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(Hypertension. 1995;25:774-778.)
© 1995 American Heart Association, Inc.

Articles

Fatty Acids Enhance Vascular -Adrenergic Sensitivity

Konrad T. Stepniakowski; Theodore L. Goodfriend; Brent M. Egan

From the Division of Clinical Pharmacology, Departments of Pharmacology and Medicine, Medical University of South Carolina, Charleston (K.T.S., B.M.E.), and the Departments of Medicine and Pharmacology, University of Wisconsin, and Veterans Administration Hospital, Madison (T.L.G.).

	Abstract

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Abstract Hypertensive patients are heavier and have a more centralized body fat distribution, which is associated with risk factor clustering and resistance to insulin's actions, including suppression of plasma nonesterified fatty acids. We postulated that abnormalities of nonesterified fatty acids contribute to the increased vascular -adrenergic reactivity and tone observed in our previous studies of obese hypertensive subjects. To test this hypothesis, in two separate protocols 10% Intralipid was infused into a dorsal hand vein with heparin to activate lipoprotein lipase and raise fatty acid levels locally. In protocol 1, the effects of Intralipid/heparin compared with those of 5% dextrose/heparin on dorsal hand vein sensitivity to phenylephrine were assessed by use of the linear variable differential transformer technique in 8 normotensive subjects. In protocol 2, the effects of Intralipid/heparin were compared with those of saline/heparin on hand vein responses to both phenylephrine and angiotensin II in 11 normotensive African American women. Intralipid/heparin reduced the dose of phenylephrine required to produce 50% of the maximal venoconstrictor response from 582 to 137 ng/min (compared with dextrose/heparin, P<.01) in protocol 1 and from 293 to 137 ng/min (compared with saline/heparin, P<.01) in protocol 2. Intralipid/heparin did not significantly alter hand vein responses to angiotensin compared with saline/heparin. These data suggest that abnormalities of nonesterified fatty acids in obese hypertensive patients with risk factor clustering may contribute to their increased neurovascular tone.

Key Words: fatty acids, nonesterified • receptors, adrenergic, alpha • phenylephrine

	Introduction

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Hypertensive patients, as a group, are heavier than normotensive persons.¹ When matched for levels of overweight, hypertensive patients have higher waist-to-hip ratios than normotensive subjects; this ratio serves as an index of abdominal-to-gluteofemoral fat distribution.² The abdominal fat pattern is linked to cardiovascular risk factor clustering³ and is associated with increased nonesterified fatty acid levels and turnover, which are resistant to suppression by insulin.⁴ Raising levels of nonesterified fatty acids in vivo by coinfusing Intralipid and heparin⁵ increases resistance in most vascular beds and raises blood pressure.⁶ These observations suggest that the abnormalities of fatty acid metabolism in obese hypertensive patients may raise their blood pressure by elevating vascular resistance.

We found that overweight and obese subjects with elevated blood pressure had evidence for increased forearm vascular -adrenergic tone and reactivity^{7 8} that were not explained by resistance to the local vascular actions of insulin.⁹ Considering the preceding information, we postulated that nonesterified fatty acid abnormalities in obese hypertensive patients might contribute to their augmented vascular -adrenergic reactivity and tone. To test this hypothesis, the effects of raising fatty acids locally on vascular tone and responses to phenylephrine were investigated by infusing Intralipid with heparin.¹⁰ Because the vascular abnormality in obese hypertensive patients includes lower basal venous distensibility,¹¹ dorsal hand veins were studied with the linear variable differential transformer technique. A second study was conducted to test the effects of Intralipid/heparin on local vascular -adrenergic reactivity in African Americans, because there is evidence for impaired ß-adrenoceptor responses in this racial group that may enhance -adrenergic reactivity.¹² The second protocol also compared the effects of Intralipid/heparin on local venous responses to phenylephrine and angiotensin to assess the specificity of fatty acid effects on vascular reactivity.

