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(Hypertension. 1995;26:193-198.)
© 1995 American Heart Association, Inc.
Articles |
Pressor Effects of Portal Venous Oleate Infusion
A Proposed Mechanism for Obesity Hypertension
From the VA Medical Center and the University of Michigan, Ann Arbor.
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Abstract |
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Abstract Increased visceral fat accumulation is a strong predictor of arterial hypertension. In this study, we explored the hypothesis that increased hepatic portal venous free fatty acid delivery results in increased blood pressure. Such an effect might explain the link between visceral obesity and hypertension. In nine conscious, instrumented rats, we studied the effects of 1-hour infusions of sodium oleate solution into the portal and femoral veins and infusions of sodium caprylate solution into the portal vein on 3 separate days. Basal blood pressure was not significantly different on the 3 study days. Mean arterial pressure increased 29±4 mm Hg during portal oleate infusion and 13±2 mm Hg during femoral oleate infusion (both significant increases over basal, P<.001). Mean arterial pressure did not change during portal caprylate infusion. The increase during portal oleate infusion was greater than that during femoral oleate infusion (P=.028). Heart rate rose during all three infusions; the increase was greatest during portal oleate infusion (334±4 to 412±2 beats per minute). During portal venous oleate infusion in five rats, plasma norepinephrine rose from 2.17±0.34 to 3.58±0.50 nmol/L, epinephrine rose from 0.79±0.28 to 1.84±0.44 nmol/L, and corticosterone rose from 147±55 to 1130±289 nmol/L. Three rats given portal venous oleate infusions for 1 week had increased blood pressure compared with baseline (mean increase, 16±4 mm Hg). These studies indicate that increases in portal venous fatty acid concentrations have significant pressor effects, perhaps mediated by increased sympathetic tone. Chronic increases in portal venous fatty acid levels may be responsible for the hypertension that accompanies visceral obesity.
Key Words: obesity • blood pressure • hypertension, obesity • fatty acids • portal vein • norepinephrine • rats
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Introduction |
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The link between obesity and hypertension has been well established. Obese individuals are at increased risk for hypertension,1 and weight loss consistently results in a decrease in blood pressure (BP).2 3 Among obese individuals, those with upper body obesity are at greater risk for hypertension than those with lower body obesity.4 5 Using computed tomography to estimate visceral and abdominal subcutaneous fat, Peiris et al6 demonstrated that visceral fat is a stronger predictor of hypertension than is the waist-hip ratio, implying that visceral fat accumulation increases the risk of hypertension and accounts for the increased incidence associated with upper body obesity. The mechanism that links visceral fat accumulation to increased BP is unknown.
In this study we explore a new hypothesis to explain the occurrence of obesity hypertension. We propose that fatty acid receptors within the liver respond to changes in fatty acid delivery by effecting an increase in neural and/or humoral pressor responses. Individuals with visceral obesity would be expected to have increased hepatic delivery of free fatty acids (FFAs) because the venous drainage of visceral fat tissue is directed into the portal venous system. In contrast, individuals with peripheral obesity should have less hepatic delivery of FFAs, because venous drainage from these sites is systemic.
As a first step in testing this hypothesis, we performed infusions of oleate (18:1), the most prevalent long-chain fatty acid in plasma, into the portal and femoral veins of conscious rats. We used caprylate (8:0), a medium-chain fatty acid, as a control. Pressor responses to portal oleate infusions provide support for the proposed hypothesis.
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Methods |
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Rats
Male Sprague-Dawley rats were obtained from Hilltop Laboratory Animals Inc (Scottdale, Pa). Animal experiments were approved by the Animal Studies Committee of the Ann Arbor VA Medical Center and were in accordance with institutional guidelines. Animals weighed 300 to 350 g and were surgically prepared under 50 mg/kg IP pentobarbital anesthesia. Booster doses of 25 mg/kg were given as required. Three indwelling catheters were placed in each rat: one in the portal vein, one in a femoral vein, and one in a femoral artery. Catheters were tunneled subcutaneously to the top of the head and externalized through a scalp incision. They were fixed to the skull with dental acrylic anchored to three skull screws. Catheters were brought to the top of an individual cage and attached to a swivel at the top of the cage to allow for free movement. Catheters within the cage were protected by a metal coil. Venous catheters were filled with heparinized saline and kept open with a continuous infusion at a rate of 1 µL/min. Arterial catheters were filled with 80% sucrose and flushed daily. Rats were allowed to recover from surgery for 72 hours before infusions were performed.
