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(Hypertension. 1997;30:1634-1639.)
© 1997 American Heart Association, Inc.

Articles

Fatty Acids Augment Endothelium-Dependent Dilation in Hand Veins by a Cyclooxygenase-Dependent Mechanism

Konrad T. Stepniakowski; Gang Lu; Rajesh K. Davda; ; Brent M. Egan

From the Division of Clinical Pharmacology, Department of Medicine and Pharmacology, Medical University of South Carolina (Charleston).

	Abstract

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Abstract Evidence supports the hypothesis that elevated nonesterified fatty acids (NEFAs) in patients with insulin resistance, eg, obese hypertensive subjects, contribute to increased vascular -adrenergic reactivity and tone by impairing endothelium-dependent vasodilation. To generate further support for this notion, we studied responses to endothelium-dependent and independent dilators under control (0.9% NaCl/heparin) conditions in one hand and with elevated NEFAs in the contralateral hand (10% intralipid/heparin). To observe venodilator responses, the dorsal hand vein diameter was first reduced by ~60% with phenylephrine. Studies were repeated with indomethacin to block the generation of cyclooxygenase products. In contrast to previous in vitro data, elevating NEFAs locally in vivo augmented rather than suppressed venodilator responses to the two endothelium-dependent dilators acetylcholine and methacholine (P<.05). Responses to the endothelium-independent dilator nitroglycerin were unaffected. Indomethacin attenuated the capacity of intralipid/heparin to enhance endothelium-dependent dilator responses to acetylcholine and methacholine. Indomethacin did not affect venodilator responses to nitroglycerin. The effect of intralipid/heparin to significantly reduce the phenylephrine infusion rate required to reduce hand vein diameter by ~60% was reversed by indomethacin. These data indicate that raising fatty acids locally augments endothelium-dependent dilation by a cyclooxygenase-dependent mechanism. The findings also suggest that NEFAs augment ₁-adrenoceptor–mediated constriction in hand veins by a cyclooxygenase-dependent mechanism. These hand vein studies do not support the notion that the elevated NEFAs in obese hypertensive patients augment ₁-adrenoceptor–mediated reactivity by reducing nitric oxide synthesis.

Key Words: fatty acids, nonesterified • nitric oxide • indomethacin • adrenoceptors • phenylephrine • vasodilation

	Introduction

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Obesity, particularly abdominal obesity, is associated with insulin resistance,¹ increased vascular -adrenergic reactivity,^2,3 and hypertension.^1,4 Insulin resistance appears to be pathogenetically related to hypertension,^4–6 but the intermediary mechanisms are not well defined. As one possibility, obese hypertensive patients have higher plasma nonesterified fatty acids (NEFAs)⁷ that are extremely resistant to suppression by insulin during a euglycemic clamp.⁸ Raising NEFAs locally in the dorsal hand veins of normal volunteer subjects to levels observed in obese hypertensive patients increases sensitivity to the constrictor effects of phenylephrine, an ₁-adrenoceptor agonist.⁹ These observations suggest a pathogenetic link between resistance to insulin's antilipolytic action with defects of NEFA metabolism and the increased neurovascular tone in obese hypertensive patients.

There are several potential mechanisms by which NEFAs could enhance ₁-adrenoceptor reactivity including effects on membrane ion transport,¹⁰ protein kinase C,^11,12 eicosanoid metabolism,¹³ and endothelial function.^7,14 With regard to endothelial function, oleic and linoleic acids suppress nitric oxide (NO) synthase activity⁷ and prostacyclin production¹⁴ in cultured endothelial cells. Oleic acid impairs endothelium-dependent vasodilation in vascular rings in vitro.⁷ These observations raise the possibility that the elevated NEFAs in obese hypertensive patients inhibit endothelial NO and prostacyclin production which then contribute to enhanced neurovascular reactivity¹⁵ and elevated blood pressure.

Given this background, the primary purpose of the present study was to determine whether raising NEFAs locally would impair the dorsal hand venodilator response to endothelium-dependent and -independent dilators. Another goal was to assess the cyclooxygenase-dependent and -independent aspects of any observed NEFA effect(s).

