Skip Navigation

Cardiovascular Research 1998 38(1):206-214; doi:10.1016/S0008-6363(97)00319-2
© 1998 by European Society of Cardiology
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Huvers, F.C
Right arrow Articles by Schaper, N.C
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Huvers, F.C
Right arrow Articles by Schaper, N.C
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 1998, European Society of Cardiology

The enhanced pressor response in type 2 diabetes is not based upon a generalized increase in vascular responsiveness

F.C Huvers*, P.W de Leeuw, C.H.A de Haan, A.J.H.M Houben, C Buijs and N.C Schaper

Dept. of Internal Medicine, Div. of Endocrinology and General Internal Medicine, Cardiovascular Research Institute Maastricht, University Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, Netherlands

* Corresponding author. Tel.: +31 (43) 3877011; fax: +31 (43) 3875006; e-mail: F.Huvers@aig.azn.nl

Received 19 June 1997; accepted 24 November 1997


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: The present study was performed to discriminate between central and peripheral effects of noradrenaline (NA) in normotensive, non-obese, type 2 diabetic patients. Methods: Study I: In 10 patients and 10 healthy volunteers (HV) cumulative doses of NA were infused intravenously until mean arterial pressure (MAP) rose with 20 mmHg, and subsequently the effects on the forearm blood flow (FBF) was measured. Also, the FBF response to intra-arterial NA (0.025, 0.1, 0.4 µg min–1) was measured. Study II: In 13 patients and 14 HV the venous constrictor response to a cumulative local infusion of NA in a dorsal hand vein was determined. Results: In study I the circulating plasma NA concentrations inducing a rise in MAP of 20 mmHg, were lower in the type 2 patients relative to the HV (p<0.01). The relationship between changes in pressure and changes in heart rate were similar in both groups. Moreover, FBF responsiveness to intra-arterial NA was not different between the two groups. The slopes of the deltaMAP/NA regression lines were correlated with basal insulin levels and relative insulin resistance in the healthy volunteers (R=0.77, p<0.01, and R=0.83, p<0.01), but not in the type 2 diabetic patients. In study II no differences were observed in the dose generating half maximum (ED50) and the maximum (Emax) response to NA between the type 2 patients and the HV. Conclusions: Non-obese normotensive type 2 patients have an increased pressor response to NA, which is not based upon a defect in skeletal muscle resistance arterioles, peripheral veins, or a defect in the baroreceptor system. Therefore, in type 2 diabetes the noradrenergic responsiveness of other vascular beds, such as the splanchnic or renal, must be enhanced.

KEYWORDS Noradrenaline; Blood pressure; Insulin; Type 2 diabetes; Forearm; Hand vein


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
Hypertension is a major cardiovascular risk factor in patients with type 2 or non-insulin-dependent diabetes mellitus [1]. Moreover, hypertension and type 2 diabetes often coexist, which has led to the hypothesis that insulin resistance may play a central role in the pathogenesis of both derangements [2]. However, the mechanisms by which insulin resistance affects blood pressure are unknown. Potential hypertensive effects of elevated insulin levels are increased sympathetic neural outflow [3], augmented renal reabsorption of sodium [4], and salt-sensitivity of blood pressure [5]. Finally, in insulin-resistant states such as type 2 diabetes and obesity, pressor responses to exogenous noradrenaline (NA) and angiotensin II (AII) are potentiated [6], suggesting enhanced responsiveness of the vascular smooth muscle cell (VSMC) to vasoconstrictor stimuli. This enhanced responsiveness, in turn, could be related to abnormal VSMC calcium homeostasis [4]. On the other hand, increased pressor responsiveness could also be the consequence of impaired baroreceptor function, even without any abnormalities in VSMC contractility [7]. Indeed, Baron and co-workers suggested that in obese insulin-resistant subjects the increased pressor response to exogenous NA is based upon a defect in baroreceptor function [8].