Pressure was monitored with a Statham transducer (Viggo-Spectramed) and Grass polygraph (Grass Instrument Co).
Solutions
Oleate solution consisted of 10 mmol/L sodium oleate in 0.45%
saline. The solution was prepared by heating to 50°C and was kept in
the dark until infusion. During long-term infusions, solutions were
kept warm by placing a heating pad around the infusion syringe.
Infusion tubing was wrapped to protect it from the light. Caprylate
solution consisted of 10 mmol/L sodium caprylate in 0.45% saline. Both
solutions remained clear throughout all experiments.
Infusions
Short-term infusions were performed in nine rats. Each rat
received three separate infusions. On separate days, oleate solution
was infused into the portal vein, oleate solution was infused into the
femoral vein, and caprylate solution was infused into the portal vein.
Each infusion was given at a rate of 25 µL/min. The order of infusion
was randomized. Solutions were delivered by an infusion pump (World
Precision Instruments, Inc). Arterial BP was measured every 6 minutes
for 1 hour before each infusion, throughout the 1-hour infusion period,
and during a 1-hour recovery period. Mean BP was determined over
30-minute intervals.
Sustained infusions of oleate solution into the portal vein were performed in three rats. Basal BP was measured over a 1-hour period from 10 to 11 AM before the infusion was begun. Infusions at a rate of 25 µL/min were then carried out for 7 days in each rat. BP determinations were obtained for 1 hour from 10 to 11 AM after 3 and 7 days of infusion.
Ten additional rats were studied for the purpose of obtaining plasma samples for analysis. In five rats, sodium oleate solution was infused into a portal vein catheter at a rate of 25 µL/min for 1 hour. In the other five, 0.45% sodium chloride solution was infused into a jugular vein at a rate of 25 µL/min for 1 hour. Blood samples of 2.5 mL volume were obtained through the indwelling arterial catheter before and at the end of infusion. Samples were analyzed for levels of aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase, norepinephrine, epinephrine, renin activity, corticosterone, fatty acids, triglycerides, glucose, and insulin.
Analytic Methods
Plasma levels of insulin, renin activity, and corticosterone
were measured by radioimmunoassay. Insulin was measured with antibody
purchased from Linco Research; renin activity with a kit purchased from
DuPont; corticosterone with kits from ICN Biochemicals; and epinephrine
and norepinephrine with a radioenzymatic method.7 FFAs
were measured enzymatically with a kit purchased from Wako Chemicals
USA, Inc, and glucose, triglycerides, AST, ALT, and alkaline
phosphatase with Ektachem slides (Eastman Kodak Co).
Statistical Analysis
All values are expressed as mean±SEM. Within each experimental
condition, measurements over 30-minute intervals were compared using
one-factor ANOVA for repeated measures followed by pairwise multiple
comparisons adjusted for the experimentwise 
error. Comparisons of
mean BP and heart rate from 0 to 60 minutes between different
experimental conditions were performed using the same analysis.
Determination of the timing of the pressure change was performed using
paired t tests with Bonferroni protection. Comparisons of
basal and stimulated plasma measurements were performed using paired
t tests, and comparisons of basal plasma levels between rats
receiving oleate and those receiving saline were performed using
unpaired t tests.
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Results |
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Fig 1 shows BP responses to 1-hour infusions. BP was significantly increased over basal after 12 minutes of sodium oleate infusion into the portal vein and after 6 minutes of sodium oleate infusion into the femoral vein. For both infusions, BP reached a plateau at 30 minutes. BP fell steadily in both oleate infusion groups after discontinuation of the fat infusion but had not returned to basal levels after 60 minutes. No changes in BP occurred during sodium caprylate infusion. During the last 30 minutes of infusion, mean BP was increased by 29±4 mm Hg compared with baseline during portal oleate infusion and by 13±2 mm Hg during femoral oleate infusion. Under both conditions the increase in BP over basal was significant at both 30 and 60 minutes (each P<.001). Mean BP during the last 30 minutes of infusion was significantly higher during portal oleate infusion than during portal caprylate (P=.002) and femoral oleate (P=.028) infusions. BP during the last 30 minutes of femoral oleate infusion was not significantly different from that during portal caprylate infusion (P=.105). Analysis of these same data as change from basal gave nearly identical results.
