Objective
BACKGROUND. Few data address the issue of the response of
resistance arteries to high serum cholesterol, or increased plasma glucose.Cholesterol-rich diet induces a reduction of microvessels reactivity in response to norepinephrine, (Am. J. Physiol.,1990, 258; H1464) and impairs the reaction of coronary arterioles to serotonin, histamine , bradykinine, etc. Administration of L-arginine restores the normal endothelium-dependent relaxing function, suggesting the involvement of EDRF production (circulation Res., 1992, 70 : 465). Initially, hypercholesterolemia induces endothelial disfunctions (FASEB J. 1993, 7: 1359). Diabetes affects the ATP-sensitive K+ channels (Am.J. Physiol. 1993, 265, H152), and arteriolar myogenic reactivity (Diabetes,1993, 42, 1226). Detection of pathobiochemical alterations induced in arteriolar endothelium by hyperlipidemia and hyperglycemia, will add to the understanding of the processes taking place in familial hyperlipidaemia (EURAD, Sub-project 5) and diabetes whose main complications are hypertension and atherosclerosis. PROPOSED PROJECT. Golden Sirian hamsters will be divided in 4 experimental groups: (1) diet-induced hypercholesterolemic animals; (2) streptozotocin-induced diabetics; (3) a combination of the two, and 4. untreated controls. Knowing that local generation of superoxide anions leads to the inactivation of endothelium-generated No (EDRF), some hamsters from group 1, will be concomitantly treated with antioxidants (captopril, probucol or SOD). Some diabetic hamsters (group 2) will be treated with aminoguanidine. The effect of either vasoconstrictors (angiotensin II, endothelin I) and vasodilators (histamine, nitroglycerine) will be determined. Animals will be sacrificed at 2 weeks and then monthly. Coronary arterioles (downstream from arterial lesions), pial vessels, and arterioles from retina, diaphragm, kidney, and cremaster muscle will be fixed in situ under controlled pressure, dissected and processed for electron microscopy, immunochemistry and cytochemistry. The ultrastructural changes will be evaluated and quantified by morphometry. By cytochemistry, the cytoskeleton and the nitric acid synthase in various conditions will be assessed.
Call for proposal
Data not availableFunding Scheme
CSC - Cost-sharing contractsCoordinator
8000 AARHUS C
Denmark