Insulin Sensitivity, Vascular Reactivity, and Clamp-Induced Vasodilatation in Essential Hypertension
Background Insulin resistance and vascular abnormalities have both been described in patients with essential hypertension. Whether these defects are associated with one another in the same individual has not been established.
Methods and Results Whole-body insulin sensitivity (by the insulin clamp technique), forearm minimal vascular resistances, and the dose-response curve to acetylcholine, sodium-nitroprusside, and norepinephrine were measured in a group of 29 male patients with untreated essential hypertension. When the patients were divided into tertiles according to their level of insulin sensitivity, resistant and sensitive hypertensives were matched on several potential confounders of insulin action and vascular function. These subgroups showed similar minimal vascular resistances (2.5±0.2 versus 3.2±0.6 mm Hg per mL · min−1 · dL−1) and superimposable responses to graded intraarterial infusions of acetylcholine, sodium-nitroprusside, and norepinephrine. No correlation was found between the vascular parameters (slope of the curve or maximal response) and insulin-mediated glucose uptake in the whole group. During the clamp, insulin sensitive patients tended to have greater increments in forearm blood flow when compared to their insulin resistant counterparts (+53±21 versus +9±7%, P=.06); in the whole group, clamp-induced vasodilatation was weakly related to insulin-mediated glucose uptake (r=.44, P<.02) as well as to the slope of the acetylcholine dose-response curve (r=.40, P<.04). Together, these two responses explained 30% (multiple r=.55, P<.01) of the variability in insulin-induced vasodilatation.
Conclusions Metabolic insulin resistance in essential hypertension is not associated with abnormalities in vascular structure, acetylcholine or nitroprusside-induced vasodilatation, or vascular adrenergic reactivity. Degree of insulin sensitivity and acetylcholine sensitivity explain a small portion of the variability of the clamp-induced vasodilatation in hypertensive patients.
Although it is well established that essential hypertension is frequently associated with insulin resistance,1 the impact of this abnormality on blood pressure homeostasis is still a matter of debate.2 Insulin and the vasculature influence each other. Specifically, the hormone causes limb vasodilatation,3 reduces adrenergic-mediated vasoconstriction,4 5 and potentiates ACh-mediated vasodilatation.6 Since all these actions appear to be protective against the development of arterial hypertension, it could be argued that, if the vasculature is resistant to insulin vasomodulation just as skeletal muscle is resistant to insulin’s metabolic actions, then one and the same defect, ie, insulin resistance, might be responsible for the development and/or maintenance of arterial hypertension. Alternatively, directly through its trophic activity7 and/or by activating the sympathetic nervous system,3 insulin could enhance vascular responsiveness and sustain arterial hypertension.8 On the other hand, clamp-induced vasodilatation9 and, more in general, optimal skeletal muscle perfusion10 have been proposed to be necessary for the hormone to exert its full action on glucose metabolism. According to this view, a primary vascular defect could contribute to insulin’s inability to normally promote skeletal muscle glucose uptake in IR states. This possibility has received indirect support from the finding that essential hypertension,11 12 similarly to other IR conditions such as IDDM and NIDDM,13 14 15 16 is associated with blunted clamp-induced vasodilatation as well as with impaired endothelium-dependent dilatation of forearm vessels.
The vascular response to intravenous insulin administration shows a large interindividual variability both in normal subjects17 and in patients with essential hypertension.18 Only a small portion of this variability, however, is explained by the rate of insulin-stimulated glucose uptake (correlation coefficients range from .1 to .6 in different reports9 18 19 20 ), suggesting that other factors modulate this action of insulin. As shown by Saccà and colleagues21 with the use of tritiated norpinephrine and the forearm balance technique, systemic insulin administration promotes norepinephrine release within the forearm tissues, an effect that is enhanced in patients with essential hypertension (and insulin resistance) despite normal rates of baseline norepinephrine release. Moreover, in normal subjects acute noradrenergic activation, obtained through the application of lower-body negative pressure, is associated with a 40% reduction in forearm glucose uptake.22 Thus, it is conceivable that this noradrenergic hypersensitivity might explain both the lower insulin sensitivity and the reduced clamp-induced vasodilatation. However, insulin-induced norepinephrine release in hypertensives (4 ng/L per minute) was substantially smaller than that evoked by lower body negative pressure (12 ng/L per minute). Therefore, unless the vascular responsiveness to noradrenergic agonists should be higher in the hypertensive, it is not clear whether insulin-induced norepinephrine release is sufficient to explain the resistance to either the metabolic or the vasodilatory action of the hormone.
