Biomedical subjects
Publications and source records attributed to D M Kramsch.
When added to hydrochlorothiazide, enalapril is as effective as captopril in the treatment of moderate to severe hypertension. It is also effective when used as monotherapy, and may be incorporated into a regimen with diuretic and methyldopa or timolol for the treatment of more resistant patients. Enalapril has a good safety profile as measured by frequency of clinical and laboratory adverse experiences.
All available evidence that exercise may protect against coronary heart disease is circumstantial, and direct evidence is difficult to obtain in human beings. Therefore, we studied the effect of moderate conditioning with treadmill exercise on developing coronary-artery disease in monkeys on an atherogenic diet. Physical training was demonstrated by slow heart rates. Serum total cholesterol was the same (approximately 600 mg per deciliter or 15.5 mmol per liter) in exercising and non-exercising monkeys, with significantly higher high-density-lipoprotein (HDL) cholesterol and much lower triglyceride and low-density-lipoprotein (LDL) plus very-low-density-lipoprotein (VLDL) triglyceride in the exercise group. Ischemic electrocardiographic changes, angiographic signs of coronary-artery narrowing, and sudden death were observed only in non-conditioned monkeys, in which post-mortem examination revealed marked coronary atherosclerosis and stenoses. Exercise was associated with substantially reduced overall atherosclerotic involvement, lesion size, and collagen accumulation; it also produced much larger hearts and wider coronary arteries, further reducing the degree of luminal narrowing. Our data suggest that moderate exercise may prevent or retard coronary heart disease in primates.
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Agents inhibiting calcium deposition into arteries are known to suppress atherosclerosis in animals. However, the precise role of calcium in atherogenesis is unknown. In this study, the specific Ca2+-antagonist lanthanum was used to attempt suppression of experimental atherosclerosis and to gain more insight into the possible effects of calcium on atherogenesis. Rabbits were fed an atherogenic diet with and without increasing doses of LaCl3. All cholesterol-fed rabbits showed marked increases in serum cholesterol and ca2+. Untreated atherogenic animals revealed pronounced gross and microscopic atherosclerosis and striking increases in the aortic content of cholesterol, collagen, "elastin," and calcium as well as of elastin calcium, polar amino acids, and cholesterol. With increasing LaCl3 dosage these abnormalities progressively decreased and were completely abolished at the highest dose. The ingested La3+ was absorbed only in small quantities and had no discernible effect on the calcium and connective tissue content of bone, skin, lung, heart, and skeletal muscle nor on myocardial function (left ventricle pressure and left ventricle dp/dt) or myocardial and muscle content in ATP and creatine phosphate. The data suggest that shifts in arterial Ca2+-distribution may play a decisive part in atherogenesis, and provision of arterial calcium homeostasis by La3+ a pivotal role in its prevention, despite hypercholesteremia. Other inhibitors of calcium deposition into arteries may exert their protective effect by similar mechanisms. However, a direct inhibition of atherogenesis by La3+ cannot entirely be ruled out in this study, although no direct effects of La3+ on tissue metabolism have as yet been reported.
Thoracic aortae of normal rabbits were perfused with pancreatic elastase in vitro at 37 degrees C and 70 mm Hg pressure in the presence or absence of elastin ligands previously shown to stimulate or inhibit the enzymatic degradation of elastin. Perfusion with elastase results in an average of 3.6 lamellae degraded, whereas addition of sodium linoleate before and during the perfusion with elastase increases this value to 7.9 (P less than 0.001). Conversely, perfusion with the cationic detergent, dodecyltrimethylammonium chloride, completely prevents the degradation of elastic lamellae by elastase. These effects do not reflect alterations of the intrinsic catalytic activity of elastase, but apparently indicate the formation of complexes between the elastin ligands and arterial elastic lamellae, as is consistent with prior studies indicating such interactions between fatty acids or detergents and purified elastin. These studies suggest that agents such as fatty acids may significantly alter the metabolic susceptibility of elastin in vivo and possibly contribute to the degradation of elastic lamellae seen in arteries with advanced atherosclerosis.
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We tested the suppressive effect of antihypercalcemic-hyperphosphatemic agents on atherogenesis. We studied five groups of rabbits for 8 weeks, one control group and four groups on a fibrogenic atherogenic diet. One group received the atherogenic diet alone, and the remaining three atherogenic groups were treated simultaneously with 2-thiophenecarboxylic acid (ThCA), 5-methyl-2-thiophenecarboxylic acid (5-CH3-ThCA), and 5-bromo-2-thiophenecarboxaldehyde (5-Br-ThCA). Rabbits receiving the atherogenic diet alone developed: (1) elevations of serum cholesterol, calcium, and phosphorus; (2) massive fibrous-fatty aortic plaques with excessive accumulation of aortic collagen, elastin, and lipids; (3) marked deposition of calcium and phosphorus in both aortic tissue and elastin; and (4) severe lipid infiltration of the liver. Treatment with all three drugs normalized the elevated serum calcium but not the cholesterol levels, and effectively inhibited all aspects of the atherosclerotic process as determined morphologically and biochemically. The order of effectiveness was: 5-CH3-ThCa greater than 5-Br-ThCA greater than ThCA. No bone resorption occurred in the treated groups. The normalizing effects of the thiophene compounds on serum phosphorus levels were not significant at the dosages used.
