Heparin, lipoproteins, and oxygenated fatty acids in blood: a cautionary note.

We measured 16 nonesterified oxygenated fatty acid derivatives (oxylipids) in plasmas from seven human subjects. Two arterial samples from each subject were analyzed, drawn approximately 2h apart. We observed a marked increase in levels of most oxylipids in the second sample, as high as 470-fold. Between the first and second samples, subjects received approximately 800-1000 IU of heparin to prevent clotting in intravascular catheters. We postulate that heparin activated lipoprotein lipases, which, in turn, released oxylipids from triglycerides and phospholipids in plasma lipoproteins. Some of that lipolysis may have occurred during sample storage. Measurements of nonesterified lipids in human plasma may be distorted if heparin is administered to subjects before blood is drawn and if lipase inhibitors are omitted from stored samples.

An oxidized derivative of linoleic acid stimulates dehydroepiandrosterone production by human adrenal cells.

We previously reported that an oxidized derivative of linoleic acid stimulated steroidogenesis in rat adrenal cells. This derivative was also detected in human plasma, and was positively correlated with visceral adiposity and plasma DHEA-S. The present study sought to characterize the effects of this derivative, 12,13-epoxy-9-keto-(10- trans)-octadecenoic acid (EKODE), on steroid production by normal human adrenocortical cells obtained during clinically-indicated adrenalectomy. Cell suspensions were incubated in the presence of varying concentrations of EKODE and ACTH. EKODE (16 microM) significantly increased DHEA production by 28% under basal conditions and by 25% in the presence of a low concentration of ACTH (0.2 ng/ml). The effect on DHEA was absent at a higher ACTH concentration (2.0 ng/ml). EKODE decreased cortisol production by 16% (low ACTH) and 25% (high ACTH), but was without effect on cortisol under basal conditions. The results suggest that EKODE affects adrenal DHEA production in the human, possibly by modulating steroidogenic enzyme activity. We postulate that excess visceral fat delivers fatty acids to the liver, where oxidized derivatives are formed that modulate adrenal steroidogenesis. This may be an important phenomenon in the genesis of changes in adrenal function associated with syndromes of obesity, especially those that include androgen excess.

An oxidized derivative of linoleic acid affects aldosterone secretion by adrenal cells in vitro.

Based on the clinical observation that humans with visceral adiposity have higher plasma aldosterone levels than controls, we postulated that endogenous fatty acids can be oxidized by the liver to form stimuli of the adrenal cortex. Although we could show that hepatocytes produced adrenal stimuli from linoleic acid in vitro, the yield was very small. To facilitate the elucidation of chemical structures, we incubated a large amount of linoleic acid with lipoxygenase, then treated the hydroperoxide with cysteine and iron. The major product of this process was 12,13-epoxy-9-keto-10-trans-octadecenoic acid. This epoxy-keto compound stimulated aldosterone production at concentrations from 0.5 to 15 microm. At higher concentrations, it was inhibitory. The epoxy-keto-octadecenoic acid exhibited the chromatographic characteristics of one product of the incubation of linoleic acid with hepatocytes. The results are consistent with the postulated conversion of linoleic acid to stimuli of aldosterone production. This may be a mechanistic link between visceral obesity and hypertension in humans.

Moderate sodium restriction enhances the pressor response to hyperlipidemia in obese, hypertensive patients.

