The prevalence of hypertension in individuals with obesity or type II diabetes is substantially elevated. Increased levels of non-esterified fatty acids (NEFAs) in abdominally obese subjects were reported to contribute in the development of various disturbances related to the metabolic syndrome, such as hepatic and peripheral insulin resistance (IR), dyslipidaemia, β-cell apoptosis, endothelial dysfunction and others. However, the involvement of NEFAs in the development of hypertension has been much less studied in comparison to other mechanisms linking IR and central obesity with blood pressure (BP) elevation. This article reviews the existing evidence on the relation between NEFA and hypertension in an attempt to shed a light on it. In vivo data from both animal and human studies support that acute plasma NEFA elevation leads to increase in BP levels, whereas epidemiological evidence suggests a link between increased NEFA levels and hypertension. Further, accumulating data indicate the existence of several pathways through which NEFAs could promote BP elevation, that is α1-adrenergic stimulation, endothelial dysfunction, increase in oxidant stress, stimulation of vascular cell's growth and others. The above data support a possible important role of NEFA in hypertension development in patients with obesity and the metabolic syndrome and raise hypotheses for future research.
In the initial modern descriptions of the insulin resistance (IR) or metabolic syndrome, IR was proposed to be the primary disorder, causally related to the development of the rest disturbances, that is impaired glucose tolerance or type II diabetes, hypertension and hypertriglyceridaemia.1, 2 However, central obesity, a factor promptly added to the above cluster,2, 3 was soon found to be connected in a more complex way with IR (i.e. to be not a consequence but rather a cause of IR), as well as to play important roles in the development of the rest disorders of the syndrome.4
One of the most important factors connecting obesity with the development of related metabolic abnormalities is the elevated release of free or non-esterified fatty acids (NEFAs) from abdominal adipocytes in patients with central obesity, which results in increase in plasma NEFA concentration and turnover.5, 6 NEFAs have been shown to induce both hepatic and peripheral IR,7, 8 to activate apoptotic pathways in pancreatic β cells,9 to promote endothelial dysfunction10 and to increase the production of plasminogen activator inhibitor-1.11 Most importantly, increased NEFA supply of the liver, primarily owing to the incomplete insulin-mediated suppression of lipolysis in this type of subjects, is the initial step for the development of the characteristic lipid disorders of the metabolic syndrome.12
With regard to hypertension, several studies have clearly shown a causal association of IR and compensatory hyperinsulinaemia with blood pressure (BP) elevation, through mechanisms like sodium retention, stimulation of the sympathetic nervous system, promotion of vascular cell's growth or impairment of insulin-mediated vasodilatation in insulin-resistant states.13 On the other hand, central obesity is also known to induce the development of hypertension through increased activity of adipose tissue renin–angiotensin–aldosterone (RAAS), sympathetic activation and other mechanisms, usually in close connection with IR.14, 15
NEFA elevation has been previously implicated to be one of the latter mechanisms linking abdominal obesity to BP elevation.15, 16 However, the research interest in this mechanism has never been particularly intense, despite the accumulation of a considerable amount of data supporting a possible relevant role for NEFAs. Therefore, the aim of this review was to summarize the existing evidence on the direct effects of NEFA elevation on BP, as well as possible pathophysiologic mechanisms connecting NEFAs with BP increase, in an attempt to shed an up-to-date light on this association and to raise hypotheses for future research.
A systematic literature search of MEDLINE/PubMed and EMBASE databases was performed to identify English-language articles published from 1966 until May 2006 that reported data on the association between NEFA and hypertension. Search terms used were ‘non-esterified fatty acids’, ‘free fatty acids’, ‘NEFA’, ‘FFA’ in combination with ‘blood pressure’ and ‘hypertension’. Reference lists of identified articles were also evaluated for additional relevant papers and information. Articles providing information on the effect of NEFAs on BP levels or on possible mechanisms linking NEFA with the development of hypertension were included.
