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(Hypertension. 1996;27:723-728.)
© 1996 American Heart Association, Inc.

Articles

Obesity Hypertension Is Related More to Insulin's Fatty Acid Than Glucose Action

Brent M. Egan; Magda M.I. Hennes; Konrad T. Stepniakowski; Irene M. O'Shaughnessy; Ahmed H. Kissebah; Theodore L. Goodfriend

From the Division of Clinical Pharmacology, Departments of Pharmacology and Medicine, Medical University of South Carolina, Charleston (B.M.E., K.T.S.); the Division of Endocrinology, Metabolism, and Clinical Nutrition, Department of Medicine, Medical College of Wisconsin, Milwaukee (M.M.I.H., I.M.O., A.H.K.); and the Departments of Medicine and Pharmacology, University of Wisconsin and William S. Middleton Veterans Memorial Hospital, Madison (T.L.G.).

	Abstract

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Abstract Although resistance to insulin-mediated glucose disposal has emerged as a link between abdominal obesity and hypertension, abnormalities of nonesterified fatty acid metabolism may play a greater role. Analyses were performed on existing data from 17 abdominally obese subjects (11 hypertensive, 6 normotensive) to determine whether fatty acid concentration and turnover were related to blood pressure independently of hyperinsulinemia and resistance to insulin-mediated glucose disposal. Glucose utilization, fatty acid concentration, and fatty acid turnover were obtained fasting and during euglycemic hyperinsulinemia at 10 and 40 mU·m^-2·min^-1. Analyses were also performed on another group of 30 subjects with a wide range of risk factors who had blood pressure data as well as glucose and fatty acid measurements during an insulin tolerance test.

Fatty acid concentration and turnover were markedly more resistant to suppression by insulin in obese hypertensive than in lean or obese normotensive individuals. In the 17 obese subjects, blood pressure measured at screening, in the laboratory, and over a period of 24 hours correlated significantly with fatty acid concentration and turnover but not with glucose disposal measured during the hyperinsulinemic clamp. These correlations remained significant after fasting insulin, the insulin area under the curve during an oral glucose tolerance test, and glucose disposal during the clamp were controlled for. In the second group of subjects, plasma fatty acids 15 minutes after intravenous insulin also correlated with blood pressure. These correlations remained significant after insulin and an index of sensitivity to insulin-mediated glucose disposal were statistically controlled for. The data indicate that blood pressure is related to the effects of insulin on fatty acid metabolism. The findings raise the possibility that resistance of hormone-sensitive lipase to insulin participates in elevating the blood pressure of abdominally obese hypertensive subjects by increasing fatty acid concentration and turnover.

Key Words: obesity • insulin • glucose • fatty acids, nonesterified

	Introduction

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Obese hypertensive patients are more likely than obese normotensive subjects to have abdominal obesity, which is associated with hyperinsulinemia, insulin resistance, and coronary risk.¹ Although some mechanistic studies have linked hyperinsulinemia and insulin resistance to hypertension,^{2 3 4} others have not confirmed this association.^{5 6 7 8 9 10} Our strategy was to focus on abdominally obese subjects, since not all of them are hypertensive. We sought to identify metabolic differences between abdominally obese subjects that are related to interindividual differences in BP.

NEFAs are one factor that may link abdominal obesity to hypertension. For example, postprandial and/or 24-hour fatty acid values are elevated in subjects with diabetes¹¹ ; obesity,¹² especially the abdominal fat pattern¹³ ; and familial combined hyperlipidemia,¹⁴ conditions that are all associated with an increased prevalence of hypertension. NEFAs may increase vascular tone and BP by increasing sympathetic drive¹⁵ and vascular ₁-adrenergic receptor reactivity and tone^{16 17} while impairing endothelium-dependent vasodilation.¹⁸

We measured fatty acid concentration and turnover, which are indicative of postprandial^{13 19} and 24-hour^{11 20} regulation of NEFAs, during a euglycemic, hyperinsulinemic clamp. In reanalyzing existing data,^{21 22} we found that NEFA concentration and turnover during the euglycemic hyperinsulinemia were related to BP in abdominally obese subjects independently of insulin-mediated glucose disposal. After these correlations were found, data were reanalyzed on another group of 30 subjects who also had multiple determinations of BP as well as plasma NEFAs and glucose measurements during an insulin tolerance test²³ to determine whether the correlation of fatty acids to BP could be confirmed.

