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Biomedical subjects

G Aberg

Publications and source records attributed to G Aberg.

At least 19 recordsLinked to original sources
PubMed1998

Enhanced reduction of atherosclerosis in hamsters treated with pravastatin and captopril: ACE in atheromas provides cellular targets for captopril.

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase and angiotensin-converting enzyme (ACE) reduce experimental atherosclerosis by different mechanisms. To determine whether dual-drug therapy additively retards the progression of early lesions, control hyperlipidemic hamsters were compared with those treated with pravastatin, captopril, and pravastatin plus captopril. After 8 weeks of treatment, pravastatin (34 mg/kg/day) reduced plasma total cholesterol and triglycerides by 41 and 84%, respectively, whereas captopril (100 mg/kg/day) reduced normal blood pressure by 21%. The combination of pravastatin and captopril (33 and 100 mg/kg/day) decreased plasma total cholesterol and triglycerides by 44 and 84%, and blood pressure was decreased by 14%. In the aortic arch, pravastatin reduced macrophage-foam cell size and fatty streak area by 21 and 31%, respectively, whereas captopril decreased macrophage-foam cell number and fatty streak area by 34 and 35%. Pravastatin plus captopril decreased macrophage-foam cell number, foam cell size, and fatty streak area by 38, 24, and 67%. ACE inhibitors were previously reported to retard atherosclerosis without affecting blood pressure, suggesting that these agents acted on the artery wall. Therefore the expression of arterial ACE was determined in normal and atherosclerotic hamster aortas. ACE messenger RNA (mRNA) and protein were detected in endothelial cells, intimal macrophage-foam cells and medial smooth-muscle cells of atherosclerotic arteries indicating an upregulation of ACE expression with hyperlipidemia and atherosclerosis. In conclusion, dual-therapy with pravastatin and captopril produced an additive reduction in fatty streak area compared with either drug alone and suggested that atherogenesis can be retarded beyond the level achieved with monotherapy. The presence of ACE in endothelial cells and intimal macrophage-foam cells provides cellular targets for captopril to directly modify the formation of early atherosclerotic lesions.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Bi-directional chiral inversion of ketoprofen in CD-1 mice.

The R enantiomers of some of the 2-arylpropionic acid non-steroidal antiinflammatory drugs (NSAIDs) are known to undergo metabolic chiral inversion to their more pharmacologically active antipodes. This process is drug and species dependent and usually unidirectional. The S to R chiral inversion, on the other hand, is rare and has been observed, in substantial extents, only for ibuprofen in guinea pigs and 2-phenylpropionic acid in dogs. After i.p. administration of single doses of racemic ketoprofen or its optically pure enantiomers to male CD-1 mice and subsequent study of the concentration time-course of the enantiomers, we noticed substantial chiral inversion in both directions. Following racemic doses, no stereoselectivity in the plasma-concentration time courses was observed. After dosing with optically pure enantiomer, the concentration of the administered enantiomer predominated during the absorption phase. During the terminal elimination phase, however, the enantiomers had the same concentrations. Our observation is suggestive of a rapid and reversible chiral inversion for ketoprofen enantiomers in mice.

Animals↗
PubMed1996

Stereoselective sulphate conjugation of salbutamol by human lung and bronchial epithelial cells.

1. The metabolism of (+)-, (-)- and (+/-)-salbutamol by sulphoconjugation was determined in vitro using human lung cytosol and bronchial epithelial BEAS-2B cell homogenate. 2. For the lungs the intrinsic clearance (Vmax/Km) value for the pharmacologically active (-)-salbutamol (0.49 +/- 0.32 ml min-1 g-1 protein) exceeded that of (+)-salbutamol (0.046 +/- 0.028 ml min-1 g-1 protein) by 11-fold. This was mainly due to a difference in Km value, which was 16 times higher for (+)-salbutamol (1300 +/- 170 microM) than for (-)-salbutamol (83 +/- 12 microM). 3. The stereoselectivity of sulphoconjugation of salbutamol was very similar in the BEAS-2B cells, although the absolute activity was considerably lower. 4. The enzyme catalyzing this reaction both in the lungs and in the BEAS-2B cells was the monoamine (M) form phenolsulphotransferase. 5. These observations emphasize that the smooth muscle of the bronchi most likely are exposed to considerably higher concentrations of the potentially toxic (+)-enantiomer than of the bronchodilating (-)-enantiomer during therapy with (+/-)-salbutamol.

