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(Hypertension. 1997;30:1150-1155.)
© 1997 American Heart Association, Inc.

Articles

Fatty Acids, Not Insulin, Modulate ₁-Adrenergic Reactivity in Dorsal Hand Veins

Konrad T. Stepniakowski; Gang Lu; Gregory D. Miller; Brent M. Egan

From the Division of Clinical Pharmacology, Departments of Pharmacology and Medicine, Medical University of South Carolina, Charleston.

	Abstract

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Abstract Resistance to the vasodilator action of insulin and its capacity to antagonize vascular -adrenergic reactivity may contribute to the increased neurovascular tone and blood pressure in obese hypertensive subjects. We showed that nonesterified fatty acids (NEFAs) were elevated in obese hypertensive subjects and that raising NEFAs locally in dorsal hand veins of healthy normotensive subjects enhances ₁-adrenoceptor reactivity. Research by others suggests that insulin antagonizes ₁-adrenoceptor tone in dorsal hand veins. Taken together with evidence that NEFAs antagonize several of the metabolic actions of insulin, these observations raise the possibility that NEFAs participate in resistance to the vascular effects of insulin and suggest that dorsal hand veins represent a good model for studying these interactions. Thus, we produced local hyperinsulinemia in the dorsal hand veins of six lean normal volunteers and quantified changes of venous distensibility in response to phenylephrine in the presence and absence of a local elevation of NEFAs. We confirmed that raising NEFAs locally decreased by twofold to threefold the phenylephrine ED₅₀ (P<.01), but this ₁-sensitizing action of NEFAs was not antagonized by insulin concentrations up to 1000 µU/mL. Moreover, local hyperinsulinemia alone did not affect vascular ₁-adrenergic sensitivity as measured by the phenylephrine ED₅₀. To address the possibility that the absence of an insulin effect reflected a lack of nitric oxide–mediated, endothelium-dependent dilation in hand veins, responses to acetylcholine were obtained. Acetylcholine relaxed preconstricted hand veins by 60% to 80% (P<.01) in the presence and absence of indomethacin, which suggests substantial endothelium-dependent, cyclooxygenase-independent vasodilation. The results confirm that raising NEFAs locally enhances vascular ₁-adrenoceptor sensitivity. Despite the presence of significant endothelium-dependent dilation in dorsal hand veins, insulin does not antagonize vascular ₁-adrenoceptor sensitivity in the presence of either ambient or locally elevated fatty acids.

Key Words: fatty acids, nonesterified • insulin • adrenoceptors • acetylcholine • indomethacin

	Introduction

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The clustering of cardiovascular risk factors in abdominally obese patients exceeds that which can be explained by chance.¹ Some investigators proposed that impairment of the vasodilator action of insulin can explain defects of glucose disposal as well as elevated blood pressures among insulin-resistant subjects.² Thus, selective resistance to the various actions of insulin emerges as a common pathogenetic denominator in the risk factor cluster.³ Moreover, several reports indicate that insulin reduces -adrenergic vasoconstriction^{4 5 6 7} and that the capacity of insulin to attenuate -adrenergic tone is impaired in subjects with insulin resistance.⁸ Retention of the sympathetic nervous system–activating properties of insulin⁴ combined with attenuation of the capacity of insulin to oppose -adrenergic vasoconstriction might contribute to the increased vascular -adrenergic tone^{9 10} and the elevated blood pressures in obese subjects.

Hyperinsulinemia and resistance to the vascular actions of insulin may not be primary explanations for the elevated blood pressures in abdominal obesity. For example, the elevated blood pressures in obese hypertensive patients were associated more strongly with resistance to the nonesterified fatty acids (NSFA)-lowering action of insulin than with defects of insulin-mediated glucose disposal.¹¹ Furthermore, the increased vascular -adrenergic reactivity observed in obesity⁹ was produced in the dorsal hand vein of lean normotensive subjects by NEFAs being raised locally to levels observed in obese subjects.¹²

NEFAs oppose several of the metabolic actions of insulin,¹³ and it is possible that NEFAs also oppose the vascular effects of insulin. Whereas NEFAs enhance ₁-adrenoceptor–mediated constrictor responses in dorsal hand veins,¹² insulin dilates phenylephrine-preconstricted dorsal hand veins.^{8 14} Consequently, insulin^{8 14} and NEFAs¹² seem to have opposing actions in dorsal hand veins. With the dorsal hand vein model,¹² we studied the separate and combined effects of local increases of insulin and NEFAs on ₁-adrenoceptor sensitivity to phenylephrine in normal volunteers.