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) and femoral (
)
veins and sodium caprylate into the portal vein (
). Blood
pressure was significantly elevated above basal after 12 minutes of
oleate infusion into the portal vein and after 6 minutes of oleate
infusion into the femoral vein. Inset, Line graph shows results as mean
arterial pressure (MAP) over the previous 30 minutes. Increase from
basal at 60 minutes was significantly greater during portal oleate
infusion than during the other two treatments. *P=.002
compared with portal caprylate; P=.028 compared with femoral
oleate (see text).Fig 2 shows changes in heart rate during oleate and caprylate infusions. Heart rate rose during fat infusion in each experimental condition. The increase was greatest in the group that received the portal oleate infusion, increasing from 334±4 beats per minute at baseline to 412±2 at 60 minutes. Heart rate remained elevated during the 1-hour recovery period after portal oleate infusion. The increase in heart rate over basal was significant in all three groups. At 60 minutes, heart rate was significantly greater during portal oleate infusion than during femoral oleate infusion (P=.031) but was not significantly greater than during portal caprylate infusion (P=.139).
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Fig 3 shows plasma levels of norepinephrine and epinephrine. Basal norepinephrine levels were higher in the group receiving portal venous oleate than in the group receiving saline (P=.024). Norepinephrine levels rose in all five rats receiving portal oleate infusion. Mean levels increased from 2.17±0.34 to 3.58±0.50 nmol/L (P=.031). During saline infusion, norepinephrine levels were not significantly different from basal. Epinephrine levels before infusion were not different between the two groups. During portal oleate infusion, epinephrine levels also rose in all five rats. Mean levels increased from 0.79±0.28 to 1.84±0.44 nmol/L (P=.040). No significant change occurred in epinephrine during saline infusion.
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Fig 4 depicts the results of corticosterone and renin measurements. Basal corticosterone levels were not different between the two groups. Corticosterone levels rose strikingly in four of five rats receiving portal venous oleate (P=.039) but did not change during saline infusion. Basal renin activity was higher in the portal oleate group than in the saline group (P=.050). Renin activity rose significantly during infusion in both rat groups (P=.049 for portal oleate group, P=.006 for femoral saline group).
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There were no significant changes in insulin, glucose, FFAs, or triglycerides during portal oleate infusion (Table 1). Insulin levels fell during the infusion, but the decrease was not statistically significant (P=.137). The rise in plasma FFAs was also not significant (P=.253). There were also no significant changes in plasma levels of alkaline phosphatase, ALT, or AST (Table 2).
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Fig 5 shows the results of 1-week oleate infusions into the portal vein in three rats. BP increased modestly in each rat and was elevated over baseline at both day 3 and day 7. Mean BP increased by 8±5 mm Hg after 3 days and 16±4 mm Hg after 7 days. Plasma levels of hepatic enzymes were obtained after 7 days in two of the three rats that received chronic oleate infusion. Mean levels of ALT, AST, and alkaline phosphatase were 170, 49, and 389 U/L.
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Discussion |
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This study explored the possibility that the hypertension associated with visceral obesity is caused by increased portal venous fatty acid delivery to the liver. The pressor response observed during portal venous infusion of oleate, the predominant circulating fatty acid in most species, suggests that the hypothesis may be correct.
Obesity is a strong predictor of hypertension.1 Abdominal or upper body obesity is associated with higher BP values than is lower body obesity.4 5 Studies with computed tomography indicate that this increased association relates primarily to the presence of visceral fat as opposed to abdominal subcutaneous fat.6
The mechanisms that relate visceral obesity to hypertension have not been explained. Jensen et al8 have demonstrated that abdominal fat cells are metabolically more active than peripheral fat cells, and Martin and Jensen9 subsequently showed that abdominal obesity was associated with increased lipolytic activity and increased FFA release and turnover. They also showed that obese individuals have elevated FFA levels compared with lean control subjects. These observations are consistent with our hypothesis, confirming that individuals with visceral obesity are likely to have increased portal venous FFA levels.
