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H R Davis

Publications and source records attributed to H R Davis.

At least 37 records · Page 2Linked to original sources
PubMed1995

Hypocholesterolemic activity of a novel inhibitor of cholesterol absorption, SCH 48461.

The amount of cholesterol that circulates in the plasma as lipoproteins can be affected by the balance of cholesterol metabolism within and between the intestines and liver. In the present report, we describe a novel hypocholesterolemic agent and document its pharmacological effects in animal models of hypercholesterolemia. The oral administration of (3R,4S)-1,4-bis-(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone (SCH 48461) reduced plasma cholesterol concentrations in cholesterol-fed hamsters, rats and rhesus monkeys with ED50s of 1, 2 and 0.2 mg/kg per day, respectively, SCH 48461 was also highly effective in reducing hepatic cholesteryl ester accumulation in cholesterol-fed hamsters and rats after 7 days of treatment. In one 3 week study, rhesus monkeys were fed a 0.25% cholesterol/22% saturated fat diet with or without SCH 48461. At the end of the 3 week period the control group's VLDL + LDL-cholesterol increased to 180 Mg/dl from a baseline of approximately 65 mg/dl while plasma apolipoprotein B levels had doubled. Animals treated daily with 1 mg/kg SCH 48461 maintained their baseline levels of VLDL + LDL-cholesterol, HDL-cholesterol, and plasma apolipoproteins B and A-I. After 3 weeks the diets of the two groups were switched. Within 1 week SCH 48461 (1 mg/kg per day) rapidly reversed the elevated VLDL + LDL-cholesterol levels of the previous control group to near baseline values. SCH 48461 exerted its hypocholesterolemic effect through the inhibition of cholesterol absorption. A dose of 10 mg/kg per day inhibited cholesterol absorption in cholesterol-fed hamsters by 68% while a similar reduction was achieved in chow-fed monkeys with 3 mg/kg per day. This latter dose inhibited cholesterol absorption in cholesterol-fed monkeys by 95%. Treatment of cholesterol-fed monkeys with 10 mg/kg per day SCH 48461 significantly increased fecal neutral sterol excretion (52 vs. 32 mg/kg) but had no effect on acidic sterol excretion. Using a 2-h absorption model in cholesterol-fed hamsters, SCH 48461 caused a 46% inhibition of unesterified [14C]cholesterol accumulation in the intestinal wall and a 90% inhibition of cholesteryl ester formation at a dose of 10 mg/kg. Similar data were observed when the plasma radioactivity was assessed, indicating inhibition of both free (61%) and esterified (85%) cholesterol appearance. In contrast, CI-976, a potent acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, did not affect the uptake of free cholesterol into the intestines while inhibiting cholesterol esterification (98% inhibition).(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1995

Amides of piperidine, morpholine and piperazine substituted 1-phenylethylamines: inhibitors of acylCoA:cholesterol acyltransferase (ACAT) activity in vitro and in vivo.

Amides of some substituted 1,2-diarylethylamines have been shown to exhibit potent acylCoA:cholesterol acyltransferase (ACAT, EC 2.3.1.26) inhibitory activity in vitro in microsomal ACAT assays but show poor in vivo activity in a cholesterol-fed hamster model. In an effort to design ACAT inhibitors that are potent in both our in vitro and in vivo assays a series of amides of piperidine, morpholine and piperazine substituted 1-phenylethylamines were synthesized. Compounds of this series were found to be very potent inhibitors of ACAT in a microsomal ACAT assay and also exhibited potent activity in a cholesterol-fed hamster model.

Amides↗
PubMed1995

The effect of acyl CoA: cholesterol acyltransferase inhibition on the uptake, esterification and secretion of cholesterol by the hamster small intestine.

Acyl CoA: cholesterol acyltransferase (ACAT) inhibitors are known to inhibit cholesterol absorption and are under investigation to reduce hypercholesterolemia. These studies examine the effect of an ACAT inhibitor 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)-dodecanamide (PD128042) on the uptake, metabolism and secretion of cholesterol by the hamster intestinal wall in a short-term model. Preliminary studies in this model indicated that the uptake of 14C-cholesterol and its subsequent esterification 2 hr postoral dosing occurs primarily in the duodenal and jejunal segments of the small intestine and most of the radiolabeled cholesterol and cholesteryl ester in the plasma was associated with chylomicrons. In both single- and multiple-dose studies, PD128042 (50 mg kg-1 day-1) did not inhibit intestinal uptake of [14C]-cholesterol but [14C]-cholesteryl ester formation was inhibited. The free [14C]-cholesterol appearing in plasma was not affected despite a large reduction in [14C]-cholesteryl ester. In contrast, cholestyramine (1 g kg-1 day-1) inhibited the uptake of the radiolabeled free cholesterol and the appearance of cholesteryl ester in the intestine and plasma. The effects of PD128042 on cholesterol and cholesteryl ester mass associated with scraped intestinal mucosa were consistent with the effects observed with the use of the radiolabeled cholesterol. In addition, PD128042 did not affect the uptake of appearance of radiolabeled triglyceride in the intestinal wall after oral gavage of 3H-trioleoylglycerol. Taken together, the data suggest that ACAT inhibition reduces cholesterol absorption by limiting cholesteryl ester incorporation into chylomicrons and has no effect on the intestinal processing of free cholesterol to be secreted into plasma.