To address these issues, in the present work we tested whether in essential hypertension, whole-body insulin resistance of glucose metabolism is associated with abnormal functional (response to ACh, nitroprusside, and norepinephrine) or structural properties (postischemic vasodilatation) of forearm arterial vessels, and whether these vascular characteristics explain the variability of clamp-induced vasodilatation.
Twenty nine male patients with essential hypertension were selected according to the following criteria: (a) office diastolic blood pressure values after 30 minutes of sitting between 90 and 110 mm Hg (secondary hypertension was excluded on the basis of routine blood chemistry and urinalysis, abdominal ultrasound and Doppler examination, plasma renin activity, plasma catecholamine, aldosterone, and cortisol concentrations), (b) BMI <30 kg/m2, (c) normal glucose tolerance (on a 75-g OGTT), (d) absence of severe hypercholesterolemia (fasting serum cholesterol <7.0 mmol/L) or hypertriglyceridemia (fasting serum triglycerides <3.0 mmol/L), and (e) acceptance to participate in the protocol, which consisted of two studies (Metabolic and Vascular) carried out on separate days 1 week apart. Previous antihypertensive treatment was stopped before the study; no patient was habitually consuming other drugs. Two weeks of washout were required if the patients were treated with ACE inhibitors or calcium antagonists (n=12), 4 weeks if the patients were receiving diuretics or β-blockers (n=5). As part of the screening procedure, LBM was measured by bioelectrical impedance analysis (BioElectrical Impedance Analyzer System BIA 109, AKERN, Firenze, Italy), the patients having fasted overnight and emptied their bladders immediately before the test. Left ventricular wall thickness and diameters were measured by echocardiography (Eco-color-Doppler SIM 7000, ESAOTE BIOMEDICA, Firenze, Italy), left ventricular mass was estimated according to standard equations,23 and normalized for body height. Both the metabolic and vascular studies were performed with the patients in the postabsorptive state, and the investigators were cross-blinded to the vascular reactivity and insulin sensitivity results. The protocol was approved by the Institutional Ethics Committee. Each subject gave his written consent after the nature, purpose, and potential risks of the study were fully explained.
Insulin sensitivity was measured by the euglycemic insulin clamp technique. Studies began at 8 am, with the patients lying supine. A polyethylene catheter was inserted retrogradely into a dorsal vein of the wrist, and another catheter was inserted into an antecubital vein of the same arm. The hand was kept in a heated box (60°C) to ensure arterialization of the blood sampled from the wrist vein; the antecubital vein was used for the infusion of insulin (Actrapid Human, NOVO Nordisk, Copenhagen, Denmark) and glucose. During the baseline period, 3 blood samples were collected at 20-minute intervals for insulin and glucose determination. Before each blood sampling, arterial blood pressure was measured by mercury sphygmomanometry, and FBF and heart rate were measured using a strain-gauge plethysmograph (Vasculab Strain-Gauge Plethysmograph SPG 16, Medasonics Inc, Mountain View, Calif) in the contralateral (not heated) arm. Each determination was the mean of at least 3 consecutive readings. At time 0, a primed (154 pmol/kg), continuous (7 pmol/min per kilogram) insulin infusion was started while plasma glucose was maintained at the basal, fasting level by an exogenous infusion of a 20% glucose solution. At 20-minute intervals during the second hour of the clamp, arterialized blood was sampled, and blood pressure, heart rate, and FBF were measured again. To avoid hemodynamic perturbation due to the blood loss (≈240 mL over 3 hours), the volume of each blood draw was replaced with an equal amount of a plasma expander (Haemagel, Behring, L’Aquila, Italy).