Albuterol↗
PubMed1995

Inversion of (R)- to (S)-ketoprofen in eight animal species.

The (R)-enantiomer of the NSAID ketoprofen was administered orally at 20 mg/kg to a series of 8 animal species. In all species, a highly significant degree of inversion occurred after 1 h which varied from 27% (gerbil) to 73% (dog) and persisted or increased in plasma samples obtained 3 h after drug administration. Although the (R)-enantiomer was inactive as an inhibitor of cyclooxygenase, the analgesic effects of that isomer was almost the same as the (S)-isomer in animal analgesic assays, following oral administration of the drugs to mice and rats. Taken together, the present results suggest that (R)-ketoprofen administered alone functioned primarily as a prodrug for (S)-ketoprofen under the experimental conditions of this study.

Administration, Oral↗
PubMed1995

Regression of early atherosclerosis in hyperlipidemic hamsters induced by fosinopril and captopril.

We determined whether inhibiting angiotensin-converting enzyme (ACE) with fosinopril or captopril induced the regression of atherosclerosis in hamsters. A pressor experiment demonstrated that 100 mg/kg fosinopril or captopril almost completely inhibited ACE activity in vivo. Another study established that feeding hamsters 0.05% cholesterol and 10% coconut oil resulted in rapid and progressive accumulation of oil red O-stained macrophage-foam cells in the aortic arch. In the regression study, three groups of hamsters were fed the same atherogenic diet for 4 weeks to induce fatty lesions in the arch. After 4 weeks, plasma lipids, blood pressure (BP), and atherosclerosis were quantified in control hamsters. Beginning at 4 weeks, the two remaining groups of hamsters were treated with 100 mg/kg/day fosinopril or 100 mg/kg/day captopril for 6 more weeks while receiving the atherogenic diet. After 6-week treatment, plasma lipids, BP, and atherosclerosis were quantified in the two treated groups (i.e., study week 10), and they were compared with the 4-week controls. As compared with that in controls, fosinopril decreased plasma low density lipoprotein (LDL) and very low density lipoprotein (VLDL) cholesterols by approximately 69%. High density lipoprotein (HDL) cholesterol decreased by 16% and total triglycerides decreased by 56% as compared with that of controls. Captopril did not alter LDL plus VLDL cholesterols or total triglycerides, but HDL cholesterol decreased by 24% as compared with that of the control group. As compared with that of control hamsters, mean arterial BP (MAP) decreased by 9% with captopril treatment, and heart rate (HR) was decreased by both fosinopril and captopril.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1994

Inhibitors of angiotensin converting enzyme decrease early atherosclerosis in hyperlipidemic hamsters. Fosinopril reduces plasma cholesterol and captopril inhibits macrophage-foam cell accumulation independently of blood pressure and plasma lipids.