To our knowledge, no studies have been performed which address both local and systemic pressor responsiveness to exogenous NA in type 2 diabetes. Therefore, in the present study we assessed in the same type 2 subjects and healthy volunteers not only blood pressure and heart rate (as a measure of baroreceptor activity) responses to systemic infusions of NA, but also the vasoconstrictor responses of forearm resistance arterioles to local infusion of NA. In a separate group of patients and controls venous responsiveness to local NA was determined. Only normoalbuminuric subjects were studied, as most microalbuminuric patients have signs of autonomic neuropathy, which in itself could modify NA pressor responsiveness [9]. Furthermore, all participants were non-obese, as obesity may also enhance pressor responses to exogenous NA [10]. Finally, all subjects were normotensive, as we wanted to avoid exaggerated pressor responses due to hypertension-induced media hypertrophy.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Subjects
Control subjects were recruited by advertisements in local newspapers, while patients with type 2 diabetes were recruited from the outpatient department of the University Hospital Maastricht and by advertisements. Type 2 diabetes was defined as the onset of diabetes after the age of 40 years, initially treated by diet and/or oral anti-diabetic medication. Supine blood pressure in these patients did not exceed 160/90 mmHg. None of the subjects studied had evidence of cardiovascular disease, nephropathy, hyperlipidaemia or neuropathy on physical examination or routine biochemical screening. Serum creatinine levels were all below 100 µmol l–1. Microalbuminuria, defined as an urinary albumin excretion (UAE) of 30–300 mg/24 h, was excluded in all patients. The presence of autonomic neuropathy was excluded by measuring heart rate (R–R interval) variations during deep breathing and Valsalva manoeuvre, and heart rate and blood pressure responses to standing under standardized conditions as described by Ewing and Clarke [11]. None of the patients had symptoms or signs (abnormal tendon reflexes and vibration sense) of distal polyneuropathy. Metabolic control in the type 2 patients was achieved by tolbutamide in eight patients, by gliclazide in three patients, by glimeperidine in one patient, by glibenclamide in three patients, while two patients were treated with diet only. None of the type 2 patients or the healthy volunteers used any medication (including NSAID's) for at least 4 weeks preceding the study, except for oral antidiabetic drugs by the diabetic patients.

All subjects were instructed to avoid caffeine-containing drinks, smoking and alcohol for 12 h preceding the studies. Experiments were performed after an overnight fast and on the morning of the experiments the type 2 patients omitted their anti-diabetic medication. All subjects gave written informed consent and the study was approved by the Ethical Review Committee of the University Hospital Maastricht. The investigations conformed with the principles outlined in the Declaration of Helsinki.

2.2 Protocol
Two different studies were performed in 17 healthy volunteers with a negative family history for diabetes or hypertension and in 17 type 2 diabetic patients. In the first study NA was infused intravenously to evaluate the effect of NA on blood pressure, heart rate and forearm blood flow (FBF) in 10 type 2 patients and 10 healthy volunteers (study I, FBF and pressor response). Subsequently, the vasoconstrictor effect of NA, administered into the brachial artery of the non-dominant arm, on FBF was determined in these same patients. In the second study the vasoconstrictor response of the dorsal hand vein to local infusion of NA was evaluated in 13 type 2 patients and 14 healthy volunteers (study II, hand vein). Seven healthy volunteers and 5 type 2 patients participated in both studies.

2.2.1 Study I
After local anaesthesia by 1.5 ml 1% lidocaine, a 20 gauge arterial catheter (Arrow, Reading, PA, USA) was inserted retrogradely into the brachial artery of the non-dominant arm for local NA infusions and blood pressure measurements. The catheter was kept patent with saline. Mean arterial pressure (MAP) was measured using a Hewlett Packard 78205C monitor (Boeblingen, Germany). FBF was determined simultaneously in both arms by ECG-triggered strain gauge venous occlusion plethysmography (Periflow, Janssen Scientific Instruments, Beerse, Belgium) as described earlier [12]. The hand circulation was excluded during FBF measurements by inflating a wrist cuff to suprasystolic pressure, starting one minute before each FBF measurement. Hence, FBF measurements represent predominantly muscle blood flow [13]. Heart rate was derived from the ECG. All signals were stored on the hard disk of a personal computer by means of a custom build data acquisition system. Subjects were studied supine in a temperature-controlled room with a mean (±SD) temperature of 24.0±0.5°C.

2.2.1.1 FBF and pressor response to systemic NA
After blood samples were taken for determination of basal arterial insulin, (nor) adrenalin, and glucose, NA was infused intravenously into the dominant arm. The starting dose was 30 ng.kg–1.min–1 followed by stepwise increases of 15 ng.kg–1.min–1 every 5 min, until the intra-arterially measured MAP was elevated by 20 mmHg or a dose of 150 ng.kg–1.min–1 was reached (NAmax). FBF was measured in the non-dominant arm, before the infusion of NA and during the NAmax dose. At these same time points arterial blood samples were taken for determination of (nor)adrenaline.

2.2.1.2 FBF, before and during local intra-arterial NA
FBF was measured during 3 min of baseline blood flow and during local infusions of three cumulative doses of NA (0.025, 0.1, 0.4 µg.min–1, each dose for three minutes) in the brachial artery of the non-dominant arm. The doses and the duration of the drug infusions were such as to reach steady-state vascular responses. The mean FBF value of the last minute of each drug step was used for calculations.

