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Title: Altered catecholamine receptor affinity in rabbit aortic intimal hyperplasia

Abstract

Intimal thickening is a universal response to endothelial denudation and is also thought to be a precursor of atherosclerosis. The authors have demonstrated selective supersensitivity in arterial intimal hyperplasia to norepinephrine and they now report a possible mechanism for this. Binding studies in rabbit aorta with the selective alpha 1-adrenergic radioligand 125I-HEAT demonstrated that there was no change in receptor density (20 {plus minus} 4 fmole/10(6) cells) in intact vascular smooth muscle cells at either 5 or 14 days after denudation. However, competition studies showed a 2.6-fold increase in alpha 1-adrenergic receptor affinity for norepinephrine in intimal hyperplastic tissue (P less than 0.05). This increased affinity for norepinephrine was associated with a greater increase in 32P-labeled phosphatidylinositol (148% intimal thickening versus 76% control) and phosphatidic acid (151% intimal thickening versus 56% control) following norepinephrine stimulation of free floating rings of intimal hyperplastic aorta. These data suggest that the catecholamine supersensitivity in rabbit aortic intimal hyperplasia is receptor mediated and may be linked to the phosphatidylinositol cycle.

Authors:
; ;  [1]
  1. (Duke University Medical Center, Durham, NC (USA))
Publication Date:
OSTI Identifier:
5227804
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Surgical Research; (United States); Journal Volume: 51:2
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; CATECHOLAMINES; RECEPTORS; VASCULAR DISEASES; PATHOGENESIS; AFFINITY; AORTA; BIOCHEMICAL REACTION KINETICS; IODINE 125; LIGANDS; MUSCLES; NORADRENALINE; PHOSPHOLIPIDS; PHOSPHORUS 32; RABBITS; TRACER TECHNIQUES; ADRENAL HORMONES; AMINES; ANIMALS; AROMATICS; ARTERIES; AUTONOMIC NERVOUS SYSTEM AGENTS; BETA DECAY RADIOISOTOPES; BETA-MINUS DECAY RADIOISOTOPES; BLOOD VESSELS; BODY; CARDIOTONICS; CARDIOVASCULAR AGENTS; CARDIOVASCULAR SYSTEM; DAYS LIVING RADIOISOTOPES; DISEASES; DRUGS; ELECTRON CAPTURE RADIOISOTOPES; ESTERS; HORMONES; HYDROXY COMPOUNDS; INTERMEDIATE MASS NUCLEI; INTERNAL CONVERSION RADIOISOTOPES; IODINE ISOTOPES; ISOTOPE APPLICATIONS; ISOTOPES; KINETICS; LIGHT NUCLEI; LIPIDS; MAMMALS; MEMBRANE PROTEINS; NEUROREGULATORS; NUCLEI; ODD-EVEN NUCLEI; ODD-ODD NUCLEI; ORGANIC COMPOUNDS; ORGANIC PHOSPHORUS COMPOUNDS; ORGANS; PHENOLS; PHOSPHORUS ISOTOPES; POLYPHENOLS; PROTEINS; RADIOISOTOPES; REACTION KINETICS; SYMPATHOMIMETICS; VERTEBRATES; 550901* - Pathology- Tracer Techniques