Studies were performed with the subject lying supine in a quiet, air-conditioned room. A Teflon cannula was inserted into the brachial artery (percutaneously, under local anesthesia with 2% lidocaine) for drug infusion at systemically ineffective rates. FBF in the two arms (by strain-gauge venous occlusion plethysmography), arterial blood pressure, and heart rate were monitored continuously. Forearm blood volume, determined by water displacement, was used for the preparation of drug solutions as all infusion rates were normalized per deciliter of forearm tissue. Three different sets of stimuli were given during the same session: (1) five 5-minute steps (0.15, 0.45, 1.5, 4.5, 15 μg/min per deciliter) of intraarterial ACh; (2) three 5-minute steps (1, 2, 4 μg/min/dL) of intraarterial NP; and (3) 13 minutes of forearm ischemia plus 1 minute of dynamic exercise of the hand. These tests explore, respectively, endothelium-dependent vasodilation,24 endothelium-independent vasodilation,25 and the structural properties of arteriolar walls.26 A subgroup of 17 patients also received a 5-step infusion of norepinephrine (0.0015, 0.0045, 0.015, 0.045, 0.15 μg/min per deciliter) superimposed on a constant infusion of propranolol (100 μg/min per deciliter) to assess α-adrenergic reactivity.
Plasma insulin was measured by radioimmunoassay (Insk 5, Sorin Biomedica, Vercelli, Italy). Plasma glucose was assayed by the glucose oxidase method (Glucose Analyzer, Beckman Instruments, Fullerton, CA, USA). Total cholesterol and triglycerides were measured by an enzymatic-spectrophotometric method (Eris Analyzer 6170, Eppendorph Geratebau, Hamburg, Germany). HDL-cholesterol was measured as total cholesterol after LDL and VLDL particles were precipitated with MnCl2 (1.06 M) and sodium heparin (2400 USP/mL).
M value was calculated as the average glucose infusion rate during the last 40 minutes of the 2-hour insulin clamp, after correction for changes in the glucose pool (with a glucose distribution volume of 250 mL/kg), and normalized for kg of LBM. Areas under plasma glucose and insulin curves during the OGTT were calculated by the trapezium rule. FBF was expressed either as absolute values (in mL/min/dL of forearm tissue) or as percent changes above baseline or else as the blood flow ratio of the infused to the contralateral (control) forearm (FBF ratio). Minimal forearm vascular resistance was calculated as the ratio of mean arterial blood pressure to maximal postischemic FBF. The vascular response to ACh or NP was estimated both as the maximal vasodilatation and as the slope of the respective dose-response curves (drug infusion rate versus FBF). The slope (% FBF increments above baseline per μg/min/dL of infused drug) was computed by a linear regression model with no intercept; for this analysis, the FBF value at the highest drug infusion rate was excluded because, with the doses here employed this value consistently falls outside the linear portion of the dose-response curve. Without this point, r2 values ranged from 0.68 to 1.00, with a mean value of 0.97 for the whole study group. For the norepinephrine studies, the sum of all FBF percent decrements was used as an integrated parameter of vascular α-adrenergic reactivity.
All data are expressed as mean±SEM. Between-group differences in mean values were analyzed by unpaired t test (for continuous variables) or χ2 test (for proportions). A 2-way ANOVA for repeated measures (within-subject repeated measures) over time was used to test the effect of the grouping variable, the effect of the experimental procedure, and their interaction. Simple and multiple regression analyses were performed by standard methods.