The effect of dietary sodium restriction on insulin, lipids, and blood pressure has been controversial. Evidence suggests that adverse short-term effects in response to very low-salt diets do not persist long-term with modest sodium restriction. In this study, the effects of modest dietary sodium restriction (60 and 120 mmol sodium) were measured for 3 weeks in 12 lean normotensives and 10 obese hypertensives. Blood pressure, plasma lipids, and the pressor response to an infusion of Intralipid and heparin were obtained. In contrast to previous reports concerning very low-salt diets, obese hypertensives did not manifest a pressor response or an adverse lipid effect with moderate salt restriction. Obese hypertensives were not more salt-sensitive than lean normotensives and did not manifest a different hemodynamic response to 4-hour infusion of Intralipid and heparin while on the 120-mmol/day salt diet. During the 60-mmol/day salt diet, however, plasma triglycerides increased more in obese than in lean volunteers during the Intralipid and heparin infusion (398+/-38 vs. 264+/-18 mg/dL; p<0.05), and there were greater increases in mean blood pressure (12+/-2 vs. 7+/-2 mm Hg; p<0.05) and systemic vascular resistance (111+/-38 vs. 225+/-44 dyne.sec.cm-5) as well as a larger decrease in small artery compliance (22.5+/-0.6 vs. 20.4+/-0.6 mL/mm Hg x 100; p<0.05). These data suggest that modest dietary sodium restriction in obese hypertensives does not adversely affect baseline blood pressure or lipids, but it does magnify their adverse lipid and hemodynamic response to fat loading.

Oxidized products of linoleic acid stimulate adrenal steroidogenesis.

Adrenal steroidogenesis is under complex control, and clinical observations suggest that not all regulators have been identified. We postulated that fatty acid oxidation products found in the diet or formed in the body could affect steroidogenesis. Linoleic acid is a prominent constituent of animal fat and is readily oxidized. We found that several products of linoleic acid oxidation affect production of aldosterone and corticosterone by isolated cells from rat adrenals. We characterized one linoleic acid derivative by gas chromatography/mass spectrometry. It is 12,13-epoxy-9-oxo-10(trans)-octadecenoic acid ("EKODE"). At concentrations between 1 and 30 microM, EKODE stimulated production of aldosterone by zona glomerulosa cells, but at concentrations above 50 microM, it was inhibitory. In zona fasciculata cells, EKODE stimulated corticosterone production at concentrations of 5 microM or greater, and there was no evidence of inhibition at high concentrations. Stimulation of steroidogenesis was observed after 15 min of incubation and continued for at least 2 hrs. The potential relevance of our findings to the hypertension of obesity is discussed.

Digitalis-like factor response to hyperinsulinemia in human pregnancy, a model of insulin resistance.

Insulin resistance is strongly associated with hypertension and is postulated to participate in the elevation of blood pressure, although the mechanisms involved are not understood. Recently, we reported that acute increases in plasma insulin levels in normal subjects resulted in increased serum levels of a sodium pump inhibitor, termed the digitalis-like factor (DLF), which has been implicated in both experimental and essential human hypertension. This study looked at the DLF response to hyperinsulinemia, achieved by an oral glucose tolerance test (OGTT), in the setting of a naturally occurring and self-resolving state of human insulin resistance, during third-trimester pregnancy. This model allowed us the further opportunity to compare the DLF response to insulin in the same subjects postpartum, after resolution of their insulin resistance. Administration of an OGTT during pregnancy and postpartum in the same subjects elicited a comparable serum glucose response but a significantly greater insulin response during third-trimester pregnancy, consistent with diminished insulin sensitivity (integrated insulin response during pregnancy: 1611+/-236 vs postpartum: 685+/-101 pmol/l, P=0.004). The time courses of the glucose and insulin responses were identical whether women were pregnant or not. Plasma free fatty acids fell significantly and to a comparable degree during pregnancy and postpartum, but the response was slower during pregnancy. DLF levels increased in response to oral glucose in both pregnant and nonpregnant states. The response was more rapid during pregnancy than after. These findings showed that the increment of insulin induced by oral glucose during pregnancy caused a more rapid rise in circulating DLF levels than it did during the nonpregnant state. At the same time, the response of circulating fatty acids to glucose is retarded during pregnancy. This suggests that the insulin resistance of pregnancy impairs insulin's influence on intermediary metabolism but not its influence on DLF. As a vasoactive substance, DLF might contribute to the hypertension characteristic of insulin-resistant states.

The pressor response to acute hyperlipidemia is enhanced in lean normotensive offspring of hypertensive parents.

