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SUMMARY The relationship between aortic metabolism and hypertension was examined in spontaneously hypertensive rats (SHR) and in the normotensive Wistar-Kyoto (WKY) strain of rats. Comparative studies between age-matched animals of both strains showed in the SHR, enhanced activities of the aortic enzymes, iV-acetyl /3-glucosaminidase (NAGA) and acid phosphatase, which are associated with lysosomes. Similar increases were shown for aortic 5 -nucleotidase activity. Antihypertensive drug treatment of 30-week-old SHR for 17 weeks effectively lowered blood pressure and reduced the activity of aortic NAGA and acid phosphatase in the SHR to control levels. 5'-Nucleotidase activity remained significantly elevated, and aortic collagen and elastin concentrations were unaffected by antihypertensive drug treatment. Hypertension was produced in WKY rats by deoxycorticosterone treatment for either 4 or 7 weeks and then was reversed by discontinuing treatment and maintaining the pretreated animals on a low-salt diet for up to 11 weeks. At the end of the treatment period, aortic enzymatic activity was increased significantly, as were heart and aortic weights. Following the reversal of hypertension, the activity of the lysosomal enzymes was decreased significantly, but 5-nucleotidase activity remained elevated. Collagen and elastin concentrations were not affected by mineralocorticoid treatment, but the total amount of connective tissue protein was increased and remained elevated following the reversal of hypertension, paralleling the changes in aortic weight. The studies indicate that etiologically different forms of hypertension result in characteristic changes in aortic metabolism which are not completely reversed by subsequent blood pressure reduction.

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SUMMARY. These studies have examined the effects of d/-propranolol, d-propranolol, and metoprolol on aortic atherogenesis in the cholesterol-fed rabbit and have correlated the vascular effects of the drugs with their influence on blood pressure, plasma lipids and lipoproteins, arterial metabolism, and arterial permeability. rf/-Propranolol, and, to a lesser extent, d-propranolol, used in clinically relevant doses of 5 mg/kg body weight per day, inhibited the development of aortic atherosclerosis in association with significant reductions in aortic free and esterified cholesterol content. No significant effects of the drugs on blood pressure or on the total amounts or types of circulating lipoproteins were apparent. Accumulation of cholesterol in the liver and adrenal gland was not influenced by propranolol. Aortic acyl CoAxholesterol acyltransferase and lysosomal enzyme activities were reduced by propranolol administration, but the inhibition may have been secondary to the lesser degrees of atherosclerosis and cholesterol accumulation present. In vitro inhibition of acyl CoAxholesterol acyltransferase activity by either dl-or d-propranolol was also observed, but occurred only at propranolol concentrations of 10~3 M or greater. Treatment with rf/-propranolol had no significant effect on the rate of transport of labeled albumin across the isolated carotid artery of cholesterol-fed rabbits. Metoprolol administration (6.25 mg/kg body weight per day) had no significant influence on atherogenesis or arterial metabolism in this model. The results suggest that propranolol inhibits in part the development of atherosclerosis in the cholesterol-fed rabbit, and that the effect may be related to a direct action on the arterial wall. (CircRes 56: 755-762, 1985)

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.