	Methods

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Data analyses were performed on two different groups of subjects included in previous reports.^{21 22 23} In brief, paid volunteers were recruited from the Hypertension Clinic and advertisement. The study protocol and potential risks were explained orally and in writing to all subjects, who each signed a copy of the approved written consent form before participation.

Subjects qualified for the euglycemic clamp study²¹ on the basis of history and physical and laboratory examinations, which included a standard 75-g, 2-hour, oral glucose tolerance test to exclude diabetics.²¹ BPs were measured in triplicate after 5 minutes in the seated position on three separate occasions with subjects off medications. Thirteen subjects (9 men, 4 women) were abdominally obese, insulin-resistant hypertensive subjects with body mass indexes >27 kg/m², waist-to-hip ratios >0.85 for women and >0.90 for men, means of three BPs on three occasions off all medications >140 mm Hg systolic and/or >90 mm Hg diastolic, and rate constants for the decline in plasma glucose <3.2 mg%/min during an insulin tolerance test.²⁴ Only two hypertensive subjects were excluded from results of the insulin tolerance test. Six men constituted the abdominally obese normotensive group, with body mass indexes >27 kg/m² and BP <140/90 mm Hg. Six volunteers were lean normotensive subjects with body mass indexes <25.5 kg/m² and BP <140/90 mm Hg.

Each subject was interviewed by the Clinical Research Center dietitian and instructed on a standardized, isocaloric diet that was controlled for sodium, potassium, calcium, and magnesium as previously described.²¹ To enhance compliance, subjects received all food and beverages from the Clinical Research Center in the week before admission.

Study Design and Protocol
After 4 weeks off medications and on the standard diet, volunteers were admitted to the Clinical Research Center. On day 1, subjects had a 3-hour oral glucose tolerance test and then continued the study diet. Ambulatory BP monitoring was then performed on the inpatient volunteers until 8 AM the following day.¹⁰ Subjects fasted overnight, and at 8 AM the next morning, BP was measured simultaneously by two observers using mercury sphygmomanometers in triplicate on opposite arms. BP was then measured simultaneously in triplicate by an observer and by a Dinamap 1846SX (Critikon, Inc) in opposite arms. At the beginning of the 2-hour basal period for the euglycemic clamp,²¹ primed-continuous infusions of ³H-3-glucose and ¹⁴C-palmitate were initiated. After this baseline, a primed-continuous infusion of human insulin was infused at 10 and then 40 mU·m^-2·min^-1 for 2 hours each, while the infusions of labeled glucose and palmitate were maintained. Plasma glucose was measured every 5 minutes, and the infusion rate of 20% dextrose was adjusted to maintain euglycemia. Plasma glucose, insulin, NEFAs by high-performance liquid chromatography, ³H-glucose, and ¹⁴C-palmitate were measured at 10-minute intervals, and O₂ consumption and CO₂ production by indirect calorimetry were measured as described during the last half hour of the three 2-hour periods.^{21 22}

In the second protocol, 30 subjects 45 years old,²³ with a wide range of cardiovascular risk factors but no overt cardiovascular disease, were studied off medications. All volunteers followed a low-NaCl (20 mEq/d), then a high-NaCl (approximately 200 mEq/d), diet for 7 days. During the last 2 days of the low- and high-salt diets, subjects underwent measurements of laboratory and ambulatory BP. On 1 of the 2 days, an insulin tolerance test was also performed after an overnight fast. After baseline measurements of glucose and fatty acids in triplicate, subjects received an intravenous bolus of 0.1 U/kg human insulin. Glucose was measured at 3, 6, 9, 12, and 15 minutes, and total NEFAs were measured at 15 minutes by the assay described by Barash and Akov based on the radioactive nickel method of Ho as described previously.²³ On the other day, a 75-g, 2-hour oral glucose tolerance test was performed with measurements of glucose and insulin fasting and at 15, 30, 60, 90, and 120 minutes.

