt diet) as opposed to a stimulated (low salt diet) renin–angiotensin–aldosterone system. Therefore, we were interested to study the ANP-induced vasoactive effects during both a high and low salt diet.
The aim of the present study was, therefore, to evaluate in healthy volunteers the effects of low-dose ANP infusion (i.v.) on both conjunctival and skin microvascular morphometry and hemodynamics under conditions of either a low or a high salt diet. These effects of ANP on the microcirculation were correlated with changes in renal hemodynamics and neurohumoral profiles.
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2 Subjects and methods |
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TopAbstract1 Introduction2 Subjects and methods3 Results4 DiscussionReferences |
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Experiments were performed in two groups of 10 healthy male volunteers each. One group, with a mean age of 22.8±1.6 (S.D.) years, was studied during a high salt diet. The second group, with a mean age of 23.1±2.1 (S.D.) years, was studied during a low salt diet. The low salt diet consisted of 55 mmol Na+/24 h and 70 mmol K+/24 h and was individually calculated during a dietetic consultation. The high salt diet was an ad libitum diet, which resulted in a mean 24 h urinary sodium excretion of approximately 170 mmol. The present study was approved by the medical-ethics committee of the Maastricht university hospital and all participants gave written informed consent. The investigation conforms with the principles outlined in the Declaration of Helsinki [15].
2.1 Protocol
All subjects were studied on the 8th and on the 12th day of the dietary period. ANP (7.5 ng/kg/min) or placebo (5% glucose) was infused (i.v.) in random order (double blind) on these occasions. The experiments started at 12.00 h and were performed in a quiet, temperature-controlled room (mean temperature 24.4±0.14 (S.D.) °C). Precautions were taken to minimize external disturbances. During the experiments subjects were in a semi-recumbent position. The microscopy of conjunctiva and nailfold was performed in the sitting position. On the day of experiments subjects were allowed to eat a small breakfast (without caffeine-containing beverages), after which no smoking, eating, or drinking was allowed till the end of the experiment. A catheter was inserted into the antecubital vein of both arms. The catheter in the right arm was used for infusions, while the catheter in the left arm was used for blood sampling. At t=0 a continuous infusion of inulin and para-amino hippurate (PAH) was started for measurement of glomerular filtration rate and effective renal plasma flow, respectively. Between t=60 and t=120 min baseline conjunctival and nailfold microscopy and skin blood flow measurements were performed. At t=120 min an intravenous infusion of ANP (7.5 ng/kg/min) or placebo (5% glucose) was started. Between t=300 and t=360 min a second set of microvascular measurements was performed (i.e. after 4 h of ANP/placebo infusion). Blood samples for measurement of Na+, K+, creatinine, hematocrit, active plasma renin concentration (APRC), aldosterone, ANP, and catecholamines were drawn at baseline (t=60). At t=180, 240, 300, and 360 blood was again drawn for ANP measurements. Catecholamines, APRC, and aldosterone were sampled after 2 and 4 h of ANP infusion (t=240 and 360). Urine samples for Na+, K+, and creatinine were collected at t=60, 150, 210, 270, 300, and 360. During the 24 h prior to the ANP and placebo experiments urine was collected for the determination of sodium and potassium.
2.2 Methods
The microcirculation of the lateral part of the bulbar conjunctiva of the right eye was studied with a custom build horizontal microscope. The subjects' head was comfortably fixed using the restrainer of a slit-lamp. By carefully focussing on the outermost layer of the eye, the microcirculation of the bulbar conjunctiva could easily be distinguished from the underlying episcleral vessels. Focussing was done with a joy-stick. Incident oblique illumination was performed with two Tungsten 10 volt lamps. In order to enhance contrast a Leitz BG38 filter was placed in the illumination pathway. The CCD-camera (Teli, Eindhoven, The Netherlands) was positioned in the intermediate image of the objective lens. Images were displayed on a monitor and stored on videotape (Sony betamax) for off-line analyses. For microvascular density measurements, recordings were made with a standard achromatic objective 2.5x (numeric aperture (N.A.): 0.10). Microvascular diameters were measured on recordings made with a 5x objective (N.A.: 0.15).