	Methods

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Human Volunteers
Eight healthy normotensive volunteer subjects, 23 to 45 years of age, including 6 women and 2 men (5 white, 3 black) were recruited through advertisement and were paid. Several of the volunteers participated in a related study.¹⁶ Each volunteer underwent a medical history and 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 and Integrity at the Medical University of South Carolina. Subjects followed an American Heart Association Phase I Diet for 1 week before the outpatient study at the General Clinical Research Center. Subjects abstained from caffeinated beverages for 24 hours and aspirin-containing medications for 2 weeks before the study.

Physiological Measurements
Dorsal hand vein distensibility was measured with the linear variable differential transducer technique (LVDT 100 MHR; Lucas Schaevitz).⁹

Study Protocols
Study 1A
After fasting overnight, 7 subjects underwent the dorsal hand vein distensibility studies as described previously.^9,16 Some of the data obtained on subjects in Study 1 were included in another report.¹⁶ In brief, a straight segment of dorsal vein in each hand at least 2 cm in length and without tributaries was selected for study. A 25-gauge butterfly needle was inserted into those 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 proximally 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. Skin temperature on the hand was maintained at 34°C to 35°C by applying servo-controlled heating pads around the forearm as described elsewhere.¹⁷ The reproducibility of hand vein distensibility was established within ±10% by repeated baseline measurements. One hand was randomly assigned as control and the contralateral hand as experimental. The infusion volume was maintained constant at 0.3 mL/min in both dorsal hand veins.

The control hand received a combined infusion of 0.9% NaCl/heparin 10 U/mL at 0.1 mL/min and 0.9% NaCl at 0.2 mL/min. In the experimental hand, Intralipid 10%/heparin 10 U/mL at 0.1 mL/min and 0.9% NaCl at 0.2 mL/min were infused. After 60 minutes, the 0.9% NaCl infusion rate was decreased to 0.1 mL/min, and a third line was added for infusion of phenylephrine at 1 to 3000 ng/min (phenylephrine hydrochloride; Elkin-Sinn) at a rate of 0.1 mL/min for each dose. Hand vein distensibility was measured between the fourth and sixth minute of each phenylephrine dose. The phenylephrine dose producing ~60% reduction in hand vein distensibility from the basal value was obtained in each hand. This phenylephrine dose was then infused for the remainder of the study.

After a minimum of 30 minutes of stable preconstriction with phenylephrine, an ascending acetylcholine infusion (0.03 to 100 nmol/min) was started. Acetylcholine was also infused at a constant rate of 0.1 mL/min in place of 0.9% NaCl at the same rate. Each dose of acetylcholine was infused for 6 minutes, and hand vein distensibility was measured between the fourth and sixth minute.

Study 1B
The same study was repeated except that an indomethacin infusion (1 µg/min at 0.1 mL/min) was begun in dorsal veins of both hands 30 minutes before the intralipid/heparin and 0.9% NaCl/heparin infusions. The indomethacin infusion was continued throughout the phenylephrine preconstriction and terminated just before infusion of acetylcholine.

Study 2A/B
A protocol identical to that of Study 1A/B was repeated in 8 subjects (Part A) and 3 subjects (Part B [with indomethacin]) except that the acetylcholine infusion was replaced by a methacholine (0.3 to 1000 ng/min) infusion.

Study3 A/B
A protocol identical to Study 1A/B was repeated in 6 subjects except that the acetylcholine infusion was replaced by a nitroglycerin (0.1 to 300 ng/min) infusion. Repeat studies in the same subject were separated by 7 to 10 days.

Data Analysis
Data are presented as mean±SEM. Analyses were performed with SPSS statistical software. The acetylcholine, methacholine, and nitroglycerin dose to venodilator response curves were assessed using two-factor ANOVA. Comparisons were made between dose-response relationships to each individual dilator (factor 1) in the presence and absence of indomethacin or intralipid/heparin versus saline/heparin (factor 2). A value of P.05 was considered statistically significant.

The phenylephrine dose required to decrease hand vein diameter ~60% was recorded for the experimental (intralipid/heparin) and control (saline/heparin) hands in the presence and absence of indomethacin. Differences between these conditions were assessed using the Student's paired t test.