Increased visceral fat accumulation is also associated with a higher risk of hyperinsulinemia, diabetes, lipid abnormalities, and coronary artery disease.10 11 Interestingly, increased fatty acids have been implicated as a causal factor in hypertriglyceridemia and insulin resistance.12 13 14 Although hyperinsulinemia has received considerable attention as a mediator of obesity-related hypertension, evidence suggests that chronic hyperinsulinemia is not responsible for sustained hypertension.15 16 17
Fatty acids have been shown to have pressor effects in pigs. Infusion of intralipid plus heparin to increase FFA levels raised BP, total peripheral resistance, and resistance in most vascular beds.18 Although the mechanism of this effect was not elucidated, the authors had previously shown that local perfusion of adipose tissue with FFAs caused vasoconstriction.19 Recently, Stepniakowski et al20 reported that infusion of intralipid plus heparin reduced hand vein distensibility in healthy volunteers and increased responsiveness to phenylephrine. These observations suggest direct pressor effects of fatty acids on vascular beds. Although similar pressor effects may be operative in the present study, the greater pressor response to portal venous infusion compared with femoral venous infusion suggests that direct effects of FFAs on resistance arteries were not the major mediators of the response to portal venous oleate infusion. The pressor response to femoral venous infusion of sodium oleate may also be mediated through hepatic delivery of the fatty acid, although the extrahepatic effects of oleate could also play a role in this response.
Fatty acids have other effects that might affect BP. They act as Na,K-ATPase inhibitors21 and inhibit aldosterone secretion.22 Neither of these appears likely to be affecting BP in the present study. Inhibitors of Na,K-ATPase may increase BP under some circumstances, but the response to systemic administration is slow, requiring hours to days.23 It is possible that portal venous infusion of an Na,K-ATPase inhibitor might have a more rapid effect. Inhibition of aldosterone would be expected to decrease BP.
We suggest that a neural pressor response is the most likely mechanism to explain these results. The marked rise in plasma norepinephrine and epinephrine levels during portal venous oleate infusion indicates increased sympathetic activity. The increased heart rate during oleate infusion also suggests a general increase in sympathetic tone.
Hepatic neural reflexes in response to alterations in delivered metabolites are well described. Glucose infusion into the portal vein alters vagal nerve traffic and activity in the hypothalamus and nucleus tractus solitarius.24 25 26 Hepatic glucose delivery increases insulin secretion mediated by a neural reflex loop.27 Orbach and Andrews28 reported that infusion of myristate and palmitate, two long-chain fatty acids, into the rabbit hepatic artery increased vagal afferent nerve activity. Short-chain fatty acid infusion had no effect. Oleate was not tested in that study, and no measurements of efferent effects were reported.28 Thus there is precedent to propose neural reflex discharge in response to alterations in hepatic fatty acid delivery.
Increased sympathetic discharge in response to increased hepatic fatty acid delivery is consistent with recent reports that obesity is associated with an increase in sympathetic nerve activity. Morgan and Mark29 reported increased renal sympathetic nerve activity in obese Zucker rats, and Scherrer et al30 found that body fat is a major determinant of muscle sympathetic nerve discharge in humans. Kassab et al31 found that renal denervation prevented the development of obesity-induced hypertension in dogs, suggesting that efferent sympathetic nerve activity plays an important role in the hypertension.
Humoral responses to oleate infusion could also mediate the pressor response. Increased plasma renin activity was observed in four of five rats, but this appears likely to have been the result of volume depletion associated with blood sampling, because similar rises were seen in control rats. Increased sympathetic discharge could also cause an increase in renin secretion. The pronounced rise in corticosterone could have been mediated by stress or could have been a direct effect of oleate on the pituitary adrenal axis.32 In either case, increases in corticosterone would not be expected to alter BP within a 1-hour time frame. Hyperinsulinemia, often proposed as a mediator of obesity hypertension, did not occur in this study.
It is possible that pressor responses observed in this study were a manifestation of toxic effects of sodium oleate rather than of physiological effects. Fatty acids have detergent properties, and infusion of high doses has been used to induce experimental lung and pancreatic damage.33 34 The increases in catecholamines and corticosterone would be consistent with a stress response. However, hepatic enzyme levels did not change, suggesting that major hepatic damage did not occur.
None of the rats reported in this study manifested an outward appearance of illness or discomfort during infusion. In subsequent studies, however, some rats have developed a stretched-out posture during oleate infusion that resolved quickly once the infusion was stopped.