The clinical characteristics of the study population are given in Table 1⇓. All patients were male, with wide ranges of BMI, glucose tolerance, and blood pressure levels (as measured after pharmacologic washout). Insulin sensitivity also ranged 3-fold. When divided into tertiles of insulin sensitivity (n=10-9-10), the upper (IS) and lower (IR) subgroups had widely different levels of insulin sensitivity and insulin response to glucose ingestion, whereas glucose tolerance was similar (Fig 1⇓). The two groups were well matched on a host of characteristics that are potential confounders for vascular function and structure (Table 2⇓). Of particular note is that severity and duration of hypertension, left ventricular mass, and serum lipid profile were similar in IS and IR hypertensives.
Minimal vascular resistance—as measured immediately after 1 minute of hand exercise superimposed on 13 minute of ischemia—was similar in IS and IR subjects (3.2±0.6 versus 2.5±0.2 mm Hg/mL per minute per deciliter, P=.4) as were the respective maximal blood flow rates (FBF ratios: IS: 12±2 versus IR: 14±1, P=.4).
During the ACh and NP infusions, intraarterial blood pressure and blood flow to the control forearm remained stable throughout (data not shown). As depicted in Fig 2⇓, the vascular responses to ACh and NP, whether expressed as absolute FBF values, as percent increments above baseline, or as FBF ratios were not different in IS and IR hypertensives. Maximal FBF increments in response to ACh (IS: 666±219 versus IR: 528±156%, P=.61) and NP (IS: 464±74 versus IR: 572±88%, P=.54) also were similar in the two groups. Likewise, no difference between IS and IR patients was evident when vascular sensitivity was estimated through the comparison of the slopes of the dose-response curves: the mean incremental rates (in % per μg/min/dL) were 89±25 versus 77±19 for ACh, and 215±35 versus 231±49 for NP (IS versus IR, P=.70 and P=.79, respectively). In the whole group (n=29), no statistically significant correlation was found to exist between insulin-mediated glucose uptake and vascular reactivity, expressed as the maximal response or the slope of the dose-response curve, nor was there any relationship with postischemic blood flow or minimal vascular resistances (Fig 3⇓).
During the insulin clamp, plasma insulin concentrations rose to similar plateaus in the two groups (IS: 603±25, IR: 562±20 pmol/L), while euglycemia was maintained throughout the study (with a mean intraindividual variability of 9±1%). At baseline, systolic and diastolic blood pressure (143±7/96±3 versus 145±6/99±3 mm Hg, IS versus IR), heart rate (61±2 versus 64±1 bpm), and FBF (4.1±0.6 versus 3.4±0.6 mL/min per deciliter of forearm tissue) were similar in the two groups. During the final 40 minutes of the clamp, systolic blood pressure remained stable, diastolic blood pressure tended to decrease (−3%), and heart rate to increase (+6%), but only the changes in heart rate reached statistical significance (P<.01 by ANOVA), with no difference between the two study groups. FBF also showed a trend toward increasing during the clamp in both groups, particularly the IS group (+53±21 versus +9±7% of the IR group, n=20, P=.06).
In the whole group, the clamp-induced changes in FBF were weakly related to the M value (r=.44, P<.02) and to the slope of the ACh dose-response curve (r=.40, P<.04), whereas no relationship was observed with BMI (r=−.30, P=.12) or the other indices of vascular reactivity or with postischemic vascular resistance. In a multiple regression model, the M value and the slope of the ACh response together explained 30% of the variability of clamp-induced vasodilatation (multiple r=.55, P<.01).
The 17 patients who received the norepinephrine infusion were also divided into tertiles (n=6-5-6). These IR and the IS subgroups were similar with respect to age (IS: 49±2, IR: 54±3 years, P=.25), BMI (IS: 25.1±0.63, IR: 26.4±0.89 kg/m2, P=.27), systolic and diastolic blood pressure (IS: 144±11/101±3, IR: 148±9/101±3 mm Hg, P=.78 to .94), and disease duration (IS: 8±1, IR: 6±2 years, P=.27). Insulin sensitivity (M value) was 61.9±2.5 and 31.5±3.4 μmol/min per kilogram of LBM in IS and IR hypertensives, respectively (P<.001). As depicted in Fig 4⇓, vasoconstriction in response to graded norepinephrine infusions was superimposable in the two subgroups by all flow indices.