Citation Formats

O'Malley, M.K., Cotecchia, S., and Hagen, P.O.. Altered catecholamine receptor affinity in rabbit aortic intimal hyperplasia. United States: N. p., 1991. Web. doi:10.1016/0022-4804(91)90086-2.
O'Malley, M.K., Cotecchia, S., & Hagen, P.O.. Altered catecholamine receptor affinity in rabbit aortic intimal hyperplasia. United States. doi:10.1016/0022-4804(91)90086-2.
O'Malley, M.K., Cotecchia, S., and Hagen, P.O.. 1991. "Altered catecholamine receptor affinity in rabbit aortic intimal hyperplasia". United States. doi:10.1016/0022-4804(91)90086-2.
@article{osti_5227804,
title = {Altered catecholamine receptor affinity in rabbit aortic intimal hyperplasia},
author = {O'Malley, M.K. and Cotecchia, S. and Hagen, P.O.},
abstractNote = {Intimal thickening is a universal response to endothelial denudation and is also thought to be a precursor of atherosclerosis. The authors have demonstrated selective supersensitivity in arterial intimal hyperplasia to norepinephrine and they now report a possible mechanism for this. Binding studies in rabbit aorta with the selective alpha 1-adrenergic radioligand 125I-HEAT demonstrated that there was no change in receptor density (20 {plus minus} 4 fmole/10(6) cells) in intact vascular smooth muscle cells at either 5 or 14 days after denudation. However, competition studies showed a 2.6-fold increase in alpha 1-adrenergic receptor affinity for norepinephrine in intimal hyperplastic tissue (P less than 0.05). This increased affinity for norepinephrine was associated with a greater increase in 32P-labeled phosphatidylinositol (148% intimal thickening versus 76% control) and phosphatidic acid (151% intimal thickening versus 56% control) following norepinephrine stimulation of free floating rings of intimal hyperplastic aorta. These data suggest that the catecholamine supersensitivity in rabbit aortic intimal hyperplasia is receptor mediated and may be linked to the phosphatidylinositol cycle.},
doi = {10.1016/0022-4804(91)90086-2},
journal = {Journal of Surgical Research; (United States)},
number = ,
volume = 51:2,
place = {United States},
year = 1991,
month = 8
}
  • Purpose: Endovascular brachytherapy for the prevention of intimal hyperplasia (IH) and restenosis after balloon/stent angioplasty has proven effective both in animal preparations and clinical trials. A variety of {beta}-emitting isotopes and catheter-based devices have been developed for the delivery of low-dose radiation in clinical coronary and peripheral trials. No platform, however, has yet been developed for brachytherapy in concert with vascular surgical operations. The purpose of this study was to evaluate the vascular histopathologic response following balloon injury to rabbit carotid arteries with and without topically applied low-dose {beta}-radiation. Methods: The {beta}-emitting isotope strontium-90 (Sr-90) was conjugated onto the matrixmore » of polypropylene (PLYP) mesh. Rabbit carotid arteries were balloon-injured with a no. 2 embolectomy catheter. Six carotid arteries were wrapped with nonradioactive PLYP mesh (controls) and Sr-90 ({approx}90 {mu}Ci) PLYP mesh in order to deliver low-dose radiation to the vessel wall from the external (adventitial) surface. Tissue was harvested at 6 weeks and processed for histologic examination. Results: There was consistent blockade of fibrocellular neointima formation with virtually no neointima present in all treated segments, compared to moderate neointima formation in controls. Medial thinning and smooth muscle cell (SMC) necrosis were also associated with topical brachytherapy. Conclusion: {beta}-Radiation applied by an externally wrapped PLYP mesh labeled with Sr-90 markedly suppressed neointima formation in an animal vascular surgical injury model. Further studies, however, are necessary to determine a suitable isotope and dosage for clinical application.« less
  • The aim of this study was to analyze the feasibility of {sup 188}Re-labeled stents to reduce neointimal formation in a rabbit atherosclerosis model and to test the long-term effects at 7 and 26 weeks. Fifty-nine male New Zealand White rabbits were fed a 0.5% cholesterol diet for 4 weeks before balloon angioplasty and insertion of Palmaz stents in the infrarenal aorta. The animals were sacrificed 7 and 26 weeks after stent implantation. Control stents were compared with {sup 188}Re stents: (dose 1) 11.3 {+-} 1.8 MBq; (dose 2) 37.3 {+-} 4.2 MBq, and (dose 3) 80.1 {+-} 7.8 MBq. Eachmore » activity group consisted of a short-term (7 weeks) and a long-term group (26 weeks), resulting in a total of eight study groups. No thrombotic occlusion was observed. The neointimal formation in the control group was 2.11 [95% confidence interval (CI): 0.68-6.52] mm{sup 2} at 7 weeks and 2.10 (0.62-7.11) at 26 weeks. In the treatment groups, neointima reduction was detectable at 7 weeks [dose 1: 0.33 (0.09-1.22) mm{sup 2}; dose 2: 0.17 (0.05-0.57) mm{sup 2}; dose 3: 0.03 (0.01-0.13) mm{sup 2}]. After 26 weeks, a catch-up of neointimal formation in the radioactive groups was most obvious in the low-dose group [dose 1: 0.80 (0.28-2.29) mm{sup 2}; dose 2: 0.18([0.06-0.52) mm{sup 2}; dose 3: 0.50 (0.17-1.42) mm{sup 2}]. Compared to the long-term control group, neointimal reduction was still >60%. No induction of neointimal formation was observed at the edges of the stents. Radiation resulted in delayed re-endothelialization. {sup 188}Re stents were capable to reduce intimal hyperplasia and did not cause thrombosis. The edge effect, which was the major limitation of {sup 32}P stents, was not observed in {sup 188}Re stents.« less