Anilides↗
PubMed1994

Demonstration of a direct effect on hepatic acyl CoA: cholesterol acyl transferase (ACAT) activity by an orally administered enzyme inhibitor in the hamster.

Orally active inhibitors of acyl CoA:cholesterol acyl transferase (ACAT), such as Lederle CL277082 (LE), are known to reduce plasma and hepatic cholesteryl ester levels, although the mechanisms are not well understood. Several groups have reported the inhibition of cholesterol absorption upon oral ACAT inhibitor administration. In this study, we used 7-day dietary and drug treatments of hamsters to examine the possible effects of LE on hepatic ACAT. ACAT assays were performed using liver homogenates in the absence and presence of a saturating level of exogenously added cholesterol. LE (100 mg/kg/day) treatment of chow or 0.5% cholesterol-fed animals caused reductions in ACAT activity without additional cholesterol as compared with non-treated animals. When a saturating level of cholesterol was added to the assays, reductions in ACAT activity upon LE treatment of chow- or cholesterol-fed animals were also observed. Treatment of cholesterol-fed animals with cholestyramine in the diet reduced ACAT activity in the absence of added cholesterol. However, ACAT activities similar to those of non-treated animals were observed at a saturating level of cholesterol. This latter effect demonstrates that inhibition of cholesterol absorption reduces cholesterol delivery to the liver but does not reduce cholesterol esterifying capacity since cholestyramine is not absorbed and has no direct effect on the liver. The decreased ACAT activity in homogenates from LE-treated animals could also be mimicked in a dose-dependent manner by the addition of exogenous LE to liver homogenates from non-treated animals. These results indicate that hepatic ACAT activity is regulated by the availability of free cholesterol, and that orally administered LE has a direct effect on hepatic ACAT activity in the liver. In addition, the data are consistent with LE activity in the liver as being responsible, in part, for the reduced hepatic and plasma cholesteryl esters in treated animals.

Animals↗
PubMed1994

Inhibition of PDGF receptor binding and PDGF-stimulated biological activity in vitro and of intimal lesion formation in vivo by 2-bromomethyl-5-chlorobenzene sulfonylphthalimide.

The proliferation of vascular smooth muscle cells (SMCs) is a key event in the development of atherosclerotic lesions and in the restenosis of arteries after angioplasty. Polypeptide growth factors are potent SMC mitogens in vitro and are believed to be involved in SMC proliferation in vivo. Strong data exist linking platelet-derived growth factor (PDGF) activity to human atherosclerosis. However, no low-molecular-weight antagonists of this growth factor have been discovered. We identified a compound, SCH 13929 (2-bromomethyl-5-chlorobenzene sulfonylphthalimide), which inhibits binding of 125I-PDGF BB to cell surface receptors with an IC50 of 0.13 mumol/L. This compound has a lesser effect on the binding of 125I-epidermal growth factor (EGF), 125I-basic fibroblast growth factor (bFGF), or 125I-endothelin to specific cell surface receptors. Exposure of cultured SMCs to SCH 13929 inhibits PDGF BB- and PDGF AA-stimulated DNA synthesis but not EGF- or bFGF-stimulated DNA synthesis. PDGF BB-stimulated SMC division is also inhibited by exposure to SCH 13929. Chemotaxis assays indicate that SCH 13929 inhibits PDGF-stimulated directional migration and suggest that the compound interacts with PDGF rather than with the receptor. Oral administration of SCH 13929 (100 mg/kg per day) to Sprague-Dawley rats or spontaneously hypertensive rats results in significant inhibition of lesion formation in the balloon catheter-deendothelialized carotid artery. These results suggest that SCH 13929 may be a useful tool for understanding the role of PDGF in intimal lesion formation.