In the present study, whole-body insulin sensitivity, forearm vascular reactivity, and minimal vascular resistances were measured in patients with essential hypertension. When the patients in the upper and lower tertile of insulin sensitivity were compared, minimal vascular resistances, endothelium-dependent and endothelium-independent vasodilatation, and α-adrenergic vasoconstriction of the forearm vessels were found to be similar. Of note is the fact that the two groups were very well matched not only for blood pressure values but also for gender distribution, age, body mass, degree and duration of hypertension, and plasma lipid profile; proportion of treated patients and duration of antihypertensive treatment were also comparable. Thus, most of the known factors that can affect vascular reactivity and structure were well balanced between the two groups. The degree of adiposity (BMI) was slightly, though not significantly, higher in IR than IS patients (Table 2⇑). However, insulin sensitivity was normalized by unit of LBM to attenuate its dependence on BMI (with this correction, the correlation coefficient between M and BMI fell from .51 to .39). In addition, since in the whole group BMI bore no relation either to minimal vascular resistances (r=.03) or to other vascular indices of forearm vasodilatation such as ACh slope (r=−.05) or maximal response (r=−.17), NP slope (r=.25) or maximal response (r=−.016), it is unlikely that a small difference in the degree of adiposity might have confounded the results.
The fact that the usual correlates of insulin resistance (ie, obesity, high serum triglycerides, low HDL-cholesterol, and higher WHR) were not significantly different between IS and IR patients may be explained by a selection bias: the present sample of hypertensive patients were all male, had multiple inclusion criteria (BMI, glucose tolerance, serum triglycerides, and total cholesterol levels), and were chosen to have mild to moderate hypertensive disease of relatively short duration. Different relations may be found in patient groups with different clinical manifestations of insulin resistance.
The mean M value of the IR hypertensives (27.3 μmol/min per kg of LBM or 3.4 mg/min per kg of body weight) is below the 20th percentile of the distribution of M values reported for a healthy cohort of 330 white males of comparable age and BMI.27 In the face of this marked insulin resistance, the absence of detectable abnormalities in adrenergic reactivity and endothelium-mediated or endothelium-independent vasodilatation militates against the hypothesis that, in patients with essential hypertension, an impaired metabolic response to insulin is involved in the genesis, or even marks the presence, of vascular abnormalities. The similarity of minimal vascular resistances in IR and IS patients protects against the possibility that the observed functional vascular responses might be confounded by differences in arteriolar structure. In addition, it argues against a major impact for insulin resistance or hyperinsulinemia (Fig 1⇑) on vascular wall hypertrophy.
The presence of endothelial dysfunction12 and insulin resistance28 in similar proportions (∼40%) of patients with essential hypertension, the finding of a blunted vasodilatory response to insulin in metabolically IR hypertensives,11 and the relation of insulin’s vascular effect to endothelial NO synthesis29 have led to the hypothesis that reduced insulin-mediated vasodilatation—due to a selective deficiency of NO synthesis—may limit insulin and glucose access to target tissues, thereby causing insulin resistance in essential hypertension. However, we report here complete dissociation between ACh-mediated vasodilatation and insulin-mediated glucose uptake, indicating that in patients with essential hypertension insulin action on glucose metabolism, at least within the physiological domain, does not depend on the efficiency of the endothelium-dependent vasodilatory pathway. In support of the present results, others have recently reported a lack of association between ACh-induced vasodilatation and insulin-mediated glucose uptake in normotensive subjects.30 In addition, in normal individuals Scherrer et al29 observed that, when insulin-induced calf vasodilatation was prevented by L-NMMA infusion, insulin-mediated glucose uptake was unchanged. Finally, we recently reported that familial hypercholesterolemia—a naturally occurring model of chronic impairment of NO synthesis31 —is not associated with insulin resistance.32 In conclusion, the hypothesis that the endothelium through NO synthesis may amplify insulin action, if attractive, is not supported by the available evidence.