	Results

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Effects of Intralipid/Heparin and Indomethacin on Venodilator Responses
Acetylcholine
Venodilator responses to acetylcholine were enhanced in the hand vein receiving intralipid/heparin as compared with the hand vein receiving 0.9% NaCl/heparin (Fig 1A), F=4.55, P<.05). At the higher acetylcholine infusion rates, venodilation in the control hand was completely reversed. In the experimental hand, the dilator response to acetylcholine was reduced ~60% at the highest infusion rate. Local indomethacin pretreatment significantly reduced the dilator response to the lower doses of acetylcholine in the hand vein infused with intralipid/heparin (Fig 1B). Nevertheless, the maximum dilator response to acetylcholine was similar in the control and experimental hand veins and was observed at the 10-nmol/min infusion. Further increases in the acetylcholine infusion rate to 30 and 100 nmol/min similarly reversed dilation in both hand veins.

View larger version (19K): [in this window] [in a new window]   Figure 1. A, Acetylcholine-induced increase of distensibility in hand veins preconstricted with phenylephrine is shown for both the experimental (intralipid/heparin) and control (saline/heparin) hand veins. As indicated, intralipid/heparin caused a significantly enhanced venodilator response to acetylcholine. B, Same as A, except that both the experimental and control hand veins were pretreated with a local infusion of indomethacin to block the generation of cyclooxygenase products. As shown, pretreatment with indomethacin blocked the ability of intralipid/heparin to significantly augment venodilator responses to acetylcholine.

Methacholine
We observed substantial intersubject variability in vasodilator responses to methacholine. The methacholine dose at which venodilation was reversed also showed large intersubject variability. To minimize this variability, the methacholine response data were truncated to include doses from 0.03 to 30.0 ng/min. At these doses, the venodilator response to methacholine was significantly greater in the hand vein receiving intralipid/heparin than in the control hand vein receiving 0.9% NaCl/heparin (F=3.64; P<.05; Fig 2A). In three subjects, the methacholine infusion was repeated after indomethacin. Indomethacin abolished the ability of intralipid/heparin to enhance venodilator responses to methacholine (Fig 2B).

View larger version (16K): [in this window] [in a new window]   Figure 2. A, Methacholine-induced increase of distensibility in hand veins preconstricted with phenylephrine is shown for both the experimental (intralipid/heparin) and control (saline/heparin) hand veins. As indicated, intralipid/heparin caused a significantly enhanced venodilator response to methacholine. B, Same as A, except that both the experimental and control hand veins were pretreated with a local infusion of indomethacin to block the generation of cyclooxygenase products. As shown, pretreatment with indomethacin blocked the ability of intralipid/heparin to significantly augment venodilator responses to methacholine.

Nitroglycerin
In contrast to the findings with the two endothelium-dependent vasodilators acetylcholine and methacholine, nitroglycerin induced similar venodilation in both the experimental hand vein infused with intralipid/heparin and in the control hand vein infused with 0.9% NaCl/heparin (Fig 3A). The venodilator response to nitroglycerin, an endothelium-independent vasodilator, was unaffected by indomethacin (Fig 3B).

View larger version (18K): [in this window] [in a new window]   Figure 3. A, Nitroglycerin-induced increase of distensibility in hand veins preconstricted with phenylephrine is shown for both the experimental (intralipid/heparin) and control (saline/heparin) hand veins. As indicated, intralipid/heparin did not affect the venodilator response to nitroglycerin. B, Same as A, except that both the experimental and control hand veins were pretreated with a local infusion of indomethacin to block the generation of cyclooxygenase products. As shown, pretreatment with indomethacin did not significantly affect the venodilator response to nitroglycerin in the experimental hand vein receiving intralipid/heparin compared with the control hand vein receiving saline/heparin.

Effects of Intralipid/Heparin and Indomethacin on Reactivity to Phenylephrine
The mean level of preconstriction achieved with phenylephrine was not significantly different under the various conditions, ie, intralipid/heparin versus saline/heparin with and without indomethacin. For example, in the studies that used acetylcholine without indomethacin, the reduction in hand vein diameter achieved with phenylephrine in the intralipid/heparin (experimental) hand was 60±4% versus 61±4% in the saline/heparin (control) hand (P=NS). With indomethacin, values for the percentage preconstriction prior to infusion of acetylcholine in the experimental and controls hand veins were 66±3% versus 64±4%, respectively (P=NS).

In the absence of indomethacin pretreatment, intralipid/heparin, compared with the saline/heparin control, significantly decreased the mean phenylephrine infusion rate required to induce ~60% reduction in hand vein diameter (Table). A similar effect of intralipid/heparin to reduce the phenylephrine dose required to preconstrict hand veins was seen prior to infusions of acetylcholine, methacholine, and nitroglycerin, which were performed on different study days. In the presence of indomethacin, intralipid/heparin no longer caused a significant decrease in the phenylephrine dose required to induce ~60% reduction in hand vein diameter (Table) on any three of the study days.

