Biomedical subjects
Publications and source records attributed to J W Huff.
A limited study was conducted to determine the biological consequences of rendering the phenyl rings of the previously reported 7-(3,5-disubstituted [1,1'-biphenyl]-2-yl)-3,5-dihydroxy-6-heptenoic acids coplanar. Such constraint substantially diminished intrinsic HMG-CoA reductase inhibitory activity.
Proper lens maintenance is required if contact lens wear is to be successful. Poor compliance or inadequate cleaning may lead to contact lens failures and potentially damage to the eye. With phase contrast microscopy, we addressed the effect of cleaning systems on the physical integrity of a surface-modified lens--the Silcon contact lens. Several cleaners were evaluated for their ability to clean Silcon lenses with minimal damage to the lens surface. The data demonstrated that: all cleaning techniques alter the surface appearance; scratches develop more readily on lenses received with surface irregularities; wettability does not correlate with the extent of surface scratching; recommended cleaning procedures do not directly alter the wettability of the contact lens material; and phase contrast microscopy may be a useful addition to laboratory quality control.
Isolated rabbit corneas bathed in Krebs-bicarbonate Ringer solution were observed for thickness changes after a 90 minute equilibration period. Control corneas swelled an average of 0.5 micron/hr, and placement of a polymethylmechacrylate (PMMA) contact lens on the epithelial surface caused the corneas to swell 24.5 microns/hr, an effect similar to 0.5 mM epithelial cyanide exposure. The pronounced swelling induced by PMMA lens placement was much less however, in the epithelial presence of 3.2 mM sodium oxalate (3.22 microns/hr) or 3.2 mM sodium oxamate (5.38 microns/hr). An equiosmotic excess of 4.8 mM NaCl was least active (15.89 microns/hr). On normal isolated corneas (without contact lenses), the Ringer containing an excess of 4.8 mM NaCl significantly deswelled the corneas (-13.44 microns/hr), which contrasted with oxalate and oxamate containing Ringer solutions (1.17 and 1.33 micron/hr respectively). The present study supports the notion that contact lens-induced edema results from stromal lactate accumulation, and suggests a potential alternative to osmotic therapy for its amelioration. These LDH inhibitors, in the concentrations used, have no acute osmotic or toxic effect on normal corneas in vitro.
In the isolated bullfrog cornea, three calcium channel antagonists had dose-dependent inhibitory effects on the Cl-originated short-circuit current (SCC). Their order of decreasing potency was bepridil, verapamil and diltiazem. One millimolar diltiazem inhibited the SCC by 98% and subsequent incubation with the calcium ionophore A23187 had no restorative effect. Increasing the bathing solution Ca concentration from 0.05 to 15 mM, however, decreased diltiazem's inhibitory efficacy. This antagonist depolarized the intracellular potential difference Vsc from -54 to -18 mV (tear:reference) and the voltage divider ratio FRo decreased from 0.58 to 0.30, suggesting an increase in basolateral membrane electrical resistance. Additional indication of a basolateral membrane effect by the drug was that preincubation with 10(-5) M amphotericin B in Cl-free Ringer's did not eliminate the inhibitory effect of the drug on the Na- and K-elicited SCC. In the absence of amphotericin B in Cl-free Ringer's (SCC = 0), 1 X 10(-3) M diltiazem depolarized the Vsc from -78 to -9 mV suggesting that the increase in basolateral membrane resistance was due to K channel blockade. Diltiazem (1 X 10(-3) M) significantly decreased cyclic AMP content; however, isoproterenol in the presence of the drug increased cyclic AMP fourfold without having any restorative effect on the inhibited SCC. Therefore, the inhibition of the Cl-originated SCC resulting from an increase in basolateral membrane K resistance is not caused by a decline in cyclic AMP content.(ABSTRACT TRUNCATED AT 250 WORDS)
A series of 5-substituted 3,5-dihydroxypentanoic acids and their derivatives have been prepared and tested for inhibition of HMG-CoA reductase in vitro. In general, unless a carboxylate anion can be formed and the hydroxy groups remain unsubstituted in an erythro relationship, inhibitory activity is greatly reduced. Furthermore, only one enantiomer of the ring-opened form of lactone 6a(+/-) possesses the activity displayed by the racemate. Insertion of a bridging unit other than ethyl or (E)-ethenyl between the 5-carbinol moiety and an appropriate lipophilic moiety (e.g., 2,4-dichlorophenyl) attenuates activity.
Mevinolin is a potent inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase; EC 1.1.1.34), an enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis. We have been studying the hepatic distribution of reductase with immunofluorescence microscopy and liver ultrastructure with electron microscopy in normal and drug-treated rats. In control animals, only about 20% of the hepatocytes were reductase positive. These cells were localized in the periportal lobular zones. The numbers of positive hepatocytes in animals given mevinolin or cholestyramine (or both) were directly proportional to the activities of the HMG-CoA reductase determined biochemically. This induction of HMG-CoA reductase immunofluorescence was centered periportally. Rats given 0.075% mevinolin alone had a homogeneous distribution of reductase staining in their hepatocyte cytoplasm, whereas a combination of 0.25% mevinolin and 3% cholestyramine caused a 150-fold increase in enzyme activity and induced prominent juxtanuclear immunofluorescent globules of HMG-CoA reductase in all hepatocytes. With electron microscopy, these bodies were composed of tightly packed stacks of smooth endoplasmic reticulum cysternae and aggregates of branched smooth endoplasmic reticulum tubules. Our data suggest that a subpopulation of periportal rat hepatocytes may be uniquely specialized for cholesterol synthesis.