Data Analysis
All data were analyzed with SPSS 6.0 for Windows (SPSS, Inc). Data are reported as mean±SEM. In the first (euglycemic clamp) protocol, comparisons between the three groups across the baseline and two-stage euglycemic clamp periods were made by one-way ANOVA followed by the post hoc Newman-Keuls multiple comparison test. Using data on the abdominally obese subjects only, relations between metabolic variables (NEFA concentration, NEFA flux, glucose disposal) and BP were assessed by multiple linear regression analysis (r values). The independent correlations between NEFA concentration and turnover to BP were examined with multiple stepwise linear regression analysis (partial r values). This allowed us to control statistically for the potential interrelations between hyperinsulinemia, resistance to insulin-mediated glucose disposal, and the effects of insulin on fatty acid metabolism. In the second protocol, the correlations between NEFAs fasting and 15 minutes after insulin versus BP at screening, in the laboratory, and over 24 hours were obtained. Partial correlation coefficients of NEFAs to BP were obtained by controlling for the rate of decline in plasma glucose disposal during the insulin tolerance test as well as fasting insulin and the insulin AUC during an oral glucose tolerance test.²³ For all analyses, values of P.05 were accepted as significant.

	Results

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Baseline Descriptive Characteristics for the Three Groups of Volunteers
Data were analyzed on 23 subjects, including 17 abdominally obese individuals. The sex composition of the three groups (M:F) was 5:1 for lean normotensive subjects, 6:0 for obese normotensive subjects, and 7:4 for obese hypertensive subjects (P=NS by one-way ANOVA followed by post hoc multiple comparison test). These three groups were of similar age, reported as 43±3, 43±3, and 45±2 years, respectively. Body mass index (23.5±0.3, 32.4±2.4, and 36.7±1.4) and waist-to-hip ratio (0.81±0.02, 0.94±0.03, and 0.94±0.02) were significantly greater (P<.05) in both abdominally obese groups than in lean normotensive subjects. Systolic and diastolic BPs (mm Hg) at the final qualifying visit (screening) were significantly greater (P<.01) in the obese hypertensive subjects (144±4/97±2) than in lean (120±2/74±3) or obese normotensive subjects (119±3/80±2).

Glucose Disposal
Data on insulin-mediated glucose disposal and fatty acid turnover in these subjects were reported.^{21 22} The amounts of glucose metabolized during the last 30 minutes of a 2-hour euglycemic clamp with insulin infused at 10 mU·m^-2·min^-1 in abdominally obese hypertensive subjects, abdominally obese normotensive subjects, and lean normotensive subjects were 77±7, 67±5, and 139±25 mg·m^-2·min^-1, respectively. Values during the 40–mU·m^-2·min^-1 clamp were 207±15, 201±30, and 375±19 mg·m^-2·min^-1, respectively. Values for glucose metabolized were similar in both obese groups and less than those in lean normotensive subjects at both insulin infusion rates.

NEFA Concentration and Turnover
Values for laboratory and ambulatory blood BPs and NEFA concentration and turnover during the last half hour of the basal period and euglycemic clamp with insulin infused at 10 and 40 mU·m^-2·min^-1 for all three groups are provided in Table 1. As shown, basal values for fatty acid concentration and turnover were greater in obese hypertensive subjects than in lean normotensive subjects but not different from those in obese normotensive subjects. However, fatty acid concentration and turnover were more resistant to suppression by insulin in obese hypertensive subjects than in either obese or lean normotensive subjects.