	Methods

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Human Volunteers
Eight healthy normotensive volunteers, which included four women and four men (five white, three black) 23 to 45 years old, were recruited through advertising and paid a stipend. Each volunteer underwent a medical history and physical examination to confirm his or her health status. All volunteers signed a written informed consent document that was approved by the General Clinical Research Center Review Committee and the Office of Research Protection at the Medical University of South Carolina. Subjects followed an American Heart Association Phase I Diet for 1 week before participating in the outpatient study at the General Clinical Research Center. Subjects abstained from caffeinated beverages for 24 hours and from aspirin-containing medications for 2 weeks before the study.

Physiological and Biochemical Measurements
Dorsal hand vein distensibility was measured with the linear variable differential transducer technique (LVDT 100 MHR; Lucas Schaevitz).¹⁵ Serum insulin was measured by radioimmunoassay as previously described.¹⁶

Study Protocols
Protocol 1, Study 1
After fasting overnight, six subjects underwent dorsal hand vein distensibility studies.¹⁷ In each hand, a straight segment of dorsal vein at least 2 cm in length and without tributaries was selected for study. A 25-gauge butterfly needle was inserted into the two veins, and an infusion of normal saline at 0.3 mL/min was started immediately. Linear variable differential transducers were placed over each dorsal hand vein 1 cm proximal to the tip of the butterfly cannula, and the forearms were elevated above heart level to collapse the hand veins. Subjects acclimatized to the room temperature of 25°C to 26°C for 30 to 60 minutes. The skin temperature of the hand was maintained at 34°C to 35°C by servocontrolled heating pads around the forearms.¹⁷ The reproducibility of hand vein distensibility was established within ±10% by repeated baseline measurements. One hand was randomly assigned as the control and the contralateral hand as experimental. The infusion rate throughout the study was maintained constant at 0.3 mL/min by the use of three different infusion lines at 0.1 mL/min each. The control hand received a combined infusion of 0.35% human serum albumin¹⁸ (Albumin, Baxter) at 0.1 mL/min, 0.9% NaCl/heparin 10 U/mL or intralipid 10%/heparin 10 U/mL in random sequence on separate days at 0.1 mL/min, and 0.9% NaCl at 0.1 mL/min. In the experimental hand, insulin (Humulin, Eli Lilly), at a concentration of 7500 µU/mL in 0.35% albumin, was infused at 0.1 mL/min or 750 µU/min. Sixty minutes later, the saline infusion was replaced by phenylephrine (Elkin-Sinn) at 1 to 10 000 ng/min at a rate of 0.1 mL/min for each dose. Hand vein distensibility was measured between minutes 4 and 6 of each phenylephrine dose. After 7 to 10 days, the protocol was repeated with the complement of either the 0.9% NaCl/heparin or 10% intralipid/heparin.

Protocol 1, Study 2
In six subjects, the same study was repeated except that the insulin infusion rate was increased from 750 µU/min to 2.5 mU/min.

Protocol 2
To document the changes of insulin concentrations in dorsal hand veins during the local infusion, 6 subjects underwent studies on another day. Blood samples were obtained 2 cm downstream from the infusion site of insulin in 0.35% human albumin at 750 µU/min in the left hand and 2.5 mU/min in the right hand at baseline and 30, 60, and 90 minutes later.

Protocol 3, Part A
The reproducibility of hand vein distensibility was established within ±10% by repeated baseline measurements. The infusion volume throughout the experiment was maintained at 0.3 mL/min. During the first hour, 0.9% NaCl/heparin 10 U/mL was infused at 0.1 mL/min and 0.9% NaCl at 0.2 mL/min. After 60 minutes, the 0.9% NaCl infusion rate was decreased to 0.1 mL/min and a third line was added for infusing phenylephrine 1 to 10 000 ng/min at a rate of 0.1 mL/min for each dose. Hand vein distensibility was measured between minutes 4 and 6 of each dose. The phenylephrine dose that produced 60% reduction in dorsal hand vein distensibility from baseline was obtained in each hand vein and infused for the remainder of the study. After 30 minutes of stable preconstriction, acetylcholine was infused at 0.03 to 100 nmol/min at a rate of 0.1 mL/min for each dose in place of 0.9% NaCl at 0.1 mL/min. Each acetylcholine dose was infused for 6 minutes, and hand vein distensibility was measured between the fourth and sixth minute.