The effect of NEFAs on BP levels
The first indications on the association of NEFAs with BP elevation came from an in vivo study in minipigs17 (Table 1). In this study, Intravenous infusions of Intralipid (a triglyceride emulsion containing primarily glycerol esters of two NEFAs, oleic and linoleic acid) and heparin (to activate endothelial lipoprotein lipase, which in turn, hydrolyses the ester bond and releases NEFA in the circulation)16, 18 were performed, in order to increase circulating NEFA levels. This NEFA elevation was associated with a significant increase in peripheral vascular resistance and a rise in BP of approximately 30 mm Hg.17
Subsequently, Grekin et al. observed that infusion of sodium oleic (which derives from combination of oleic acid with sodium) in portal or femoral veins of rats resulted in acute increases in mean BP of 29 and 13 mm Hg, respectively. Moreover, chronic (1 week) administration of sodium oleic was associated with an elevation of 16 mm Hg in mean BP vs baseline.19 Portal infusion of sodium oleic also resulted in an increase in plasma catecholamines, suggesting that BP elevation could be related to sympathetic activation. In another study of the same group, acute and chronic portal infusions of oleic acid, as well as acute infusion of linoleic acid were again associated with significant increases in BP.20
Previous human studies provided indirect evidence in favour of an association between NEFA and the development of hypertension. Egan et al.21 observed that baseline plasma levels and turnover rate of NEFAs were increased in obese compared to lean individuals, but similar between obese hypertensive and obese normotensive subjects. However, the decrease in plasma NEFA levels after insulin administration was much smaller in obese hypertensive than obese normotensive subjects; in other words, obese hypertensives displayed resistance in insulin-mediated NEFA reduction. Another finding connecting high levels of NEFAs with hypertension was that BP levels were significantly correlated with NEFA levels and turnover rate, but not glucose disposal rate. These correlations remained significant after adjustment for fasting insulin levels, IR and other parameters.21
Data from the population-based Paris Prospective Study also support these associations. In almost 3000 non-diabetic, non-hypertensive men followed for 3 years, baseline NEFA elevation was a highly significant risk factor for the subsequent development of hypertension (hazard ratio of 1.58) after controlling for several known risk factors and other abnormalities of the metabolic syndrome.22
In addition to the above data, several human studies have clearly shown that acute plasma NEFA elevation leads to increase in BP (Table 1).23, 24, 25, 26, 27 Most of these studies aimed primarily to evaluate the effect of NEFAs on other parameters (i.e. endothelial function) with complicated experiments and are described in detail below, in the sections of the possible pathways linking NEFAs with hypertension. Of particular interest, however, is a study suggesting a possible link between NEFA elevation, family history of hypertension and BP regulation. In this study, 4-h Intralipid and heparin infusions were performed in lean healthy subjects with negative or positive family history of hypertension. Although NEFAs increased similarly in both groups during the infusion, diastolic BP (DBP), mean BP (MBP) and pulse pressure increased significantly only in subjects with a family history of hypertension. Systolic BP (SBP) increased in both groups, but the increase was significantly greater in subjects with positive than those with no family history of hypertension (14±2 vs 10±2 mm Hg).26
Based on such data, it can be speculated that in subjects that typically exhibit chronic NEFA elevation, that is those with central obesity, IR and type II diabetes,4, 5, 6 this NEFA increase can be an important factor promoting the development of hypertension in subjects with normal BP levels, or deteriorating BP control in patients with already elevated BP. Further, some of the above data21, 22 support not only a close association between NEFA and BP, but also that this relation could be independent from the degree of IR and other parameters of the metabolic syndrome. This can be another interesting possibility, but needs further examination by background and epidemiological studies. The following sections describe pathophysiologic mechanisms that can be possibly involved in a NEFA–hypertension relationship.
