Abolition of flow-dependent EDRF release before that evoked by agonists in hypercholesterolaemic rabbits.
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 microM) were not influenced after 4 weeks and only partially attenuated (by 60% of the maximal response, EC50 unchanged at 6.45 +/- 0.04 vs. 6.4 +/- 0.1 microM) 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 l-1) and 8 weeks (56.2 +/- 3.8 vs 1.3 +/- 0.1 mmol l-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 l-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.
Hutcheson
I R
IR
Department of Diagnostic Radiology, University of Wales College of Medicine, Heath Park, Cardiff.
Smith
J A
JA
Griffith
T M
TM
D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000375:Aging / Q000502:physiology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology; D001809:Blood Viscosity; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000494:pharmacology; D003911:Dextrans / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000378:metabolism*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000819:agonists* / Q000378:metabolism*; D010477:Perfusion; D011817:Rabbits
D002791:Cholesterol, Dietary; D003911:Dextrans; D009569:Nitric Oxide; D001120:Arginine; D002784:Cholesterol; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester