Biomedical subjects

D R Feller

Publications and source records attributed to D R Feller.

At least 55 records · Page 3Linked to original sources

PubMed1991

Molecular aspects of the receptor activation by imidazolines: an overview.

Based on the pharmacological activity of chiral imidazolines the steric requirements for the activation of the alpha-adrenoceptor are provided. Importantly, the sequence of interaction of the critical groups of the asymmetric carbon of imidazolines and catecholamines with the alpha-adrenoceptor is postulated. Thus, initial determinants of molecular efficacy are hypothesized. The effect of aromatic fluoro-substitution and introduction of a double bond in the imidazoline moiety on the pharmacologic activity is discussed. The unique mechanism of non-adrenergic vascular activity of isothiocyanato-tolazoline is presented.

Animals↗

PubMed1991

Structure-activity studies of new imidazolines on adrenoceptors of rat aorta and human platelets.

Potencies of new aromatic substituted fluoro or iodo analogues of catecholimidazolines on functional responses in rat aorta (alpha 1) and platelets (alpha 2) were quantified. (1) When compared either on the basis of EC50 or the dissociation constant (KA), 5-fluorocatecholimidazoline was as potent as the reference alpha 1-adrenoceptor agonist, phenylephrine in the vascular tissue. The maximum contraction of aorta produced by the fluoro analogue was, however, 17% higher than that of phenylephrine. The time required for 1/2 relaxation of the tissue after 5-fluoro hydroxy imidazoline was at least twice as long as that of the phenylephrine. The catechol moiety as well as fluorine substitution at the critical 5-position of the aromatic ring is essential for higher alpha 1 adrenoceptor-mediated potency. (2) As compared to the fluoro analogues, the adrenoceptor-mediated potencies of iodo-analogues were relatively weak on vascular tissue. Naphazoline and its analogues were partial agonists on vascular tissue with dissociation constants which ranged from 110 to 2600 nmol/l. (3) Imidazole analogues were generally less potent agonist than the imidazolines by one order of magnitude. (4) The vacular effects of all agonists were competitively blocked by prazosin with KB values which ranged from 0.04 to 0.48 nmol/l. Since the variation in KB values were within normal limits, the action of new imidazolines on rat aorta appears to be mediated mainly by the activation of the alpha 1-adrenoceptor. Prazosin 10 nmol/l abolished the vascular response of some partial agonists. This indicates a slightly different mode of interaction of agonists with the transduction process. (5) Carbon 4-substituted imidazolines produced little or no alpha 1 adrenoceptor-mediated intrinsic activity, but competitive receptor blocking potency was comparable to that of phentolamine. (6) Medetomidine was a partial agonist on the rat aorta with a KA of 260 nmol/l. When investigated as a blocker, the KB of medetomidine against phenylephrine was approximately 5600 nmol/l. The variation in the latter value was high. (7) In acetylsalicylic acid-treated human platelets, the alpha 2-adrenoceptor-mediated aggregatory effect of all fluoro analogues was weak. Iodo or naphazoline analogues did not initiate platelet aggregation but blocked the aggregation induced by epinephrine. The affinity of naphazoline for the alpha 2-adrenoceptor was 1100 nmol/l. The IC50 of medetomidine for platelet anti-aggregatory effect was 3300 nmol/l, which compares favorably with other imidazoline type of blockers of platelet aggregation. (8) Sympathomimetic vasoconstrictor actions and platelet aggregation effects of these compounds can be dissociated.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1991

Pharmacological properties of novel bicyclic isoquinoline analogs in isolated guinea pig atria, trachea and in human platelets: relationship to trimetoquinol.

1. Antiplatelet and beta-adrenoceptor activities of a set of secondary and tertiary N-methyl substituted amine analogs of trimetoquinol (TMQ, I and II, respectively) and 5,8-ethano-l-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquin oline (bicyclic isoquinoline compounds III and IV, respectively) were examined. 2. Compounds III and IV induced relaxations of guinea pig trachea which were blocked by propranolol whereas neither compound acted as an agonist nor antagonist of beta-adrenoceptors (chronotropy) in guinea pig atria. TMQ analogs (I and II) were agonists in both beta-adrenoceptor systems. 3. When tested in human platelets, compounds III and IV, like the TMQ analogs, blocked several inducers of the prostaglandin-dependent and -independent pathways, and the alpha 2-adrenoceptor-mediated pathway of platelet activation. 4. The bicyclic isoquinoline analogs (III and IV) possessed more selective beta 2-adrenoceptor stimulatory activity and equal or greater inhibitory activity against inducers of the prostaglandin-independent pathways of platelet function than the corresponding TMQ analogs (I and II). 5. These chemically novel lipophilic bicyclic compounds provide a new lead to the development of agents useful for the treatment of asthma and thrombotic disorders.

Adrenergic beta-Agonists↗

PubMed1990

In vivo and in vitro peroxisome proliferation properties of selected clofibrate analogues in the rat. Structure-activity relationships.

We have examined, relative to clofibric acid (CPIB), the effects of a chemical series of phenoxyacetic acids and of two asymmetric CPIB analogues, the R(+)- and S(-)-enantiomers of 2-(4-chlorophenoxy)propionic acid (4-CPPA) and 2-(4-chlorophenoxy)butyric acid (4-CPBA), on hepatic peroxisome proliferation both in vivo and in vitro utilizing cholesterol-fed rats and primary cultured rat hepatocytes respectively. Peroxisome proliferation was assessed by measuring changes in peroxisomal fatty acyl-CoA oxidase (FACO) and microsomal laurate hydroxylase (LH) activities as well as by electron microscopic examination of 3,3'-diaminobenzidine-stained liver slices. CPIB and enantiomers of 4-CPPA and 4-CPBA (0.6 mmol/kg/day for 7 days) produced hepatomegaly, lowered serum cholesterol levels, and caused 4.7- to 12.9-fold and 2.9- to 6.1-fold increases in hepatic FACO and LH activities, respectively, in cholesterol-fed rats. Electron micrographs of liver cells showed an increased number of peroxisomes from cholesterol-fed rats given S(-)-4-CPBA and CPIB. Likewise, these compounds (0.03 to 1.0 mM) induced FACO and LH in primary rat hepatocyte cultures after 72 hr. R(+)- and S(-)-Enantiomers of 4-CPPA produced similar concentration-dependent and maximal increases in both FACO and LH activities, whereas enantiomeric selectivity [S(-) greater than R(+)] for the induction of these two enzymes was observed with the isomers of 4-CPBA. The increases in the activities of FACO and LH caused by S(-)-4-CPBA were similar to those elicited by 1.0 mM CPIB (58.6- and 9.8-fold respectively). These results show that the enantiomers of 4-CPPA and 4-CPBA induce the peroxisome proliferation-associated enzymes FACO and LH in vivo and in vitro, and that the S(-)-isomer of 4-CPBA causes a greater induction of FACO and LH in vitro than its corresponding R(+)-isomer, indicating that these two enzymes are induced in an enantioselective manner. Optimal induction of the peroxisome proliferation-associated enzymes FACO and LH in rat hepatocyte cultures was produced by phenoxyacetic acids possessing (1) a chlorine atom at the 4-position of the phenyl ring, (2) a dimethyl or mono-ethyl substitution at the alpha-carbon atom of the carboxylic acid side chain; and (3) an S(-)-orientation for chiral analogues possessing a mono-ethyl group at the alpha-carbon atom of the carboxylic acid side chain.(ABSTRACT TRUNCATED AT 400 WORDS)

2-Methyl-4-chlorophenoxyacetic Acid↗

PubMed1990

Pharmacological evaluation of the beta-adrenoceptor agonist properties of N-benzyl substituted trimetoquinol analogues.

The beta 1- and beta 2-adrenoceptor agonist properties of trimetoquinol (TMQ, I) and N-benzyl ring substituted TMQ analogues (II, 4'-methylbenzylTMQ; III, 4'-chloro-benzylTMQ; IV, 4'-methoxybenzylTMQ; V, 4'-nitrobenzylTMQ; VI, 3',4'-dichlorobenzylTMQ; and VII, 4'-aminobenzylTMQ) were studied in guinea pig atria and trachea. All compounds gave concentration-dependent responses in atria and trachea, and the rank order of beta-adrenoceptor agonist potency was I greater than VII greater than II greater than V greater than IV greater than VI greater than III and I greater than VII greater than IV = VI greater than V greater than III greater than II, respectively. Whereas the N-benzyl substitution reduced potency for beta-agonist activity, the beta 2/beta 1-selectivity ratio was enhanced by addition of groups to the N-benzyl ring, and the rank order of beta 2-selectivity was VI (10-fold) greater than III (8-fold) = IV (8-fold) greater than VII (3-fold) greater than V = I greater than II. The results show that varying the nature of substituents on the N-benzyl ring of TMQ produces compounds which retain greater beta 2-selectivity.