View this table: [in this window] [in a new window]   Table 1. Phenylephrine Infusion Rates (ED60-80 in ng/min) Used to Preconstrict Hand Veins in All Three Studies

	Discussion

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The principal finding of this study is that intralipid/heparin increases venodilator responses to acetylcholine and methacholine but not nitroglycerin. The effects of intralipid/heparin on dorsal hand vein reactivity are reversed by indomethacin. The data suggest that raising fatty acids locally in dorsal hand veins enhances endothelium-dependent dilation by a cyclooxygenase-mediated mechanism.

Our in vitro experiments showed that oleic and linoleic acids induced a concentration-dependent reduction of NO synthase activity in cultured endothelial cells.⁷ The in vitro effects of these cis-unsaturated NEFAs on NO synthase activity occurred within the range of concentrations measured in vivo.⁷ Moreover, oleic acid impaired the relaxation response to acetylcholine but not to nitroglycerin in vascular rings. Coinfusing intralipid and heparin, to activate endothelial lipoprotein lipase and hydrolyze fatty acids from glycerol, approximately doubles the sum of linoleic and oleic acid concentrations locally in the dorsal hand vein.¹⁸ However, raising linoleic and oleic acid concentrations in dorsal hand veins did not suppress but rather enhanced endothelium-dependent dilator responses to acetylcholine and methacholine in dorsal hand veins by a cyclooxygenase-dependent mechanism (Figs 1 and 2).

There are several potential explanations for the difference between our in vitro and in vivo findings. First, the in vitro work was performed on bovine pulmonary artery endothelial cells and rabbit femoral artery rings, whereas the in vivo work was performed in human dorsal hand veins. Differences in endothelium-dependent responses between species and vascular beds^19–21 may have accounted for the differences between this and our previous reports. In support of this point, raising NEFAs systemically inhibits the regional dilator response to methacholine in the lower extremity.²² Thus, suppression of NO synthesis by fatty acids observed in vitro^7,14 may occur in selected vascular beds in vivo.²² Another possible explanation is that the in vitro experiments did not include blood cells. Leukocytes and platelets are responsive to NEFAs and may liberate numerous vasoactive products which could confound the interpretation of in vivo studies.^23,24 The design of the present study does not explain the difference between our in vitro and in vivo experiments.

The data with acetylcholine suggest that the dilator response is not mediated by NO alone, especially at low acetylcholine doses (Fig 1). In fact, two components of the endothelium-dependent dilator response to acetylcholine were apparent. Venodilation at the lower doses of acetylcholine (~0.1 to 1.0 nmol/min) was almost entirely cyclooxygenase-dependent, since this response was blocked by indomethacin. However, the maximal venodilator response to acetylcholine, although shifted to the right, remained largely intact in the presence of indomethacin, which suggests that acetylcholine has important cyclooxygenase-independent dilating capacity. Reversal of the dilator response to high-dose acetylcholine persisted with indomethacin (Fig 1B). This suggests that de novo formation of prostaglandin H₂ (PGH₂), an endothelial contracting factor,²⁵ was not essential in reversing the dilator response to acetylcholine. Our data are consistent with previous reports that low-dose acetylcholine is venodilator, whereas high-dose acetylcholine is venoconstrictor.^26,27

Previous work similarly indicates that acetylcholine induces endothelium-dependent dilation by both an NO and cyclooxygenase-dependent mechanism.²⁸ However, studies on mechanisms of the dilator response to acetylcholine in dorsal hand veins produced conflicting conclusions. The venodilator response of human hand veins to acetylcholine was blocked by coinfusion of N-monomethyl L-arginine, which reduces NO synthesis, but not by oral aspirin administration, which reduces cyclooxygenase products.²⁶ Removing the endothelium from dorsal hand veins essentially eliminated the dilator response to acetylcholine.²⁷ In contrast, acetylcholine induced a minimal and identical dilator response in dorsal hand veins both in the endothelium-intact and endothelium-denuded state.²⁰ The explanation for the discrepancies between studies is not clear. Whereas the cyclooxygenase-independent vascular effect of acetylcholine in our study was presumably mediated by NO,^26,27 other mechanisms (eg, activation of endothelium-dependent hyperpolarizing factor) cannot be excluded.²⁹

