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Cardiovascular Research 2001 49(1):161-168; doi:10.1016/S0008-6363(00)00198-X
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Copyright © 2000, European Society of Cardiology

Capillary recruitment is impaired in essential hypertension and relates to insulin's metabolic and vascular actions

Erik H Sernéa,c, Reinold O.B Gansb, Jan C ter Maatenb, Piet M ter Weea,c, Ab J.M Donkera,c and Coen D.A Stehouwera,*

aDepartment of Medicine, Academic Hospital Vrije Universiteit, De Boelelaan 1117, 1007 MB Amsterdam, The Netherlands
bDepartment of Medicine, University Hospital Groningen, 9700 RB Groningen, The Netherlands
cInstitute for Cardiovascular Research-Vrije Universiteit, 1081 BT Amsterdam, The Netherlands

* Corresponding author. Tel.: +31-20-444-0531; fax: +31-20-444-0502 cda.stehouwer{at}azvu.nl

Received 5 June 2000; accepted 21 July 2000


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: In patients with essential hypertension, defects in both the metabolic and vascular actions of insulin have been described. Impaired microvascular function, a well-established abnormality in essential hypertension, may explain part of these defects. In the present study we investigated whether microvascular function is impaired in essential hypertension and relates to insulin's metabolic and vasodilatatory actions. Methods: We measured 24-h ambulatory blood pressure, capillary recruitment after arterial occlusion, and skin blood flow responses to iontophoresis of acetylcholine and sodium nitroprusside in 18 subjects with untreated essential hypertension and in 18 control subjects. Whole body insulin sensitivity and leg insulin-mediated vasodilatation were assessed with the hyperinsulinaemic clamp technique and plethysmography. Results: Hypertensive, as compared to normotensive, subjects had a decreased insulin sensitivity (0.8±0.3 vs. 1.7±0.6 mgkg–1min–1 per pmoll–1; P<0.001), capillary recruitment after arterial occlusion (21.5±5.8 vs. 45.9±10.4%; P<0.001), acetylcholine-mediated vasodilatation (331±84 vs. 688±192%; P<0.001), and insulin-mediated vasodilatation (median 29.3 vs. 47.2%; P<0.05). Correlation analyses with adjustment for sex, age, body mass index and waist-to-hip ratio showed significant relationships of capillary recruitment after arterial occlusion with blood pressure (r = –0.68; P<0.01), insulin sensitivity (r = +0.55; P<0.01) and insulin-mediated vasodilatation (r = +0.51; P<0.05), which extended from the normotensive to the hypertensive range. Conclusion: Skin microvascular function is associated with blood pressure and insulin's metabolic and vasodilatatory actions, both in normotensive and hypertensive subjects. These findings offer a potential mechanistic explanation of the links among insulin resistance, impaired insulin-mediated vasodilatation and hypertension.

KEYWORDS Blood flow; Capillaries; Endothelial function; Hypertension


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
Impaired microvascular function is a well-established abnormality that occurs in patients with essential hypertension [1]. In many tissues of these patients a decreased number of capillaries and arterioles, so-called microvascular rarefaction, can be demonstrated [1–4]. Experimental [5,6] and human studies [1,4,7,8] suggest that microvascular rarefaction contributes to an increase in vascular resistance and antedates the onset of hypertension [7,8]. In addition, microvascular rarefaction, by causing impairment of capillary recruitment, has been invoked as a partial explanation for the demonstrated defects in the ability of insulin to increase glucose uptake, limb blood flow and blood volume in patients with essential hypertension [9–12]. In support of this hypothesis, we recently demonstrated that impaired post-ischaemic capillary recruitment is associated with both decreased insulin-mediated glucose uptake and increased blood pressure, and statistically explained part of the association between insulin sensitivity and blood pressure in normal subjects [12]. Moreover, in hindleg muscles of anaesthetised rats insulin has recently been shown to cause capillary recruitment [13]; acute vasoconstriction, which prevented recruitment of capillaries and induced a systemic rise in vascular resistance, caused impaired muscle glucose uptake in the same animal model [14]. Hence, microvascular rarefaction, by affecting both pressure and flow patterns, may be an important explanatory mechanism of the link between hypertension and the impaired metabolic and vascular actions of insulin.