View this table: [in this window] [in a new window]   Table 1. Data on BP and Fatty Acids in the Three Volunteer Groups in Study 1

Correlations of BP to Measures of Fatty Acid and Glucose Metabolism
Study 1
Correlations between various BPs and NEFA metabolism in the 17 abdominally obese subjects are shown in Table 2. As shown, NEFA concentration and turnover during the 40–mU·m^-2·min^-1 insulin infusion were generally significantly correlated with BP, whereas glucose metabolized (M) and glucose disposal corrected for insulin concentration (M/I) were not. Correlations between BP and NEFA concentration and turnover at baseline and NEFA values during the 10–mU·m^-2·min^-1 insulin infusion were less robust (data not shown), whereas NEFA turnover at the lower insulin infusion rate correlated significantly with BP. The value for M and M/I obtained during the 10–mU·m^-2·min^-1 insulin infusion did not correlate significantly with BP (data not shown).

View this table: [in this window] [in a new window]   Table 2. Correlation Coefficients (r Values and Partial r Values) Between Measures of Fatty Acid, Glucose Metabolism, and BP and in Abdominally Obese Subjects in Study 1

The independent correlations of NEFA turnover during the 40–mU·m^-2·min^-1 insulin infusion and BP were obtained by multiple stepwise linear regression analysis, while fasting insulin, the insulin AUC during the oral glucose tolerance test, and glucose disposal during the 40–mU·m^-2·min^-1 clamp were controlled for separately (Table 2). The correlations between NEFA flux and BP remained significant after the other variables shown were controlled for.

Study 2
Data on the 30 subjects in this analysis were described.²³ The data were reanalyzed to determine whether the independent relation between fatty acids and BP could be confirmed in another group of volunteers. In brief, this group included 7 women and 23 men, age 40±5 (SD) years, with a BP of 138±16/91±11 mm Hg and body mass index of 29.6±7.2 kg/m². Plasma NEFAs at 15 minutes of the insulin tolerance test correlated with BP measured under different conditions (Table 3). As shown in Table 3, the correlation between NEFAs during the insulin tolerance test and BP, especially diastolic BP, was generally independent of fasting insulin, the insulin AUC during the glucose tolerance test, and the rate of decline in plasma glucose during the insulin tolerance test, an index of insulin sensitivity.²⁴ Scatterplots showing correlations of NEFA turnover during the 40–mU·m^-2·min^-1 euglycemic insulin infusion and plasma NEFAs at 15 minutes of the insulin tolerance test to diastolic BP are shown in the Figure.

View this table: [in this window] [in a new window]   Table 3. Correlation Coefficients (r Values and Partial r Values) of Fatty Acids at Baseline and During the ITT to BP During the Low-Salt Diet in Study 2

View larger version (18K): [in this window] [in a new window]   Figure 1. Left, Correlation is shown between fatty acid turnover during the 40–mU·m-2·min-1 insulin infusion (NEFA turnoverclamp40) and diastolic BP at screening for the 17 abdominally obese subjects in study 1. Right, Correlation between fatty acid concentration at minute 15 of the insulin tolerance test (NEFAITT) and diastolic BP at screening is shown for the 30 subjects in study 2.

	Discussion

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Although abdominal obesity is associated with hypertension, not all abdominally obese subjects are hypertensive. We studied both glucose and fatty acid metabolism during euglycemic hyperinsulinemia as possible determinants of elevated BP within abdominally obese subjects. The principal finding of this report is that NEFA concentration and turnover during euglycemic hyperinsulinemia are positively and independently correlated with BP measured at different times. The data suggest that variations in resistance to the antilipolytic action of insulin within abdominally obese subjects are one factor explaining BP differences within this high-risk group.

With respect to the relation between fatty acids and BP, at least three possible explanations exist. First, the hemodynamic, neurohumoral, and/or microvascular abnormalities present in hypertensive patients may elevate NEFA concentration and turnover.^{25 26 27} These explanations are limited by the finding that lean hypertensive patients were not more resistant to suppression of NEFAs during euglycemic hyperinsulinemia than normotensive controls.²⁸

Second, NEFA concentration and turnover may be related to hypertension by association with other factors such as hyperinsulinemia and resistance to insulin-mediated glucose disposal. However, the literature on this point is conflicting.^{2 3 4 5 6 7 8 9 10 29 30 31} And among abdominally obese subjects in our study, correlations between NEFA metabolism and BP were stronger than and independent of the correlations between insulin, insulin-mediated glucose, and BP.