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Arterial elastin appears to be a proteinlipid complex with the lipid component being bound to elastin peptide groups. In atherosclerotic lesions the lipid content of elastin increases progressively with increasing severity of atherosclerosis. The increases in the lipid content of plaque elastin are mainly due to large increases in cholesterol with about 80% of the cholesterol being cholesterol ester. This deposition of cholesterol in elastin accounts for a substantial part of the total cholesterol accumulation in atherosclerotic lesions of all stages. The present in vitro study suggests that the mechanism involved in the deposition of lipids in arterial elastin may be an interaction of the elastin protein with serum or arterial low density or very low density lipoproteins (LDL and VLDL) resulting in a transfer of lipids, but not of lipoprotein protein to the elastin. No significant lipid transfer occurred from the high density lipoproteins or chylomicrons. The amount of lipid taken up by plaque elastin was strikingly higher than by normal elastin and consisted mainly of cholesterol with over 80% of the cholesterol being cholesterol ester. The precondition for the lipid accumulation in plaque elastin appeared to be an altered amino acid composition of the elastin protein consisting of an increase in polar amino acids and a reduction in cross-linking amino acids. Subsequent treatment of lipoprotein-incubated arterial elastin with hot alkali and apolipoproteins did not reverse the binding of lipoprotein lipid to diseased elastin.
Elastin preparations from intimal layers and the media of normal and atherosclerotic human aortae were analyzed for protein and lipid content. In atherosclerotic aortae, elastin from plaques was compared with elastin from adjacent normal appearing areas of the same aorta. Arterial elastin purified by alkaline extraction appeared to be a protein-lipid complex containing free and ester cholesterol, phospholipids, and triglycerides. The lipid component of normal arterial elastin was small (1-2%). With increasing severity of atherosclerosis, there was a progressive accumulation of lipid in intimal elastin from plaques, reaching a mean lipid content of 37% in severe plaques. The increase in the lipid content of plaque elastic preparations was mainly due to large increases in cholesterol, over 80% of which was cholesteryl ester. This deposition of cholesterol in plaque elastin accounted for 20-34% of the total cholesterol content of the plaque. The increased lipid deposition in plaque elastin was associated with alterations in the amino acid composition of plaque elastin. In elastin from plaque intima, the following polar amino acids were increased significantly: aspartic acid, threonine, serine, glutamic acid, lysine, histidine, and arginine; whereas, cross-linking amino acids: desmosine, isodesmosine, and lysinonorleucine were decreased significantly. The amino acid and lipid composition of elastin from normal appearing aortic areas was comparable to that of normal arterial elastin except for intimal elastin directly adjacent to and medial elastin directly below the most severe plaques.The data indicate that the focal lipid deposition in early atherosclerotic plaques is due to a large extent to lipid accumulations in altered elastin protein of localized intimal areas. Continued lipid deposition in altered elastin appears to contribute substantially to the progressive lipid accumulation in the plaque. The study suggests that elastin of intimal elastic membranes may play an important role in the pathogenesis and progression of atherosclerosis.
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Coarctation of the mid-thoracic aorata was surgically produced in mongrel dogs which were sacrificed from 4-12 wk after the operation. As compared to the findings in control animals, the sodium, chloride, and water content of the hypetensive portion of the coarcted thoracic aorta was significantly elevated, whereas the electrolyte and water content of the relatively normotensive portion of the coarcted aorta was normal. The sodium, potassium, and water content of the pulmonary artery, skeletal muscle, and cardiac muscle of the coarcted dog was not altered. These observations suggest that an elevated arterial pressure may influence the electrolyte and water composition of the arteries. The arterial pressure also may influence the content and synthesis of acid mucopolysaccharides (MPS) in the arteries since the content of sulfated MPS and the incorporation of injected radiosulfate into sulfated MPS were significantly increased in the hypertensive portion of the coarcted thoracic aorta but were significantly reduced in the relatively normotensive ("hypotensive") portion of the coarcted aorta. The observed increase in MPS may have been a factor directly responsible for the increase in the sodium content of the hypertensive aorta since MPS can act as polyelectrolytes and bind cations. Although the arterial pressure may influence certain metabolic functions in the arteries, it did not appear to have a direct effect on the arterial lipids since the lipid content of the hypertensive and of the relatively normotensive portions of the coarcted aorta were comparable to the values found in the normal aorta.
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