Adrenergic beta-Agonists↗

PubMed1990

Pharmacological evaluation of the beta-adrenoceptor agonist and thromboxane receptor blocking properties of 1-benzyl substituted trimetoquinol analogues.

The beta 1- and beta 2-adrenoceptor agonist and thromboxane A2 (TXA2) antagonist properties of trimetoquinol (TMQ, I) and 1-benzyl substituted TMQ analogues [3'-iodo-4',5'-dimethoxy TMQ, II; 3',5'-diiodo-4'-dimethoxy TMQ, III; 3',4'-dimethoxy-5'-nitro TMQ, IV; 3',4'-dimethoxy-5'-amino TMQ; V; and 3',4'-dimethoxy TMQ, VI] were studied in guinea pig atria (beta 1) and trachea (beta 2), and in rat thoracic aorta and human platelets, respectively. The rank order of agonist activities in beta 1- and beta 2-adrenoceptor tissues was IV greater than or equal to I greater than II greater than V greater than III greater than VI and I greater than II = IV = V greater than VI greater than III, respectively. An increase of beta 2/beta 1-selectivity (2- to 3-fold) was observed for analogues V and VI as compared to TMQ. The rank order of inhibitory potency against U46619-induced contraction of rat aorta and human platelet aggregation and secretion was the same (I = II = III greater than IV greater than V greater than VI). The results show that varying the substituents at the 3'- and 5'-positions of the trimethoxybenzyl group of TMQ produces compounds which give different profiles of biological activity for beta-adrenoceptor agonism versus TXA2 antagonism. Certain TMQ analogues, notably analogue V, showed a greater selectivity as beta 2-receptor agonists and TXA2 antagonists in vascular smooth muscle than the parent drug (TMQ), and the iodinated analogues (II and III) have promise as potential radioligands or photoaffinity probes for thromboxane A2 receptors.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1990

Effects of thromboxane A2 on thoracic aorta of young and old rats: use of selective thromboxane receptor antagonists.

Thromboxane A2 (TXA2) is a bioactive metabolite of arachidonic acid which produces vascular smooth muscle contraction and blood platelet aggregation. The goal of this study is to establish whether there are age-dependent differences of vascular contractility to TXA2. Thoracic aorta of F-344 rats of age 4-6 months (young) and 22-23 months (old) were used as a model to examine responses to U46619 [(15S)-hydroxy-11 alpha, 9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid; a TXA2 agonist] alone or in the presence of prostanoid (SQ 29,548) or nonprostanoid (trimetoquinol, TMQ) endoperoxide/TXA2 receptor antagonists. Maximal contractile responses (84 and 89% relative to KCl) and EC50 values (23 and 55 nmol/l, respectively) to U46619 were the same in aortic strips of young and old animals. Experimentally determined pA2 and pKB values for SQ 29,548 and TMQ as antagonists of U46619-mediated contraction were unchanged in aorta of young (9.09 and 5.83, respectively) and old (9.41 and 6.10, respectively) rats. We conclude that the reactivity and population of TXA2 receptors in rat vascular smooth muscle are unaffected by the aging process.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1990

Stereostructure activity relationships of catecholamines on human platelet function.