Third, NEFAs may actively raise BP. Raising plasma NEFAs to approximately 2 mmol/L in minipigs elevates BP.³² Similar NEFA values were documented after a high-fat meal in subjects with familial combined hyperlipidemia,¹⁴ who are disproportionately represented among the hypertensive compared with the general population.³³ Raising plasma NEFAs may increase BP by eliciting a neurogenic reflex originating in the liver¹⁵ and by increasing vascular ₁-adrenergic tone and reactivity.^{16 17} Thus, NEFAs may contribute to the increased regional vascular -adrenergic tone observed in an overweight group of hypertensive subjects.³⁴ NEFAs may also increase vascular tone by inducing a mitogenic response in vascular smooth muscle cells,³⁵ impairing endothelium-dependent vasodilation,¹⁸ and changing membrane transport.³⁶

In our study, resistance to the effects of insulin on NEFA concentration and turnover was extreme in the hypertensive subset. In a previous report, NEFAs were suppressed in upper-body obese subjects by roughly half and turnover by approximately one third when insulin levels were raised only approximately 5 µU/mL above basal levels.¹³ By contrast, in our study, abdominally obese hypertensive subjects failed to suppress their NEFA concentration and turnover by 50% even when systemic insulin concentrations were raised approximately 100 µU/mL above basal values to a mean level of approximately 120 µU/mL.

The greater resistance to the fatty acid–lowering action of insulin in obese hypertensive subjects than in obese normotensive subjects could reflect impairment of the ability of insulin to inhibit hormone-sensitive lipase or a defect either in esterification of fatty acids or in oxidation of fatty acids. Since the turnover of NEFAs is greater during euglycemic hyperinsulinemia in obese hypertensive subjects than obese normotensive subjects, while suppression of oxidation is similarly impaired,²² the data suggest that a defect of insulin action at the level of hormone-sensitive lipase is related to BP. If resistance of hormone-sensitive lipase to inhibition by insulin participates in raising BP, then suppressing hormone-sensitive lipase by other means should lower BP. Pyrazinoylguanidine, which inhibits hormone-sensitive lipase and lowers plasma NEFAs,³⁷ decreases BP in patients with renal insufficiency, diabetes, and hypertension,^{37 38 39} three conditions associated with insulin resistance.⁴⁰

Limitations of our study include the following: First, while obese hypertensive subjects were selected on the basis of a screening test for resistance to insulin-mediated glucose disposal,²⁴ only two volunteers were excluded by this test. In addition, glucose disposal during the clamp was equally and markedly impaired in the obese hypertensive and obese normotensive subjects.²¹ More importantly, abdominally obese hypertensive subjects were not selected for defects in NEFA metabolism, which were strongly and independently associated with BP. Second, the observations represent an analysis of a relatively small number of abdominally obese subjects. To expand the number of subjects, data were analyzed on a different group with a broad range of cardiovascular risk factors who had measurements of plasma NEFAs at baseline and at 15 minutes of an insulin tolerance test. Again, the insulin tolerance test data, like the clamp results, showed that BP correlated with plasma NEFAs obtained during the hyperinsulinemic period.

We did not observe correlations between fasting NEFAs and BP in either the first or second study. As one possible explanation, resistance to insulin's NEFA-lowering actions in abdominally obese¹³ and diabetic subjects¹¹ coincides with impaired suppression of NEFAs during a mixed meal¹⁹ and higher plasma fatty acids over 24 hours.²⁰ Thus, subjects with the most resistance to the antilipolytic actions of insulin probably have higher NEFAs at other times during a normal day. The higher NEFAs may have sustained effects on BP by altering membrane composition and signal transduction processes with relatively prolonged actions, such as protein kinase C.⁴¹

In summary, the association between insulin resistance and BP in abdominally obese subjects appears to be more closely related to impairment of the capacity of insulin to suppress NEFA concentrations and turnover than to hyperinsulinemia or resistance to glucose disposal. These observations point to the adipocyte and resistance to suppression of hormone-sensitive lipase by insulin, with subsequent elevations in fatty acid concentration and turnover, as potentially important factors in BP homeostasis.