This study was not designed to examine the effects of fatty acids on vascular ₁-adrenoceptor reactivity. However, the findings indicate that infusion of intralipid/heparin reduces the phenylephrine dose required to preconstrict hand veins by ~60%. This observation is consistent with our prior research, which showed that raising fatty acids locally with an intralipid/heparin infusion increased ₁- but not ₂-adrenoceptor–mediated venoconstrictor responses.^9,16–18 NEFAs have several actions that could potentially account for the increased vascular ₁-adrenoceptor sensitivity. These include actions on one or more effectors such as membrane transport,¹⁰ protein kinase C,^11,12 eicosanoid metabolism,¹³ and endothelial function.^7,14 This study focused on endothelium-dependent dilation and the cyclooxygenase pathway in an attempt to better understand the effects of NEFAs on ₁-adrenoceptor sensitivity. As noted, we could not confirm the hypothesis that NEFAs impair endothelium-dependent dilation, which, in turn, might explain the increased vascular ₁-adrenoceptor reactivity.

The increase of ₁-adrenoceptor reactivity, assessed by the dose of phenylephrine required to induce ~60% reduction in dorsal hand vein diameter, was reversed by indomethacin (Table). These results suggest that a vasoconstrictor cyclooxygenase product explains the increased vascular ₁-adrenoceptor sensitivity when fatty acids are raised by a coinfusion of intralipid and heparin. The identity of that cyclooxygenase product is not revealed by our study. Thromboxane probably is not the explanation, since the vascular wall is not a major site of de novo synthesis for this eicosanoid.³⁰ The intralipid/heparin infusion raises linoleic acid,¹⁶ which can be elongated and desaturated to arachidonic acid.¹³ NEFAs also stimulate mitogen-activated protein kinase¹² with subsequent activation of phospholipase(s)³¹ and release of arachidonic acid.³² Arachidonic acid in the presence of cyclooxygenase is metabolized to PGH₂,²⁵ which can elicit vasoconstrictor responses by acting as an agonist at the thromboxane receptor. Thus, generation of PGH₂ during the intralipid/heparin infusion may account for the enhanced reactivity to phenylephrine that is blocked by indomethacin.

The indomethacin infusion rate of 1 µg/min, given a dorsal hand vein flow rate of ~1 to 2 mL/min,³³ would result in local concentrations of 0.5 to 1 µg/mL (~1.5 to 3 µmol/L), which are above the IC₅₀ of <1 µmol/L for inhibition of cyclooxygenase.³⁴ Indomethacin also inhibits phospholipase A₂ and phosphodiesterase and uncouples oxidative phosphorylation.^35,36 The effect of indomethacin on phosphodiesterase probably does not account for the capacity of NEFAs to enhance venodilator responses to acetylcholine and methacholine, since responses to nitroglycerin were unaffected. The indomethacin concentrations required for effects on phospholipase A₂ and oxidative phosphorylation are greater than levels we likely achieved.^35,36 Thus, indomethacin's effects on venous reactivity probably reflect cyclooxygenase inhibition.

In summary, NEFAs augment endothelium-dependent dilator responses by a cyclooxygenase-dependent mechanism. While the effects of fatty acids in the arterial and venous circulations may differ,²² this hand vein study does not support the notion that elevated NEFAs in obese hypertensive patients augment ₁-adrenoceptor–mediated constriction by inhibiting NO synthesis. This conclusion is consistent with a previous report that inhibiting NO synthesis with N-monomethyl L-arginine in dorsal hand veins blunted the dilator response to acetylcholine but did not augment the constrictor response to norepinephrine.²⁷ Our findings also suggest that NEFAs enhance ₁-adrenoceptor reactivity by a cyclooxygenase-dependent mechanism.

	Acknowledgments

 
This work was supported by the National Heart Lung and Blood Institute R01-HL43164, General Clinical Research Grant RR 01070 from the Division of Research Resources, and the University Research Committee at the Medical University of South Carolina. We thank the outpatient GCRC nursing staff for their superb technical support. Studies with acetylcholine were performed under FDA IND #47,934.

	Footnotes

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

Received May 26, 1997; first decision June 23, 1997; accepted July 14, 1997.

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