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Circulation. 1996;93:1403-1410

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(Circulation. 1996;93:1403-1410.)
© 1996 American Heart Association, Inc.

Articles

Insulin Modulation of ß-Adrenergic Vasodilator Pathway in Human Forearm

Giuseppe Lembo, MD, PhD; Guido Iaccarino, MD; Carmine Vecchione, MD; Virgilio Rendina, MD; Lucia Parrella, PhD; Bruno Trimarco, MD

From the Istituto Neurologico Mediterraneo, Neuromed, Pozzilli (IS) (G.L., C.V., B.T.), and the Department of Internal Medicine, School of Medicine, Federico II University, Naples (G.I., V.R., L.P., B.T.), Italy.

Correspondence to Bruno Trimarco, MD, Medicina Interna, Università di Napoli Federico II, Via S Pansini 5, 80131 Napoli, Italy. E-mail trimarco@ds.cised.unina.it.


*    Abstract
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 *Abstract
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Background Insulin modulates sympathetic vasoconstriction, but the mechanisms underlying this effect are not completely elucidated. We have recently investigated the insulin effect on the {alpha}1- and {alpha}2-adrenergic vasoconstriction pathway, where it is still conflicting with the possible insulin influence on the ß-adrenergic vasodilator pathway. The aim of the present study was to investigate this issue.

Methods and Results The study was performed on the forearm of healthy humans, and all test substances were infused into the brachial artery at systemically ineffective rates. In five subjects, we evaluated isoproterenol-induced vasodilation (1, 3, 6, and 9 ng·kg-1·min-1) both under control conditions and during insulin infusion (0.05 mU·kg-1·min-1). In another group of five subjects, we tested whether the vasorelaxant effect of sodium nitroprusside (1, 2, 4, and 8 ng·kg-1·min-1) was modified by insulin. Moreover, to explore whether the interaction between insulin and forearm ß-adrenergic pathway participates in insulin modulation of sympathetic-evoked vasoconstriction, we measured in six normal subjects the forearm vascular response to lower-body negative pressure under control conditions and during intrabrachial infusion of insulin alone and in combination with a selective ß-adrenergic blocking agent (propranolol 10 µg/100 mL per minute). Finally, to verify whether insulin interaction with the ß-adrenergic pathway may also account for insulin modulation of {alpha}2-adrenergic vasoconstriction, we assessed the vascular response to a selective {alpha}2-adrenergic agonist before and after propranolol administration. Insulin exposure potentiated the vascular responsiveness to isoproterenol but did not affect the vasodilator response to sodium nitroprusside. Furthermore, the insulin-induced attenuation of sympathetic vasoconstriction was partially corrected by propranolol. In contrast, the insulin modulation of {alpha}2-adrenergic vasoconstriction was not influenced by ß-adrenergic blockade.

Conclusions Taken together, our results suggest that insulin modulation of sympathetic-induced vasoconstriction is carried out through an interaction of the hormone with the pathways of both {alpha}2- and ß-adrenergic receptors.


Key Words: forearm vascular resistance • nervous system • receptors, adrenergic, alpha


*    Introduction
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 *Introduction
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The actions of insulin are characterized by a wide variety of effects, including modulation of glucose and amino acid transport, activities of key enzymes in intermediary metabolism, rates of protein, DNA and RNA synthesis, transcription of specific genes, and cellular growth and differentiation. Recently, a large body of studies clearly showed that insulin also has relevant effects on the cardiovascular function through both a direct vasorelaxant action on peripheral vasculature1 2 3 and an indirect effect on the autonomic nervous system.4 5 6 In humans, in particular, although insulin evokes a net reflex increase in sympathetic outflow, it coincidentally can blunt the vasoconstrictive effect resulting from the reflex sympathetic activation.7 The balance between these different insulin actions might play an important role in the setting of hypertensive conditions.8 Thus, understanding the precise mechanisms by which insulin exerts its cardiovascular effects represents a significant challenge.