The effect of two angiotensin converting enzyme (ACE) inhibitors on the development of atherosclerosis was determined in hyperlipidemic hamsters. Preliminary studies indicated that only fosinopril (50 mg/kg) temporarily decreased mean arterial pressure, while after chronic dosing fosinopril and captopril (50 mg/kg) were ineffective. The same dose of fosinopril and captopril inhibited the angiotensin I pressor response, indicating these agents suppressed ACE activity in vivo. In the 3 week atherosclerosis experiment, all hamsters were fed chow supplemented with 0.05% cholesterol and 10% coconut oil. Control hamsters were compared with those receiving either 50 mg/kg per day of fosinopril or 50 mg/kg per day of captopril. After 3 weeks, fosinopril reduced plasma total cholesterol, low density lipoprotein (LDL) plus very low density lipoprotein cholesterol and total triglycerides by 17%, 27% and 45%, respectively. Captopril only reduced high density lipoprotein cholesterol by 20%. Neither fosinopril or captopril altered blood pressure at 3 weeks. Atherosclerosis was quantified from en face preparations of the lesion-prone aortic arch that were stained with oil red O (for cholesteryl ester and triglycerides). In control hamsters, oil red O labeled numerous subendothelial macrophage-foam cells located along the inner curvature of the aortic arch. Compared with controls, fosinopril reduced the number of intimal macrophage-foam cells/mm2, foam cell size and the fatty streak area by 85%, 38% and 90%, respectively. Captopril decreased these parameters by 44%, 16% and 53%. Thus captopril decreased early atherosclerosis without affecting plasma LDL cholesterol or blood pressure, which suggested that inhibiting ACE (or kininase II) directly impeded the accumulation and formation of macrophage-foam cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Antiatherosclerotic effects of the angiotensin-converting enzyme inhibitors captopril and fosinopril in hypercholesterolemic minipigs.

We evaluated the two angiotensin-converting enzyme (ACE) inhibitors captopril and fosinopril with regard to possible antiatherosclerotic effects in minipigs. Experimental hypercholesterolemia and atherosclerosis was produced in 33 minipigs of the Göttingen strain by an egg yolk/cholesterol-enriched diet for 1 year. One group (n = 11) was fed the atherogenic diet alone and served as a control. A second group (n = 11) received captopril (80 mg/kg/day) added to the atherogenic diet, and a third group (n = 11) was treated in the same manner but with fosinopril (8 mg/kg/day). The drug treatments produced significant reduction in serum ACE activity associated with a reactive increase in plasma renin activity (PRA), but had only minor effects on plasma lipids and lipoproteins. At the end of the treatment period, all animals were killed and examined for degree of atherosclerosis. The percentage of atherosclerotic area in the abdominal aorta was significantly lower in both drug-treated groups as compared with controls. Furthermore, accumulation of cholesterol in the thoracic and abdominal aorta was inhibited by drug treatment. Finally, the percentage of intimal thickening in abdominal aorta was significantly reduced in the drug-treated groups. In conclusion, the ACE inhibitors captopril and fosinopril inhibited development of atherosclerosis in hypercholesterolemic minipigs.

Aldosterone↗
PubMed1992

Gastroprotective effects of thromboxane receptor antagonists.

The recent discovery of potent, specific, long-acting thromboxane receptor antagonists, like SQ 33,961, mandated that studies be conducted to follow up an earlier study, which showed potential antiulcer activity of the short-acting thromboxane antagonist, SQ 28,668, in the taurocholic acid gastric erosion model in rats. In experiments conducted with the same taurocholic acid protocol, SQ 33,961 caused a dose-related reduction in taurocholate-induced gastric erosions, with an ID50 value of 12 micrograms/kg, i.p. In additional studies, aspirin and indomethacin were shown to produce gastric erosions in rats, and SQ 33,961 also inhibited gastric erosion in response to these anti-inflammatory drugs. The ID50 values were 0.24 and 0.26 mg/kg i.p. vs. aspirin (200 mg/kg, p.o.) and indomethacin (200 mg/kg, s.c.), respectively. The inhibition of aspirin-induced gastric injury by SQ 33,961 was confirmed histologically. This gastroprotective activity was not peculiar to SQ 33,961, because the structurally unrelated thromboxane receptor antagonist, BM 13,505, also significantly inhibited the development of aspirin-induced gastric lesions. In a more severe model, SQ 33,961 (10 mg/kg, i.p.) reduced gastric erosions by only 32% (not significant) 1 hr after ethanol ingestion (1 ml, p.o.) in rats. SQ 33,961 did not inhibit the antiphlogistic activity (carrageenan paw edema assay) of indomethacin, nor did it inhibit the analgesic activity (phenylquinone writhing assay) of aspirin. A dose of SQ 33,961 producing > or = 95% inhibition of nonsteroidal anti-inflammatory drug-induced gastric erosion (10 mg/kg, i.p.) produced a 37% reduction in the volume of gastric secretion without changing the titratable acidity of gastric contents.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Effects of captopril on atherosclerosis in cynomolgus monkeys.