NEFA and α1-adrenergic activation
In the above-mentioned study from Grekin et al.,20 the increase in BP following portal oleic acid infusion was blunted from prazosin, an α1-adrenergic antagonist, but not from an angiotensin II receptor inhibitor, findings indicating the involvement of an α1-adrenergic mechanism in this BP elevation (Figure 1). These observations in favour of an α1-adrenergic-mediated action of NEFAs are in agreement with previous findings from Egan et al. in humans. This group reported an increase in vascular tone and vascular responsiveness in α1-adrenergic stimulation in obese hypertensive patients,28, 29, 30 which could not be explained from resistance in the vasodilating action of insulin.31 Assuming that this increase is caused by NEFA elevation, the investigators studied the infusion of Intralipid and heparin in hand veins of two groups of normotensive subjects. Local NEFA increase substantially reduced the dose of phenylephrine required to produce 50% of the maximal venoconstrictor response, whereas the response to angiotensin II was not altered.32
In a subsequent study, the involvement of α1- or both α1- and α2-adrenergic mechanism was examined, again by local infusion of Intralipid and heparin in normotensive individuals. The relevant increase in oleic and linoleic acid was again related to an increased vasoconstrictor response to phenylephrine, which is a non-selective α1- and α2-adrenergic agonist but not to clonidine, which is a rather selective α2-agonist.33 In conjunction with the above study, elevation of plasma NEFAs after infusion of Intralipid alone or Intralipid and heparin in lean normotensive subjects similarly reduced the dose of phenylephrine required to raise MBP by 20 mm Hg.34 These data suggest that raising levels of plasma NEFAs and/or triglycerides enhance α1-adrenoceptor-mediated venoconstriction and pressor sensitivity. Other investigators reported comparably adverse effects of NEFAs on vascular function. For example, the post-ischaemic vasodilatory response of brachial artery in healthy lean subjects was significantly reduced after transient hypertriglyceridaemia that increased plasma NEFA levels.35
NEFA, nitric oxide and endothelial dysfunction
Previous studies in vitro suggest an interference of NEFA with nitric oxide (NO) production from endothelial cells. Both oleic and linoleic acids were reported to cause dose-dependent reduction of endothelial NO synthase (NOS) activity in bovine pulmonary artery endothelial cells.36 In another study, addition of NEFAs in endothelial cells in culture was associated with dose-dependent reductions of NO production. This reduction was also attributed to a decrease in NOS activity, as NOS concentration in endothelial cells remained unaltered.37 Further, in ex vivo experiments in rabbit femoral artery rings oleic acid inhibited the acetylcholine-mediated vasodilatation, which is endothelium-dependent. In contrast, the endothelium-independent vasodilatating action of sodium nitroprusside was not altered, a finding indicating that NEFAs were only interfering with endothelium-dependent vasodilatation.36
In addition to the above findings, elegant in vivo experiments provided detailed information for the effects of NEFAs on endothelial function in humans. Steinberg et al.23 observed that intra-arterial infusion of metacholine in femoral artery of lean healthy individuals during intravenous normal saline infusion resulted in an increase of leg blood flow up to about 300% in relation to baseline levels. After 2 h of systemic administration of either low- or high-dose Intralipid and heparin, which both increased plasma NEFA concentration, repeat of metacholine infusion caused a significantly lower increase in leg blood flow than before (maximum increase up to about 200%). Similarly, plasma NEFA elevation with the use of somatostatin, which inhibited insulin production, thus increasing lipolysis, produced a comparable disturbance of endothelium-dependent vasodilatation. In contrast, elevated NEFAs did not interfere with endothelium-independent vasodilatation, caused by sodium nitroprusside infusion. In all these experiments, during Intralipid and heparin infusion SBP measured invasively was 3–6 mm Hg higher than during the respective saline infusion, whereas DBP was not significantly different.23 Another in vivo study confirmed these findings on NEFAs causing endothelial dysfunction, showing that NEFA elevation resulting from 2-h infusion of long- or medium-chain triglycerides and heparin depressed the acetylcholine-induced increase in forearm blood flow. However, in this latter study, MBP changes in all the experiments were small and insignificant.38
NEFAs were also shown to interfere with basic NO production. In particular, Steinberg et al.24 measured leg blood flow before and after infusion of N-monomethyl-L-arginine (L-NMMA), which is an inhibitor of endothelial NOS, in two groups of lean healthy subjects. In one group the leg blood flow response measurements were performed during saline infusion and in the other, after a 2-h infusion of Intralipid and heparin. In the group not receiving Intralipid and heparin, a decrease of leg blood flow of about 17% was observed after the L-NMMA infusion. This reduction practically reflected the contribution of NO in preservation of vascular tone under normal circumstances. However, after Intralipid and heparin administration, the L-NMMA-induced leg blood flow decrease was only 9%, which suggests that short-term NEFA elevation decreased basic NO release for about 50%.24