At present, it is not known whether microvascular function is associated with insulin's metabolic and vascular actions in human essential hypertension. Therefore, the aim of the present study was to examine whether the demonstrated relationships of microvascular function with insulin sensitivity and blood pressure extend from the normotensive to the hypertensive range. Furthermore, we investigated for the first time whether microvascular function was associated with insulin's vascular effects in humans.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Subjects
Eighteen non-diabetic subjects with essential hypertension and 18 normotensive healthy control subjects matched for age and sex participated in these studies (Table 1). All were Caucasians and non-smokers. Data on four of the normotensive controls have been published before [12]. The inclusion criteria for the hypertensive subjects were: blood pressure as determined by triplicate office measurement >140/90 and (for ethical reasons) <180/110; age 30–70 years; normal fasting glucose according to ADA criteria [15]; and no signs or symptoms of cardiovascular or other concomitant disease. Secondary forms of hypertension were excluded by medical history and standard laboratory tests. None of the participants used any medication during the studies. Fourteen hypertensive subjects were taking antihypertensive medication at the time of the inclusion. Five of these subjects were treated with β-blockers alone (n = 3) or in combination with a thiazide diuretic (n = 2); six were treated with ACE inhibitors and four with a calcium antagonist with (n = 2) or without a diuretic (n = 2).Their medication was discontinued 4 weeks before the studies, and this washout period is comparable to washout periods used in similar studies irrespective of the duration of treatment or the type of antihypertensive treatment used [16,17]. In the normotensive group, two subjects had a first-degree relative with diabetes mellitus type 2, whereas in the hypertensive group this was the case in three subjects. The study protocol was approved by the local Ethics Committee and conforms with the principles outlined in the Declaration of Helsinki.


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  		Table 1 Characteristics of the study population

 
2.2 Ambulatory blood pressure
Ambulatory blood pressure recordings were assessed as previously described [12].

2.3 Microvascular measurements
The microvascular measurements were conducted at 8.00 a.m. after 30 min of acclimatisation in a quiet, temperature-controlled room (T = 23.4±0.4°C), with the subjects in the sitting position and the investigated, non-dominant hand at heart level. The measurements were performed after a 10- to 12-h fast and all subjects abstained from caffeine- and alcohol-containing drinks overnight. Nailfold and iontophoresis studies were performed on the same day. Skin temperature was monitored continuously during the tests. The microvascular and metabolic studies (see below) were carried out on separate days approximately 1 week apart (median; range: 1–12 weeks), and performed by two different investigators (EHS and JCTM). Both investigators were cross-blinded to the microvascular reactivity and insulin sensitivity results. The results of the 24-h ambulatory blood pressure monitoring were also not available to these investigators.

Perfused nailfold capillaries in the dorsal skin of the third finger were visualised by a capillary microscope [12]. Two separate visual fields of 1 mm2 were recorded before and after 4 min of arterial occlusion with a digital cuff and the images were stored on videotape. The number of continuously perfused capillaries at baseline and directly after release of the cuff were counted off-line for, respectively, 15 and 30 s by a single experienced investigator (EHS) from a freeze-framed reproduction of the videotape and from the running videotape when it was uncertain whether a capillary was present or not. (The major part of the increase in capillary number occurs within a few seconds). Capillary density was defined as the number of erythrocyte-perfused capillaries per square millimetre of nailfold skin. Percentage capillary recruitment was assessed by dividing the increase in capillary density after 4 min of arterial occlusion by the baseline capillary density. The day-to-day coefficient of variation (CV) was 8.3±4.9%, as determined in nine subjects on two occasions.