A striking feature of this study is the magnitude of the response to a very low dose of sodium oleate. Rats received 0.25 µmol of oleate per minute during the infusion. Using estimates of portal and hepatic flow in the rat of 1.5 mL/min per gram35 and assuming basal plasma FFA concentrations of 500 µmol/L and oleate concentrations of 15% of total FFAs,36 we estimate that endogenous hepatic fatty acid delivery is approximately 14 µmol/min and that oleate delivery is approximately 2 µmol/min. Thus, the exogenous infusion of oleate in this study increased hepatic oleate delivery by only 12% and total fatty acid delivery by 2%. Measured increases in FFAs were only 60 µmol/L and were not statistically significant. Given the variability of FFA in these rats, we would have been able to detect FFA increases of 140 µmol/L.
It appears likely that the biological effects of this very small dose of sodium oleate are due to a more substantial increase in unbound oleate concentrations. Using a formula published by Spector et al,37 we calculate that the concentration of unbound FFAs in rat plasma under equilibrium conditions is 0.24% of total FFAs, or 1.2 µmol/L. Thus, delivery of unbound FFAs to the liver is only 0.03 µmol/min. If only half of the exogenously administered oleate binds to albumin during the very short transit time from the portal vein to the liver, hepatic delivery of unbound fatty acids would increase approximately fivefold during the infusion. It is also likely that some micelle formation may occur in our oleate solution.38 Although micelles would be expected to break up rapidly in vivo, some micelle delivery to the liver may occur. Whether micelles would have biological effects distinct from those of FFAs is uncertain.
Based on the results of this study, we propose that increases in portal venous delivery of FFAs to the liver stimulate a neurally mediated reflex that results in an increase in vascular sympathetic tone and an increase in BP. Such a reflex might serve to conserve energy during states of caloric deprivation because vasoconstriction, particularly in skeletal muscle tissue, would decrease glucose utilization.39 If this reflex is operative, increased fatty acid delivery to the liver would be an appropriate trigger, because caloric deprivation rapidly increases lipolysis and raises plasma FFA levels.40 Although most measurements of sympathetic activity during fasting demonstrate decreased activity,41 42 there is some evidence that muscle sympathetic nerve activity is increased during fasting.43
We postulate that individuals with visceral obesity have increased hepatic FFA delivery, even during the fed state, because the mass of fat cells that drain into the portal venous system is markedly increased. Preliminary evidence in hypertensive patients with abdominal obesity is consistent with this suggestion.44 In response to this chronic increase in portal FFA delivery, these individuals would be expected to have chronic increases in sympathetic nerve activity and a sustained increase in BP.
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Acknowledgments |
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This work was supported by the Research Service of the Department of Veteran's Affairs and by grant HL-18575 of the National Heart, Lung, and Blood Institute. The authors are grateful to Dr Paul Weinhold for advice and suggestions and to Dr Jeffrey Halter for providing catecholamine measurements.
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Footnotes |
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Reprint requests to Roger J. Grekin, MD, 2215 Fuller Rd, Ann Arbor, MI 48105.
Received November 22, 1994; first decision January 3, 1995; accepted March 8, 1995.
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A. M. Sironi, A. Gastaldelli, A. Mari, D. Ciociaro, V. Postano, E. Buzzigoli, S. Ghione, S. Turchi, M. Lombardi, and E. Ferrannini Visceral Fat in Hypertension: Influence on Insulin Resistance and {beta}-Cell Function Hypertension, August 1, 2004; 44(2): 127 - 133. [Abstract] [Full Text] [PDF]
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M. P. Stojiljkovic, D. Zhang, H. F. Lopes, C. G. Lee, T. L. Goodfriend, and B. M. Egan Hemodynamic effects of lipids in humans Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2001; 280(6): R1674 - R1679. [Abstract] [Full Text] [PDF]
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L. Benthem, K. Keizer, C. H. Wiegman, S. F. de Boer, J. H. Strubbe, A. B. Steffens, F. Kuipers, and A. J. W. Scheurink Excess portal venous long-chain fatty acids induce syndrome X via HPA axis and sympathetic activation Am J Physiol Endocrinol Metab, December 1, 2000; 279(6): E1286 - E1293. [Abstract] [Full Text] [PDF]
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