2.2.2 Study II
2.2.2.1 Hand vein
Venous responsiveness to NA was assessed by the linear variable differential transformer (LVDT) technique, which measures alterations in the distension of superficial hand veins during drug infusions [14]. The hand vein was used as an in-vivo model of an isolated vessel to study the interaction between the endothelium and the VSMC in response to NA. With this model local vascular responsiveness, independent of systemic and reflex responses, can be measured by infusion of minute amounts of NA. Subjects were studied supine in a temperature-controlled room with a mean (±SD) temperature of 26.0±0.5°C, in order to minimize vascular tone. In the non-dominant arm a dorsal hand vein was cannulated with a 23-Gauge butterfly needle. This arm was resting on a padded support, 30° above the horizontal, so that the vein, which was above heart level, was completely collapsed. A cuff was attached around the upper arm. Changes in vein diameter were measured using the LVDT (model 100 HMR, Schaevitz Engineering, Pennsauken, NJ) and an ATA signal conditioner (Schaevitz Engineering). The LVDT was mounted on the back of the hand using a tripod. The tip of the steel core of the LVDT was positioned over the centre of the vein approximately 1 cm proximal to the tip of the butterfly needle. After an acclimatization period of 30 min, three baseline measurements of venous distension were performed with a cuff pressure of 40 mmHg. The difference between the collapsed and fully distended readings represented the maximum vein diameter, i.e. the diameter at 0% constriction. Subsequently, a cumulative stepped infusion of NA, 0.3–160 ng.min–1, dissolved in 0.9% saline was delivered into the hand vein by a syringe driver pump (Terufusion syringe pump model STC-521, Terumo, Tokyo, Japan) at an infusion rate of 0.1 ml.min–1. Each dose of NA was infused during 7 min with inflation of the cuff during the last 2 min. Vein diameter was measured during the 7th minute of the infusion. Prior to the present studies the variability of the ED50 to NA was evaluated in healthy volunteers (n=18). The within-day coefficient of variance of the ED50 in these experiments was 28%, which is compatible with that in other studies [15].

2.3 Assays
Fasting blood glucose concentration was measured by the glucoxidase method, cholesterol, triglyceride, creatinine by commercial methods, HbA1c using the Diamat HPLC analyzer. Serum insulin was determined by a modified RIA assay (Pharmacia Upjohn, Uppsala, Sweden) to exclude cross reactivity with human pro-insulin and with auto-antibodies. Plasma catecholamines were determined by HPLC followed by fluorescence detection. Microalbuminuria was measured by a commercial immuno-turbidimetric method. UAE was expressed as the mean of two 24-h urine collections, taken within a 6-month period.

2.4 Calculations and statistics
2.4.1 Study I
2.4.1.1 FBF and pressor response to systemic NA
The individual slope of the MAP response to the respective doses of NA (dMAP/NA) and the individual slope of the change in heart rate to the change in MAP (dHR/dMAP) were calculated by Pearson's linear regression. The mean and 95% confidence intervals of the dMAP/NA and of the dHR/dMAP slopes were calculated using GraphPad (GraphPad Software, San Diego, CA, USA). Forearm vascular resistance (FVR) was calculated as MAP divided by concomitant FBF and expressed in arbitrary units (AU). Relative insulin resistance was calculated from fasting glucose and insulin according to the HOMA formula [16, 17].

2.4.1.2 FBF before and during local intra-arterial NA
For each NA dose the FBF-ratio (FBF of the infused arm divided by FBF of the contralateral arm) was calculated. This calculated ratio corrects for systemic factors that affect the regulation of FBF in both arms (e.g. changes in blood pressure, level of arousal, hormonal changes etc.), and ensures that only the direct effects of locally infused substances on FBF are taken into account [18]. The stepwise NA doses were chosen in such a way that vasoconstrictor responses in the linear part of the dose–response curve were obtained. The response to the various NA doses are expressed as percentage change in FBF-ratio from baseline.

2.4.2 Study II
2.4.2.1 Hand vein
The percentage reduction in maximal vein diameter in response to each dose of NA was calculated. For each subject an individual dose–response curve was constructed, using GraphPad, after logarithmic transformation of the infusion doses. The maximal venous constrictor responses (Emax) and the log NA doses generating half maximal responses (logED50) were calculated.