Endothelium-dependent and -independent vasodilatation of skin microcirculation was evaluated by iontophoresis of acetylcholine and sodium nitroprusside in combination with laser Doppler fluxmetry. Both acetylcholine and sodium nitroprusside were delivered in multiple fixed doses (current intensityxdelivery time) [12,18]. Acetylcholine (1%, Miochol, Iolab, Bournonville Pharma, The Netherlands) was delivered using an anodal current; seven doses (0.1 mA for 20 s) were delivered, with a 60-s interval between each dose resulting in an incremental dose–response curve [12]. A 60-s interval between each iontophoresis period was required to achieve the plateau of the response following each delivery of acetylcholine [12,18]. Sodium nitroprusside (0.01%, Nipride, Roche, The Netherlands) was delivered using a cathodal current; nine doses (0.2 mA for 20 s) were delivered, with a 90-s intervals between each dose resulting in an incremental dose–response curve [12]. A 90-s interval between each iontophoresis period was required to achieve the plateau of the response following each delivery of sodium nitroprusside [12,18]. Acetylcholine-dependent laser Doppler flux was measured on dorsal skin of the middle phalanx of the third finger, whereas nitroprusside-dependent laser Doppler flux was measured on the same spot of the opposite hand. Approximately 15 min elapsed between these two measurements. Dorsal skin of the middle phalanx of the third finger was chosen for several reasons. First, in the present study we were mainly interested in the nutritive function of skin microcirculation as opposed to its thermoregulatory function. Dorsal skin of the middle phalanx is considered devoid of arteriovenous anastomoses (AVA), which serve the thermoregulatory function of skin microcirculation [19]. Second, selection of this site made it possible to measure capillary density, capillary recruitment and the vasodilatory effects of acetylcholine close together on almost the same spot. Third, the iontophoresis equipment and electrodes were especially designed to measure on digits. The responses to acetylcholine and sodium nitroprusside were expressed uncorrected for their respective vehicle responses. The day-to-day variation coefficient of the percentage increase from baseline to the final 2 min of the plateau phase was 9.8±5.6% for acetylcholine and 8.3±5.4% for sodium nitroprusside, as determined in nine healthy subjects on two occasions.

2.4 Whole body glucose uptake
Sensitivity to insulin-mediated glucose uptake was assessed by the hyperinsulinaemic, euglycaemic clamp technique with the subjects in the post-absorptive state. Insulin (Velosulin; Novo Nordisk) was infused in a primed continuous manner at a rate of 50 mU kg–1 h–1 for 90 min. Normoglycaemia was maintained by adjusting the rate of a 20% glucose infusion based on plasma glucose measurements performed at 5-min intervals. Whole body glucose uptake (M) was calculated from the glucose infusion rate during the last 30 min and expressed per unit of plasma insulin concentration (M/I), thereby correcting for differences in steady-state plasma insulin levels [20]. Plasma insulin levels were measured with an immunoradiometric assay (Medgenix Diagnostics). For convenience, the M/I ratio was multiplied by 100. Several arguments suggest that steady-state insulin concentrations were reached during these relatively short 90-min clamps. Steady state insulin concentrations during a physiological hyperinsulinaemic, euglycaemic clamp study are usually reached within 40–45 min [20], and the insulin levels attained in the present study are well in the reported range of steady-state plasma insulin levels during a 120-min clamp [20].

2.5 Insulin-mediated leg blood flow
At baseline and 15 min before the end of the clamp, leg blood flow was measured by mercury-in-silastic strain gauge venous occlusion plethysmography with the subjects in the supine position [21]. An occlusive cuff was placed proximally around the right leg, and the strain gauge was placed around the calf at the largest circumference. A paediatric cuff inflated to suprasystolic pressure was placed at the ankle to exclude the foot circulation. Flow measurements were expressed in terms of ml flow per dl, and represent the average of 7–10 separate recordings. In our hands, this technique has a CV of 14% [21]. To exclude non-specific changes in leg blood flow, a time- and volume-control study was performed within 1 week after the clamp procedure in 22 subjects.