Effects of NEFAs on insulin-mediated vasodilatation
In healthy subjects, acute administration of insulin is long known to produce endothelium-dependent vasodilatation.39, 40 However, numerous studies have shown that this action of insulin is severely impaired in subjects with various components of the metabolic syndrome41, 42 and this impairment is considered a basic mechanism linking IR and compensatory hyperinsulinaemia with BP elevation.13, 43
In a different protocol of the above-mentioned study,24 the investigators evaluated the possible involvement of NEFAs in this impairment of insulin action. Lean healthy individuals underwent two sets of euglycaemic hyperinsulinaemic clamp experiments with and without parallel increases of Intralipid and heparin. The subjects were divided into two groups, one receiving Intralipid and heparin infusion of short (2 or 4 h) and the other of long (8 h) duration. Short infusion did not produce any significant changes, but long infusion was associated with significant reductions in glucose uptake during the clamp of about 35%, in insulin-induced leg blood flow increase of 40% and in insulin-mediated NO production of 80%. In both the groups, the changes in IR during NEFA elevation was strongly correlated with the changes in insulin-mediated leg blood flow increase, which suggests a similar impact of NEFAs in the tightly coupled metabolic and vascular actions of insulin.24 As far as BP is concerned, basic MBP levels were similar between the groups and did not change during the clamps performed without Intralipid and heparin infusion. Short plasma NEFA elevation did not cause significant changes in MBP either before or during the clamp experiment. However, long plasma NEFA elevation was associated with an increase of 10 mm Hg in MBP both before and during the clamp. As a result, MBP during the clamp in the group with the long NEFA elevation was significantly higher than that in the group with the short elevation.
This effect of NEFAs on insulin-mediated vasodilatation can be partly explained from their action on phosphatidyloinositol 3-kinase (PI3-K), an enzyme playing a central role in insulin intracellular signalling. Both insulin-mediated glucose uptake in skeletal muscle cells and insulin-mediated NO production from endothelial cells take place through activation of PI3-K pathway.44, 45 NEFAs have been repeatedly shown to interfere with insulin-mediated glucose uptake in skeletal muscle cells by inhibiting intracellular insulin signalling through blocking of PI3-K activation.46, 47 Therefore, it is highly possible that NEFA interfere with insulin-mediated vasodilatation through the same mechanism.
Taken together, the above findings suggest that plasma NEFA elevation for about 2 h in healthy humans results in the reduction of basic vascular NO production and endothelium-dependent vasodilatation, as well as slight increases in BP. Long-term elevations (8 h) on the other hand, additionally blunt insulin-mediated glucose uptake and vasodilatation and produce more pronounced BP increases. It has been postulated that chronic NEFA elevation in insulin-resistant states, apart from interfering with insulin-mediated glucose uptake, is the main factor responsible for the observed endothelial dysfunction and impaired insulin-mediated vasodilatation (Figure 1).10 Thus, it can also be one of the basic mechanisms for the increase incidence of hypertension in these patients.
NEFA and oxidant stress
An additional mechanism connecting NEFA and BP elevation could be an increase of oxidative stress.16 In vitro studies support the notion that NEFAs can induce oxidant stress.48 In vivo, elevation of NEFAs with Intralipid and heparin infusions has been shown to increase the concentrations of various biomarkers of oxidant stress.49, 50 On the other hand, the contribution of oxidant stress in hypertension development is supported by preliminary animal data,51 and indirect evidence from studies where diet rich in fruits and vegetables, containing high amounts of antioxidant substances, significantly reduced BP.52
Egan et al.16 suggested that a relatively high intake of antioxidants could be responsible for the limited BP increases in some of the above studies.23, 38 To test this hypothesis, the investigators administered Intralipid and heparin for 4 h in healthy individuals being for the former 3 weeks on a diet low in antioxidants. This infusion was associated with significant increases in SBP and DBP of 10 and 3 mm Hg, respectively, whereas respective infusion of saline and heparin did not significantly affect BP.25 However, it is obvious that to effectively assess the effect of antioxidants in NEFA-induced BP increase, a comparison of two groups receiving diets of low and high concentrations of antioxidants should be performed.
