Charles F. Simpson

Modulation by propranolol of the lysyl cross-links in aortic elastin and collagen of the aneurysm-prone turkey

dl-Propranolol (propranolol) fed to immature and mature aneurysm-prone turkeys (Broad-Breasted White, BBW) for 6 weeks significantly raised the tensile strength of tissue rings from the abdominal aorta. The drug-mediated increase in tensile strength values was dose-related and independent of its heart rate- and arterial pressure-lowering effects. Propranolol acts, in part, by (a) stimulating lysyl oxidase to produce greater amounts of reactive aldehydes for intermolecular cross-links, (b) enhancing the progression of chemically unstable to stable forms of intermolecular elastin cross-links (lysinonorleucine and the desmosines), and (c) reducing the density of the age-related intermolecular cross-linking of collagen (pyridinoline). These propranolol effects on the lysyl cross-links were demonstrated in both the immature and mature animals and suggest a heretofore unrecognized potential for this widely used cardiovascular drug.

Pathology of the aorta of chicks fed a copper-deficient diet

Abstract Day-old chicks were fed normal and copper-deficient diets for 6 weeks. Approximately 50% of the birds on the deficient diet died of hemorrhages. The principal pathologic alteration found in the syndrome was elastic fiber degeneration of the aorta. According to electron microscopy, elastic fiber degeneration occurred in three steps. Initially, there was swelling of elastic fibrils and increased electron density of involved elastic fibers. Secondly, there was partial dissolution of the matrix portion of elastic fibers so that they had a vacuolated pattern. The last retrograde stage consisted of complete dissolution of the matrix with persistence of naked, twisted, swollen elastic fibrils. Degeneration of elastic fibers originated in the periphery and eventually extended to the central area.

Influence of d-, l-, and dl-propranolol, and practolol on β-aminopropionitrile-induced aortic ruptures of turkeys☆

Turkeys were fed five diets: β-aminopropionitrile (BAPN) only; BAPN plus d-propranolol, l-, or dl-propranolol; and BAPN plus practolol. Mortality from aortic dissecting aneurysms and rhexis was as follows: BAPN 54.2%; BAPN plus d-propranolol 62.5%; BAPN plus l-propranolol 0.0%; BAPN plus dl-propranolol 0.0%; and BAPN plus practolol 13.1%. Blood pressure, heart rate, and dpdtmax, as judged by carotid artery cannulation, were lowest in turkeys fed BAPN plus l- or dl-propranolol, and BAPN plus practolol. Aortic tensile strengths were higher in turkeys fed BAPN plus l- or dl-propranolol, or practolol, than in turkeys fed BAPN plus d-propranolol or BAPN alone. As assessed by light microscopy, elastic fiber alteration was most severe in the aortas of turkeys fed only BAPN, or BAPN plus d-propranolol. When electron miroscopy was used, elevations on the surface of altered aortic elastic fibers of turkeys fed BAPN plus dl- or l-propranolol containing striated bands were observed. Such striations were not seen on altered aortic elastic fibers of turkeys fed BAPN alone, BAPN plus d-propranolol, or BAPN plus practolol. It was concluded that the reason more turkeys died of aortic rupture when fed BAPN plus practolol (13.1%) than when fed BAPN plus l- or dl-propranolol (0%) was that the latter two drugs, in combination with BAPN, not only lowered dpdtmax, but also directly or indirectly affected the ultrastructural morphology of altered aortic elastic fibers. However, among these three treatment groups, pulse pressure was greater in those fed BAPN and practolol.

The use of propranolol for the protection of turkeys from the development of beta-aminopropionitrile-induced aortic ruptures.

From the Departments of Veterinary Science and Pharmacology and Therapeutics, University of Florida, Gainesville, Florida 32601. This work was supported in part by a grant (H3776) from the National Heart Institute, United States Public Health Service. Florida Agricultural Experiment Stations Journal Series No. 2728. * Markle Scholar in academic medicine. Spontaneous dissecting aneurysms of the aorta occur commonly in both

Beta-aminopropionitrile-induced dissecting aneurysms of turkeys: treatment with propranolol.