Classification of arterioles, capillaries and venules was facilitated by using videomicroscopy, because of moving red blood cells. Vessels were identified on the basis of their branching pattern, position in the vascular tree, and direction of the red blood cell flow (convergent or divergent). Arteriolar, capillary, and venular density were measured separately using image analysis software (OPTIMAS version 5.0, Breda, The Netherlands). As a measure of density the total length of each microvascular class per square millimeter of conjunctiva was determined in several videoframes and averaged. Microvascular diameters (represented by the widths of the red blood cell columns; average of ten vessels) were measured using a shearing monitor [16].
Nailfold capillary density, capillary blood cell velocity (CBV), and capillary diameters were measured using intravital microscopy, as described earlier [17]. For the capillary density measurements, recordings were made a few millimeters proximal to the terminal row of capillaries. Baseline skin capillary density was defined as the amount of erythrocyte-filled capillaries in one videoscreen (1.6 mm2 of skin). The recruitment of functionally available capillaries was defined as the increase in the number of erythrocyte-filled capillaries after 4 min of arterial occlusion (200 mm Hg at the wrist). CBV (measured with CAPIFLOW, Sweden) and capillary diameters (measured with shearing monitor) were calculated as the mean value of four capillaries in the distal row of the fourth finger of the left hand.
Skin (predominantly thermoregulatory)blood flow (SBF) was determined simultaneously with CBV using laser-Doppler fluxmetry (Periflux PF3; Perimed, Järfälla, Sweden), with probe PF 308, wide band (12 kHz) mode, and time constant 0.2 s. The probe was placed on the dorsum of the interphalanx of the same finger CBV was measured in. This probe remained in the same position throughout the experiment. Flux values are expressed as arbitrary perfusion units, calibrated against an external standard. SBF was measured before and during reactive hyperemia following 4 min of arterial occlusion (200 mmHg).
Blood pressure and heart rate were measured every ten min during the experiments using a Dinamap monitor (Tampa, Florida, USA).
Renal hemodynamics, i.e effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were measured by continuous infusion of PAH (MSD, West Point, PA, USA) and inulin (Inutest, Laevosan Gesellschaft, Linz, Austria), respectively [18]. Effective renal blood flow (ERBF) was calculated using the formula: ERPF/1-hematocrit. The GFR/ERPF ratio was used for filtration fraction (FF). Renal vascular resistance (RVR) was calculated according to the formula: MAP/ERBF*80000. At the start of the clearance study subjects took a water load of 200 ml. Throughout the remainder of the clearance study additional water matching urine output was supplied.
Active plasma renin concentration (APRC) was measured by the IRMA-method (Nichols Institute Diagnostics, Wychen, The Netherlands). Aldosterone was assayed by means of solid-phase protein-binding RIA antibody coated tubes (Diagnostic Products Corporation, LA, USA) [19]. Both PAH and inulin were measured spectrophotometrically [20, 21]. Atrial natriuretic peptide was measured by a competitive protein-binding radioimmunoassay (RIA) (Nichols Institute Diagnostics) following extraction of plasma over Sep-Pak C18 columns [22]. Catecholamines were assayed by high-performance liquid chromatography (HPLC) with fluorescence detection [23].
2.3 Statistics and calculations
Since the distribution of the microvascular data was not normal, data are presented as median values with interquartile ranges, unless otherwise indicated, and the Wilcoxon paired sign test was used for analysis of paired samples (both within one visit and between the ANP and placebo infusion). When appropriate, the Bonferroni correction was used for multiple comparisons. P values below 0.05 were considered statistically significant.
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3 Results |
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At baseline no differences in blood pressure or heart rate were observed between the ANP and placebo experiments in both the HIGH and LOW SALT group (Table 1). Blood pressure and heart rate were not influenced by infusion of ANP during either diet (data not shown). In both groups urinary excretion of sodium and potassium was similar during the 24 h prior to the ANP or placebo experiments (Table 1).
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3.1 Microcirculation
No difference was observed in any baseline microcirculatory variable between the ANP and placebo experiments in the HIGH or LOW SALT group.