2.6 Statistical analysis
Data are expressed as mean±S.D. unless stated otherwise. ANOVA was used to compare vasodilatatory responses before and following drug and vehicle administration. Comparison of normotensive and hypertensive subjects was performed with a t-test or a non-parametric variant (triglycerides). MANOVA was used to compare microvascular measurements between the groups after adjustment for differences in body mass index (BMI) and waist-to-hip ratio (WHR). Correlation analysis was used to investigate the associations among blood pressure, insulin sensitivity, insulin-mediated vasodilatation, and microvascular measurements. An interaction analysis was performed in the pooled data to investigate whether hypertensive status influenced the associations among the different variables. Subsequently, a stepwise multiple regression analysis was used to analyse whether microvascular function influenced blood pressure and insulin sensitivity, and whether the observed associations between blood pressure and insulin sensitivity remained. BMI, age and sex were always entered into the model when performing the correlation or regression analyses. A two-tailed P value of <0.05 was considered significant. All analyses were performed on a personal computer using the statistical software package SPSS version 9.0.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
3.1 Blood pressure and heart rate
Table 1 shows blood pressure and heart rate values in hypertensive and normotensive subjects. In the pooled group, systolic and diastolic blood pressure data during daytime had a normal distribution with values of 140±16 and 88±13 mmHg, respectively.

3.2 Microvascular measurements
Table 2 shows the microvascular measurements. The responses to acetylcholine–vehicle and sodium nitroprusside–vehicle were non-significant in both the hypertensive subjects (18.5±5.9 vs. 22.4±12.3 PU; P = 0.13 and 19.6±8.9 vs. 21.4±9.7 PU; P = 0.12, respectively) and the normotensive subjects (17.9±6.5 vs. 18.7±6.8 PU; P = 0.39 and 19.2±5.5 Vs. 22.2±10.9 PU; P = 0.58, respectively).


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  		Table 2 Microvascular measurements in the hypertensive and normotensive subjects

 
3.3 Insulin sensitivity
Normoglycaemia (4.8±0.4 mmol/l) was maintained during the insulin infusion. Possibly due to the facts that insulin was infused per kilogram body weight and that the hypertensive subjects were more obese, higher levels of insulin were attained in the hypertensive subjects (527±132 vs. 451±81 pmol/l; P = 0.046). This is supported by the fact that, after adjustment for body weight, no significant difference existed between the insulin concentrations reached in both groups (adjusted means: 506 vs. 472 pmol/l; P = 0.3). An additional explanation for the higher insulin concentrations in the hypertensive subjects may be a decreased insulin metabolic clearance rate in essential hypertension [22]. Because the glucose disposal rate is proportional to the plasma insulin levels within the physiological insulin concentration range [20], the somewhat higher insulin levels in the hypertensive group may result in an overestimation of the glucose disposal rate. We therefore expressed whole body glucose uptake (M) per unit of plasma insulin concentration (M/I), a method to correct for differences in steady-state insulin levels [20]. The rate of glucose uptake (M), expressed per kilogram of body weight, was 3.9±1.2 and 7.8±2.6 mgkg–1min–1 in the hypertensive and the control group, respectively (P<0.001), which is comparable to values in the literature [20,23]. After adjustment for BMI and WHR, insulin sensitivity (M/I) remained significantly different between the groups (P<0.05).

3.4 Insulin-mediated vasodilatation
Data on insulin-mediated vasodilatation were obtained in 18 hypertensive and 11 normotensive subjects. Mean leg blood flow at baseline was not significantly different between the hypertensive and normotensive subjects (1.6±0.4 vs. 1.9±0.7 mlmin–1dl–1 of tissue, P = 0.15). During physiological hyperinsulinaemia, mean leg blood flow rose to 2.1±0.6 and 3.0±1.2 mlmin–1dl–1 (both P<0.05 vs. baseline) in the hypertensive and normotensive subjects, respectively. The percentage increase was significantly lower in the hypertensive subjects as compared to the normotensive subjects (29.3% (median, range 0.4–56.9) vs. 47.2% (median, range 7.1–110.9); P<0.05). During a control study in 22 subjects, mean leg blood flow did not change over time (1.54±0.4 at baseline vs. 1.58±0.5 at the end of the procedure; P = 0.93).Therefore, the blood flow responses to insulin were used for statistical analyses without further adjustment.