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Unidirectional fluxes of bicarbonate, sodium and chloride were measured across the isolated rabbit corneal endothelium. Bicarbonate and sodium fluxes were measured between 13 and 37 degrees C and were found to be temperature-sensitive. Ouabain (10(-6)M), which inhibits endothelial fluid transport, reduced the net bicarbonate flux by 32% but had no significant effect on sodium fluxes. Amiloride (10(-4)M) did not alter sodium transport, but slightly increased the unidirectional bicarbonate fluxes. Sodium fluxes were unchanged in chloride-free and potassium-free Ringer solutions, and net sodium transport was unaffected in the presence of carbonic anhydrase, acetazolamide, or low (5 mM) bicarbonate Ringer, but was reduced by 45% in bicarbonate-free Ringer. A net chloride flux was found in the same direction (stroma to aqueous) as bicarbonate and sodium. This chloride flux (2.18 muEq/cm2/hr) was of the same magnitude as bicarbonate but was sodium-independent. These findings suggest that: (1) like bicarbonate and fluid transport, sodium transport is bicarbonate-dependent, temperature-sensitive, and chloride-independent; (2) sodium transport is not stoichiometrically coupled to bicarbonate; and (3) neither sodium nor bicarbonate transport are coupled to that of chloride.
Mevinolin, a fungal metabolite isolated from cultures of Aspergillus terreus, is a potent competitive inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A reductase, the rate-controlling enzyme in cholesterol biosynthesis. In the current studies we demonstrate that mevinolin significantly lowers serum cholesterol in rabbits fed a cholesterol free, low-fat semi-synthetic diet. Rabbits maintained on this diet developed endogenous hypercholesterolemia with average cholesterol concentrations of 310 mg/dl over a 66-day period. Treatment with mevinolin for 39 days at a dose of 2 mg/kg per day lowered serum cholesterol levels by an average of 37% (P less than 0.05), while a dose of 6 mg/kg per day resulted in a 48% (P less than 0.05) decrease when compared with the control group. When the administration of mevinolin was discontinued, serum cholesterol levels of the 6 mg/kg per day group increased significantly to a maximum post-treatment value of 319 mg/dl (P less than 0.0001). The results of this study demonstrate that rabbits with endogenous hypercholesterolemia are a useful animal model for the study of cholesterol biosynthesis inhibitors like mevinolin.
The recent demonstration of sodium-sensitivity and chloride-insensitivity of the bicarbonate transport system of the rabbit corneal endothelium promoted a further examination of sodium fluxes across this membrane. Unidirectional fluxes were measured on paired endothelia at steady state. A net sodium flux from stroma to aqueous was found with a value of 3.5 muequiv/cm2/hr (almost double that of bicarbonate transport), which was independent of the ambient bicarbonate concentration.
The relative activity of three bile acid binding polymers in increasing cholesterol biosynthesis in the rat from 14C-acetate was determined by measuring blood levels of 14C-cholesterol after intraperitoneally administered 14C-acetate. CAT-FLOC and 3,3-ionene were 4-5 times more active than cholestyramine in this study which correlated well with the results of hypocholesteremic testing in dogs.
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The in vitro bile acid binding properties of 2 water-soluble, linear, cationic resins, poly-[(dimethylimino)trimethylene chloride] or 3,3-ione C1, and poly-diallyldimethylammonium chloride) or CAT-FLOC were determined. Both polymers were substantially more active than cholestyramine. All were compared for hypocholesterolemic effect in normo-cholesterolemic dogs. CAT-FLOC and 3,3-ionene C1, administered at 1.8 and 1.2 g/day, respectively, exhibited cholesterol-lowering action equivalent to cholesteryramine given at 12 g/day. The results of this study suggest that effective reduction of plasma cholesterol may be achieved with significantly lower doses of bile acid sequestrants.
In vitro, 2-[3-(2-thiazolylthio)phenyl]propionic acid (TPA) at plasma concentrations ranging from 0.02 to 1.0 microgram/ml prevents aggregation of human platelets induced by various aggregating agents. Oral administration of TPA to guinea pigs inhibits platelet aggregation; the estimated dose to reduce aggregation by 50% is 0.3 mg/kg. TPA protects rabbits against arachidonate-induced thromboembolic death (50% protection at 0.79 mg/kg i.p.). TPA is a potent hypotriglyceridemic agent in rats when present in the diet in concentrations as low as 0.003%. In chimpanzees, TPA is uricosuric at oral doses of 0.625 and 2.5 mg/kg. This rare combination of pharmacological properties suggests that TPA is a potentially useful antithrombotic agent.
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