2.4.3 Statistics
As the data were not distributed normally, all data are expressed as median values and interquartile ranges unless otherwise indicated. Group comparisons were made using non-parametric tests. Within group analyses of multiple related samples were made using Friedman's test (non-parametric analysis of variance), while the Wilcoxon paired rank test was used for paired analyses. The Kruskal Wallis test was used for multiple group comparisons and the Mann Whitney U test for two group comparisons. When multiple comparisons were made, Shaffer adjusted p-values were used [19]. Correlations were made by Spearman Rank tests. Statistical significance is defined as a p-value <=0.05.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
As expected HbA1c, fasting blood glucose, and serum insulin levels were higher in the type 2 patients (p<0.01, p<0.05, and p<0.05, respectively, Table 1). Furthermore, no differences were observed between the groups in study I and II, except for triglyceride levels, which were higher in type 2 patients than in healthy volunteers (p<0.05, Table 1).


View this table:
[in this window]
[in a new window]

  		Table 1 Clinical and laboratory characteristics

 
3.1 Study I
3.1.1 Pressor and FBF response to systemic NA
Systemic NA infusion resulted in a dose dependent increase in blood pressure in all subjects, both healthy volunteers (Friedman p<0.001, Fig. 1) and type 2 patients (Friedman p<0.001, Fig. 1). The increase in blood pressure was accompanied by a decrease in heart rate in the healthy volunteers and the type 2 patients (Friedman p<0.001 and p<0.01, Fig. 2). The circulating plasma concentrations of NA, inducing a rise in MAP of 20 mmHg, were lower in the type 2 patients in comparison to healthy volunteers: 13.1 (10.8–15.4) vs. 20.0 (18.8–26.7) nmol.l–1, (p<0.01, Table 2). The slopes of the dMAP/NA regression lines were steeper in the type 2 patients in comparison to the healthy volunteers: 0.27 (0.23–0.35) vs. 0.16 (0.13–0.19) mmHg.ngNA–1.kg–1, (p<0.01, Fig. 1). In contrast, the slopes of the dHR/dMAP regression lines were not different: –0.3 (–0.2–0.5) vs. –0.2 (–0.1–0.3) BPM.mmHg–1 (Fig. 2).


Figure 1
View larger version (13K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Pressor responsiveness to systemic noradrenaline (NA) in healthy volunteers and type 2 patients. MAP: mean arterial pressure. Mean regression line and 95% confidence interval. *p<0.05 slope regression type 2 patients vs. healthy volunteers.

 

Figure 2
View larger version (12K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Heart rate (HR) response to changes in mean arterial pressure (MAP) in healthy volunteers and type 2 patients. BPM: beats per minute. Mean regression line and 95% confidence interval.

 

View this table:
[in this window]
[in a new window]

  		Table 2 Haemodynamic parameters and catecholamine levels during systemic noradrenaline

 
Basal FBF and FVR were not different between the healthy volunteers and the type 2 diabetic patients (Table 2). FVR did not change during systemic NA infusion in either group, and there was no difference between both groups during the highest NA dose (Table 2).

Systemic NA infusion resulted in a rise in arterial blood glucose levels in healthy volunteers from 4.6 (4.4–4.7) to 5.9 (5.2–6.8) mmol.l–1 (p<0.01). In type 2 patients blood glucose levels did not change: 8.5 (7.2–13.4) vs. 8.3 (8.1–15.7) mmol.l–1.

The slopes of the dMAP/NA regression lines were related to basal insulin levels (R=0.77, p<0.01) and to the relative insulin resistance (R=0.83, p<0.01) in the healthy volunteers, but not in the type 2 diabetic patients (Fig. 3).


Figure 3
View larger version (9K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Relationships (with 95% confidence interval) between basal insulin levels (left panel), and between relative insulin resistance (right panel), with sensitivity to noradrenaline in healthy volunteers ({blacktriangleup}) and in type 2 diabetic patients ({blacksquare}). As no significant correlations were observed in the diabetic patients, only the correlations (with 95% confidence interval) in the healthy volunteers is shown in both panels. Slope: the slope of the MAP response to NA. MAP: mean arterial pressure.

 
3.1.2 Local intra-arterial NA infusion
At the start of the intra-arterial infusions FBF did not differ between healthy volunteers and type 2 patients: 3.2 (2.3–3.6) vs. 2.6 (1.5–3.0) ml.100 ml–1.min–1, p=0.15. Whereas blood pressure and heart rate did not change during intrabrachial NA infusion, this infusion caused a dose-dependent decrease in FBF-index in all subjects, both healthy volunteers (Friedman p<0.001, Fig. 4) and type 2 patients (Friedman p<0.001, Fig. 4). However, no difference could be discerned in FBF responses to the three NA-doses between the groups (Fig. 4).


Figure 4
View larger version (12K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 Vasoconstrictor response of the forearm to intra-arterial infusion of noradrenaline (NA) in healthy volunteers and type 2 patients. FBF ratio=forearm blood flow infused/control arm. Data expressed as median and interquartile ranges (boxes) and ranges (T-bars).

