This proposal concerns the use of light microscopic autoradiography (AR) to determine the types, locations, prevalences and affinities of some of the receptors which control pressure, flow and permeability in human pial, intracerebral, coronary and renal blood vessels. Experiments involve labeling frozen sections with receptor bioligands and a dry-mount AR technique. Rabbits are used for preliminary studies and methods then applied to postmortem human tissue.
Specific aims examine and extend ideas arising from current work with pial vessels. Binding sites for H3-prazosin (presumptive alpha-1 receptors) have been found in the outer tunica media near sites of adrenergic innervation of smooth muscle, as expected, but also in the non-innervated intima, suggesting a different receptor mechanism and activation by circulating amines, primarily epinephrine. Further studies should show that H3-prazosin follows the thickness of the media, in keeping with the control of pressure by neural norepinephrine, and also show a decline in these receptors as vessels get smaller. Studies of intimal prazosin-sites will show their relative affinities for norepinephrine and epinephrine. Parallel work with Il25-angiotension II is expected to show more sites in efferent than afferent renal arterioles, thus controlling trans-bed pressure, and may reveal receptors in intracerebral capillaries as well as glomeruli, suggesting control of permeability. Binding sites for H3-azidoclonidine (presumptive alpha-2 receptors) are in the intima, and sites for I125-pindolol (beta receptors) may be. A relative increase in these receptors, which control flow, is expected as vessels get smaller and become more sensitive to calcium blockers; their colocalization will be studied to test the idea that alpha-2 receptors cause contraction by inhibiting adenylate cyclase activated by beta receptors H3-QNB sites (muscarine receptors) are mostly in the intima, and other receptors mediating dilation (5-HT, adenosine and dopamine) are expected to be. The status of receptors in vessels will be examined with aging, atherosclerosis and varient angina, in part to test the idea that any damage to vascular endothelium may shift control and drug sensitivity away from stress mechanisms permitting dilation. These studies thus relate directly to the pathogenesis is of human cerebral, coronary and renal vascular diseases.
| Pearce, B D; Potter, L T (1991) Coupling of m1 muscarinic receptors to G protein in Alzheimer disease. Alzheimer Dis Assoc Disord 5:163-72 |