The concentration-dependent effects of clonidine, isomers of epinephrine, norepinephrine (NE), isoproterenol, cobefrin and alpha-methyldopamine, and related desoxy analogs (epinine, dopamine, N-isopropyldopamine) were examined on human platelets. The rank order of aggregatory potency (pD2 values) was R(-)-epinephrine (6.3) greater than R(-)-NE (5.9) greater than (+/-)-erythro-cobefrin (5.3) greater than S(+)-epinephrine (4.7) = S(+)-NE (4.7) = clonidine (4.7) = dopamine (4.6) greater than epinine (4.4) greater than S(+)-alpha-methyldopamine (4.3) = R(-)-alpha-methyldopamine (4.3) greater than (+/-)-threo-cobefrin (3.7). The isoproterenol isomers and N-isopropyl-dopamine were inactive as agonists. In 9 of 16 platelet-rich plasma preparations, R(-)-epinephrine, R(-)-NE, and (+/-)erythro-cobefrin were agonists and the remaining analogs blocked R(-)-NE-induced aggregation with a rank order of inhibitory potencies (pKB values) of clonidine (6.2) greater than S(+)-alpha-methyldopamine (5.0) greater than dopamine (4.6) = R(-)-alpha-methyldopamine (4.4) greater than or equal to S(+)-NE (4.3) greater than N-isopropyldopamine (4.1) greater than S(+)-isoproterenol (3.7) = R(-)-isoproterenol (3.5). Each compound was also able to reverse prostaglandin E1 (PGE1) (0.1 microM)-induced blockade of the maximal aggregation response to ADP. At high concentrations, R(-)-isoproterenol was more potent than either the S(+)-isomer or desoxy analog, N-isopropyldopamine, in the reversal of PGE1 inhibition of ADP aggregation. Phentolamine blocked these alpha 2-adrenoceptor-mediated actions against PGE1 on ADP aggregation. The rank order of potency for the reversal of PGE1-mediated inhibition of ADP aggregation by these catecholamines was similar to that observed for platelet aggregation. Our results indicate that (i) the stereochemical requirements for the interaction of catecholamines with platelet alpha 2-adrenoceptors are in agreement with the Easson-Stedman hypothesis and other alpha-adrenoceptor tissues; (ii) catecholamines lacking a benzylic hydroxyl group in the R-configuration and/or possessing an N-isopropyl group were alpha 2-adrenoceptor antagonists; (iii) clonidine gave quantitatively different responses compared with catecholamines for interaction with alpha 2-adrenoceptors; and (iv) inhibition of platelet adenylate cyclase is correlated to the inhibition of epinephrine-induced aggregation response for this series of compounds.

Adenosine Diphosphate↗

PubMed1989

Quantitative assessment of enzyme induction by peroxisome proliferators and application to determination of effects on triglyceride biosynthesis in primary cultures of rat hepatocytes.

Potencies for the induction of peroxisomal fatty acyl-CoA oxidase (FACO) and microsomal laurate hydroxylase (LH) were determined for clofibric acid (CPIB), ciprofibrate (Cipro) and gemfibrozil (Gem) in primary cultures of rat hepatocytes based on complete concentration-response analysis and determination of theoretical maximum inductive responses for Cipro. CPIB and Cipro each induced FACO and LH in a concentration-dependent manner. Scatchard analysis of the data allowed calculation of EC50 values (mM) of 0.82 and 0.028 (for FACO) and 0.22 and 0.0081 (for LH) for CPIB and Cipro respectively. The EC50 ratios (CPIB/Cipro) were identical (29-fold) for induction of FACO and LH, supporting the concept that these enzymes are induced by CPIB and Cipro through a common mechanism. By comparison, Gem was relatively ineffective as an inducer of FACO and LH. Furthermore, Gem did not antagonize Cipro-mediated enzyme inductions, suggesting that Gem is a peroxisome proliferator of low potency rather than a partial agonist. Based on the potency and time-course profiles observed for induction of FACO and LH, the effects of CPIB, Cipro and Gem on triglyceride (TG) biosynthesis were determined in the cultured rat hepatocytes. Conditions of maximal FACO and LH induction by the drugs did not result in inhibition of TG biosynthesis in the cells. These results support the in vivo evidence which indicates that FACO and LH induction are not causally linked to the hypotriglyceridemic actions of peroxisome proliferating drugs.

Acyl-CoA Oxidase↗

PubMed1989

Potent antiplatelet effects of cyclic clofibric acid (CPIB) analogs on human platelets.