3T3 Cells↗
PubMed1993

NG-nitro-L-arginine methyl ester does not affect balloon catheter-induced intimal hyperplasia in rats.

The L-arginine derived NO-cGMP pathway's role in the response of the arterial wall to balloon catheter injury was examined. Rats were given the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (10 mg/kg po twice daily) or vehicle for 6 days before and 2 weeks after balloon catheter injury. NG-nitro-L-arginine methyl ester treatment increased blood pressure and inhibited acetylcholine responses in aortic rings but did not alter the lesions produced by balloon injury. Our results suggest that the L-arginine derived NO-cGMP pathway does not play a significant role in the response of the artery wall to balloon injury in the rat.

Acetylcholine↗
PubMed1991

Human and monkey corneal endothelium expression of low-density lipoprotein receptors.

Receptors for low-density lipoprotein are necessary for high-affinity uptake of lipid and protein essential to cell structure and function. Distinct receptors for acetoacetylated low-density lipoprotein internalize oxidized or enzymatically modified low-density lipoprotein and extracellular matrix components. We identified low-density lipoprotein receptors on cultured human and monkey corneal endothelial cells by the avid incorporation of fluorescently labeled low-density lipoprotein that was competitively inhibited by excess unlabeled low-density lipoprotein but not by unlabeled acetoacetylated low-density lipoprotein. Specific uptake of labeled low-density lipoprotein was greatest in nonconfluent, growing cells and increased after low-density lipoprotein deprivation. Intact endothelial monolayers of whole human cornea also incorporated low-density lipoprotein but not acetoacetylated low-density lipoprotein. After scratch injury of human corneas, spreading endothelium adjacent to areas of cell loss internalized more fluorescent low-density lipoprotein than cells distant from the injury. Blood-aqueous barrier breakdown occurring in ocular diseases and after surgical and nonsurgical trauma may allow leakage of circulating low-density lipoprotein, which provides a rich supply of lipid and protein for endothelial use. Efficient, receptor-mediated, low-density lipoprotein uptake may facilitate repair of damaged corneal endothelial membranes and regeneration of intact, functional cell monolayers.

Acetoacetates↗
PubMed1989

Suppression of atherogenesis by nifedipine in the cholesterol-fed rhesus monkey.

Diet-induced atherosclerosis in rhesus monkeys was suppressed in the carotid arteries and thoracic aorta by the calcium antagonist nifedipine given orally for a period of 1 year at a dose of 10 mg b.i.d. The extent of atherosclerosis was determined by quantitative micromorphometric studies. No change in serum blood cholesterol or biochemical composition of the major vessels was detected, but the intimal area and thickness of the atherosclerotic plaques in the carotid arteries of the nifedipine group were markedly less than those found with the control group (p less than 0.05). However, no statistically significant differences were seen in the degree of atherosclerotic involvement of the other major arterial vessels. Although the mechanism is not clear, nifedipine may be useful in the treatment of carotid artery disease.

Animals↗
PubMed1988

Aortic wall metabolism in relation to susceptibility and resistance to experimental atherosclerosis.

Different segments of the aorta and its branches show differing susceptibilities to atherosclerosis. To identify metabolic features that may account for plaque formation and sparing, we studied aortic wall respiration and glycolysis proximal and distal to an aortic coarctation in 30 rabbits fed a standard or atherogenic diet. Three months after coarctation, blood pressure in the proximal aorta was elevated, and plaque occupied 98% +/- 28% of the intimal surface compared with 57% +/- 26% for control animals (p less than 0.05). Aortic pressure distal to the stenosis remained normal, but plaque formation was markedly decreased (5% +/- 4%) compared with controls (30% +/- 27%, p less than 0.05). Metabolic studies included measurement of oxygen consumption of proximal and distal aortic walls, lactic acid production, and 2-deoxyglucose uptake. Elevated pressure or hyperlipidemia increased respiration (22.6 +/- 4.0 or 16.3 +/- 6.0 pmol oxygen consumed/min/microgram deoxyribonucleic acid [DNA] vs 5.8 +/- 5.2 for controls; p values less than 0.05) without increasing glycolytic metabolism. The coexistence of hypertension and hyperlipidemia resulted in maximal plaque formation and a sevenfold increase in both oxidative metabolism (46.6 +/- 27.2 pmol oxygen consumed/min/microgram DNA vs 5.8 +/- 5.2 for controls, p less than 0.004) and glycolytic metabolism (44 +/- 10 ng lactic acid produced/90 min/microgram DNA vs 6 +/- 3 for controls, p less than 0.004). In the spared aortic segment distal to coarctation, glycolytic metabolism was increased (10 +/- 8 ng lactic acid produced/90 min/microgram DNA vs 2 +/- 1 for controls, p less than 0.05) but oxidative metabolism remained normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effect of an elastin growth substrate on cholesteryl ester synthesis and foam cell formation by cultured aortic smooth muscle cells.