In a more recent study, these investigators examined basic BP levels and the effects of NEFA elevation in obese hypertensive and lean normotensive subjects under their usual diet, the Dietary Approaches to Stop Hypertension combination diet (DASH-CD), which is rich in antioxidants, and a low-antioxidant diet.27 SBP, DBP and MBP declined significantly in obese hypertensives after 3 and 4 weeks on the DASH-CD compared with values on their usual and the low-antioxidant diet. After 4 weeks on the DASH-CD, BP in obese hypertensives was 8.1/7.4 mm Hg lower than on the low-antioxidant diet. In lean normotensives, SBP tended to rise during the low-antioxidant diet, but the difference compared with that of the DASH-CD was not significant. After 4 h of Intralipid and heparin infusion, SBP increased significantly in obese hypertensives (about 4–5 mm Hg) and in lean normotensives (from 8 to 13 mm Hg) on all three diets and DBP followed similar trends. However, during this acute elevation of FFA, SBP and DBP in both the groups remained lower on the DASH-CD than on the usual and low-antioxidant diets.27 Although these data are intriguing, as direct mechanisms connecting oxidative stress with hypertension development have not yet been established, future studies should explore this potential pathway linking NEFAs with BP elevation.
Possible trophic actions of NEFAs
Another possible mechanism connecting NEFAs with BP increase is their possible mitogenic actions on the vascular wall, as increased proliferation of vascular smooth muscle cells (VSMCs) has been long connected to vascular hypertrophy and arterial stiffness, one of the basic mechanisms of hypertension development.53, 54 In vitro studies have reported that unsaturated NEFAs, including oleic and linoleic acid, can directly activate the typical and atypical isoforms of protein kinase C (PKC) in various cell types, including VSMCs.55, 56, 57, 58 Among other deleterious effects on human vasculature, PKC has been shown to play a central role in mitogenic processes in VSMCs.59, 60 Several studies have clearly shown that NEFAs induce proliferation of VSMCs via PKC activation,55, 56, 57 implicating a potential involvement of plasma NEFA elevation in vascular remodelling and hypertension in obese subjects. In addition, oleic and linoleic acid were reported to increase the trophic action on VSMC of other growth factors, for example insulin-like growth factor-1 (IGF-1).61 In the cardiovascular system, IGF-1 is produced from VSMCs after stimulatory effects of various factors, including insulin; thus, its release is also elevated in states of IR and hyperinsulinaemia.62
Other pathways potentially connecting NEFAs with BP elevation
In addition to the mechanisms described so far, preliminary evidence for other actions of NEFAs that can contribute in the development of hypertension also exist (Table 2). For example, NEFAs can counteract with RAAS in several points. In some of the above-mentioned studies, oleic acid did not only induce VSMC proliferation, but also stimulated the mitogenic response of these cells in angiotensin II, findings supporting a synergistic effect of NEFAs and angiotensin II on vascular growth.56, 57 NEFAs were also reported to activate the expression of angiotensinogen gene in preadipocytes,63 an action possibly contributing in the upregulation of adipose tissue RAAS in subjects with central obesity. Further, an oxidized derivative of linoleic acid was recently reported to stimulate aldosterone production from rat adrenal cells, providing an alternative explanation for unexpectedly elevated aldosterone levels in some obese subjects.64
In addition, previous in vitro studies suggest that both oleic and linoleic acids are endogenous inhibitors of Na+,K+-ATPase.65, 66 Reduction of Na+,K+-ATPase activity in VSMCs through increase in intracellular Na+ and decrease of passive Na+–Ca2+ exchange or through partial depolarization of cell membrane and activation of voltage-dependent Ca2+ channels would result in increased intracellular Ca2+ concentration and a relative elevation of vascular tone. Thus, inhibition of Na+,K+-ATPase has been suggested to promote the development of hypertension.67 Reduced activity of Na+,K+-ATPase has been noted in both animal models and humans with obesity and type II diabetes and has been long implicated in the development of hypertension in these states.68, 69 Therefore, it can be speculated that NEFA elevation is a basic mechanism for this downregulation of Na+,K+-ATPase activity.
NEFA elevation has been extensively studied as a cause of IR, β-cell apoptosis, dyslipidaemia, endothelial dysfunction and other disturbances in subjects with obesity and type II diabetes. Less attention has been specifically paid to the possible involvement of NEFAs in the development of hypertension, which is a major contributing factor in increased cardiovascular morbidity and mortality of such subjects. However, several studies on related actions also provide information implicating a connection of NEFAs with BP elevation. A close examination of these data reveals an important acute effect of plasma NEFA elevation on BP as well as several pathways through which NEFA increase can lead to hypertension. Thus, it can be speculated that in subjects with features of the metabolic syndrome chronic NEFA elevation could be an important mechanism contributing to either the development of hypertension in previously normotensives or inadequate BP control in patients with already elevated BP. The above data underline the need for future studies to elucidate this important field.