Family history is an important predictor of the cardiovascular risk factor cluster associated with insulin resistance. The dyslipidemia associated with insulin resistance may contribute to elevated blood pressure (BP). This study was undertaken to further explore the link between family history, dyslipidemia, and BP regulation. Twenty-three lean normal volunteers with a negative family history (FH-, n = 11) or positive family history (FH+, n = 12) of hypertension were evaluated under baseline conditions and during a 4-h infusion of intralipid and heparin (acute hyperlipidemia). Fasting blood was drawn for lipids including nonesterified fatty acids (NEFA). After 2 and 4 h of intralipid and heparin, blood was drawn for NEFA. The BP was measured at baseline and every 30 min after starting the intralipid and heparin infusion. Baseline triglycerides and very low density lipoprotein cholesterol concentrations were higher in FH+ than FH- subjects (P < .05). However, NEFA increased similarly in both groups during the infusion of intralipid and heparin. The BP and heart rate increased with acute hyperlipidemia in all subjects combined (P < .05). Despite the similar increase of NEFA, mean BP, pulse pressure, and pressure-rate product increased significantly in FH+ subjects but not in FH- volunteers with acute hyperlipidemia. Although systolic BP increased in both groups, the increase was greater in FH+ than in FH- volunteers during acute hyperlipidemia (14 +/- 2 v 10 +/- 2 mm Hg, P < .05). These results suggest that higher plasma lipids combined with a greater pressor response to hyperlipidemia may contribute to the development of high BP in subjects with a family history of hypertension.

Insulin resistance and cardiovascular disease.

Cardiovascular risk factors cluster in obese individuals. Insulin resistance emerges as a common pathogenetic denominator underlying the risk factor cluster. Defects in nonesterified fatty acids metabolism have been implicated in the abnormal lipid and glucose metabolism which characterize the cluster. Other evidence also leads to the adipocyte as an important contributor to the risk factor cluster and cardiovascular complications through effects not only on fatty acids but also on leptin, plasminogen activator inhibitor-1, and angiotensinogen, to name a few. Fatty acids are elevated among abdominally obese individuals, are more resistant to suppression by insulin, and may contribute to hypertension. Fatty acids may affect blood pressure by inhibiting endothelial nitric oxide synthase activity and impairing endothelium-dependent vasodilation. Fatty acids increase alpha1-adrenoceptor-mediated vascular reactivity and enhance the proliferation and migration of cultured vascular smooth-muscle cells. Several effects of fatty acids are mediated through oxidative stress. Fatty acids can also interact with other facets of cluster, including increased angiotensin II, to accentuate oxidative stress. Oxidative stress, in turn, is implicated in the pathogenesis of insulin resistance, hypertension, vascular remodeling, and vascular complications. A clearer delineation of the key reactive oxygen signaling pathways and the impact of various interventions on these pathways could facilitate a rationale approach to antioxidant therapy and improved outcomes among the rapidly growing number of high-risk, insulin-resistant, obese individuals.

Hemodynamic effects of lipids in humans.

Evidence suggests lipid abnormalities may contribute to elevated blood pressure, increased vascular resistance, and reduced arterial compliance among insulin-resistant subjects. In a study of 11 normal volunteers undergoing 4-h-long infusions of Intralipid and heparin to raise plasma nonesterified fatty acids (NEFAs), we observed increases of blood pressure. In contrast, blood pressure did not change in these same volunteers during a 4-h infusion of saline and heparin. To better characterize the hemodynamic responses to Intralipid and heparin, another group of 21 individuals, including both lean and obese volunteers, was studied after 3 wk on a controlled diet with 180 mmol sodium/day. Two and four hours after starting the infusions, plasma NEFAs increased by 134 and 111% in those receiving Intralipid and heparin, P < 0.01, whereas plasma NEFAs did not change in the first group of normal volunteers who received saline and heparin. The hemodynamic changes in lean and obese subjects in the second study were similar, and the results were combined. The infusion of Intralipid and heparin induced a significant increase in systolic (13.5 +/- 2.1 mmHg) and diastolic (8.0 +/- 1.5 mmHg) blood pressure as well as heart rate (9.4 +/- 1.4 beats/min). Small and large artery compliance decreased, and systemic vascular resistance rose. These data raise the possibility that lipid abnormalities associated with insulin resistance contribute to the elevated blood pressure and heart rate as well as the reduced vascular compliance observed in subjects with the cardiovascular risk factor cluster.