	Selected Abbreviations and Acronyms

 

AUC = area under the curve BP = blood pressure NEFA = nonesterified fatty acid

	Acknowledgments

 
This research was supported by NHLBI grants R01-43164 and R01-34989, the Department of Veterans Affairs, General Clinical Research Center (GCRC) grants M01-RR-00058 to the Medical College of Wisconsin and M01-RR-01070 to the Medical University of South Carolina, and a clinical investigator fellowship award from the Medical University of South Carolina (Dr Stepniakowski). The authors appreciate the expertise and support of the GCRC nursing, nutrition, core laboratory, and biostatistical staff at the Medical College of Wisconsin.

	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.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Stern M, Haffner S. Body fat distribution and hyperinsulinemia as risk factors for diabetes and cardiovascular disease. Arteriosclerosis. 1986;6:123-129. [Abstract/Free Full Text]

2. Rocchini AP, Katch V, Kveselis D, Moorehead C, Martin M, Lampman R, Gregory M. Insulin and renal sodium retention in obese adolescents. Hypertension. 1989;14:367-374. [Abstract/Free Full Text]

3. Lind L, Lithell H, Pollare T. Is it hyperinsulinemia or insulin resistance that is related to hypertension and other metabolic cardiovascular risk factors? J Hypertens. 1993;11(suppl 4):S11-S16.

4. Baron AD, Brechtel-Hook G, Johnson A, Hardin D. Skeletal muscle blood flow: a possible link between insulin resistance and blood pressure. Hypertension. 1993;21:129-135. [Abstract/Free Full Text]

5. Muller DC, Elahi D, Pratley RE, Tobin JD, Andres R. An epidemiological test of the hyperinsulinemia-hypertension hypothesis. J Clin Endocrinol Metab. 1991;76:544-548. [Abstract]

6. Hall JE, Coleman TG, Mizelle HL. Does chronic hyperinsulinemia cause hypertension? Am J Hypertens. 1989;2:171-173. [Medline] [Order article via Infotrieve]

7. Hall JE, Brands MW, Kivlighn SD, Mizelle HL, Hildebrandt DA, Gaillard CA. Chronic hyperinsulinemia and blood pressure: interaction with catecholamines? Hypertension. 1990;15:519-527. [Abstract/Free Full Text]

8. Anderson EA, Balon TW, Hoffman RP, Sinkey CA, Mark AL. Insulin increases sympathetic activity but not blood pressure in borderline hypertensive humans. J Clin Invest. 1992;87:2247-2252.

9. Neahring JM, Stepniakowski K, Greene AS, Egan BM. Insulin does not reduce forearm -vasoreactivity in obese hypertensive or lean normotensive men. Hypertension. 1993;22:584-590. [Abstract/Free Full Text]

10. Egan BM, Stepniakowski K, Nazzaro P. Insulin levels are similar in obese salt-sensitive and salt-resistant hypertensive subjects. Hypertension. 1994;23(suppl I):I-1-I-7.

11. Reaven GM, Hollenbeck C, Jeng C-Y, Wu MS, Chen Y-DI. Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with NIDDM. Diabetes. 1988;37:1020-1024. [Abstract]

12. Golay A, Swislocki ALM, Chen Y-DI, Jaspan JB, Reaven GM. Effect of obesity on ambient plasma glucose, free fatty acid, insulin, growth hormone, and glucagon concentrations. J Clin Endocrinol Metab. 1986;63:481-484. [Abstract/Free Full Text]

13. Jensen MD, Haymond MW, Rizza RA, Cryer PE, Miles JM. Influence of body fat distribution on free fatty acid metabolism in obesity. J Clin Invest. 1989;83:1168-1173.