Exposure of smooth muscle cells cultured on plastic or glass to hyperlipidemic serum did not result in the formation of foam cells. Since elastin binds serum lipids, and vascular smooth muscle cells are normally closely associated with elastin, we investigated the effects of an elastin substrate on lipid metabolism and on the accumulation of lipid vacuoles by rabbit aortic smooth muscle cells in culture. When cells were grown in plastic petri dishes, cholesteryl ester synthesis, as measured by [14C]oleate incorporation into cholesteryl esters, was 3 times greater in rabbit hyperlipidemic serum (HLS) than in normolipemic serum (NLS) (P less than 0.001). For cells of the same subculture grown on the elastin substrate, the synthetic rate was 6-fold greater in HLS compared to NLS (P less than 0.005). The cells grown on the elastin membranes in the presence of HLS contained large numbers of Oil red O stainable lipid vacuoles and resembled foam cells, while those grown in petri dishes and exposed to HLS showed only an occasional cell containing a few vacuoles. Pre-incubation in lipoprotein-deficient serum markedly enhanced the stimulatory effect of HLS on cholesteryl ester synthesis for cells growing in plastic petric dishes but had much less stimulatory effect on the cells growing on elastin membranes. These studies indicate that close association with elastin modulates the response of smooth muscle cells to hyperlipidemia and suggest a role for elastin in the formation of foam cells of smooth muscle origin during atherogenesis.

Animals↗
PubMed1987

Lysosomal enzyme activities in cultured trabecular-meshwork cells.

We examined the lysosomal enzyme levels in cultured trabecular meshwork cells. Histochemical studies revealed that bovine trabecular meshwork cells stained prominently for acid lipase, acid phosphatase, and acid esterase activities. Following phagocytic challenges, such as incubations with latex microspheres or zymosan particles, lysosomal enzyme staining was visibly enhanced. The uptake of foreign particles by trabecular-meshwork cells was evident. Data from biochemical assays for acid lipase, cholesteryl esterase, and acid esterase confirmed the histochemical findings. These results indicate that trabecular meshwork cells are actively phagocytic in culture and that lysosomal enzyme levels in these cells may be modulated by phagocytic challenge.

Acid Phosphatase↗
PubMed1987

The sympathetic nervous system and atherosclerosis.

Morphometric and chemical changes in the arterial wall were studied after 12 months of diet-induced atherosclerosis in rhesus monkeys treated with either bilateral surgical thoracic sympathectomy or propranolol. There was a marked reduction in the progression of atherosclerosis in the carotid arteries and a moderate reduction in the disease found in the thoracic aorta of monkeys treated initially with a sympathectomy, in comparison to control monkeys fed an atherogenic diet alone. Propranolol at a dose of 40 mg/12 hrs also seemed to reduce the progression of atherosclerosis in the carotid arteries and thoracic aorta, although the differences were less dramatic. There were minimal differences in the extent of atherosclerosis in the abdominal aorta or femoral arteries of animals in either treatment group as compared with the control group. Similarly, the chemical composition of these same major vessels showed no significant differences. Therefore, in the face of severe atherogenic stimuli, chemical or surgical sympathectomy may be useful in controlling atherosclerosis in specific arterial beds.

Animals↗
PubMed1987

Protection from atherosclerotic lesion formation by reduction of artery wall motion.

We have studied mechanical factors that could determine how stenosis protects against distal atherosclerosis in cynomolgus monkeys fed an atherogenic diet. Critical aortic stenosis was produced by coarctation of the thoracic aorta. After 3 months, coarcted monkeys had a mean aortic pressure gradient of 25 +/- 1 mm Hg and a 76% +/- 2% lumen stenosis. Aortic wall motion was measured by means of in vivo ultrasonic sonomicrometry. Dynamic tracings of aortic pressure and diameter were recorded simultaneously at standard locations proximal and distal to the stenosis and at comparable sites in noncoarcted control animals. In the proximal aorta, mean blood pressure and pulse pressure were increased (p less than 0.05), but wall motion and intimal lesion area were not different from those determined in control monkeys. In the aorta distal to the coarct, mean blood pressure was no different from that in control animals but pulse pressure was diminished; in addition, there was marked reduction of arterial wall motion (p less than 0.001). This was accompanied by a significant reduction of intimal plaque area (p less than 0.05) and acid lipase activity (p less than 0.001). Thus, inhibition of plaque formation in the distal aorta coincided with reduction of pulse pressure and aortic wall motion rather than with blood pressure or hypercholesterolemia. Inhibition of arterial wall motion may account for the sparing effect often encountered in human arteries distal to stenosing atherosclerotic plaques.

