FATTY-ACIDS AUGMENT ENDOTHELIUM-DEPENDENT DILATION IN HAND VEINS BY ACYCLOOXYGENASE-DEPENDENT MECHANISM

Evidence supports the hypothesis that elevated nonesterified fatty aci ds (NEFAs) in patients with insulin resistance, eg, obese hypertensive subjects, contribute to increased vascular alpha-adrenergic reactivit y and tone by impairing endothelium-dependent vasodilation. To generat e further support for this notion, we studied responses to endothelium -dependent and independent dilators under control (0.9% NaCl/heparin) conditions in one hand and with elevated NEFAs in the contralateral ha nd (10% intralipid/heparin). To observe venodilator responses, the dor sal hand vein diameter was first reduced by similar to 60% with phenyl ephrine. Studies were repeated with indomethacin to block the generati on of cyclooxygenase products. In contrast to previous in vitro data, elevating NEFAs locally in vivo augmented rather than suppressed venod ilator responses to the two endothelium-dependent dilators acetylcholi ne and methacholine (P<.05). Responses to the endothelium-independent dilator nitroglycerin were unaffected. Indomethacin attenuated the cap acity of intralipid/heparin to enhance endothelium-dependent dilator r esponses to acetylcholine and methacholine. Indomethacin did not affec t venodilator responses to nitroglycerin. The effect of intralipid/hep arin to significantly reduce the phenylephrine infusion rate required to reduce hand vein diameter by similar to 60% was reversed by indomet hacin. These data indicate that raising fatty acids locally augments e ndothelium-dependent dilation by a cyclooxygenase-dependent mechanism. The findings also suggest that NEFAs augment alpha(1)-adrenoceptor-me diated constriction in hand veins by a cyclooxygenase-dependent mechan ism. These hand vein studies do not support the notion that the elevat ed NEFAs in obese hypertensive patients augment alpha(1)-adrenoceptor- mediated reactivity by reducing nitric oxide synthesis.