14. Cabezas MC, de Bruin TWA, de Valk HW, Shoulder CC, Jansen H, Erkelens DW. Impaired fatty acid metabolism in familial combined hyperlipidemia: a mechanism associating hepatic apolipoprotein B overproduction and insulin resistance. J Clin Invest. 1993;92:160-168.

15. Grekin RJ, Vollmer AP, Sider RS. Pressor effects of portal venous oleate infusion: a proposed mechanism for obesity hypertension. Hypertension. 1995;26:193-198. [Abstract/Free Full Text]

16. Stepniakowski KT, Egan BM. Additive effects of hypertension and obesity to limit venous distensibility. Am J Physiol. 1995;268:R562-R568. [Abstract/Free Full Text]

17. Stepniakowski KT, Goodfriend TL, Egan BM. Fatty acids enhance vascular -adrenergic sensitivity. Hypertension. 1995;25(part 2):II-774-II-778.

18. Davda RK, Stepniakowski KT, Lu G, Ullian ME, Goodfriend TL, Egan BM. Oleic acid inhibits endothelial cell nitric oxide synthase by a PKC-independent mechanism. Hypertension. 1995;26:764-770. [Abstract/Free Full Text]

19. Roust LR, Jensen MD. Postprandial free fatty acid kinetics are abnormal in upper body obesity. Diabetes. 1993;42:1567-1573. [Abstract]

20. Chen Y-DI, Golay A, Swislocki ALM, Reaven GM. Resistance to insulin suppression of plasma free fatty acid concentrations and insulin stimulation of glucose uptake in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1987;64:17-21. [Abstract/Free Full Text]

21. O'Shaughnessy IM, Myers TM, Stepniakowski K, Nazzaro P, Kelly TM, Hoffman RG, Egan BM, Kissebah AH. Glucose metabolism in obese hypertensives and normotensives. Hypertension. 1995;26:186-192. [Abstract/Free Full Text]

22. Hennes MM, O'Shaughnessy IM, Egan BM, Kissebah AH. Angiotensin converting enzyme inhibition and improvement of insulin's antilipolytic action in abdominally obese hypertensives. J Invest Med.. 1995;43:239. Abstract.

23. Goodfriend TL, Egan B, Stepniakowski K, Ball DL. Relationships among plasma aldosterone, high-density lipoprotein cholesterol, and insulin in humans. Hypertension. 1995;25:30-36. [Abstract/Free Full Text]

24. Bonora E, Moghetti P, Zancanara C, Cigolini M, Querena M, Cacciatori V, Aorgnati C, Muggeo M. Estimates of in vivo insulin action in man: comparison of insulin tolerance tests with euglycemic and hyperglycemic glucose clamp studies. J Clin Endocrinol Metab. 1989;68:374-378. [Abstract/Free Full Text]

25. Egan BM. Neurohumoral, hemodynamic, and microvascular changes as mechanisms of insulin resistance in hypertension: a provocative but partial picture. Int J Obes. 1991;15:133-139.

26. Jamerson KA, Julius S, Gudbrandsson T, Andersson O, Brant DO. Reflex sympathetic activation induces insulin resistance in the human forearm. Hypertension. 1993;21:618-623. [Abstract/Free Full Text]

27. Pollare T, Lithell H, Berne C. A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl J Med. 1989;321:868-873. [Abstract]

28. Ferrannini E, Buzzigoli G, Bonadonna R, Guiorico MA, Leggini M, Graziadei L, Pedrinelli R, Brandi L, Bevilacqua S. Insulin resistance in essential hypertension. N Engl J Med. 1987;317:350-357. [Abstract]

29. Istfan NW, Plaisted CS, Bistrian BR, Blackburn GL. Insulin resistance versus insulin secretion in the hypertension of obesity. Hypertension. 1992;19:385-392. [Abstract/Free Full Text]

30. Anderson EA, Hoffman RP, Balon TW, Sinkey CA, Mark AL. Hyperinsulinemia produces both sympathetic activation and vasodilation in normal humans. J Clin Invest. 1991;87:2246-2252.