Distinct from vascular function—as explored by the local dose-responses of vasoagonists—are the vascular effects of insulin. Although our experiments were not designed to specifically address this issue, we did find that systemic insulin administration was associated with variable degrees of forearm vasodilatation (mean FBF increase=22±8%, P<.02 versus zero) ranging from −23% to +188%. This change in FBF, in the whole population, was positively related to both whole-body insulin sensitivity and to local vascular sensitivity to ACh (as estimated by the ACh dose-response slope). In contrast, there was no relationship between clamp-induced vasodilatation and minimal vascular resistances or vascular reactivity to NP or norepinephrine. The hyperemia observed during systemic insulin administration is probably the sum of complex local and systemic insulin effects whose relation to metabolic insulin resistance is at present unclear. In fact, insulin interacts with multiple vasoconstrictive and vasodilatory mechanisms4 5 6 29 33 ; therefore, its net effect depends on the balance of these forces. This might well explain the high interindividual variability of the vascular response to systemic insulin infusion as well as the relatively weak relationship between this response and insulin-mediated glucose uptake or ACh sensitivity.
Our hypertensive patients showed similar vasoconstriction to exogenous norepinephrine regardless of insulin resistance. This observation does not support the possibility that IR hypertensives might be characterized by a higher adrenergic vascular reactivity, as has been described in obese and diabetic patients.34 35 On the other hand, we cannot exclude that a higher basal α-adrenergic tone, as has been reported in essential hypertension,36 may be related to insulin resistance. Similarly, we cannot exclude the possibility that insulin resistance is coupled with a greater vascular sensitivity to other vasoconstrictors, such as angiotensin II or L-NMMA. With regard to the latter, it has recently been reported that, in healthy volunteers the proportion of basal blood flow that is dependent on NO synthesis (L-NMMA inhibitable) is positively associated with insulin sensitivity.30 Unfortunately, in that study clamp-induced vasodilatation was not assessed; therefore, the cause-effect link between the vascular and metabolic effect of insulin remains indeterminate. In addition, in the basal state the NO-dependent proportion of blood flow is modest (20%), but it rises to 40% of total flow in the insulinized state.37 Therefore, the sensitivity of the NO pathway appears to be a more relevant parameter than its basal tone. Our experiments were, in fact, planned in order to see whether the vascular bed of essential hypertensives with insulin resistance was normally responsive to stimuli that use the NO pathway. Since a normal NO generation could still result in a blunted vascular response if smooth muscle cells are resistant to nitrates or in the presence of structural abnormalities of the vascular wall, we used ACh, NP, and maximal ischemia as probes for a host of possible abnormalities of the dilatory function as a whole.
In summary, the present results indicate that in essential hypertension metabolic insulin resistance does not segregate with abnormal vascular structure, ACh and NP vasodilatation, or α-adrenergic reactivity. Systemic insulin infusion elicits variable forearm vasodilatation, which is only partially explained by whole-body glucose metabolism and forearm vascular responsiveness to ACh.
Selected Abbreviations and Acronyms
|BMI||=||body mass index|
|FBF||=||forearm blood flow|
|IDDM||=||insulin-dependent diabetes mellitus|
|LBM||=||lean body mass|
|M||=||whole-body insulin-mediated glucose uptake|
|NIDDM||=||non–insulin-dependent diabetes mellitus|
|OGTT||=||oral glucose tolerance test|
- Received January 6, 1997.
- Revision received February 18, 1997.
- Accepted March 2, 1997.
- Copyright © 1997 by American Heart Association
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