	Methods

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Human Volunteers
Healthy, normotensive volunteers were studied: there were 8 subjects in protocol 1 and 11 African American women in protocol 2. Each volunteer had a medical history taken, and each underwent a physical examination to confirm his or her health status. All volunteers signed a written informed consent document 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 each outpatient study day at the General Clinical Research Center. Compliance was verified by questionnaire and calculated by use of NUTRITIONIST IV (N-Squared Computing).

Physiological, Anthropometric, and Biochemical Measurements
Dorsal hand vein distensibility was measured with the linear variable differential transducer (LVDT) technique.¹³ In brief, a 25-gauge butterfly needle 1 cm long was inserted into a dorsal hand vein. An infusion of 5% dextrose in water (protocol 1) or 0.9% NaCl (protocol 2) was started immediately at a rate of 0.1 mL/min with an infusion pump. The LVDT (100 MHR, Lucas Schaevitz) was placed on the dorsum of the hand with the core centering the vein 1 cm proximal to the tip of the infusion needle. The hand was elevated above heart level and the congesting cuff on the arm was connected to a rapid cuff inflator and air source (model E-20 and model AG-101, respectively; DE Hokanson). The forearm was encircled with a warming pad that was servocontrolled to maintain hand temperature at 35°C (CN76000 series, Omega Engineering Inc). Displacement of the LVDT core was amplified (ATA-101, Lucas Schaevitz) and recorded (EasyGraf TA240, Gould, Inc) for further analysis. The linear range of the LVDT core movement was ±2.5 mm. The LVDT was calibrated (Mitutoyo micrometer 197-101, MTI Corp), and the signal was amplified so that a 1-mm displacement of the core represented a 50-mm deflection on the recorder. All measurements of hand vein distensibility were made with the congesting cuff inflated to 45 mm Hg for 2 minutes. The coefficient of variation for baseline hand vein distensibility on different days was 11%.¹¹

Anthropometric measurements and calculations were performed as described.⁹

Study Protocols
Protocol 1
After fasting overnight, subjects underwent studies of dorsal hand vein distensibility with the LVDT on 2 separate days. Either 10% Intralipid or 5% dextrose was coinfused with 1 U/min heparin on 1 of the 2 study days in random sequence. Heparin was infused to activate lipoprotein lipase and hydrolyze fatty acids from the triglycerides in the Intralipid.⁵ The infusion rate was constant at 0.1 mL/min for 90 minutes. Phenylephrine was diluted in 5% dextrose and infused in sequential ascending doses of 2.5 to 5120 ng/min at a constant rate of 0.1 mL/min while the infusion of either dextrose/heparin or Intralipid/heparin was continued. Measurements were performed between the fourth and sixth minutes of each phenylephrine dose.

Protocol 1A was performed in four subjects (one woman, three men) on a separate day to determine the effects of locally infused Intralipid/heparin compared with 5% dextrose/heparin on fatty acid concentration in the dorsal hand vein. A 25-gauge butterfly cannula was placed in a dorsal vein of each hand. Approximately 3 cm from the point of entry for the 25-gauge butterfly, a 21-gauge butterfly was placed retrogradely so the tips of the two cannulas were separated by approximately 1.5 cm. Blood was drawn at baseline and at 0, 60, 120, and 180 minutes after the beginning of the infusion of dextrose/heparin and Intralipid/heparin for measurement of fatty acids. Samples were collected into evacuated tubes containing disodium EDTA and paraoxon (Sigma Chemical Co) to prevent in vitro lipolysis.¹⁴ Total nonesterified fatty acids in plasma were determined by the ⁶³Ni method.¹⁵

Protocol 2
Protocol 2, carried out in 11 African American women, was similar to protocol 1 except for the following points. First, dorsal hand vein distensibility was measured simultaneously in both upper extremities. In one hand, 0.9% NaCl and heparin (1 U/min) were coinfused, while in the contralateral hand 10% Intralipid/heparin was infused; the rate was 0.1 mL/min in each hand. After 60 minutes a sequential ascending dose of phenylephrine (1 to 3000 ng/min) diluted in 0.9% NaCl was infused at a rate of 0.1 mL/min while the saline/heparin or Intralipid/heparin was continued. Dorsal hand vein distensibility at a cuff inflation pressure of 45 mm Hg was obtained as described for protocol 1. After a separate baseline period of 30 to 45 minutes for reestablishment of stable hand vein distensibility, angiotensin in 0.9% NaCl was infused in ascending sequential doses ranging from 0.1 to 300 ng/min.