31. Nazzaro P, Stepniakowski K, O'Shaughnessy IM, Kissebah AH, Egan BM. Elevated blood pressures in obese young men with mild hypertension are sustained during the day and night. Am J Hypertens. 1994;7:609-614. [Medline] [Order article via Infotrieve]

32. Bülow J, Madsen J, Hojgaard L. Reversibility of the effects on local circulation of high lipid concentrations in blood. Scand J Clin Lab Invest. 1990;50:291-296. [Medline] [Order article via Infotrieve]

33. Williams RR, Hunt SC, Hopkins PN, Stults BM, Wu LL, Hasstedt SJ, Barlow GK, Stevenson SH, Lalouel JM, Kuida H. Familial dyslipidemic hypertension. JAMA. 1988;259:3579-3586. [Abstract/Free Full Text]

34. Egan B, Panis R, Hinderliter A, Schork N, Julius S. Mechanism of increased -adrenergic vasoconstriction in human essential hypertension. J Clin Invest. 1987;80:812-817.

35. Rao GN, Alexander RW, Runge MS. Linoleic acid and its metabolites, hydroperoxy-octadecadienoic acids, stimulate c-fos, c-jun, and c-myc mRNA expression, mitogen-activated protein kinase activation, and growth in rat aortic smooth muscle cells. J Clin Invest. 1995;96:842-847.

36. Ordway RW, Singer JJ, Walsh JV. Direct regulation of ion channels by fatty acids. Trends Neurosci. 1991;14:96-100. [Medline] [Order article via Infotrieve]

37. Vesell ES, Chambers CE, Passananti T, Demers LM, Beyer KH. Effects of pyrazinoylguanidine on the glucose-fatty acid cycle innormal subjects and patients with non-insulin dependent diabetes mellitus. J Clin Pharmacol. 1993;33:823-831. [Abstract]

38. Beyer KH, Gelarden RT, Vary JE, Brown LE, Vesell ES. Novel multivalent effects of pyrazinoylguanidine in patients with azotemia. Clin Pharmacol Ther. 1990;47:629-638. [Medline] [Order article via Infotrieve]

39. Chambers CE, Vesell ES, Helm C, Passananti GT, Beyer KH. Pyrazinoylguanidine: antihypertensive, hypocholesterolemic, and renin effects. J Clin Pharmacol. 1992;32:1128-1134. [Abstract]

40. Stout RW. Insulin and atheroma: an update. Lancet. 1987;1:1077-1079. [Medline] [Order article via Infotrieve]

41. Khan WA, Blobe G, Halpern A, Taylor W, Wetsel WC, Burns D, Loomis C, Hannun YA. Selective regulation of protein kinase C isoenzymes by oleic acid in human platelets. J Biol Chem. 1993;268:5063-5068.[Abstract/Free Full Text]

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				M. Carlsson, Y. Wessman, P. Almgren, and L. Groop High Levels of Nonesterified Fatty Acids Are Associated With Increased Familial Risk of Cardiovascular Disease Arterioscler Thromb Vasc Biol, June 1, 2000; 20(6): 1588 - 1594. [Abstract] [Full Text] [PDF]

				A. T. Haastrup, K. T. Stepniakowski, T. L. Goodfriend, and B. M. Egan Intralipid Enhances {alpha}1-Adrenergic Receptor–Mediated Pressor Sensitivity Hypertension, October 1, 1998; 32(4): 693 - 698. [Abstract] [Full Text] [PDF]

				K. T. Stepniakowski, G. Lu, G. D. Miller, and B. M. Egan Fatty Acids, Not Insulin, Modulate {alpha}1-Adrenergic Reactivity in Dorsal Hand Veins Hypertension, November 1, 1997; 30(5): 1150 - 1155. [Abstract] [Full Text]

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