Nonesterified fatty acids in blood pressure control and cardiovascular complications.

The fact that cardiovascular risk factors cluster among individuals with the insulin resistance syndrome strongly suggests a common pathogenetic denominator. For many years, abnormalities of nonesterified fatty acid metabolism have been implicated in the disturbances of carbohydrate and lipid metabolism that characterize the cluster. However, until more recently, evidence implicating fatty acids in the hemodynamic and vascular abnormalities that affect patients with this syndrome was lacking. Observations from epidemiological, clinical, and basic science suggest that fatty acids can raise blood pressure and contribute to the development of hypertension. The effects of fatty acids on blood pressure may be mediated in part by inhibition of endothelial nitric oxide synthase activity and endothelium-dependent vasodilation. Fatty acids can also increase alpha1-adrenoceptor-mediated vascular reactivity and induce vascular smooth muscle migration and proliferation. The adverse effects of fatty acids appear to be mediated in part through induction of oxidative stress. Fatty acids interact with other components of the risk factor cluster, including increased angiotensin II, to synergistically augment oxidative stress in cultured vascular smooth muscle cells. Oxidative stress is implicated in the pathogenesis of insulin resistance, hypertension, vascular remodeling, and vascular complications. A clearer definition of the specific reactive oxygen signaling pathways involved and interventions aimed at altering these pathways could lead to more rationale antioxidant therapy and improved outcomes.

Angiotensin receptors: history and mysteries.

Angiotensin receptors became relatively easy to study when radioactive derivatives of the peptide were synthesized for radioimmunoassays. Binding assays in vitro led to the discovery of receptors in many tissues different from those involved in the classic actions of angiotensin. The physiologic significance of receptors in sites such as the gonads, other endocrine organs, peripheral blood cells, and many regions of the brain is still uncertain. Kinetics of the binding reaction are susceptible to intracellular guanine nucleotides, and extracellular cations, fatty acids, steroids, and eicosanoids. Synthesis of receptors is under equally complex control. Receptor binding assays simplified screening for angiotensin antagonists. Nonpeptide antagonists proved so specific they revealed the existence of receptor subtypes. The two principal subtypes are found in different tissues and trigger different postreceptor cascades. Studies of receptors, the genes that code for them, and the drugs that block them have led to a growing awareness of angiotensin's effects on the structure of the heart, vessels, and kidneys, some of which are pathologic. The existence of receptor subtypes, the different signal transduction cascades they stimulate, the widespread location of receptors, and the range of effects they mediate suggest that the angiotensins are of broad relevance in biology and pathology. This multidimensional matrix also indicates that receptor antagonists may have effects not yet described.

Neonatal hypoxic hyperlipidemia in the rat: effects on aldosterone and corticosterone synthesis in vitro.

Neonatal hypoxia increases aldosterone production and plasma lipids. Because fatty acids can inhibit aldosterone synthesis, we hypothesized that increases in plasma lipids restrain aldosteronogenesis in the hypoxic neonate. We exposed rats to 7 days of hypoxia from birth to 7 days of age (suckling) or from 28 to 35 days of age (weaned at day 21). Plasma was analyzed for lipid content, and steroidogenesis was studied in dispersed whole adrenal glands untreated and treated to wash away lipids. Hypoxia increased plasma cholesterol, triglycerides, and nonesterified fatty acids in the suckling neonatal rat only. Washing away lipids increased aldosterone production in cells from 7-day-old rats exposed to hypoxia, but not in cells from normoxic 7-day-old rats or from normoxic or hypoxic 35-day-old rats. Addition of oleic or linolenic acid to washed cells inhibited both aldosterone and corticosterone production, although cells from hypoxic 7-day-old rats were less sensitive. We conclude that hypoxia induces hyperlipidemia in the suckling neonate and that elevated nonesterified fatty acids inhibit aldosteronogenesis.