Protocol 3, Part B
The same study was repeated on another day in six subjects except that an indomethacin infusion (1 µg/min at 0.1 mL/min) was begun in a dorsal hand vein 30 minutes before the 0.9% NaCl/heparin infusions. Indomethacin was continued throughout the phenylephrine preconstriction and terminated just before the infusion of acetylcholine.

Data Analysis
Data are presented as mean±SEM. Analyses were performed with SPSS. The dose-response curves to phenylephrine were analyzed with a four-parameter logistic equation with Prism 1.0 (GraphPad Software).¹² Values for ED₅₀ are presented as geometric means and were compared with an independent-sample Mann-Whitney test. The venous responses to acetylcholine in the presence and absence of indomethacin were analyzed with two-factor ANOVA (with or without indomethacin [factor 1]; acetylcholine dose [factor 2]). A value of P<.05 was accepted as statistically significant.

	Results

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Protocol 1, Study 1
As shown in Fig 1, the local infusion of insulin at 750 µU/min (Fig 1A) did not significantly affect the phenylephrine-dose, venoconstrictor-response curve (ED_50, 342 ng/min) compared with the infusion of 0.35% human serum albumin in the control hand (ED_50, 275 ng/min; P=NS). Compared with the 0.9% NaCl/heparin control day, the infusion of intralipid/heparin reduced the ED₅₀ for phenylephrine (69 versus 275 ng/min, P<.01). The enhancement of vascular ₁-receptor reactivity in the experimental hand (Fig 1B) produced by raising NEFAs locally was not affected by the coinfusion of insulin at 750 µU/min (ED_50, 71 ng/min; P=NS).

View larger version (20K): [in this window] [in a new window]   Figure 1. A local insulin infusion at 750 µU/min in the experimental hand compared with 0.35% human serum albumin in the control hand did not significantly affect venoconstrictor responses to phenylephrine (A). Coinfusion of intralipid/heparin into both dorsal hand veins similarly enhanced constrictor responses to phenylephrine (reduced the ED50) in experimental (insulin) and control (vehicle) hands (B).

Protocol 1, Study 2
As shown in Fig 2, insulin infused at 2.5 mU/min did not change vascular ₁-adrenergic reactivity compared with the control infusion of 0.35% human serum albumin (ED_50, 349 versus 297 ng/min; P=NS; Fig 2A). Raising fatty acids locally through infusion of intralipid/heparin decreased the phenylephrine ED₅₀ similarly both in the control hand (106 ng/min, P<.05) and in the experimental hand receiving the insulin infusion (98 ng/min, P<.05; Fig 2B). Thus, the higher insulin infusion rate did not attenuate the effect of NEFAs to reduce the phenylephrine ED₅₀.

View larger version (20K): [in this window] [in a new window]   Figure 2. A local insulin infusion at 2.5 mU/min in the experimental hand compared with 0.35% human serum albumin in the control hand did not significantly affect venoconstrictor responses to phenylephrine (A). Coinfusion of intralipid/heparin into both dorsal hand veins similarly enhanced constrictor responses to phenylephrine in both the experimental (insulin) and control (vehicle) hands (B).

Protocol 2
Data on insulin concentrations at the time of local insulin infusion were obtained on five subjects. Technical difficulties precluded measurements in one volunteer. Infusion of insulin into the dorsal vein of the left hand at 750 µU/min increased the local serum concentration of insulin from baseline values of 14±1 to 656±236, 574±90, and 645±120 µU/mL at 30, 60, and 90 minutes, respectively. Comparable values in the right hand, which received the 2.5 mU/min insulin infusion, were increased from 13±1 at baseline to 1087±269, 1054±321, and 1052±276 µU/mL at 30, 60, and 90 minutes, respectively.

Protocol 3
Acetylcholine dilated hand veins preconstricted with phenylephrine in both the presence and absence of indomethacin (Fig 3, P<.01). In the presence of indomethacin to block the generation of cyclooxygenase products, the venodilator response to acetylcholine was shifted to the right (ie, a significant difference was noted between the two curves in the two-factor ANOVA when comparing the response to the 0.01 and 1.0 nmol/min acetylcholine infusion rates were compared; F, 5.11; P<.03). However, when the curves of the entire dose-response relation (0.01 to 100 nmol/min) were compared, no significant differences were found between the two curves. Both with and without indomethacin, the venodilator response was reversed at higher acetylcholine infusion rates, which is consistent with previous reports¹⁹ and probably reflects a direct constrictor action of this compound on vascular smooth muscle.²⁰

View larger version (19K): [in this window] [in a new window]   Figure 3. Hand veins were preconstricted with phenylephrine. Acetylcholine was then infused on two separate days in the absence () and presence () of indomethacin to block the generation of cyclooxygenase products. Error bars are shown in only one direction to enhance clarity.