Reaven GM . Banting Lecture 1988. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595–1607.
Sarafidis PA, Nilsson PM . The metabolic syndrome: a glance in its history. J Hypertens 2006; 24: 621–626.
Kaplan NM . The deadly quartet. Upper body obesity, glucose intolerance, hypertriglyceridemia and hypertension. Arch Intern Med 1989; 149: 1514–1520.
Wajchenberg BL . Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000; 21: 697–738.
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.
Martin ML, Jensen MD . Effects of body fat distribution on regional lipolysis in obesity. J Clin Invest 1991; 88: 609–613.
Bevilacqua S, Bonadonna R, Buzzigoli G, Boni C, Ciociaro D, Maccari F et al. Acute elevation of free fatty acid levels leads to hepatic insulin resistance in obese subjects. Metabolism 1987; 36: 502–506.
Boden G, Chen X, Ruiz J, White JV, Rosseti L . Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest 1994; 93: 2438–2446.
Shimabukuro M, Zhou YT, Levi M, Unger R . Fatty acid-induced β cell apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci USA 1998; 95: 2498–2502.
Steinberg HO, Baron AD . Vascular function, insulin resistance and fatty acids. Diabetologia 2002; 45: 623–634.
Nilsson L, Banfi C, Diczfalusy U, Tremoli E, Hamsten A, Eriksson P . Unsaturated fatty acids increase plasminogen activator inhibitor-1 in endothelial cells. Arterioscler Thromb Vasc Biol 1998; 18: 1679–1685.
Abate N . Obesity and Cardiovascular disease. Pathogenic role of the metabolic syndrome and therapeutic implications. J Diabetes Complications 2000; 14: 154–174.
Sarafidis PA, Lasaridis AN . Actions of PPARγ agonists explaining a possible blood pressure lowering effect. Am J Hypertens 2006; 19: 646–653.
Rocchini AP . Obesity hypertension. Am J Hypertens 2002; 15: 50S–52S.
Sharma AM, Engeli S, Pischon T . New developments in mechanisms of obesity-induced hypertension: role of adipose tissue. Curr Hypertens Rep 2001; 3: 152–156.
Egan BM, Greene EL, Goodfriend TL . Nonesterified fatty acids in blood pressure control and cardiovascular complications. Curr Hypertens Rep 2001; 3: 107–116.
Bulow 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.
Meng HC, Edgren B . Source of plasma free fatty acids in dogs receiving fat emulsion and heparin. Am J Physiol 1963; 204: 691–695.
Grekin RJ, Vollmer AP, Sider RS . Pressor effects of portal venous oleate infusion. A proposed mechanism for obesity hypertension. Hypertension 1995; 26: 193–198.
Grekin RJ, Dumont CJ, Vollmer AP, Watts SW, Webb RC . Mechanisms in the pressor effects of hepatic portal venous fatty acid infusion. Am J Physiol 1997; 273: R324–R330.
Egan BM, Hennes MMI, Stepniakowski KT, O'Shaughnessy IM, Kissebach AH, Goodfriend TL . Obesity hypertension is related more to insulin's fatty acid than glucose action. Hypertension 1996; 27: 723–728.
Fagot-Campagna A, Balkau B, Simon D, Warnet JM, Claude JR, Ducimetiere P et al. High free fatty acid concentration: an independent risk factor for hypertension in the Paris Prospective Study. Int J Epidemiol 1998; 27: 808–813.
Steinberg HO, Tarshoby M, Monestel R, Hook G, Cronin J, Johnson A et al. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest 1997; 100: 1230–1239.
Steinberg HO, Paradisi G, Hook G, Crowder K, Cronin J, Baron AD . Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production. Diabetes 2000; 49: 1231–1238.
Stojiljkovic MP, Zhang D, Lopes HF, Lee CG, Goodfriend TL, Egan BM . Hemodynamic effects of lipids in humans. Am J Physiol Regul Integr Comp Physiol 2001; 280: R1674–R1679.
Lopes HF, Stojiljkovic MP, Zhang D, Goodfriend TL, Egan BM . The pressor response to acute hyperlipidemia is enhanced in lean normotensive offspring of hypertensive parents. Am J Hypertens 2001; 14: 1032–1037.