Plasma aldosterone, plasma lipoproteins, obesity and insulin resistance in humans.

Aldosterone production in vitro can be affected by many hormones, autacoids, ions, and lipids, but regulation in humans is incompletely understood. We measured plasma aldosterone in adult subjects with a wide range of obesity and insulin resistance. Aldosterone levels correlated with measures of visceral obesity in one predominantly male cohort and in the women of a second cohort. In the same subjects, aldosterone correlated with insulin resistance. Aldosterone also correlated with plasma cortisol in men and women, and with DHEA-S in women. The data suggested that visceral fat stimulates adrenal steroidogenesis. We found that certain fatty acids stimulated aldosterone production in vitro by rat adrenal cells incubated with rat hepatocytes, but not adrenal cells alone. The results suggested that fatty acids from visceral adipocytes induce hepatic formation of an adrenal secretagogue. This may explain the correlation of plasma steroids with visceral obesity. Aldosterone may contribute to vascular diseases that complicate obesity.

Visceral obesity and insulin resistance are associated with plasma aldosterone levels in women.

OBJECTIVE: Both obesity and insulin resistance increase the risk of hypertension and other cardiovascular diseases, but the mechanisms linking these abnormalities are unknown. The current study was undertaken to examine the effects of obesity, fat distribution, and insulin resistance on plasma levels of aldosterone and other adrenal steroids that might contribute to sequelae of obesity. RESEARCH METHODS AND PROCEDURES: Twenty-eight normotensive premenopausal women and 27 normotensive men with a wide range of body fat underwent measurements of visceral adipose tissue by CT scan, total fat mass by dual energy X-ray absorptiometry, blood pressure, insulin sensitivity, and plasma levels of three adrenal steroid hormones. RESULTS: Plasma aldosterone in women correlated directly with visceral adipose tissue (r=0.66, p<0.001) and inversely with insulin sensitivity (r=-0.67, p<0.001), and these associations were independent of plasma renin activity. There were no corresponding correlations in men. Plasma aldosterone was significantly correlated with plasma cortisol and dehydroepiandrosterone sulfate in women. Seventeen women and 15 men completed a weight-reduction regimen, losing an average of 15.1+1.2 kg. After weight loss, plasma aldosterone was significantly lower and insulin sensitivity higher; however, the correlations of aldosterone with visceral adipose tissue and insulin sensitivity in women persisted (p = 0.09 and 0.07, respectively). Although none of the women were hypertensive, blood pressure correlated with plasma aldosterone both before and after weight loss. DISCUSSION: We conclude that visceral adiposity and insulin resistance are associated with increased plasma aldosterone and other adrenal steroids that may contribute to cardiovascular diseases in obese women.

Docosahexaenoic acid is an antihypertensive nutrient that affects aldosterone production in SHR.

The effects of dietary docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, on blood pressure and some pressure-regulating systems were measured in young spontaneously hypertensive rats (SHR). Plasma aldosterone and corticosterone levels, adrenal aldosterone production in vitro, and characteristics of adrenal angiotensin receptors were measured after 6 weeks of diet. Renal cytochrome P450 (CYP) 4A gene expression and arachidonic acid metabolism by renal microsomes were also investigated. Plasma cholesterol, triglycerides, and high-density lipoprotein cholesterol were measured. Diets contained either corn/soybean oil alone (CSO), or oil enriched with DHA. After 6 weeks, rats fed DHA had systolic blood pressures averaging 34 mmHg less than controls (P < 0.001). Plasma aldosterone levels were 33% lower in the DHA-fed animals than in controls (22 +/- 3 vs. 33 +/- 3.7 ng/dl, P < 0.05). Plasma levels of corticosterone were 18% lower in animals fed DHA than in controls, but this difference was not statistically significant. Adrenal glomerulosa cells from DHA-fed rats produced less aldosterone in vitro in response to angiotensin II, ACTH, or potassium. The difference was less marked when aldosterone production was stimulated by supplying exogenous corticosterone, suggesting an effect of DHA on postreceptor steps in signal transduction or the early pathway of aldosteronogenesis. We found no significant differences in angiotensin receptor subtype, number, or affinity. Production of arachidonic epoxides by renal microsomes was 17% lower in DHA-fed animals than in controls (P < 0.05). Renal cortical mRNA levels of CYP4A genes and formation of 19- and 20-hydroxyeicosatetraenoic acid (HETE) did not differ between dietary groups. Plasma total cholesterol and high-density-lipoprotein (HDL) levels were significantly reduced in SHR fed the DHA supplement, but triglyceride levels were not significantly different. The effects of DHA on steroid and eicosanoid metabolism may be part of the mechanism by which this fatty acid prevents some of the hypertension in growing SHR.