3.5 Correlation and linear regression analyses
Fig. 1 and Table 3 show the correlations among the main variables and demonstrate that insulin sensitivity, blood pressure and estimates of microvascular function were significantly correlated. Interaction analysis indicated that these associations, in general, were not significantly influenced by the hypertensive status (data not shown).


Figure 1
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  		Fig. 1 Correlations between capillary recruitment after 4 min of arterial occlusion and SBP during daytime, insulin sensitivity, and insulin-mediated vasodilatation in hypertensive (bullet) and normotensive subjects ({circ}). Correlation coefficients adjusted for age, sex, BMI and WHR. Data on insulin-mediated increase in blood flow concern 18 hypertensive subjects and 11 normotensive subjects.

 

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  		Table 3 Correlation analysis of blood pressure, insulin sensitivity, insulin-mediated vasodilatation, microvascular function and measures of obesitya

 
Next, we examined whether the relationship between blood pressure and insulin sensitivity can be explained by microvascular function (Table 4). Model 1 shows that insulin sensitivity (independent variable), after adjustment for age, sex and body mass index, was related to blood pressure (dependent variable). Model 2 shows that the relationship between insulin sensitivity and blood pressure was lost when microvascular function (in particular capillary recruitment after arterial occlusion) was entered into the regression analysis. WHR was independently associated with systolic blood pressure (model 3), but was not a strong confounder of the relationship between capillary recruitment and blood pressure since the regression coefficient (β) of capillary recruitment decreased only slightly as compared to Model 2.


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  		Table 4 Multiple regression analyses with SBP and insulin sensitivity as dependent variablea

 
Microvascular function might to some extent also determine insulin sensitivity [12]. Table 4 shows that both capillary recruitment after arterial occlusion and WHR were independently associated with insulin sensitivity.

Similar conclusions were reached when statistical analyses were performed using absolute responses to acetylcholine instead of the percentage increase after iontophoresis. Adjustment for vehicle responses also did not affect the analyses significantly. The same held true for the absolute versus the percentage increase of capillary density or the absolute peak capillary density versus the percentage increase. Also, the pattern of associations was not substantially different when using different indices of insulin sensitivity (M value vs. M/I value). In the correlation analyses, diastolic blood pressure and mean arterial blood pressure during day- and night-time were also significantly associated with insulin sensitivity and microvascular function, but less strongly than systolic blood pressure during daytime (data not shown).


   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
The present study demonstrates that post-occlusive capillary recruitment and microvascular endothelium-dependent vasodilatation were significantly impaired in mildly obese hypertensive subjects, as compared to age- and sex-matched normotensive control subjects, even after adjustment for differences in BMI and WHR. It extends our observations of significant associations between microvascular function, insulin sensitivity and blood pressure in subjects with normal blood pressure [12] to subjects with essential hypertension (Fig. 1). An important novel finding was that both capillary recruitment after arterial occlusion and endothelium-dependent microvascular vasodilatation were significantly associated with insulin's vascular action. This is the first study demonstrating an association between capillary recruitment in the skin and the ability of insulin to increase leg blood flow in humans (Fig. 1).

A reduction in the number of capillaries and arterioles (rarefaction) is a well-established abnormality in patients with essential hypertension [1,3,4,7,8]. We observed a 19% difference in capillary number after arterial occlusion between hypertensive and normotensive subjects, which is similar in magnitude to the 12–20% of capillary rarefaction demonstrated by others [1,3,4,8]. Capillary and arteriolar rarefaction have been proposed to contribute to the increased vascular resistance observed in essential hypertension [1,3,4,8,12], and to be a primary or very early abnormality rather than a consequence of sustained hypertension [7,8]. In accord, a significant association between capillary recruitment and blood pressure in both the normotensive and hypertensive subjects could be demonstrated. Experimental studies suggest that capillary rarefaction not only shifts pressure distribution but also causes a non-uniform flow distribution in tissues [5,6]. Alterations in (capillary) flow distribution have been demonstrated to influence skeletal muscle metabolism in the perfused rat hindlimb model [24]. Hence, capillary rarefaction may have consequences for peripheral vascular resistance, skeletal muscle perfusion and metabolism [12].