Animals↗
PubMed1986

Lectin binding to distinguish cell types in fixed atherosclerotic arteries.

In order to assess the possible utility of lectin binding to identify the cellular components of fixed arterial lesions we studied lectin binding in experimental rabbit and monkey vessels, as well as in human atherosclerotic arteries obtained at surgery. The avidin-biotin-peroxidase technique was used to localize the binding of the following biotinylated lectins: Concanavalin A (Con A), Dolicho biflorus agglutinin (DBA), soybean agglutinin (SBA), peanut agglutinin (PNA), Phaseolus vulgaris agglutinin (PHA), Ricinus communis agglutinin (RCA), wheat germ agglutinin (WGA), and Ulex europaeus agglutinin (UEA). PHA demonstrated specific cytoplasmic staining of macrophages in rabbit, monkey, and human tissues and differentiated macrophages from other cell types in atherosclerotic lesions. When morphometric comparisons were made between lesion PHA staining and another macrophage marker, acid lipase, very similar results were obtained. Con A, RCA, and WGA stained macrophages intensely and differentiated them from other cell types in normal reticuloendothelial tissues and lesions, but also stained smooth muscle cells and endothelial cells when these cells developed lipid vacuoles. UEA stained the endothelium of vasa vasorum consistently in human arteries, but staining of artery lumen endothelium was variable. Endothelial cells of rabbit or monkey vessels did not stain with UEA. DBA, PNA, and SBA did not consistently stain any cellular structures in arteries. PHA was found to be an excellent marker to differentiate and quantify macrophages in glutaraldehyde or formalin-fixed, paraffin-embedded experimental and human atherosclerotic lesions. Con A, RCA and WGA merit further detailed study in conjunction with other histochemical tests as possible markers of functional changes in arterial cells during lesion development.

Animals↗
PubMed1985

Role of acid lipase in cholesteryl ester accumulation during atherogenesis. Correlation of enzyme activity with acid lipase-containing macrophages in rabbit and human lesions.

Purified acid lipase was previously shown to hydrolyze the artificial substrate, alpha-naphthyl palmitate, as well as triglycerides and cholesteryl esters and to form cholesteryl esters. To determine to what extent these activities are associated with acid lipase-containing cells in atherosclerotic plaques, we examined rabbit aortas at different stages of experimental lesion induction and human atherosclerotic arteries. Assays of cholesteryl ester formation, and alpha-naphthyl palmitate and cholesteryl ester hydrolysis were performed on homogenates of lesions and the hydrolysis of the artificial fatty acid ester was used as a histochemical marker to identify acid lipase positive foam cells in sections of the same lesions. The volume of lesions occupied by cells stained for acid lipase correlated strongly with the enzyme activities of the arterial homogenates. These results suggest that acid lipase-containing cells may mediate the accumulation of cholesteryl ester during atherogenesis. Since acid lipase activity marks macrophages, these methods may be useful for relating macrophage distribution and function to lesion progression, regression, and complication.

Animals↗
PubMed1984

Reticuloendothelial system response to hyperlipidemia in rhesus and cynomolgus monkeys.

A detailed study of the effect of various periods of hyperlipidemia on the reticuloendothelial system (RES) lipid accumulation in rhesus and cynomolgus monkeys was conducted. The cynomolgus serum cholesterol and triglyceride levels were on the average more elevated than the rhesus levels throughout a 12-month period when both species were fed a diet containing 12.5% coconut oil, 12.5% butter fat, and 2% cholesterol. After cynomolgus monkeys were fed this diet, their reticuloendothelial system became more lipid laden than that of the rhesus monkeys, in both the liver and the spleen. This was also true for the circulating monocytes. Furthermore, the parenchymal cells of the cynomolgus livers also become more fat filled, and chemical analyses demonstrated more cholesterol (total, free, and esterified) and triglycerides in the liver and the spleen. Xanthomata development in the cynomolgus, although similar in type and distribution, was more extensive than that in the rhesus monkey after similar periods of experimental diet feeding. Therefore, the RES of two species of macaque monkeys are affected differently when challenged with the same high fat, high cholesterol diet, with the cynomolgus RES being much more involved with lipid and cholesterol storage than the rhesus RES.

Animals↗