Data Analysis
Data are presented as mean±SEM. Geometric or logarithmic means are used to describe the dorsal hand vein response data because of the large intraindividual differences that were reported previously.¹⁶ The final data analyses were performed with SPSS 6.0 (SPSS Inc). The dose-response curves generated from the hand vein studies were analyzed by use of a four-parameter logistic equation, as described below, with INPLOT 4 (GraphPad Software) curve-fitting software to define 50% of the maximal venoconstrictor response (ED₅₀, an indication of sensitivity). The equation used was

where Y=effect, X=logarithm of concentration, A=E_min, B=E_max (E_min and E_max are minimum and maximum venoconstrictor responses to phenylephrine, respectively), C=log ED₅₀, and D=Hill coefficient of slope factor. A Wilcoxon matched-pairs, signed-ranks test was performed to compare ED₅₀ and E_max values for phenylephrine in both protocol 1 and protocol 2.

In protocol 2, the dorsal hand vein responses to angiotensin were generally small and showed evidence of tachyphylaxis, as previously noted.¹⁷ Because the angiotensin data did not fit the models available with the INPLOT 4 software, repeated-measures ANOVA was used to determine whether significant differences in dorsal hand vein distensibility from baseline occurred during either the saline/heparin or Intralipid/heparin infusion. Repeated-measures ANOVA was used to determine whether the responses to angiotensin were different during the Intralipid/heparin infusion compared with the saline/heparin infusion. Repeated-measures ANOVA was also used to compare the responses to phenylephrine coinfused with saline/heparin compared with Intralipid/heparin. A value of P.05 was considered statistically significant.

	Results

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Protocol 1
Descriptive characteristics of the eight volunteers in this study are shown in Table 1. Despite substantial intersubject variability in the response to phenylephrine, Intralipid/heparin consistently shifted the intraindividual dose-response curve to the left in each volunteer and reduced the ED₅₀ for phenylephrine compared with dextrose/heparin (Table 2, Fig 1). E_max, defined as the percentage reduction from the baseline value, was also enhanced by Intralipid/heparin to 87±3%, compared with 70±6% by dextrose/heparin (P<.01). In protocol 1A, total nonesterified fatty acid concentration increased by 49±32% after the first hour and by 93±38% after the second hour of the Intralipid/heparin infusion. At the same time points, changes of nonesterified fatty acids in the control vein (dextrose/heparin) were 0±12% and 12±10%. These differences of fatty acids on Intralipid/heparin were found by use of a one-sided Wilcoxon test to be marginally significant compared with those on dextrose/heparin (P=.07), given the limited number of subjects (n=4).

View this table: [in this window] [in a new window]   Table 1. Descriptive Characteristics of Subjects in Protocols 1 and 2

View this table: [in this window] [in a new window]   Table 2. Response of the Hand Vein to Phenylephrine During Infusions of 5% Dextrose and 10% Intralipid With Heparin in Protocol 1

View larger version (16K): [in this window] [in a new window]   Figure 1. Plot shows individual changes for the dose of phenylephrine required to produce 50% of the maximal venoconstrictor response (ED50) during infusion of 5% dextrose/heparin compared with infusion of 10% Intralipid/heparin (protocol 1).

Protocol 2
Descriptive characteristics of volunteers are provided in Table 1. The effects of Intralipid/heparin compared with saline/heparin on hand vein distensibility and the phenylephrine ED₅₀ and E_max are shown in Table 3. Although the decline in phenylephrine ED₅₀ was statistically significant on Intralipid/heparin compared with 0.9% NaCl/heparin, and the changes in E_max (P=.07) and hand vein distensibility (P=.08) were directionally similar to those observed in protocol 1, the changes narrowly missed statistical significance. The dose-response curve to phenylephrine during Intralipid/heparin was shifted to the left (F=4.04, P=.05) and also was nonparallel to the curve obtained during the infusion of phenylephrine with 0.9% NaCl/heparin. This interaction between phenylephrine dose and Intralipid/heparin compared with 0.9% NaCl/heparin (F=2.1, P<.05) indicates that Intralipid/heparin increased the slope of the hand vein response to this ₁-adrenoceptor agonist. The phenylephrine ED₅₀ during control infusion was statistically greater in protocol 1 than in protocol 2 (geometric mean, 582 versus 293 ng/min; P<.05).