 
3.2 Study II (local venous NA infusion)
Blood pressure and heart rate did not change during local intravenous infusion of NA (data not shown). The Emax and the ED50 of the dorsal hand vein to NA were not different between healthy volunteers and type 2 patients: 94 (83–100) vs. 100 (85–100)%, and: 0.84 (0.52–1.4) vs. 1.01 (0.69–1.25) log ng.min–1, respectively (Fig. 5).


Figure 5
View larger version (11K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 5 Vasoconstrictor response of the dorsal hand vein to local infused noradrenaline (NA) in healthy subjects ({blacktriangleup}), and type 2 diabetic patients ({blacksquare}). Data expressed as mean and standard deviation.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
The present study clearly indicates that the systemic pressor response to NA is increased in normotensive non-obese type 2 patients without microalbuminuria, thus confirming earlier studies [6, 20, 21]. Moreover, in the healthy volunteers, but not in the type 2 patients, pressor responsiveness to NA was correlated with basal insulin levels and relative insulin resistance. Although pressor responsiveness to NA can be modified by sodium depletion [22], we were merely interested in the localization of the defect that determines the enhanced responsiveness. Therefore, all subjects continued their habitual diet.

Theoretically, the difference in systemic pressor response to exogenous NA could be related to a decreased clearance rate of the administrated NA, as can be observed in obese insulin-resistant subjects [8]. However, Tack et al. failed to find, in a recent study using the [3H]-noradrenaline tracer method, differences in total body clearance and forearm NA kinetics between normotensive type 2 patients and healthy volunteers [23]. Moreover, in the present study circulating plasma levels inducing a MAP rise of 20 mmHg were clearly lower in the type 2 patients, indicating NA enhanced pressor responsiveness. Thus it is unlikely that our results are due to reduced NA clearance in the type 2 patients.

NA raises arterial pressure primarily by increasing systemic vascular resistance [9]. At the same time, cardiac output falls as a consequence of baroreceptor stimulation [7]. From a theoretical point of view, therefore, an increased pressor responsiveness in type 2 diabetes could be related to impaired baroreceptor functioning. Such a mechanism has, indeed, been proposed by Baron and co-workers [8]. However, baroreceptor responsiveness to the NA induced rise in MAP was not different between type 2 diabetic subjects and healthy volunteers in the present study. We assessed baroreceptor performance from the relationship between the rise in MAP and the concurrent reduction in heart rate. For any given rise in blood pressure, we found that the fall in heart rate was similar in type 2 patients and controls, suggesting that in our patients baroreceptor function was intact. This could be the result of the meticulous selection of our type 2 patients. Since autonomous neuropathy was excluded in the type 2 patients, it is unlikely that the sympathetic nervous system was defective in these patients. Thus, our findings led us to conclude that an enhanced vascular reactivity (or sensitivity) was the main reason for the increased pressor responses in type 2 diabetes.

Our data further suggest that the increased pressor response is not the result of a generalized vascular defect. First of all, systemic administration of NA had no effect on FVR in type 2 patients, despite an adequate rise in arterial NA levels. Similar findings have been obtained in healthy subjects in whom FVR also remained unaltered or even decreased during systemic NA infusion [24, 25]. Secondly, local administration of NA elicited similar vasoconstrictor responses of forearm arterioles in type 2 patients and controls. It could be argued that during intrabrachial infusion far higher NA levels were reached in the forearm vascular bed in comparison to the levels reached during the systemic infusion. However, estimated NA levels during the local infusion of 0.1 µg/min are similar to the levels measured during the highest dose of systemic NA administration. Finally, local administration of NA in a dorsal hand vein showed similar venoconstrictor responses in type 2 patients and controls. From these data we conclude that the increased systemic pressor response to NA is not related to an exaggerated vascular responsiveness in skeletal muscle resistance arterioles or peripheral veins. It is tempting to speculate, therefore, that type 2 patients display an enhanced responsiveness of their visceral (i.e. splanchnic and/or renal) circulation. However, currently no data are available about the responsiveness of the splanchnic bed or renal vasculature to NA in type 2 diabetes.