Recent studies clarified that insulin affects sympathetic outflow by a central neural mechanism6 acting on the anteroventral third ventricle.9 On the contrary, the mechanism by which insulin exerts its modulating action on reflex sympathetic vasoconstriction is not completely elucidated, but new knowledge is shedding light on this issue. In particular, we recently explored in humans the interaction between insulin and sympathetic vasoconstrictive pathways, demonstrating that insulin interacts selectively with the {alpha}2-adrenergic pathway.10 However, a recent study on aortic rings of normotensive rats also indicated that part of the modulating effect of insulin on adrenergic vasoconstriction could be ascribed to a facilitating effect on the ß-adrenergic vasodilator pathway.11 Conflicting results have been described in humans. In particular, Creager et al12 reported in 1985 that the vasorelaxant effect of insulin was abolished by a ß-adrenergic receptor blocking agent; more recently, Randin et al13 showed that propranolol administration could not modify the vascular action of insulin.

Therefore, we planned the present study to clarify whether insulin interacts with the ß-adrenergic pathway in the human forearm and eventually to verify whether the interaction between insulin and the ß-adrenergic pathway may also account for the modulation of {alpha}2-adrenergic vasoconstriction.


*    Methods
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 *Methods
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Subjects
The study group consisted of 28 normal volunteers (22 men, 6 women) ranging from 19 to 40 years of age (average, 30±1 years). Medical history, physical examination, and laboratory analyses were performed to evaluate the subjects' normalcy. Renal, liver, and endocrine functions were normal. Body weight was 77±2 kg; body mass index was 24.7±0.5 kg/m2. No subject had had recent changes in body weight or dietary habits. All subjects had a normal tolerance to a 75-g oral glucose load (according to the criteria of the National Diabetes Data Group).14 No subject was engaged in competitive sports or did intense physical activity during the days immediately before the study. Written informed consent was obtained from all participants. The experimental protocol was in accordance with institutional guidelines for human research.

Procedures
The study began at 8 AM in a quiet room with a constant temperature of 22°C to 24°C. All subjects were studied in a postabsorptive state in the supine position after a 12- to 15-hour overnight fast. No premedication was administered. On a subject's arrival at the laboratory, forearm volume was measured by water displacement. The forearm perfusion technique was performed as previously described.15 A plastic cannula was introduced in a retrograde manner into a large antecubital vein and threaded as deeply as possible. In the same arm, a second double-lumen catheter with the distal and proximal holes separated by {approx}3 cm (Arrow International Inc) was introduced into the brachial artery. The distal hole was used to infuse insulin and other test substances, and the proximal lumen was used to sample arterial blood entering the forearm that was uncontaminated by solutions infused downstream and to measure arterial blood pressure by means of a Statham P23Db pressure transducer. Systolic and diastolic pressures were recorded on a multichannel polygraph (Gould Instruments). Heart rate was determined from a simultaneously obtained ECG signal and calculated from the R-R interval. Bilateral blood flow (expressed in milliliters per 100 mL of tissue per minute) was measured by strain-gauge plethysmography16 with a Digimatic DM2000 (Medimatic) instrument with a calibrated mercury-in-Silastic strain gauge applied on each arm {approx}5 cm below the antecubital crease. Both arms were supported above heart level. Forearm blood flow (FBF) was measured simultaneously in both arms from the rate of the increase in forearm volume while venous return from the forearm was prevented by inflating a cuff around the upper arm. Forearm vascular resistance was calculated as the ratio of mean arterial pressure (diastolic pressure plus one third of the pulse pressure) to the FBF and expressed as arbitrary units reflecting millimeters of mercury per milliliter per 100 mL of tissue per minute. The intrasubject coefficient of variation was 7% based on two consecutive measurements taken at 1-minute intervals.

Protocols
All test substances were dissolved in NaCl 0.9% on the day of the study. The infusion rate of all substances into the brachial artery was chosen to act selectively in the experimental forearm without causing systemic effects.

The intra-arterial infusion of insulin (0.05 mU·kg-1·min-1), insulin plus propranolol (10 µg/100 mL per minute), or propranolol alone was performed 30 minutes before and throughout the application of the various vasoactive tests. Insulin infusion induced an increase in deep venous insulin concentration (from 51±6 to 506±35 pmol/L, n=22, P<.01) without affecting the systemic levels of the hormone (from 50±7 to 51±7 pmol/L, n=22, P=NS).

After complete instrumentation, all subjects rested at least 30 minutes to establish a stable baseline before data collection. Fig 1Down shows flow diagrams of the protocols.