View this table: [in this window] [in a new window]   Table 3. Response of the Hand Vein to 60-Minute Infusions of 0.9% Saline or 10% Intralipid and to Phenylephrine in Protocol 2

Angiotensin did not induce significant venoconstriction during the saline/heparin infusion, as depicted in Fig 2. In contrast, angiotensin produced a significant decline in dorsal hand vein distensibility during the Intralipid/heparin period (F=3.12, P<.05). However, by repeated-measures ANOVA, the venous responses to the sequential ascending dose infusion of angiotensin were not significantly different on Intralipid/heparin compared with 0.9% NaCl/heparin (F=1.6, P=.22).

View larger version (12K): [in this window] [in a new window]   Figure 2. Line graph shows effects of infusion of 0.9% NaCl/heparin compared with infusion of Intralipid/heparin on changes in dorsal hand vein distensibility during the infusion of angiotensin II (protocol 2).

	Discussion

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The principal finding of this study is that raising fatty acid levels locally by coinfusing Intralipid and heparin significantly reduced the dose of phenylephrine required to induce 50% of the maximal venoconstrictor response in dorsal hand veins. These data support the hypothesis that in obese hypertensive patients, the increased fatty acid concentration and turnover that are highly resistant to suppression by insulin¹⁸ may contribute to their increased neurovascular tone, as observed in our previous studies.^{7 8}

Other reports in the literature are also consistent with the position that the marked abnormality of nonesterified fatty acid metabolism in obese hypertensive patients may contribute to their increased vascular tone and blood pressure. For example, Bülow and colleagues⁵ reported that a systemic infusion of Intralipid and heparin to raise fatty acid levels increased resistance in most vascular beds and elevated systemic arterial pressures in healthy minipigs.⁶ Although the fatty acid levels achieved in that study were relatively high at approximately 2 mmol/L, these concentrations are comparable to levels seen after a high-fat meal in patients with familial combined hyperlipidemia,¹⁹ in whom there appears to be a high prevalence of hypertension.²⁰

We decided to test the hypothesis that fatty acids increase vascular -adrenergic responses by studying the effects of Intralipid/heparin on dorsal hand vein responses to phenylephrine. The rationale for this approach is based on our previous research, which indicated that vascular -adrenergic reactivity and tone are increased in overweight⁷ and obese subjects⁸ with elevated blood pressure and that the vascular abnormality in obese hypertensive subjects includes the veins.¹¹ The results indicate that Intralipid/heparin infusion increases both the dorsal hand vein sensitivity to phenylephrine, as measured by intraindividual changes in the ED₅₀, and maximum responses to phenylephrine in a group of predominantly white subjects.

The studies were repeated in African American women because compared with white women this group is disproportionately affected by high-risk obesity, which is associated with an excess of hypertension, non–insulin-dependent diabetes, and cardiovascular events.²¹ Moreover, previous reports suggest that the enhanced vascular -adrenergic reactivity in African Americans reflects their diminished ß-adrenoceptor sensitivity.¹² In the present study, the phenylephrine ED₅₀ was lower (P<.05) in normotensive African American women (293 ng/min) than in normotensive white volunteers (582 ng/min), which is consistent with other reports of increased vascular -adrenoceptor sensitivity in blacks. Of note, the combination of Intralipid and heparin lowered the phenylephrine ED₅₀ to a mean of 137 ng/min in both groups.