Several mechanisms could be involved in the enhanced NA pressor responsiveness in type 2 diabetes. Firstly, treatment with sulphonylurea drugs could have influenced NA responsiveness in the type 2 patients [26]. These drugs inhibit ATP-sensitive potassium channels, thereby stimulating Ca2+ influx and possibly enhancing vasoconstrictor responses [27]. However, in study I (pressor response) only one patient was using glibenclamide, which seems to be the only sulphonylurea drug with such vascular effects in therapeutic concentrations [28]. Secondly, glucose and triglyceride levels were different. Alterations in vascular noradrenergic responsiveness have been described in hyperglycemic, streptozotocin induced diabetic rats, a model for type 1 diabetes [29]. However, studies in healthy volunteers showed that acute elevation of glucose and triglycerides have no effect on NA responsiveness [12, 30, 31], suggesting that hyperglycaemia and hypertriglyceridaemia are not important factors in NA pressor responsiveness. Thirdly, it is likely that the type 2 patients had elevated circulating levels of free fatty acids (FFA). Some data suggest that elevated FFA levels, which were not determined in the present study, could enhance the {alpha}-adrenergic responsiveness in man [32]. Further studies are needed to assess the potential role of FFA in the enhanced pressor response in type 2 diabetes.

Apart from sulfonylurea treatment and differences in metabolic factors, hyperinsulinaemia and/or insulin resistance could play a role in the enhanced pressor response in type 2 diabetes. A striking finding in the present study were the strong correlations between NA pressor responsiveness and both basal insulin levels and calculated insulin resistance in healthy volunteers. Several authors suggest that hyperinsulinaemia or insulin-resistance is associated with enhanced VSMC contractility [33]. This enhanced constrictor responsiveness could contribute to the enhanced NA pressor responses and could promote the development of hypertension [34]. Insulin affects trans-membrane calcium transport by several mechanisms and there is some evidence which suggests that insulin resistance is associated with an increase in intracellular calcium [33]. This rise in intracellular calcium could result in enhanced VSMC contractile responsiveness to NA and other agonists [33].

Insulin also stimulates the production of endothelium-derived nitric oxide (EDNO), thereby increasing peripheral blood flow [35, 36]. In type 2 diabetics EDNO production and action are impaired in several vascular beds, including that of the forearm [37, 38]. In-vitro, EDNO attenuates NA constrictor responses [39]and it has been suggested that the impaired EDNO production in type 2 diabetes could contribute to enhanced VSMC contractility [40]. However, as reported earlier in this journal (acute) hyperinsulinaemia induces vasodilatation in the forearm, without any effects on NA constrictor responses [36]. Whether this also holds true for other vascular beds remains to be determined. As insulin levels in the splanchnic bed are up to three times higher than in peripheral vessels [41], this vascular bed is exquisitely exposed to long-term hyperinsulinaemia.

In contrast to the healthy volunteers, no correlation was observed between basal serum insulin levels and calculated relative insulin resistance in the type 2 patients. At present this discrepancy is difficult to explain. It is unlikely that the increased insulin levels in the type 2 patients were (partly) based upon a rise in proinsulin, as a specific insulin assay was used. Relative insulin resistance was calculated using basal insulin and glucose levels [16]. Estimation of insulin resistance could, therefore, have been less accurate in the type 2 patients. Further studies, in which insulin resistance is quantified in more detail (e.g. the hyperinsulinemic–euglycemic clamp technique), are needed to determine the relationship between insulin/insulin resistance and NA pressor responsiveness in type 2 patients. Alternatively, if the enhanced pressor responsiveness is based upon a severe defect in EDNO production, as discussed above, this could have resulted in a loss of association between insulin and pressor responsiveness in the type 2 patients.

In conclusion, our data suggest that the enhanced pressor responses to NA in type 2 diabetic patients are not based upon enhanced constrictor responses in the skeletal arterioles and veins. The potential role of the visceral circulation in blood pressure regulation in these patients needs to be explored.

Time for primary review 33 days.