A study was performed to investigate if oral dosing of captopril could influence the development of atherosclerosis in cholesterol-fed cynomolgus monkeys. Twenty-four monkeys were divided into four groups: (a) a control group given a normal monkey diet and placebo medication; (b) a high cholesterol group given a high cholesterol diet and placebo medication; (c) a low-dose captopril group given the cholesterol diet and 25 mg/kg of captopril twice daily; and (d) a high-dose captopril group given the cholesterol diet and 50 mg/kg of captopril twice daily. The doses of captopril used in this study did not change the levels of total serum cholesterol, high-density lipoprotein (HDL), or triglycerides. The total cholesterol/HDL ratio was also unaffected by captopril. The animals were killed after 6 months of treatment. The progression of atherosclerosis was assessed by gross pathology, histopathology, and biochemical methods. The results showed a significantly reduced progression of arterial lesions in monkeys given captopril; the effects of captopril were most evident in the coronary arteries, which were practically free from atherosclerosis in captopril-treated animals.

Animals↗
PubMed1987

Substituted 1,2,3,4-tetrahydroaminonaphthols: antihypertensive agents, calcium channel blockers, and adrenergic receptor blockers with catecholamine-depleting effects.

Substituted 1,2,3,4-tetrahydroaminonaphthols were found to be calcium channel blockers with antihypertensive properties. These compounds also possessed adrenergic beta-receptor blocking activity. From the structure-activity studies, no clear correlation emerged between the in vitro calcium channel blocking activity and the acute anti-hypertensive activity in cannulated spontaneously hypertensive rats. Extensive pharmacological testing of selected compounds indicated that aminonaphthols are antihypertensive agents with many pharmacological properties. The relative contribution of various pharmacological actions toward the observed antihypertensive activity is unclear. Since the clinically useful calcium channel blocker verapamil is structurally related to these compounds, one of the aminonaphthols, trans-3-[(3,3-diphenylpropyl)amino]-1,2,3,4-tetrahydro-6,7 -dimethoxy-2-naphthalenol (12), was compared with verapamil for calcium channel blocking activity, adrenergic blocking activity, and catecholamine-depleting activity. Both compounds were found to be equipotent in these test systems.

Action Potentials↗
PubMed1983

Arrhythmogenic assessment of prenalterol in conscious dogs.

Possible arrhythmogenic side-effects of the positive inotropic agent prenalterol were studied in conscious dogs, three to four days after coronary artery ligation. Prenalterol showed a propensity to cause arrhythmias in one out of eight dogs, thereby confirming published data from clinical studies.

Animals↗
PubMed1983

Antiarrhythmic effects of tocainide and lidocaine in dogs.

To compare the antiarrhythmic activities of tocainide and lidocaine in dogs, a protocol was designed where the drug plasma levels were increased stepwise. This was achieved by computerizing bolus doses and infusion rates, using pharmacokinetic equations with constants, derived from previous experiments in similar animals. In conscious coronary-ligated dogs with ischaemic arrhythmias both compounds were active, causing a 50% reduction in VPB's at plasma concentrations of 5.0 micrograms/ml (tocainide) and 3.5 micrograms/ml (lidocaine). "Clearing" of catecholamine-induced arrhythmias was not obtained in any of six dogs given tocainide and only in two out of six dogs given lidocaine.

Animals↗