Vasorelaxant and antiaggregatory properties of the endothelium: a comparative study in normocholesterolaemic and hereditary and dietary hypercholesterolaemic rabbits.

1. A comparison of the effects of dietary and genetically-induced hypercholesterolaemia on the vasodilator and antiaggregatory capacity of the endothelium was made in rabbit isolated subclavian artery rings. 2. Dietary-induced hypercholesterolaemia in NZW rabbits decreased the maximum relaxation to carbachol (0.01-10 microM) and calcimycin (0.01-0.1 microM) in vessel rings precontracted with 5-hydroxytryptamine (5-HT), 0.1 microM), when compared to responses observed in rings obtained from control normocholesterolaemic NZW rabbits. The relaxant responses to SIN-1 (3-(4-morpholinyl)-sydnonimine hydrochloride) were attenuated but were not significantly different from controls. In Froxfield genetically hypercholesterolaemic (FHH) rabbits, the maximum relaxations to carbachol, calcimycin and SIN-1 were all reduced significantly. 3. Neither genetic nor dietary-induced hypercholesterolaemia modified the contractile responses of vessel rings to either KCl (10-100 mM) or 5-HT (0.01-10 microM). 4. Endothelium-dependent inhibition of collagen-induced platelet aggregation in whole blood was demonstrated by stimulation of a vessel ring, incorporated into the blood sample, with carbachol (10 microM, final blood concentration). This effect was inhibited by NG-nitro-L-arginine (L-NOARG, 100 microM). SIN-1 (10 microM, final blood concentration) also decreased whole blood platelet aggregation, but only in the presence of an unstimulated vessel ring, and this was unaffected by L-NOARG. Superoxide dismutase (150 u ml-1) did not influence the inhibition of aggregation by either a carbachol-stimulated vessel ring or by SIN-1. 5. Carbachol-stimulated artery rings from FHH rabbits inhibited platelet aggregation to a similar extent to that seen with rings from control normocholesterolaemic rabbits. Rings from hypercholesterolaemic NZW rabbits, however, did not significantly inhibit platelet aggregation when stimulated with carbachol. SIN-1 inhibited platelet aggregation in the presence of rings from either group of hypercholesterolaemic rabbits. 6. Hypercholesterolaemia induced by dietary modification induces changes in endothelial function which are characteristically different from those seen in genetically hypercholesterolaemic rabbits. It appears that dietary-induced hypercholesterolaemia primarily decreases NO release from the endothelium, while in genetically-induced hypercholesterolaemic vessel rings NO is released but there is a decreased responsiveness of the vascular smooth muscle cells to NO. This may reflect differences in the age and severity of the atherosclerotic lesions in the two groups of rabbits.