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

  1. The Hypertension in Diabetes Study Group. Hypertension in Diabetes Study (HDS): II. Increased risk of cardiovascular complications in hypertensive type 2 diabetic. J Hypertens (1993) 11:319–325.[CrossRef][Web of Science][Medline]
  2. Reaven G.M. Role of insulin resistance in human disease. Banting lecture 1988. Diabetes (1988) 37:1595–1607.[Abstract]
  3. Anderson E.A, Hoffman R.P, Balon T.W, Sinkey C.A, Mark A.L. Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans. J Clin Invest (1991) 87:2246–2252.[Web of Science][Medline]
  4. Sowers J.R, Standley P.R, Ram J.L, Jacober S, Simpson L, Rose K. Hyperinsulinemia, insulin resistance, and hyperglycemia: contributing factors in the pathogenesis of hypertension and atherosclerosis. Am J Hypertens (1993) 6:260S–270S.[Medline]
  5. Tuck M, Corry D, Trujillo A. Salt-sensitive blood pressure and exaggerated vascular reactivity in the hypertension of diabetes mellitus. Am J Med (1990) 88:210–216.[CrossRef][Web of Science][Medline]
  6. Beretta Piccoli C, Weidmann P. Exaggerated pressor responsiveness to norepinephrine in nonazotemic diabetes mellitus. Am J Med (1981) 71:829–835.[CrossRef][Web of Science][Medline]
  7. Shepherd JT, Luscher TF, Mancia G. Circulatory Regulation, Basic Considerations. In: Willerson JJ, Conn JN, editors, Cardiovascular Medicine. New York: Churchill Livingstone, 1995:1053–1067.
  8. Baron A.D, Brechtel G, Johnson A, Fineberg N, Henry D.P, Steinberg H.O. Interactions between insulin and norepinephrine on blood pressure and insulin sensitivity. Studies in lean and obese men. J Clin Invest (1994) 93:2453–2462.[Web of Science][Medline]
  9. Dejgaard A, Andersen P, Hvidberg A, Hilsted J. Cardiovascular, metabolic, and hormonal responses to noradrenaline in diabetic patients with autonomic neuropathy. Diabetic Med (1996) 13:983–989.[CrossRef][Web of Science][Medline]
  10. Egan B.M, Schork N.J, Weder A.B. Regional hemodynamic abnormalities in overweight men. Focus on alpha-adrenergic vascular responses. Am J Hypertens (1989) 2:428–434.[Web of Science][Medline]
  11. Ewing D.J, Clarke B.F. Diagnosis and management of diabetic autonomic neuropathy. Br Med J (1982) 285:916–918.[Free Full Text]
  12. Houben A.J, Schaper N.C, De Haan C.H, Huvers F.C, Slaaf D.W, De Leeuw P.W, Nieuwenhuijzen Kruseman A.C. The effects of 7-hour local hyperglycaemia on forearm macro and microcirculatory blood flow and vascular reactivity in healthy man. Diabetologia (1994) 37:750–756.[CrossRef][Web of Science][Medline]
  13. Johnston C.I, Cooper M.E, Nicholls G.M. Meeting report of the International Society of Hypertension Conference on Hypertension and Diabetes. J Hypertens (1992) 10:393–397.[CrossRef][Web of Science][Medline]
  14. Bodmer C.W, Schaper N.C, Janssen M, De Leeuw P.W, Williams G. Selective enhancement of alpha 2-adrenoceptor-mediated vasoconstriction in insulin-dependent diabetic patients with microalbuminuria. Clin Sci (1995) 88:421–426.[Web of Science][Medline]
  15. Eichler H.G, Blaschke T.F, Kraemer F.B, Ford G.A, Blochl Daum B, Hoffman B.B. Responsiveness of superficial hand veins to alpha-adrenoceptor agonists in insulin-dependent diabetic patients. Clin Sci (1992) 82:163–168.[Web of Science][Medline]
  16. Matthews D.R, Hosker J.P, Rudenski A.S, Naylor B.A, Treacher D.F, Turner R.C. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia (1985) 28:412–419.[CrossRef][Web of Science][Medline]
  17. Wolffenbuttel B.H, Weber R.F, Van Koetsveld P.M, Verschoor L. Limitations of diet therapy in patients with non-insulin-dependent diabetes mellitus. Int J Obes (1989) 13:173–182.[Web of Science][Medline]
  18. Greenfield A.D.M, Patterson G.C. Reactions of the blood vessels of the human forearm to increase in transmural pressure. J Physiol Lond (1954) 125:508–524.[Free Full Text]
  19. Shaffer J.P. Modified sequentially rejective multiple test procedures. J Am Stat Assoc (1986) 81:826–831.[CrossRef][Web of Science]
  20. Weidmann P, Beretta Piccoli C, Trost B.N. Pressor factors and responsiveness in hypertension accompanying diabetes mellitus. Hypertension (1985) 79:33–42.
  21. Ciavarella A, Mustacchio A, Ricci C, Capelli M, Vannini P. Enhanced pressor responsiveness to norepinephrine in type II diabetes. Effect of ACE inhibition. Diabetes Care (1994) 17:1484–1487.[Abstract]