3.1.1 Skin blood flow
The effects of ANP in the HIGH SALT group on both basal and hyperemic peak skin (thermoregulatory) blood flow are shown in Fig. 1 and Table 2. As compared to placebo, ANP infusion induced a reduction in both basal and hyperemic peak skin blood flow (P<0.01 and P<0.05, respectively). Time-to-peak hyperemic blood flow and duration of hyperemia were not influenced by ANP (Table 2). Although skin perfusion also tended to decline during placebo, these changes were not statistically significant.
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The effects of ANP in the LOW SALT group on basal and hyperemic skin (thermoregulatory) blood flow are shown in Fig. 2 and Table 2. Both ANP and placebo experiments decreased basal skin blood flow to the same extent: –44% (–60––35) and –25% (–59–2), respectively (P<0.01 vs baseline). The same was true with respect to the duration of hyperemia. Hyperemic peak flow and time-to-peak hyperemic blood flow, however, were not influenced by ANP (Table 2).
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3.1.2 Nailfold microcirculation
In the HIGH SALT group ANP infusion induced a 49% reduction in capillary blood cell velocity (CBV) (Fig. 3), while no change in nutritive blood flow was observed during placebo infusion (P<0.02, ANP vs placebo). ANP did not induce any changes in capillary diameters, density, or post-occlusive recruitment (Table 3).
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As shown in Fig. 4, both ANP and placebo infusion induced a similar reduction in capillary blood cell velocity in the LOW SALT group (P<0.01 vs baseline for both). No further changes were observed in capillary diameters, density, or post-occlusive recruitment during either ANP or placebo experiments (Table 3).
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3.1.3 Conjunctival microcirculation
In the HIGH SALT group, capillary density did not change significantly (–5% (–13–16)) during ANP, but increased (28% (13–56); P<0.05 vs baseline) during placebo infusion (P<0.05; ANP vs placebo; Table 4). Arteriolar and venular density and diameters did not change during ANP infusion (Table 4).
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In the LOW SALT group, conjunctival microvascular densities and diameters were similar during ANP or placebo (Table 4). Arteriolar diameter tended to decrease with a few percent during ANP infusion (–3% (–48–4)), but increased during placebo infusion (8% (–15–23)) (P<0.05; ANP vs placebo).
ANP-induced changes in microvascular variables did not correlate with changes in renal hemodynamics, (neuro)hormones, or hematocrit.
3.2 Renal effects
3.2.1 Renal hemodynamics
Baseline renal hemodynamics did not differ between ANP and placebo on both diets (data not shown). In both the HIGH and LOW SALT diet groups the largest effects of ANP were observed after 4 h of infusion. In the HIGH SALT group, GFR decreased by approximately 7% in both ANP and placebo experiments. ERPF decreased by 16% (6–19) (P=0.05 vs baseline) during ANP, while RVR increased by 16% (10–24) (P<0.05 vs baseline). During placebo infusions these variables did not change. The FF tended to increase (12% (6–21), P=0.07 vs baseline) during ANP, while it decreased (–5% (–20–4), P<0.05 vs baseline) during placebo infusions.
In the LOW SALT group, GFR did not change during ANP (1% (–5–5)) but decreased (–5% (–9–0), P<0.05 vs baseline) in placebo experiments. ERPF decreased by approximately 8% during both ANP and placebo infusions. RVR did not change during ANP (2% (–21–10), while it increased during placebo infusions (10% (2–13), P<0.05). FF tended to increase during both ANP and placebo infusions, by 7% (–5–16) and 4% (–7–10) respectively.
3.2.2 Natriuresis and diuresis
ANP infusion during HIGH SALT resulted in a significant natriuresis and diuresis compared to placebo infusions. Cumulative urinary sodium excretion was 68 (28–94) during ANP vs 46 (24–54) mmol during placebo (P<0.02), and cumulative urinary volume was 2715 (1998–3015) vs 2005 (1585–2310) ml (P<0.02).
Also in the LOW SALT group infusion of ANP resulted in a significant natriuresis and diuresis compared to placebo infusions. Cumulative urinary sodium excretion was 38 (21–46) during ANP and 13 (6–15) mmol during placebo (P<0.01), and cumulative urinary volume was 2035 (1429–2304) vs 1458 (1041–1885) ml (P<0.01). Nota bene, the relatively high urine output was related to water suppletion during the renal clearance study protocol.
3.3 ANP/neurohormones
3.3.1 Plasma ANP levels
Baseline plasma ANP levels did not differ in either group (Table 5). In the HIGH SALT group plasma ANP levels rose to 155 (110–178) [after 1h], 158 (120–184) [2 h], 135 (112–143) [3 h], and 125 (91–147) [4h] pg/ml during ANP infusion.
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In the LOW SALT group plasma ANP levels rose to 106 (74–178) [1 h], 135 (87–166) [2 h], 90 (74–171) [3 h], and 104 (101–145) [4 h] pg/ml during ANP infusion. During placebo experiments plasma ANP levels did not change from baseline.
3.3.2 (Neuro)hormones and hematocrit
No differences were observed in baseline plasma (neuro)hormone-concentrations and hematocrit (Table 5). In both the HIGH and LOW SALT group an almost identical pattern was observed during ANP infusion, with a rise in plasma noradrenaline and hematocrit, and a fall in aldosterone and APRC (Table 5).
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4 Discussion |
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TopAbstract1 Introduction2 Subjects and methods3 Results4 DiscussionReferences |
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Animal microvascular studies have shown that ANP infusion results in venular but not arteriolar constriction, a phenomenon which contributes to an decrease in venous return and decrease in cardiac output [8]. The present data demonstrate that in humans, on a high (ad libitum) salt diet, low-dose infusion of ANP results in vasoconstriction of skin microvasculature and a functional decrease in conjunctival capillary density. Furthermore, during low salt diet effects of ANP were not different from the effects of placebo infusion.
Non-invasive studies of the microcirculation in man using intravital microscopy can be performed only in skin (nailfold) and conjunctiva. Both tissues are of ectodermal origin suggesting that they are comparable, although the function of the (micro)circulation in skin and conjunctiva is not similar. In the present study we aimed to investigate effects of ANP on small peripheral blood vessels. Despite the fact that these two vascular beds are part of the peripheral vasculature, we cannot dismiss the possibility that vessels in other tissues respond differently. With the microscope only erythrocyte-filled capillaries can be seen in the skin. These capillaries are perpendicular to the skin surface, except for the nailfold area where they run in parallel to the surface. For capillary density measurements the nailfold area is not appropriate because it underestimates true density. Hence, for density measurements in skin we counted the number of capillaries per area skin proximal to the nailfold. On the other hand, in conjunctiva erythrocyte-filled arterioles, capillaries, and venules can be seen. Since the bulbar conjunctiva is a membrane over the eyeball, blood vessels run in parallel to the surface. As a measure of vascular density one can determine vessel length per area of conjunctiva.
In the present study low-dose infusion of ANP resulted in increased plasma levels of ANP, which were still within the (patho)physiological range. Infusion dose and duration were based on pilot experiments. As the vasoactive effects of ANP are dose-related [24–26], we aimed to study the effects of a physiological and not of a pharmacological dose of ANP on the vasculature. In subjects consuming a high salt diet these slightly elevated plasma ANP levels resulted in a decrease of both thermoregulatory and nutritive skin blood flow, and a relative decrease in conjunctival capillary density. In addition, ANP induced vasoconstriction in the renal microvasculature, as indicated by the increase in renal vascular resistance, which was maximal after 4 h of ANP infusion. Since blood pressure and heart rate did not change, and since the observed microvascular changes did not correlate with changes in renal hemodynamics, catecholamines, renin, or hematocrit, ANP probably had a direct effect on the microvasculature. On theoretical grounds, an increase in hematocrit would even result in higher skin blood flow values, as the laser-Doppler flux signal is a product of red cell velocity and concentration [27]. Faber et al [28]suggested that ANP may inhibit 