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  		Figure 1. Study protocols. LBNP indicates lower-body negative pressure.

Series 1: Effects of Insulin on Isoproterenol- and Sodium Nitroprusside–Induced Forearm Vasodilation
To evaluate the effect of insulin on the forearm vasodilation induced by the ß-adrenergic receptor selective stimulation, we assessed in five subjects the responses to intrabrachial infusion of isoproterenol before and during intrabrachial infusion of insulin. Isoproterenol was administered at 1, 3, 6, and 9 ng·kg-1·min-1. Each drug dose was maintained for 10 minutes to analyze the vascular steady state response. To rule out the hypothesis that insulin could not specifically interact with the isoproterenol-induced vasodilation, we tested in another group of five subjects the hemodynamic effect of intra-arterial infusion of sodium nitroprusside17 18 (1, 2, 4, and 8 ng·kg-1·min-1) before and during insulin administration.

Series 2: Effects of Insulin and Insulin Plus Propranolol on Forearm Neurogenic Vasoconstriction
Lower-body negative pressure (LBNP; applied incrementally at 5, 10, 15, and 20 mm Hg for 5 minutes each) was used to cause a graded reflex forearm sympathetic vasoconstriction. An airtight chamber, similar to that described by Mark and Kerber,19 was placed over the lower portion of each subjects' body from the iliac crest down. Negative pressure applied to the chamber was monitored by a pressure transducer. FBF was measured in both arms during the last 90 seconds of each level of LBNP. To simplify the experimental protocol, we decided not to measure the changes in central venous pressure induced by LBNP, which represent the stimulus for sympathetic reflex activation. Thus, we used the simultaneous assessment of FBF in the contralateral arm to rule out the possibility that the changes in the vascular response in the experimental arm could result from a different decrease in central venous pressure during LBNP.

To verify the possible interaction between insulin and forearm ß-adrenergic pathways during insulin modulation of the forearm neurogenic vasoconstriction, we evaluated in six normal subjects LBNP-evoked hemodynamic responses under control conditions, during intrabrachial insulin infusion, and during simultaneous administration of insulin and propranolol, a ß-adrenergic receptor blocking agent. In addition, we evaluated the effect of propranolol on LBNP-evoked vasoconstriction in another group of six subjects.

Series 3: Effects of Insulin and Insulin Plus Propranolol on Forearm Vasoconstrictive Responses Induced by BHT-933
To rule out the possibility that an interaction between insulin and ß-adrenergic pathways may contribute to the insulin modulation of the {alpha}2-adrenergic vasoconstriction, we assessed the vascular response to intrabrachial infusion of the {alpha}2-adrenoceptor selective agonist BHT-933 under control conditions, during intrabrachial infusion of insulin, and during simultaneous intra-arterial infusion of insulin and propranolol in a group of six subjects. Dose-response curves were generated for each period. In particular, BHT-933 was infused at 0.5, 1, 2, and 4 µg·kg-1·min-1. Each drug dose was maintained for 10 minutes to analyze the vascular steady state response.

Analytical Methods
Plasma insulin was measured by radioimmunoassay.20

Data Analysis
Comparison of plasma insulin levels obtained in basal state and during intra-arterial infusion of the hormone was evaluated by Student's t test. One-way repeated-measures ANOVA was used to evaluate the responses to graded LBNP, isoproterenol, sodium nitroprusside, and BHT-933. To estimate the effect of insulin, insulin plus propranolol, or propranolol alone on the responses to LBNP, isoproterenol, sodium nitroprusside, and BHT-933, repeated-measures ANOVA with a grouping factor was performed. Post hoc simultaneous multiple comparisons were done by Bonferroni's analysis.21 Results are presented as mean±SE.


*    Results
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 *Results
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Effects of Insulin on Isoproterenol or Sodium Nitroprusside Forearm Vasodilation
The infusion of increasing amounts of isoproterenol in the brachial artery did not modify arterial blood pressure and heart rate but induced a dose-dependent vascular response in the experimental arm (Table 1Down and Fig 2Down). During insulin infusion, no significant difference could be detected in the hemodynamic parameters. Under these conditions, isoproterenol administration also induced significant vasodilation. However, the isoproterenol-induced vasodilator response was significantly increased in the presence of insulin (F=3.285, P<.05 by ANOVA; Fig 2Down).