Abstract Immature turkeys were fed 0.04% propranolol and 0.07% β-aminopropionitrile (BAPN) for 20 days following the feeding of 0.07% BAPN alone for 15 days (after 3 deaths had occurred from aortic ruptures). There were 2 deaths from aortic ruptures (8.3%) among 24 turkeys fed BAPN-propranolol, and 73.8% mortality from aortic ruptures among those fed BAPN alone. Aortic ruptures resulted from dissecting aneurysms. The feeding of propranolol alone caused no deaths from dissecting aneurysms. There was hypotension and bradycardia among turkeys fed propranolol-BAPN or only propranolol. The histologic and ultrastructural architecture of the abdominal aorta was influenced by the diets consumed. There was profound alteration of the elastic fibers in the tunicae of the aorta when BAPN alone was fed for the entire trial. Alterations of aortic elastic fibers were much less severe when both BAPN and propranolol were fed. The tensile strengths of aortic tissue were highest in turkeys fed only propranolol, and lowest in poults fed only BAPN. Tensile strengths of aortas of turkeys fed BAPN and propranolol were 1.5 times higher than the strengths of arotas of birds fed only BAPN. The efficacy of propranolol as a beta adrenergic blocking agent was indicated by lack of influence of isoproterenol on blood pressure and heart rate of propranolol-treated turkeys. In consideration of the abrupt cessation of mortality that followed propranolol treatment, it is possible that the beneficial therapeutic results achieved with the drug resulted from its influence on both the myocardium and the aorta.

Skeletal and cardiovascular lesions in turkeys induced by feeding beta-aminopropionitrile☆

Abstract Beta-aminopropionitrile toxicosis in turkeys induced skeletal and cardiovascular lesions. Enlarged hocks with widening of the epiphyseal plate and articular cartilage, green tinting of the skin over swollen joints, and synovitis were the skeletal defects that were found. Joint lesions apparently resulted from impediment of endochondral mineralization and maturation of chondrocytes in the epiphyseal plate and articular cartilage. Cardiovascular alterations resulting from BAPN feeding included ground substance increase, swelling and disorganization of collagenous fibers, and elastolysis. These changes cause polypoid intimal thickenings and the induction of dissecting aneurysms. Intimal arteriosclerotic plaques were found in the posterior aorta of “normal” turkey poults. There is a possibility that such lesions are a prerequisite for the development of dissecting aneurysms.

Electron microscopy of the cardiovascular system of the normal and beta-aminopropionitrile fed turkey

Abstract The ultrastructure of the cardiovascular system of the normal and BAPN-fed turkey poult is described. The posterior aorta of normal birds contained smooth muscle cells in the tunica intima; smooth muscle cells bound together by elastin and collagen in the tunica media; and collagen, elastin, spindle-shaped cells, nerves and vasa vasorum in the tunica adventitia. The essential aortic pathology caused by BAPN toxicosis included endothelial cell swelling and proliferation, elastic fiber fragmentation, collagenous fiber swelling and matting, and ground substance increase.

Similarity of aortic pathology in Marfan's syndrome, copper deficiency in chicks and B-aminopropionitrile toxicity in Turkeys

Abstract The abdominal aortas of a human with Marfans syndrome, chicks fed a copper-deficient diet and turkeys fed B-aminopropionitrile (BAPN) were studied by light- and electron microscopy. The alterations in the aortic media in all three conditions were similar. The degenerative changes included shrinkage of smooth muscle cells, swelling and fragmentation of elastic fibers, scattering of collagenous fibers, pooling of mucopolysaccharide, and dilatation of extracellular spaces. Only in Marfans syndrome was there thickening of the basement membrane of smooth muscle cells. The microscopic lesions agree with the biochemical changes of connective tissue reported to occur in the three conditions.

Glomerulosclerosis in Canine Heartworm Infection

The kidneys of seven dogs with natural infections of heartworm disease, four dogs with experimental infections, and six control (uninfected) dogs raised in isolation were examined by light, fluorescent, and electron microscopy. Swelling and fragmentation of the basement membranes accompanied by denudations of endothelial cells and fusion and atrophy of foot processes occurred in the glomeruli of dogs with heartworm disease, but not in control dogs. The severity of tissue damage correlated with the degree of microfilaremia. There was no evidence that the glomerular lesions were caused by immune complexes deposited in the basement membranes; and the alterations of glomerular capillaries were probably caused by motile microfilariae in the capillaries.

Pathology of aortic atherosclerosis and dissecting aneurysms of turkeys induced by diethylstilbestrol

Abstract A high incidence of aortic ruptures due to dissecting aneurysms occurs in male turkeys following treatment with diethylstilbestrol (DES). About 5% of the birds examined at the termination of the experiment had saccular aneurysms of the posterior aorta. Aortic atherosclerosis was also produced by DES treatment. Smooth muscle cells in the tunica media developed lipidosis. Adjacent smooth muscle cells became widely separated from each other by extracellular lipid, serum, and particles that appeared to be lipoprotein. The accumulation of extracellular material caused weakening of the aortic wall, the development of dissecting aneurysms, and eventual rupture. Most of these ingredients apparently entered the vascular wall through breaks which developed between adjacent endothelial cells and less frequently by way of dilated intercellular boundaries between endothelial cells.