	Discussion

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The principal findings of this study are twofold. First, the results confirm that local elevations of NEFAs increase vascular ₁-adrenergic reactivity in dorsal hand veins. Second, despite the presence of significant endothelium-dependent, cyclooxygenase-independent dilation, insulin does not modify vascular ₁-adrenergic responses in dorsal hand veins in the presence of either ambient or locally elevated NEFAs.

Given the important competitive metabolic interactions between insulin and NEFAs,^{21 22 23} and in view of the vascular actions of both insulin^{2 8} and NEFAs,^{12 24 25} surprisingly little is known about their vascular interactions. In fact, this is the first study to examine the interactions between insulin and NEFAs in the regulation of vascular ₁-adrenergic reactivity. We confirmed our previous report that fatty acids raised locally significantly enhanced vascular ₁-adrenoceptor sensitivity as measured by a reduction of the phenylephrine ED₅₀ (Fig 1).¹² However, the addition of local hyperinsulinemia with concentrations in the upper pathophysiological range of 600 to 1000 µU/mL did not attenuate the capacity of NEFAs to enhance vascular reactivity to phenylephrine. Thus, even very high concentrations of insulin in normal volunteers did not diminish the effect of fatty acids to augment local venous ₁-adrenoceptor responses.

A strong positive correlation was observed between abnormalities in NEFA concentration and turnover during euglycemic hyperinsulinemia and blood pressure values in obese subjects.¹¹ These correlations were independent of insulin resistance, defined as glucose disposal during the euglycemic clamp, and hyperinsulinemia, assessed by the integrated insulin response to an oral glucose tolerance test. NEFAs raised locally in lean normotensive subjects to levels observed in obese hypertensive subjects augmented dorsal hand vein reactivity to phenylephrine, an ₁-adrenoceptor agonist, but did not significantly augment responses to angiotensin II¹² or clonidine,²⁴ a partial ₂-adrenoceptor agonist. NEFAs raised locally also increased the magnitude and duration of reflex venoconstriction to thigh cuff inflation.²⁴ This study, combined with the results of our previous investigations,^{12 24 26} raises the possibility that abnormalities of NEFAs, through vascular effects, participate in the enhanced neurovascular tone^{9 10} in obese hypertensive subjects independently of resistance to the vascular actions of insulin.

Previous studies in animals showed that raising the fatty acid/albumin molar ratio with an intralipid/heparin infusion reversibly increased resistance in most vascular beds and raised blood pressure systemically.²⁵ Mechanisms by which acute elevation of circulating NEFAs augment vascular tone remain unknown. However, our present and previous reports^{12 24} indicate that an interaction of NEFAs with ₁-adrenoceptor–mediated contraction may contribute to increased vascular resistance when fatty acids are raised systemically. This notion also finds support from studies in rats that showed interactions between dietary fatty acid content and sympathetic neuronal function.²⁷ Diets rich in olive oil (C18:1) and corn oil (C18:2) augmented ₁-adrenergic sensitivity and endogenous norepinephrine release compared with low-fat diets.²⁸ Long-term manipulation of dietary fatty acid content results in alterations of the fatty acid composition of membrane phospholipids and membrane fluidity, which can modify adrenergic processes.²⁹

The acute increase of local oleic and linoleic fatty acid concentrations²⁴ produced in our study is unlikely to change the composition of membrane phospholipids. However, ₁-adrenoceptor–mediated contraction uses a phosphoinositol pathway as a second messenger system with the activation of protein kinase C.³⁰ The direct activation of protein kinase C by fatty acids,³¹ which occurs in vascular smooth muscle cells,³² may contribute to the enhanced vascular responses to phenylephrine. Alternatively, infusion of lipid emulsions may generate oxygen radicals that inhibit prostaglandin synthetase.³³ Linoleic acid, which makes up 50% of the NEFAs esterified to glycerol in the intralipid used in this study, serves as a substrate for arachidonic acid formation.³⁴ Arachidonic acid is metabolized by cyclooxygenase, lipoxygenase, and cytochrome P-450 pathways to several vasoactive products.³⁵

