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Abolition of flow‐dependent EDRF release before that evoked by agonists in hypercholesterolaemic rabbits
Author(s) -
Hutcheson Iain R.,
Smith Jerry A.,
Griffith Tudor M.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb16192.x
Subject(s) - pulsatile flow , endocrinology , medicine , acetylcholine , chemistry , cholesterol , endothelium derived relaxing factor
1 We have used a pulsatile cascade bioassay system to investigate the effects of dietary‐induced hypercholesterolaemia on EDRF release evoked by acetylcholine and by the oscillatory and time‐averaged components of flow, in isolated segments of rabbit abdominal aorta. 2 Flow pulsatility (frequency range 0.1–10 Hz) was studied with constant flow (9 ml min −1 ) at a pulse pressure amplitude of 2 mmHg. Frequency‐related EDRF release, maximal at 6 Hz, was slightly attenuated after 4 weeks and abolished after 8 weeks of cholesterol feeding. 3 Time‐averaged shear stress was manipulated with dextran (1–4% w/v, 80000 mol. wt.), to increase perfusate viscosity. EDRF release induced by increased perfusate viscosity was unaffected after 4 weeks but abolished after 8 weeks of cholesterol feeding. 4 Endothelium‐dependent relaxations to acetylcholine (0.1–10 μ m ) were not influenced after 4 weeks and only partially attenuated (by 60% of the maximal response, EC 50 unchanged at 6.45 ± 0.04 vs. 6.4 ± 0.1 μ m ) after 8 weeks of cholesterol feeding. 5 Blood cholesterol levels were significantly ( P <0.001) increased after 4 weeks (26 ± 3.6 vs 2.6 ± 0.6 mmol 1 −1 ) and 8 weeks (56.2 ± 3.8 vs 1.3 ± 0.1 mmol 1 −1 ) of cholesterol feeding but after 8 weeks plasma L‐arginine levels were not significantly different from the age‐matched controls (0.2 ± 0.05 vs. 0.19 ± 0.04 mmol 1 −1 ). 6 We conclude that hypercholesterolaemia impairs flow‐related (pulsatile‐ and time‐averaged shear‐induced) EDRF release earlier than acetylcholine‐induced relaxation in rabbit aorta. This is consistent with the view that different transduction mechanisms mediate EDRF release in response to agonists and flow.