Defects in insulin-mediated glucose uptake [23] and insulin-mediated increases in blood flow and blood volume [11] have been reported in patients with established essential hypertension. Whereas the defect in insulin's metabolic action has been ascribed to post-receptor defects [25], and defects in insulin's vascular actions are not consistently reported in these patients [26], it has been hypothesised that insulin's metabolic and vascular actions are functionally coupled [9,27] with an important role for microvascular function [9,13,14]. Specifically, insulin may cause capillary recruitment and redirect blood flow from non-nutritive vessels to nutritive capillary beds with subsequent recruitment of areas of tissue that were previously involved in predominantly anaerobic metabolism, thereby influencing glucose uptake in skeletal muscle [9,12,27,28]. Consistent with this hypothesis, insulin has recently been shown to cause capillary recruitment in hindleg muscles of anaesthetised rats [13]. Impaired capillary recruitment may therefore contribute to defects in insulin's metabolic and vascular actions [9,13,11]. In the present study in humans, recruitment of skin capillaries was impaired in the hypertensive subjects and positively associated with insulin-mediated glucose uptake and insulin-mediated vasodilatation. Regression analysis suggested that capillary recruitment may explain part of the link between blood pressure and insulin sensitivity. Since control of capillary recruitment resides partly in small precapillary arterioles, our data may also explain why minimal forearm vascular resistance of the precapillary resistance vessels is strongly related to glucose disposal rate in young men with borderline elevation of blood pressure [29]. These data are consistent with the notion that microvascular rarefaction, by affecting both pressure and flow patterns, may be an important explanatory mechanism of the link between hypertension and the impaired metabolic and vascular actions of insulin.

At this point it should be emphasised that any interpretation of our results must take into account the cross-sectional design of the study. We cannot exclude the possibility that the demonstrated associations can all be explained by an as yet unmeasured variable. Physical fitness, as judged from the maximal aerobic power (VO2max), is associated with insulin sensitivity, insulin-mediated vasodilatation [26] and acetylcholine-mediated vasodilatation in human skin [30], and may explain some of the demonstrated associations. However, since physical fitness, indexed as VO2max, partly depends on muscle capillary supply [31], it seems unlikely that it confounds the relationship between capillary recruitment and insulin's metabolic and vascular actions. Non-esterified free fatty acids were also not measured in the present study, but may be of pathophysiological importance. The subjects with essential hypertension were more obese and had a more central fat distribution compared to the normotensive subjects. Free fatty acids, which have been found to be increased in obesity and to be capable of inducing insulin resistance [32], have been shown to increase vasoconstrictor responses in dorsal hand veins [33], and to impair endothelium-dependent and insulin-dependent vasodilatation at the level of the resistance vessels [34,35]. Nevertheless, statistical adjustment for differences in obesity and body fat distribution did not confound the reported relationships between microvascular function, insulin sensitivity and blood pressure.

Although muscle is the main site of insulin resistance [25] and of peripheral vascular resistance, it appears reasonable to investigate the skin when assessing the potential role of microvascular function in linking insulin sensitivity and blood pressure. In hypertension, microvascular defects, such as capillary rarefaction and impaired acetylcholine-mediated vasodilatation, can be demonstrated both in muscle and in skin [1,3,4,36,37]. Our finding of an association between skin microvascular function and insulin-mediated increases in leg blood flow also seems to justify this view.

In summary, skin microvascular function was associated with blood pressure and insulin's metabolic and vasodilatatory actions, even in the hypertensive range. These findings offer a potential mechanistic explanation of the links among insulin resistance, impaired insulin-mediated vasodilatation and hypertension.

Time for primary review 32 days.


   Acknowledgements
 
Supported by grants from the Diabetes Fonds Nederland (CDAS, EHS) and the Dutch Kidney Foundation (JCM). We are grateful to Professor Dr. J.S. Yudkin for critically reviewing the manuscript.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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