Intralipid enhances alpha1-adrenergic receptor mediated pressor sensitivity.

The dyslipidemia in obese hypertensive persons may contribute to their increased vascular alpha-adrenergic receptor reactivity and tone. To further examine this notion, we conducted 2 studies of pressor sensitivity to phenylephrine, an alpha1-adrenergic receptor agonist, in lean normotensive subjects. In the first study (n=6), pressor responses to phenylephrine were obtained before and during a saline and heparin infusion. On another day, pressor reactivity to phenylephrine was measured before and during infusion of 20% Intralipid at 0.5 mL . m-2 . min-1 with heparin at 1000 U/h to increase lipoprotein lipase activity and raise nonesterified fatty acids (NEFAs). In the second study (n=8), baseline reactivity to phenylephrine was obtained on 2 separate days and repeated after raising NEFAs and triglycerides either with 0.8 mL . m-2 . min-1 of 20% Intralipid alone or together with heparin. The infusion of saline and heparin did not significantly change plasma NEFAs from baseline (516+/-90 versus 512+/-108 micromol/L, respectively; P=NS) or the dose of phenylephrine required to raise mean blood pressure by 20 mm Hg ([PD20PE]; 1.00+/-0.14 versus 0. 95+/-0.10 microg . kg-1 . min-1, respectively, P=NS). Intralipid at 0.5 mL . m-2 . min-1 with heparin raised plasma NEFAs to 793+/-30 micromol/L per liter (P<0.05 versus baseline) and reduced PD20PE from 1.01+/-0.10 to 0.80+/-0.09 microg . kg-1 . min-1 (P<0.05). Compared with baseline, Intralipid alone increased plasma NEFAs to 946+/-80 micromol/L (P<0.05), and NEFAs increased further with the addition of heparin to 2990+/-254 micromol/L (P<0.01). Despite an apparently greater increase of plasma NEFAs with Intralipid and heparin, Intralipid alone and together with heparin similarly reduced PD20PE. Across all study conditions, changes in levels of triglycerides and NEFAs correlated with changes in mean arterial pressure responses to phenylephrine, especially at the 0.4- microg . kg-1 . min-1 infusion rate of phenylephrine (r=0.64, P<0.01 and r=0. 54, P<0.01, respectively). These data suggest that raising levels of plasma NEFAs and/or triglycerides enhances alpha1-adrenoceptor mediated pressor sensitivity. The findings suggest that lipid abnormalities in obese hypertensives, which include elevated NEFAs and triglycerides, contribute to greater vascular alpha1-adrenergic reactivity.

Torsemide inhibits aldosterone secretion in vitro.

Torsemide inhibited aldosterone secretion by adrenal cells from rats, cows, and guinea pigs stimulated in vitro by potassium, angiotensin, dibutyryl cyclic AMP, ACTH, or corticosterone. Inhibitory concentrations for adrenal cells (micromolar) were comparable with those reported to inhibit ion transport in isolated renal tubules. Inhibition of aldosterone secretion could reduce kaliuresis, and that may explain why torsemide causes less kaliuresis than other diuretics.