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  		Table 1. Effects of Intrabrachial Infusion of Isoproterenol Under Control Conditions and During Intrabrachial Insulin Infusion on Arterial Pressure and Experimental FBF



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  		Figure 2. Forearm vascular responses to intrabrachial infusions of isoproterenol under control conditions ({circ}) and during insulin administration ({bullet}). Bases 1 and 2 represent values before and 30 minutes after the start of vehicle or insulin infusion, respectively. Each point represents mean±SEM. *P<.05 vs the same situation under control conditions.

In another set of experiments, the infusion of increasing amounts of sodium nitroprusside in the brachial artery did not influence arterial blood pressure (from 95±3 to 98±4 mm Hg, P=NS) and heart rate (from 81±3 to 77±7 beats per minute, P=NS) but induced a dose-dependent vasodilation in the experimental arm (Fig 2Up). In the same way, during insulin exposure sodium nitroprusside administration induced a dose-dependent vasodilation comparable in magnitude with that observed earlier (F=0.358, P=NS; Fig 2Up).

Effects of Insulin and Insulin Plus Propranolol on Forearm Neurogenic Vasoconstriction
As Table 2Down shows, mean blood pressure and heart rate remained substantially unmodified during graded LBNP both under control conditions and during infusion of insulin alone or insulin combined with propranolol. In contrast, LBNP induced a significant decrease in FBF and consequently an increase in forearm vascular resistance in both the experimental and contralateral arms (Fig 3Down). Furthermore, intra-arterial insulin infusion did not affect systemic and forearm hemodynamics. During insulin administration, however, LBNP induced a vascular response in the experimental arm that was significantly decreased compared with that observed when LBNP was applied under control conditions (F=19.683, P<.01; Fig 3Down). In contrast, the LBNP-induced forearm vascular response in the contralateral arm was comparable to that observed previously (F=0.485, P=NS). Finally, during intrabrachial infusion of both insulin and propranolol, LBNP induced a forearm vascular response in the contralateral arm that was comparable in magnitude to those observed both under control conditions and during infusion of insulin alone (F=0.634, P=NS; Fig 3Down), whereas in the experimental arm, LBNP-induced vasoconstriction was potentiated compared with that recorded during infusion of insulin alone (F=4.250, P<.05; Fig 3Down) but still blunted compared with that observed under control conditions (F=2.976, P<.05; Fig 3Down).


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  		Table 2. Effects of Graded LBNP on Arterial Pressure and FBF Under Control Conditions, During Insulin Infusion, and During Insulin Plus Propranolol Infusion



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  		Figure 3. Changes in forearm vascular resistance induced by the application of graded lower-body negative pressure (LBNP) under control conditions ({circ}) and during infusion in the experimental arm of insulin alone ({bullet}) or insulin plus propranolol (). Bases 1 and 2 represent values before and 30 minutes after the start of vehicle, insulin, or insulin plus propranolol infusion, respectively. Each point represents mean±SEM. *P<.05 vs the same situation under control conditions. {dagger}P<.05 vs the same situation during insulin alone.

In another set of experiments, intrabrachial propranolol infusion was not able to modify the LBNP-induced forearm vascular response (Table 3Down).


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  		Table 3. Effects of Graded LBNP on Arterial Pressure and FBF Under Control Conditions and During Propranolol Infusion

Effects of Propranolol on Insulin Modulation of the Forearm Vasoconstrictive Responses Induced by BHT-933
Under control conditions, the intrabrachial infusion of increasing amounts of BHT-933 did not modify blood pressure and heart rate but induced a dose-dependent decrease in FBF (Table 4Down) and consequently an increase in forearm vascular resistance in the experimental arm (Fig 4Down). During insulin administration, the intra-arterial infusion of increasing doses of BHT-933 still induced a dose-dependent vasoconstriction, but this response was significantly blunted compared with that produced by infusion of the same agent under control conditions (F=7.380, P<.05; Fig 4Down). During simultaneous intrabrachial infusion of insulin and propranolol, arterial blood pressure, heart rate, and FBF remained substantially unmodified (Table 4Down). Under these conditions, administration of BHT-933 induced a vasoconstrictive response similar to that observed during infusion of insulin alone (F=0.060, P=NS; Fig 4Down) and still significantly blunted compared with that observed under control conditions (F=6.319, P<.01; Fig 4Down).