Lopes HF, Martin KL, Nashar K, Morrow JD, Goodfriend TL, Egan BM . DASH diet lowers blood pressure and lipid-induced oxidative stress in obesity. Hypertension 2003; 41: 422–430.
Egan BM, Panis R, Hinderliter A, Shork N, Julius S . Mechanism of increased alpha-adrenergic vasoconstriction in human essential hypertension. J Clin Invest 1987; 80: 812–817.
Egan BM, Shork NJ, Weder AB . Regional hemodynamic abnormalities in overweight men: focus on α-adrenergic vascular responses. Am J Hypertens 1989; 2: 428–434.
Stepniakowski KT, Egan BM . Additive effects of hypertension and obesity to limit venous distensibility. Am J Physiol 1995; 268: R562–R568.
Neahring JM, Stepniakowski K, Greene AS, Egan BM . Insulin does not reduce forearm alpha-vasoreactivity in obese hypertensive or lean normotensive men. Hypertension 1993; 22: 584–590.
Stepniakowski KT, Goodfriend TL, Egan BM . Fatty acids enhance vascular α-adrenergic sensitivity. Hypertension 1995; 25: II774–II778.
Stepniakowski KT, Sallee FR, Goodfriend TL, Zhang Z, Egan BM . Fatty acids enhance neurovascular reflex responses by effects on alpha 1-adrenoceptors. Am J Physiol 1996; 270: R1340–R1346.
Haastrup AT, Stepniakowski KT, Goodfriend TL, Egan BM . Intralipid enhances alpha1-adrenergic receptor mediated pressor sensitivity. Hypertension 1998; 32: 693–698.
Lundman P, Eriksson M, Schenck-Gustafsson K, Karpe F, Tornvall P . Transient triglyceridemia decreases vascular reactivity in young, healthy men without risk factors for coronary heart disease. Circulation 1997; 96: 3266–3268.
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.
Gupta MP, Steinberg H, Baron A, Hart CM . Fatty acids impair nitric oxide production in cultured endothelial cells [Abstract]. J Investig Med 1998; 46: 288A.
de Kreutzenberg SV, Crepaldi C, Marchetto S, Calo L, Tiengo A, Del Prato S et al. Plasma free fatty acids and endothelium-dependent vasodilation: effect of chain-length and cyclooxygenase inhibition. J Clin Endocrinol Metab 2000; 85: 793–798.
Scherrer U, Randin D, Vollenweider P, Vollenweider L, Nicod P . Nitric oxide release accounts for insulin's vascular effects in humans. J Clin Invest 1994; 94: 2511–2515.
Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD . Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent: a novel action of insulin to increase nitric oxide release. J Clin Invest 1994; 94: 1172–1179.
Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD . Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest 1996; 97: 2601–2610.
Laine H, Knuuti MJ, Ruotsalainen U, Raitakari M, Iida H, Kapanen J et al. Insulin resistance in essential hypertension is characterized by impaired insulin stimulation of blood flow in skeletal muscle. J Hypertens 1998; 16: 211–219.
Sartori C, Scherrer U . Insulin, nitric oxide and the sympathetic nervous system: at the crossroads of metabolic and cardiovascular regulation. J Hypertens 1999; 17: 1517–1525.
Shepherd PR, Wither DJ, Siddle K . Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem J 1998; 333: 471–490.
Zeng G, Quon MJ . Insulin-stimulated production of nitric oxide is inhibited by wortmannin: direct measurement in vascular endothelial cells. J Clin Invest 1996; 98: 894–898.
Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW et al. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 1996; 97: 2859–2865.
Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 1999; 103: 253–259.
Lu G, Greene EL, Nagai T, Egan BM . Reactive oxygen species are critical in the oleic acid-mediated mitogenic signaling pathway in vascular smooth muscle cells. Hypertension 1998; 32: 1003–1010.
Stojiljkovic MP, Lopes HF, Zhang D, Morrow JD, Goodfriend TL, Egan BM . Increasing plasma fatty acids elevates F2-isoprostanes in humans: implications for the cardiovascular risk factor cluster. J Hypertens 2002; 20: 1215–1221.
Lopes HF, Morrow JD, Stojiljkovic MP, Goodfriend TL, Egan BM . Acute hyperlipidemia increases oxidative stress more in African Americans than in white Americans. Am J Hypertens 2003; 16: 331–336.