Effects of dietary gamma-linolenic acid on blood pressure and adrenal angiotensin receptors in hypertensive rats.

In a previous study, we showed that dietary gamma-linolenic acid (GLA), an omega-6 polyunsaturated fatty acid found in borage oil (BOR), attenuates the development of hypertension in young spontaneously hypertensive rats (SHR). The purpose of this study was to determine the effects of dietary GLA on established hypertension in adult rats, as well as its effects on components of the renin-angiotensin-aldosterone axis. For 5 weeks, male SHR (14-15 weeks old) were fed a basal fat-free diet to which 11% by weight of sesame oil (SES) or BOR was added. Systolic blood pressure (SBP), determined by the tail cuff method, and weight were measured weekly. Plasma renin activity (PRA), aldosterone (PA), and corticosterone (PC) levels were measured at the end of the dietary treatments. The adrenal glands were homogenized, and angiotensin II (ANG II) binding was measured and plotted according to Scatchard. Systolic blood pressure was 12 mmHg lower at Week 5 in SHR fed the BOR diet compared to SES-fed rats (P < 0.005). Weight gains were similar in both dietary groups. Plasma aldosterone was lower, PRA was higher, and the PA/PRA ratio was significantly lower (P < 0.05) in BOR-fed rats. Levels of PC were the same in both groups. The BOR-enriched diet reduced adrenal ANG II receptor density and affinity compared to the SES diet. Results suggest that BOR inhibits adrenal responsiveness to ANG II by an action on adrenal receptors. Our findings demonstrated that dietary GLA lowers SBP in adult SHR. This effect may be mediated, at least in part, by interference with the renin-angiotensin-aldosterone system at the level of adrenal ANG II receptors.

Aldosterone in obesity.

Plasma aldosterone levels were measured in adults whose body mass index ranged from lean to obese. Blood was drawn while subjects rested supine for 30-90 minutes. Aldosterone was higher in obese subjects, but could not be explained by renin or K+. The best predictors of plasma aldosterone were abdominal obesity measured as waist/hip ratio or by CT scan, and insulin resistance measured by insulin or oral glucose tolerance tests, or euglycemic clamp. In one cohort, these correlations were limited to women; in the other, they were also found in men. In the women with a strong correlation between aldosterone and visceral fat, aldosterone also correlated with cortisol and DHEA-S. The data are consistent with an effect of visceral fat on adrenal steroidogenesis. Visceral adipocytes have a high rate of triglyceride turnover, and their circulation drains directly to the liver. In an experiment based on these characteristics, rat hepatocytes responded to fatty acids by releasing an unidentified secretagogue that stimulated aldosterone production by rat adrenal glomerulosa cells. The clinical data suggest that aldosterone participates in hypertension associated with the "Insulin Resistance Syndrome". The adrenal in viscerally obese subjects may be driven by a secretagogue released from the liver by fatty acids from abdominal adipocytes.

Nonesterified fatty acids in the pathogenesis of hypertension: theory and evidence.

This paper approaches the hypothesis that fatty acids contribute to hypertension by examining possible interactions of nonesterified fatty acids with renal pressure-natriuresis, peripheral vascular resistance, and the central nervous barostat, three loci where long-term regulation of blood pressure is probably controlled. By inhibiting aldosterone secretion, nonesterified fatty acids may lower blood pressure by facilitating pressure-natriuresis. Oxygenated metabolites of fatty acids appear to stimulate aldosterone secretion. In different experimental situations, fatty acids either constrict or dilate arteries. There is no evidence of an effect of fatty acids on the central nervous barostat, but they do sensitize peripheral vessels to alpha-adrenergic stimuli. Obesity and diabetes are marked by increased incidence of hypertension, and elevated levels of fatty acids or their P450 oxygenated metabolites may contribute to this association. Drugs that influence plasma fatty acids, like heparin, do not have reproducible effects on blood pressure. Experimental evidence suggests but does not prove that nonesterified fatty acids can affect the long-term set-point of blood pressure.