Differential efficacy of vasodilators in hypercholesterolaemic rabbits

The effects of hypercholesterolaemia on the endothelium-dependent and -inde pendent vascular reactivity of the superior mesenteric artery has been exam ined in anaesthetized rabbits in-vivo. Rabbits were fed with either standar d or cholesterol-enriched diet for 24 weeks. Plasma lipids and changes in t he endothelin content of plasma and vascular tissue were measured in the su perior mesenteric artery and in the thoracic aorta. The functional severity of atherosclerosis was determined by examining vascular responses in the i solated thoracic aorta. The blood flow in the superior mesenteric artery wa s measured by transit-time flowmetry and drugs were injected through an int ra-abdominal aortic catheter. Acetylcholine (5, 10, 20 mu g kg(-1)) elicited dose-dependent, mesenteric v asodilation in normocholesterolaemic rabbits. In hypercholesterolaemic anim als the response to acetylcholine was completely abolished and even became a vasoconstriction. Endothelin levels in plasma and in the vascular tissue were significantly elevated in hypercholesterolaemic animals compared with controls. Cromakalim at a dose of 3 mu g kg(-1), elicited similar mesenteri c vasodilation in hypercholesterolaemic and normocholesterolaemic animals. These experiments show that the endothelium-dependent responses of the supe rior mesenteric artery to acetylcholine are functionally impaired by prolon ged hypercholesterolaemia, that this altered vascular reactivity is associa ted with the elevation of endothelin levels in the circulation and in vascu lar tissues, and that in hypercholesterolaemia the mesenteric vasodilator e ffect of the K+-channel opener cromakalim is entirely preserved, suggesting that severe hypercholesterolaemia does not depress the function of ATP-sen sitive potassium channels in mesenteric vascular smooth muscle.