  22. Rankin L.I, Luft F.C, Henry D.P, Gibbs P.S, Weinberger M.H. Sodium intake alters the effects of norepinephrine on blood pressure. Hypertension (1981) 3:650–656.[Abstract/Free Full Text]
  23. Tack C.J, Smits P, Willemsen J.J, Lenders J.W, Thien T, Lutterman J.A. Effects of insulin on vascular tone and sympathetic nervous system in NIDDM. Diabetes (1996) 45:15–22.[Abstract]
  24. Kjeldsen S.E, Petrin J, Weder A.B, Julius S. Contrasting effects of epinephrine on forearm hemodynamics and arterial plasma norepinephrine. Am J Hypertens (1993) 6:369–375.[Web of Science][Medline]
  25. Barcroft H, Gaskell P, Shepherd J.T, Whelan R.F. The effect of noradrenaline infusions on the blood flow through the human forearm. J Physiol Lond (1954) 123:443–450.[Free Full Text]
  26. Schotborgh C.E, Wilde A.A.M. Sulfonylurea derivatives in cardiovascular research and in cardiovascular patients. Cardiovasc Res (1997) 34:73–80.[Abstract/Free Full Text]
  27. Bijlstra P.J, Lutterman J.A, Russel F.G, Thien T, Smits P. Interaction of sulphonylurea derivatives with vascular ATP-sensitive potassium channels in humans. Diabetologia (1996) 39:1083–1090.[Web of Science][Medline]
  28. Bijlstra P.J, Russel F.G, Thien T, Lutterman J.A, Smits P. Effects of tolbutamide on vascular ATP-sensitive potassium channels in humans. Comparison with literature data on glibenclamide and glimepiride. Horm Metab Res (1996) 28:512–516.[Web of Science][Medline]
  29. Rinaldi G.J, Cingolani H.E. Effect of diabetes on fast response to norepinephrine in rat aorta. Diabetes (1992) 41:30–34.[CrossRef][Web of Science][Medline]
  30. Houben A.J.H.M, Schaper N.C, De Haan C.H.A, Huvers F.C, Slaaf D.W, De Leeuw P.W, Nieuwenhuijzen Kruseman A.C. Local 24-h hyperglycemia does not affect endothelium-dependent or -independent vasoreactivity in humans. Am J Physiol: Heart Circ Physiol (1996) 270:H2014–H2020.[Abstract/Free Full Text]
  31. Steinberg H.O, Tarshoby M, Monestel R, Hook G, Cronin J, Bayazeed B, Baron A.D. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest (1997) 100:1230–1239.[Web of Science][Medline]
  32. Stepniakowski K.T, Goodfriend T.L, Egan B.M. Fatty acids enhance vascular alpha-adrenergic sensitivity. Hypertension (1995) 25:774–778.[Abstract/Free Full Text]
  33. Sowers J.R, Khoury S, Standley P, Zemel P, Zemel M. Mechanisms of hypertension in diabetes. Am J Hypertens (1991) 4:177–182.[Web of Science][Medline]
  34. Resnick L.M. Cellular calcium and magnesium metabolism in the pathophysiology and treatment of hypertension and related metabolic disorders. Am J Med (1992) 93:11S–20S.[CrossRef][Medline]
  35. Steinberg H.O, Brechtel G, Johnson A, Fineberg N, Baron A.D. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. J Clin Invest (1994) 94:1172–1179.[Web of Science][Medline]
  36. De Haan C.H.A, Van Dielen F.M.H, Houben A.J.H.M, De Leeuw P.W, Huvers F.C, De Mey J.G.R, Wolffenbuttel B.H.R, Schaper N.C. Peripheral blood flow and noradrenaline responsiveness: the effect of physiological hyperinsulinemia. Cardiovasc Res (1997) 34:192–198.[Abstract/Free Full Text]
  37. McVeigh G.E, Brennan G.M, Johnston G.D, McDermott B.J, McGrath L.T, Henry W.R, Andrews J.W, Hayes J.R. Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia (1992) 35:771–776.[Web of Science][Medline]
  38. Huvers F.C, Schaper N.C, Houben A.J.H.M, Hofstra L, Kitslaar P.E.J.H.M, De Leeuw P.W, Nieuwenhuijzen Kruseman A.C. Impaired arterial but not venous responsiveness to nitroglycrin in non-insulin-dependent diabetes mellitus. Eur J Clin Invest (1997) 27:360–365.[CrossRef][Web of Science][Medline]
  39. Carrier G.O, White R.E. Enhancement of alpha-1 and alpha-2 adrenergic agonist-induced vasoconstriction by removal of endothelium in rat aorta. J Pharmacol Exp Ther (1985) 232:682–687.[Abstract/Free Full Text]
  40. Cipolla M.J, Harker C.T, Porter J.M. Endothelial function and adrenergic reactivity in human type-II diabetic resistance arteries. J Vasc Surg (1996) 23:940–949.[CrossRef][Web of Science][Medline]
  41. Peiris A.N, Mueller R.A, Smith G.A, Struve M.F, Kissebah A.H. Splanchnic insulin metabolism in obesity. Influence of body fat distribution. J Clin Invest (1986) 78:1648–1657.[Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Huvers, F.C
Right arrow Articles by Schaper, N.C
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Huvers, F.C
Right arrow Articles by Schaper, N.C
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?