Abdominally obese subjects have elevations of plasma NEFAs and insulin that may both increase sympathetic drive.^{4 36} Retention of the sympathetic nervous system–activating properties of insulin⁴ combined with a defective vasodilator action^{2 8} may lead to increased vascular -adrenergic tone and blood pressure in obese, insulin-resistant subjects. Previous studies suggest that dorsal hand veins provide a useful model for studying the vascular actions of insulin, because resistance to the venodilator action of insulin has been observed in obese and insulin-resistant subjects.^{8 14} Despite the apparent utility of the hand vein model, results from the present study indicate that local hyperinsulinemia does not affect ₁-adrenergically mediated constriction in dorsal veins of the human hand (Figs 1 and 2). These data parallel our report on insulin and -adrenergic reactivity in the arterial circulation of the human forearm.²⁶

Our data do not exclude the possibility that resistance to the local actions of insulin contributes to increased -adrenergic tone in some vascular beds. Insulin induces a nitric oxide–mediated, endothelium-dependent dilation.^{37 38} Although variable,³⁹ some reports indicate that acetylcholine does not cause significant endothelium-dependent dilation in dorsal hand veins.⁴⁰ The absence of the vascular actions of insulin may have reflected a lack of endothelium-dependent dilation in the hand veins of our volunteers.⁴¹ Previous studies showed that the dilation response of hand veins to acetylcholine is substantially nitric oxide–mediated³⁹ and endothelium dependent.¹⁹ Other research indicates that the response to acetylcholine is also prostaglandin dependent.⁴² In this study, differences were noted in the venodilator response to acetylcholine in the presence and absence of indomethacin, which suggests a role for cyclooxygenase products, especially in the response at low acetylcholine doses. Nevertheless, acetylcholine dilated hand veins by 65% and 85% in the presence and absence of indomethacin, respectively (Fig 3). These findings combined with previous reports^{19 39} suggest that the absence of the vascular actions of insulin do not reflect an inability of hand veins to generate an endothelium-dependent dilator response.

The discrepancies in studies of the effects of insulin on hand veins are also evident in studies of the effects of insulin on arterial responses. In one study, euglycemic hyperinsulinemia augmented the systemic pressor effects of norepinephrine.⁴³ In contrast, another investigation⁴⁴ found that euglycemic hyperinsulinemia reduced pressor reactivity to norepinephrine among lean insulin-sensitive volunteers. The effect of insulin to attenuate norepinephrine pressor reactivity was reduced in obese subjects.

Previous studies on vascular interactions between fatty acids and insulin found that maintaining plasma NEFAs during a euglycemic clamp, instead of allowing them to decline, decreased carbohydrate oxidation without affecting insulin-induced vasodilation and sympathetic responses.⁴⁵ These findings suggest that fatty acids do not affect the systemic vasodilator response to hyperinsulinemia, whereas our data indicate that local hyperinsulinemia does not alter the ₁-vasoreactivity to a local elevation of NEFAs.

In addition to the concern about the extrapolation from a dorsal hand vein to the systemic vasculature, other limitations should be noted. We could not evaluate whether insulin reduced basal vascular tone, because dorsal hand veins are almost completely dilated at the servocontrolled skin temperature of 34°C to 35°C used in this study.⁴⁶ In addition, hand vein responses to phenylephrine were analyzed by dose and not concentration, with the phenylephrine ED₅₀ serving as an index of vascular ₁-adrenoceptor sensitivity. Another concern is time-dependent interactions between fatty acids and insulin. When intralipid was infused at the beginning instead of after 2 hours of the insulin clamp study, the increase in insulin-mediated glucose oxidation was completely inhibited and the rise of nonoxidative glucose disposal diminished.⁴⁷ On the basis of these data, infusions of intralipid/heparin and insulin were begun simultaneously.

In summary, in healthy volunteers, NEFAs raised locally in dorsal hand veins augment the vascular responses to phenylephrine. Despite the presence of endothelium-dependent dilator responses, local hyperinsulinemia neither affects ₁-adrenergic vasoreactivity nor attenuates the capacity of NEFAs to augment vascular ₁-adrenoceptor reactivity in hand veins. These observations add to the evidence that NEFAs have vascular effects that may participate in the pathophysiology of obesity hypertension.

	Acknowledgments

 
This research was supported by grant RO1-HL-43164 from the NIH, General Clinical Research Center grant 5M01-RR-01070 from the NIH, and a grant-in-aid from the American Heart Association, South Carolina affiliate. The authors thank the nursing staff in the outpatient General Clinical Research Center for expert assistance in conducting the study. We are also grateful to Dr Mary Walsh, Division of Endocrinology, Wayne State University School of Medicine, for directing the insulin assays.

	Footnotes

 
Reprint requests to Brent M. Egan, MD, Division of Clinical Pharmacology, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29425.

Received August 15, 1996; first decision December 25, 1996; accepted May 28, 1997.

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