1-mediated basal tone of large arterioles while not influencing postjunctional 2-adrenoceptors on venules. This would lead to an increase in both blood flow and capillary pressure with subsequent activation of the veno-arteriolar response [29]which normalizes capillary pressure (and blood flow) by precapillary constriction. Increasing circulating levels of noradrenaline during ANP, as found in the present study, would counteract these effects. However, we could not demonstrate a correlation between changes in catecholamines and microvascular variables. Although a direct effect of ANP on arterioles cannot be ruled out, it is more likely that akin to the aforementioned animal studies [8], the decrease in microvascular blood flow and density are secondary to ANP-induced venular constriction. This would result in an increased capillary pressure with subsequent activation of the veno-arteriolar response and thus lowering of blood flow, which was precisely what we found in the present study. Subsequently, precapillary vasoconstriction (veno-arteriolar response) must lead to a reduction in erythrocyte perfused capillaries, which we found as well. The rise in hematocrit during ANP supports the venular constriction concept. Increased capillary pressure (due to a change in pre- to postcapillary resistance ratio) may well lead to a fluid shift to the extravascular compartment [30], although additional mechanisms such as a change in capillary membrane characteristics resulting in increased extravasation of fluid, cannot be disregarded. Indeed, it has been demonstrated in rat intestine, kidney, and skeletal muscle but not in skin, heart, and lung that ANP infusion lowers oncotic pressure due to an increase in albumin transport into tissue [31]. The fact that we did not observe a change in conjunctival venular diameters during ANP is possibly related to the size of these venules and/or the dose of ANP used. For instance, in the rat De Vries [8]demonstrated vasoconstriction predominantly in the larger venules (50–120 µm) during infusion of 250–2000 ng/kg/min of ANP. Perhaps the low dose of ANP that we employed had an effect on small venules (30–40 µm) only, since the peptide exhibits regional vasoactive heterogeneity due to non-homogeneous distribution of high affinity receptors [32].
Some studies reported arterial/arteriolar vasodilatation following infusion of pharmacological dosages of ANP (20–22) with no effects on the veins [33]. Bussien et al [34]reported vasodilation of the skin parallel to a decrease in blood pressure and an increase in heart rate following infusion of high doses of ANP. In the present study low-dose infusion of ANP resulted in plasma ANP levels which remained within the physiological range, but which led to microvascular vasoconstriction. These findings indicate that the vascular effects of ANP are related to the infused dosage of ANP.
In the low salt diet group ANP infusion did not exert any effects on the microcirculation, although the dosage was sufficient to induce natriuresis and diuresis. In rodents it has been demonstrated that the direction of ANP-induced vasoactivity (dilatation or contraction) depend on the level of vascular preconstriction and the dosage of ANP [35, 36]. Possibly, the lack of effect of ANP on the microcirculation during sodium restriction is related to the higher level of peripheral vascular tone. The latter is, at least in part, related to the higher plasma levels of noradrenaline, renin, and aldosterone, and is reflected also by lower renal blood flow values. The fall in thermoregulatory skin blood flow (SBF) during placebo infusions with both the high and the low salt diet is likely to be related to the experimental circumstances (e.g. physical inactivity) [37]. Due to physical inactivity there is less heat production. Hence, there is less need for the body to waste heat, and thus skin perfusion (in particular SBF) will fall a little bit. The combination of low salt diet (higher level of peripheral vascular tone) and experimental circumstances (physical inactivity) even induced a larger decline in skin blood flow, leading to a reduction in skin nutritive blood flow (CBV). This is because skin nutritive and thermoregulatory blood flow share the same feeding blood vessels. Apparently, the fall in CBV was not enhanced by ANP, although we cannot rule out the possibility that the decrease in microvascular flow during low salt diet masked a vasoconstrictor effect of ANP.
Infusion of ANP reduced the plasma levels of renin and aldosterone. However, we found no correlations between the microvascular effects of ANP and the prevailing activity of the renin–angiotensin–aldosterone system. Therefore, it seems unlikely that there is an interaction between ANP and the renin–angiotensin–aldosterone system at the level of the peripheral vasculature outside the kidney.
In conclusion, infusion of low doses of ANP into humans on an ad libitum salt diet resulted in vasoconstriction of the microcirculation, probably on the venular side. The lack of effect of ANP on the microcirculation during low salt diet was probably related to increased pre-infusion levels of peripheral vascular tone.
Time for primary review 33 days
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Acknowledgements |
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This study was supported by a grant from the Dutch Kidney Foundation (C.91.1172). We would like to thank Paul Schiffers and Jet Bost for their accurate determinations of plasma neurohormones.
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