Intralipid Enhances α ₁ -Adrenergic Receptor–Mediated Pressor Sensitivity

Abstract

Abstract-The dyslipidemia in obese hypertensive persons may contribute to their increased vascular ␣-adrenergic receptor reactivity and tone. To further examine this notion, we conducted 2 studies of pressor sensitivity to phenylephrine, an ␣ 1 -adrenergic receptor agonist, in lean normotensive subjects. In the first study (nϭ6), 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 ⅐ m Ϫ2 ⅐ min Ϫ1 with heparin at 1000 U/h to increase lipoprotein lipase activity and raise nonesterified fatty acids (NEFAs). In the second study (nϭ8), baseline reactivity to phenylephrine was obtained on 2 separate days and repeated after raising NEFAs and triglycerides either with 0.8 mL ⅐ m Ϫ2 ⅐ min Ϫ1 of 20% Intralipid alone or together with heparin. The infusion of saline and heparin did not significantly change plasma NEFAs from baseline (516Ϯ90 versus 512Ϯ108 mol/L, respectively; PϭNS) or the dose of phenylephrine required to raise mean blood pressure by 20 mm Hg ([PD 20PE ]; 1.00Ϯ0.14 versus 0.95Ϯ0.10 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-g ⅐ kg Ϫ1 ⅐ min Ϫ1 infusion rate of phenylephrine (rϭ0.64, PϽ0.01 and rϭ0.54, PϽ0.01, respectively). These data suggest that raising levels of plasma NEFAs and/or triglycerides enhances ␣ 1 -adrenoceptor-mediated pressor sensitivity. The findings suggest that lipid abnormalities in obese hypertensives, which include elevated NEFAs and triglycerides, contribute to greater vascular ␣ 1 -adrenergic reactivity. (Hypertension. 1998;32:693-698.) Key Words: fatty acids Ⅲ phenylephrine Ⅲ receptors, adrenergic Ⅲ blood pressure I nsulin resistance is associated with a cluster of cardiovascular risk factors including hypertension, but the intermediary mechanisms linking metabolic and hemodynamic abnormalities are not well defined.1-7 Abdominally obese hypertensive persons have increased vascular ␣-adrenergic tone and reactivity, 8 as well as increased plasma concentrations 9 and turnover of nonesterified fatty acids (NEFAs) that are highly resistant to suppression by insulin.10 Evidence implicates abnormalities of NEFAs as one potential pathogenetic link between abdominal obesity and hypertension. 3,9 -12 We observed a positive correlation between plasma fatty acids during euglycemic clamp and blood pressure (BP) in obese subjects that was independent of hyperinsulinemia and insulin-mediated glucose disposal. 10 In minipigs, raising fatty acid levels increases systemic vascular resistance and BP. 13Our previous research has shown that raising fatty acids in the dorsal hand vein of normal volunteers to concentrations observed in obese hypertensives significantly increases venoconstrictor responses to phenylephrine as well as a neuroreflex stimulus.11,14 These observations raise the possibility that the e...

Non-esterified fatty acids and blood pressure elevation: a mechanism for hypertension in subjects with obesity/insulin resistance?

“…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 a 1 -adrenoceptor-mediated venoconstriction and pressor sensitivity. Other investigators reported comparably adverse effects of NEFAs on vascular function.…”

Glycine intake decreases plasma free fatty acids, adipose cell size, and blood pressure in sucrose-fed rats

“…Nevertheless, experimental studies in humans and in animals support a relationship between NEFA and hypertension. In humans, the acute action of Intralipid/heparin infusion to raise BP suggests the involvement of NEFA in enhancing ␣ 1 -adrenoreceptormediated pressor sensitivity (25). In pigs, BP rises when plasma NEFA are elevated during an acute infusion of Intralipid/heparin (10).…”

High Levels of Nonesterified Fatty Acids Are Associated With Increased Familial Risk of Cardiovascular Disease

“…NEFA levels are elevated in type 2 diabetes 9,10 and confer in nondiabetic individuals an increased risk of type 2 diabetes. 11,12 In addition, elevated NEFA levels are associated with insulin resistance [13][14][15] and hypertension, 16,17 two conditions that have been ascribed an increased risk of CVD and cerebrovascular disease. 18 -20 To address this question, we measured NEFA concentrations in diabetic and nondiabetic individuals from families with clustering of type 2 diabetes and related the findings to history of CVD in their parents.…”