  • The present study was designed to determine whether binding of low density lipoprotein (LDL) to endothelial LDL receptors contributes significantly to the penetration of LDL into the normal rabbit aorta. Initial flux rate was used as a measure of uptake of LDL. Reductive methylation of LDL is known to block its recognition by the LDL receptor. Therefore, the difference in flux rates of native LDL and reductively methylated LDL (methyl-LDL) was assumed to represent the receptor-dependent uptake. Native LDL and methyl-LDL were labeled with different isotopes (/sup 125/I or /sup 131/I) and both were injected simultaneously into the same rabbit.more » After 30 to 60 minutes, trichloroacetic acid-precipitable counts were determined in aortic specimens. The initial flux rates, expressed as plasma clearance (nl/g/hr), were 1787 for native LDL and 1924 for methyl-LDL. The difference was not significant, which suggests that the flux of LDL into the aorta is not significantly dependent upon, or regulated by, endothelial LDL receptors, but is mediated by other mechanisms.« less
  • To determine whether ..cap alpha..-adrenergic desensitization of vascular smooth muscle is due to an alteration in ..cap alpha../sub 1/-adrenergic receptor coupling, the authors determined the relationship between receptor occupancy and maximal receptor-coupled Ca/sup 2 +/ efflux in cultured rabbit aortic smooth muscle cells (i) under basal conditions as defined by receptor inactivation with phenoxybenzamine and (ii) after 48 hr of exposure to several concentrations of 1-norepinephrine (NE). Neither phenoxybenzamine nor NE exposure caused a change in binding affinity for (/sup 3/H)prazosin or NE. Maximal (/sup 3/H)prazosin binding capacity and maximal NE-stimulated /sup 45/Ca/sup 2 +/ efflux decreased progressively with exposuremore » of incubated cells to increasing concentrations of phenoxybenzamine or NE. An approximately 80% decrease in maximal (/sup 3/H)prazosin binding capacity caused by either phenoxybenzamine or NE resulted in complete loss of NE-stimulated /sup 45/Ca/sup 2 +/ efflux, indicating that under these conditions approximately 20% of ..cap alpha../sub 1/-adrenergic receptors are not coupled to the Ca/sup 2 +/ efflux. Under basal conditions, the relationship between maximal (/sup 3/H)prazosin binding capacity and maximal NE-stimulated /sup 45/Ca/sup 2 +/ efflux was markedly nonlinear, so that a near maximal response could be elicited by occupancy of only approximately 40% of the receptors. Thus, an alteration in occupancy-response coupling at a step proximal to Ca/sup 2 +/ mobilization and/or influx, rather than a reduction in receptor number, is of primary importance in the process of agonist-induced ..cap alpha..-adrenergic receptor desensitization of vascular smooth muscle cells.« less
  • To demonstrate the effect of {gamma} radiation on proliferating smooth muscle cells in vivo, a standardized bilateral carotid balloon catheter arterial injury was produced in 45 rats and doses from 0-20 Gy were delivered to the right carotid artery at 24 h after injury. At 20 days after injury, cross-sectional area of intima was determined from axial histological sections. Compared to contralateral, nonirradiated balloon-injured arteries, radiation produced a significant dose-dependent reduction in intimal cross-sectional area, with a 50% decrease at 5-7.5 Gy. To determine the effect of timing of irradiation on intimal hyperplasia, 30 rats with bilateral carotid injury receivedmore » unilateral cervical irradiation at doses of 1,5 or 10 Gy administered at either 1,3 or 5 days after injury. The radiation dose, timing of irradiation and an interaction between timing and dose were significantly associated with reduction in neointimal cross-sectional area. To determine the effects of radiation on intimal hyperplasia at later intervals, rats irradiated with 15 or 20 Gy were euthanized at 3 months after injury. A significant persistent reduction in intimal cross-sectional area for irradiated arteries at 3 months was associated with minimal apparent radiation effects upon adjacent tissue. These data suggest that external {gamma} irradiation at the single doses used effectively inhibits smooth muscle proliferation and intimal hyperlasia in the rat balloon catheter injury model in a time- and dose-dependent manner. 54 refs., 6 figs., 1 tab.« less