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  		Table 4. Effects of Intrabrachial Infusion of BHT-933 Under Control Conditions, During Intra-arterial Insulin Infusion, and During Infusion of Insulin Plus Propranolol on Arterial Pressure and Experimental FBF



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  		Figure 4. Forearm vascular responses to intrabrachial arterial infusions of {alpha}2-adrenergic selective agonist BHT-933 under control conditions ({circ}) and during infusion of insulin alone ({bullet}) or insulin plus propranolol (). Bases 1 and 2 represent values before and 30 minutes after the start of vehicle, insulin, or insulin plus propranolol infusion, respectively. Each point represents mean±SEM. *P<.05 vs the same situation under control conditions.


*    Discussion
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 up arrowMethods
 up arrowResults
 *Discussion
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The present results in humans show that forearm insulin exposure can sensitize the vascular ß-adrenergic receptor responsiveness. Furthermore, the interaction between insulin and ß-adrenergic signal pathways also is supported by the evidence that insulin-induced attenuation of sympathetic vasoconstriction is partially reduced by a selective ß-adrenergic blockade.

There is much evidence in humans that insulin stimulates peripheral sympathetic efferent outflow but is simultaneously able to attenuate the vascular effects of sympathetic overactivity. One potential mechanism by which insulin modulates the vasoconstrictive effects of sympathetic nervous system activation could be a sensitizing action on the vascular ß-adrenergic receptor pathway. In vitro studies seem to support this hypothesis because an insulin-induced enhancement of vascular ß-adrenergic responsiveness was shown recently in aortic rings.11 Moreover, the interaction between insulin and the ß-adrenergic signal pathway also has been described in other cellular systems,22 23 24 further encouraging us to verify in humans the possible interaction between these two signal pathways at the vascular level.

On this issue, it is critical to consider the results of two previous studies reporting conflicting conclusions. Creager et al12 evaluated the cardiovascular response to insulin by administering increasing amounts of the hormone into the brachial artery, starting from 0.1 mU·kg-1·min-1, which was twofold higher than the dose used in our and similar studies designed to investigate the effects of physiological increases of insulin levels.6 10 25 26 Under these conditions, insulin spilled significantly into the systemic circulation, resulting in hypoglycemia and epinephrine release, and the forearm vasodilator response was completely abolished by the intrabrachial infusion of a ß-adrenergic blocking agent. In this setting, the conclusion that insulin-induced vasodilation was mediated through a ß-adrenergic mechanism was troubled by the concomitant confounding effect of hypoglycemia. Subsequently, to avoid the effects of systemic insulinization, Creager et al clamped blood glucose at its basal values. Under these conditions, a significant increase in FBF was observed only at the highest level of intrabrachial insulin infusion rate (1 mU·kg-1·min-1), which obviously exposed the forearm at elevated pharmacological amounts of insulin. In contrast, Randin et al13 recently reported that insulin, delivered intravenously and maintaining euglycemic conditions, could evoke an increase in calf blood flow and that such an effect was completely unaltered by systemic propranolol administration. In this setting, the conclusion that ß-adrenergic mechanisms were not involved in the vasodilator effect of insulin was troubled by the systemic infusion of propranolol, which has been reported to interfere heavily with the vascular response.27 28 In particular, systemic ß-blockade dissociates the response of calf vascular resistance from activation of muscle sympathetic nervous system,29 which represents the main component of the complex insulin action on the cardiovascular system. Thus, such an experimental approach cannot verify whether the vascular effects of insulin are mediated at least in part by an interaction between the hormone and the ß-adrenergic receptors.

