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.
Division of Clinical Pharmacology, Departments of Pharmacology and Medicine, Medical University of South Carolina, Charleston, SC, USA.
A T
AT
Haastrup
K T
KT
Stepniakowski
T L
TL
Goodfriend
B M
BM
Egan
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000328:Adult; D000925:Anticoagulants / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005217:Fat Emulsions, Intravenous / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology*; D011311:Pressoreceptors / Q000187:drug effects*; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D014280:Triglycerides / Q000097:blood
D000316:Adrenergic alpha-Agonists; D000925:Anticoagulants; D005217:Fat Emulsions, Intravenous; D005230:Fatty Acids, Nonesterified; D011942:Receptors, Adrenergic, alpha; D014280:Triglycerides; D010656:Phenylephrine; D006493:Heparin