Nosratola D, Vaziri D, Wang XQ, Oveisi F, Rad B . Induction of oxidative stress by glutathione depletion causes severe hypertension in normal rats. Hypertension 2000; 36: 142–146.
Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP, Sacks FM et al. A clinical trial of the effects of dietary patterns on blood pressure. N Engl J Med 1997; 336: 1117–1124.
Kaplan NM . Primary hypertension: pathogenesis. In: Kaplan NM (ed). Clinical Hypertension, 8th edn. Lippincott Williams & Wilkins: Philadelphia, PA, 2002, pp 56–135.
Lever AF, Harrap SB . Essential hypertension: a disorder of growth with origins in childhood? J Hypertens 1992; 10: 101–120.
Lu G, Morinelli TA, Meier KE, Rosenzweig SA, Egan BM . Oleic acid-induced mitogenic signaling in vascular smooth muscle cells. A role for protein kinase C. Circ Res 1996; 79: 611–618.
Lu G, Meier KE, Jaffa AA, Rosenzweig SA, Egan BM . Oleic acid and angiotensin induce a synergistic mitogenic response. Hypertension 1998; 31: 978–985.
Greene EL, Lu G, Zhang D, Egan BM . Signaling events mediating the additive effects of oleic acid and angiotensin II on vascular smooth muscle cell migration. Hypertension 2001; 37: 308–312.
Khan WA, Blobe G, Halpern A, Wetsel WC, Burns D, Loomis C et al. Selective regulation of protein kinase C isoezymes by oleic acid in human platelets. J Biol Chem 1993; 268: 5063–5068.
Berra E, Diaz-Meco MT, Dominguez I, Municio MM, Sanz L, Lozano J et al. Protein kinase C-z is critical for mitogenic signal transduction. Cell 1993; 74: 555–563.
Liao D-F, Monia B, Dean N, Berk BC . Protein kinase C-z mediates angiotensin II activation of ERK-1 and -2 in vascular smooth muscle cells. J Biol Chem 1997; 272: 6146–6150.
Askari B, Carroll MA, Capparelli M, Kramer F, Gerrity RG, Bornfeldt KE . Oleate and linoleate enhance the growth-promoting effects of insulin-like growth factor-I through a phospholipase D-dependent pathway in arterial smooth muscle cells. J Biol Chem 2002; 277: 36338–36344.
Sowers JR . Insulin and insulin-like growth factor in normal and pathological cardiovascular physiology. Hypertension 1997; 29: 691–699.
Safonova I, Aubert J, Negrel R, Ailhaud G . Regulation by fatty acids of angiotensinogen gene expression in preadipose cells. Biochem J 1997; 322: 235–239.
Goodfriend TL, Ball DL, Egan BM, Campbell WB, Nithipatikom K . Epoxy-keto derivative of linoleic acid stimulates aldosterone secretion. Hypertension 1004; 43: 358–363.
Tamura M, Kuwano H, Kinoshita T, Inagami T . Identification of linoleic and oleic acids as endogenous Na+,K+-ATPase inhibitors from acute volume-expanded hog plasma. J Biol Chem 1985; 260: 9672–9677.
Ng LL, Hockaday TD . Non-esterified fatty acids may regulate human leucocyte sodium pump activity. Clin Sci (London) 1986; 71: 737–742.
Lijnen P . Alterations in sodium metabolism as an etiological model for hypertension. Cardiovasc Drugs Ther 1995; 9: 377–399.
Sowers JR, Whitfield L, Beck FW, Catania RA, Tuck ML, Dornfeld L et al. Role of enhanced sympathetic nervous system activity and reduced Na+,K+-dependent adenosine triphosphatase activity in the maintenance of elevated blood pressure in obesity: effects of weight loss. Clin Sci 1982; 63: 121S–124S.
Weder AB . Sodium metabolism, hypertension and diabetes. Am J Med Sci 1994; 307: S53–S59.
This paper was not supported by any source and represents an original effort on our part.
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Sarafidis, P., Bakris, G. Non-esterified fatty acids and blood pressure elevation: a mechanism for hypertension in subjects with obesity/insulin resistance?. J Hum Hypertens 21, 12–19 (2007). https://doi.org/10.1038/sj.jhh.1002103
- non-esterified fatty acids
- insulin resistance
- type II diabetes
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