This study was not designed to identify potential mechanisms for the difference in ED₅₀ for the venoconstrictor response to phenylephrine. Although saline replaced dextrose as the diluent for phenylephrine in protocol 2, the combined effects of glucose and fatty acids on the endothelium (R.K. Davda et al, unpublished data, 1994, and Reference 22²² ) in protocol 1 would have been expected to augment rather than depress sensitivity to phenylephrine.^{23 24} Moreover, dextrose would tend to prevent the oxidation of phenylephrine more than saline, which, if anything, would have produced greater sensitivity in protocol 1 than in protocol 2. Another possibility, which was not addressed, is that dextrose, compared with saline, limited the capacity of heparin to activate lipoprotein lipase.

Despite the difference in subject selection and the substitution of saline for dextrose, the data generated in protocol 2 are directionally comparable to those in protocol 1; coinfusion of Intralipid/heparin increases sensitivity to phenylephrine, as quantified by a significant reduction in the ED₅₀. In fact, in both protocol 1 and protocol 2, Intralipid/heparin infusion significantly reduced the phenylephrine ED₅₀ to 137 ng/min. In both protocols, Intralipid/heparin infusion also increased maximum venous tone and E_max as well as basal venous tone, although the changes were marginally significant in protocol 2 (.05<P<.1).

Protocol 2 was designed to examine the specificity of the effect of fatty acids on local vascular reactivity by comparing responses to phenylephrine and angiotensin II. Phenylephrine, a relatively selective ₁-adrenoceptor agonist, and angiotensin exert their physiological effects by similar signal transduction mechanisms, ie, G protein–coupled receptors linked to the activation of phospholipase C. Although they are inconclusive, the results suggest that Intralipid/heparin enhances venoconstrictor responses to phenylephrine more than those to angiotensin. The failure of Intralipid/heparin to significantly enhance dorsal hand vein responses to angiotensin compared with the saline/heparin control may reflect several factors, including a limited sample size (n=11) or the comparatively poor venoconstrictor effects of angiotensin. The latter possibility is partially supported by the observation that Intralipid/heparin significantly enhanced responses to angiotensin when the analysis was restricted to the 7 subjects who manifested a venoconstrictor effect to angiotensin in the control (saline/heparin) hand. Other potential explanations for the failure of Intralipid/heparin to significantly enhance responses to angiotensin in all 11 subjects include tachyphylaxis to angiotensin and effects of fatty acids to lower the affinity of angiotensin for its receptor.^{17 25}

Previous research showed that heparin activates lipoprotein lipase and raises plasma nonesterified fatty acid levels by hydrolyzing triglycerides.¹⁰ The mechanisms by which fatty acids augment vascular -adrenergic sensitivity and maximum responsiveness were not examined in this study. Other studies indicate that fatty acids may raise vascular smooth muscle tone and resistance by inhibiting Na⁺,K⁺-ATPase,²⁶ decreasing membrane fluidity, altering transmembrane ionic fluxes,²⁷ changing the composition of membrane phospholipids, which may affect signal transduction, and directly activating protein kinase C.²⁸ Additional studies are required to discern which of these or other mechanisms explain the capacity of fatty acids to enhance vascular -adrenergic sensitivity.

In summary, these data indicate that fatty acids increase vascular ₁-adrenoceptor sensitivity in vivo and support the hypothesis that the abnormality of fatty acids in obese hypertensive subjects contributes to their enhanced -adrenergic tone.

	Acknowledgments

 
This work was supported by National Heart, Lung, and Blood Institute grant R01-43164; General Clinical Research Center grants to the Medical University of South Carolina (RR-01070) and the Medical College of Wisconsin (RR-00058); and the Department of Veterans Affairs. Dr Stepniakowski is the recipient of a Clinical Research Fellowship Award from the Medical University of South Carolina. The authors greatly appreciate the expert assistance of the General Clinical Research Center nursing, nutrition, core laboratory, and biostatistical staff at the Medical University of South Carolina and the Medical College of Wisconsin. Angiotensin was generously donated by CIBA-Geigy under our IND #25,421.

	Footnotes

 
Reprint requests to Brent M. Egan, MD, Division of Clinical Pharmacology, Medical University of South Carolina, 171 Ashely Ave, CSB 826H, Charleston, SC 29425.

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