Our approach takes into account the pitfalls of the above-mentioned studies and tries to overcome them by providing a model in which both insulin and propranolol are infused into the brachial artery at rates that do not induce systemic effects. Under these conditions, we could better evaluate the interaction of insulin and the sympathetic control of vascular function without the complex effects evoked by systemic insulinization. Confirming our findings6 7 10 and other observations,25 30 31 32 33 we could not detect significant changes in vascular resistance during forearm insulin exposure, whereas the vascular effects of the hormone were recognized only during forearm vasoconstriction evoked by sympathetic nervous system activation. In this study, we have observed that insulin potentiates the vasodilatation elicited by a selective pharmacological stimulation of ß-adrenergic receptors. Moreover, the parallel observation that insulin does not affect the vasodilation induced by sodium nitroprusside rules out the hypothesis that the hormone may elicit a generalized facilitation of vasodilation and suggests a specific interference with the ß-adrenergic receptor response. Our results also support the possibility that insulin-induced enhancement of the ß-adrenergic vascular response may play a role in a physiological recruitment of sympathetic vasoconstriction. Actually, the combined observations that intrabrachial propranolol administration partially restores the forearm vasoconstrictive response to LBNP during insulin infusion but could not influence the LBNP-evoked vasoconstriction per se further support the hypothesis that the interaction between insulin and ß-adrenergic pathways plays a role in insulin modulation of sympathetic-evoked vascular response. However, we have recently observed that the vascular {alpha}2-adrenergic pathway also is modulated by insulin; consequently, it was imperative to discern whether our previous observation should be at least partially modified after the disclosure of the relationship between insulin and ß-adrenergic pathways at the vascular level. Our data with the selective {alpha}2-adrenergic receptor agonist BHT-933 during propranolol administration clearly indicate that insulin modulation of {alpha}2-adrenergic vasoconstriction is not affected by simultaneous ß-adrenergic blockade. Taken together, our findings suggest that insulin exerts its modulatory role on sympathetic vasoconstriction through both a facilitation of ß-adrenergic signal and an impairing of {alpha}2-adrenergic vasoconstriction. On this issue, we also must emphasize that during insulin infusion ß-adrenergic blockade was able to restore the sympathetic-evoked vasoconstriction only partially, further suggesting that the {alpha}2-adrenergic component was still sensitive to the insulin-modulating action.

Several hypothetical mechanisms can be suggested to explain how insulin interacts with {alpha}2- and ß-adrenergic signals. In particular, both these adrenergic receptors regulate the intracellular level of cAMP, the second messenger in the transduction of these two signal pathways, and studies in cell culture systems indicate insulin to be a primary regulator of receptor-stimulated adenylyl cyclase activity.22 34 35 36 37 Moreover, a growing body of evidence suggests that the hemodynamic effect of insulin may be mediated by an enhanced endothelial function.38 39 In particular, a recent study on rat aortic rings preconstricted with norepinephrine showed that the ability of insulin to attenuate the adrenergic vasoconstriction is abolished when NG-monomethyl-L-arginine was used to inhibit nitric oxide synthase.40 In the same way, it should be mentioned that the ß-adrenergic potentiation observed in vitro during insulin exposure is not observed after endothelium stripping of aortic rings, thus indicating that insulin modulation of the ß-adrenergic vasodilation is endothelium dependent.11 Furthermore, the relevance of the insulin-enhanced endothelium-dependent vasorelaxation might be taken into account even for the modulation of the {alpha}2-adrenergic vasoconstriction. Actually, the {alpha}2-adrenergic receptors also are present on endothelial cells, and activation of the {alpha}2-adrenergic receptor signal transduction pathway represents a strong stimulus for endothelium-derived relaxing factor release.41 42 Thus, it could be reasonable to hypothesize a potential interaction of insulin at the endothelial {alpha}2- and ß-adrenergic signal transduction levels that promotes the generation of vasorelaxing products, which may modulate the vascular effects of sympathetic overactivity simultaneously evoked by insulin.

The strong epidemiological evidence linking essential hypertension to insulin resistance8 43 44 and the recent observations that this abnormality of insulin action is an inherited trait detected before the development of high blood pressure44 45 46 obviously encourage us to identify the precise physiological relationships between insulin effects and cardiovascular functions. Our current results, reporting a specific interaction between insulin and vascular {alpha}2- and ß-adrenergic signal pathways, may address in a more detailed way the next studies in hypertensive patients in whom a loss of insulin-induced attenuation of the sympathetic-evoked vasoconstriction has been reported.47 48

Received September 13, 1995; revision received October 30, 1995; accepted October 31, 1995.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
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 *References
 

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