CPIB possesses antiplatelet as well as hypolipidemic activities. Two cyclic CPIB analogs, 6-phenylchroman-2-carboxylic acid (PCCA) and 6-cyclohexylchroman-2-carboxylic acid (CHCCA) were also found to be antagonists of the prostaglandin (PG)-dependent pathway of human platelet activation. PCCA and CHCCA were inhibitors of aggregation (AGG) and secretion (SEC) induced by ADP or epinephrine (E) [second waves only] and arachidonic acid (AA) with IC50 values ranging from 2.3-8.7 microM for PCCA and 3.7-12.1 microM for CHCCA. Neither compound antagonized the proaggregatory effects of the thromboxane A2 (TXA2) receptor agonist, U46619. CPIB blocked ADP and E-induced AGG and SEC (IC50's greater than 1200 microM) but not AA- or U46619-induced responses. Only CPIB blocked thrombin-induced AA release. Data showed that PCCA and CHCCA inhibited AA-induced malondialdehyde formation (IC50's = 9.3 and 11.3 microM, respectively) and thrombin-induced production of prostaglandin E2, prostaglandin F2 alpha, and TXB2 with IC50's ranging from 2.9 to 13.4 microM. PCCA and CHCCA were at least 200- to 500-fold more potent than CPIB as inhibitors of the PG-dependent pathway of human platelet activation. We conclude that PCCA and CHCCA act by inhibiting platelet cyclooxygenase activity whereas CPIB blocks the activity of phospholipase A2. Hypolipidemic PCCA and CHCCA represent a potent class of cyclooxygenase inhibitors which may be more useful than CPIB for treatment of atherosclerotic and thrombotic disorders.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1989

In vivo and in vitro studies of the hepatotoxic effects of 4-chlorophenol in mice.

4-Chlorophenol (4-CP) was studied for its toxicological effect on liver by using both in vivo and in vitro approaches. Male mice were administered 4-CP, 1.5 mmol/kg body weight, i.p., and were killed at 10, 20, 30 and 50 min after drug injection. Either i.p. or oral 4-CP administration significantly lowered total liver thiol levels by 20-30% after 30 min and 3 hr respectively. This time-dependent effect of 4-CP after i.p. treatment was enhanced when mice were pretreated with hepatic microsomal enzyme inducers (phenobarbital, 40 mg/kg body weight, b.i.d., 7 days; and beta-naphthoflavone, 80 mg/kg body weight once daily, 4 days). Further, the microsomal cytochrome P-450 inhibitor, SKF 525-A, 75 mg/kg body weight injected i.p. to mice 30 min prior to 4-CP administration, blocked the reduction of liver thiol content produced by 4-CP. The results suggest that a chemically reactive intermediate of 4-CP may be formed in liver which is responsible for the observed decrease in liver thiol content. Other investigations were done to characterize the in vitro irreversible binding of [14C]4-CP. [14C]4-CP was bound irreversibly to mouse liver microsomal proteins in a concentration-dependent manner. Binding was NADPH dependent and gave a maximal binding of 12.0 nmol/mg protein/20 min and an apparent binding constant of 0.222 mM. [14C]-Binding of 4-CP was increased by 155 and 127% in liver microsomes of phenobarbital- and beta-naphthoflavone. SKF 525-A, and CO:O2 (4:1, v/v)] and selected nucleophilic compounds (glutathione, L-cysteine or L-lysine) significantly reduced [14C]4-CP binding to mouse liver microsomes. An epoxide hydrolase inhibitor, cyclohexene oxide, did not alter the extent of irreversible binding, whereas scavengers of superoxide anions or agents that are reported to reduce accumulation of active semiquinone and quinone species (L-ascorbic acid, superoxide dismutase or epinephrine) decreased the binding of [14C]4-CP to mouse liver microsomal proteins by 56, 31 and 92% respectively. The data suggest that semiquinone and quinone species of 4-CP may be the chemically reactive intermediates leading to the in vivo reduction of liver thiol levels. Since 4-CP is a minor contaminant and possible metabolite of clofibrate and chemically related hypolipidemic agents, 4-CP and its metabolites may be partly responsible for some of the hepatotoxic effects seen after long-term administration of this therapeutic class of drugs.

Administration, Oral↗

PubMed1989

Inhibition of human platelet aggregation and secretion by ant venom and a compound isolated from venom.

Venom from the tropical ant, Pseudomyrmex triplarinus, has activity against rheumatoid arthritis. Since platelets are involved in inflammatory responses, they were employed to study the effects of venom on prostaglandin-dependent human platelet aggregation and secretion. The assay is very sensitive and uses microliter volumes, which makes it useful as a screen during isolation and characterization of venom components. Whole venom inhibited arachidonic acid- and U46619-induced platelet aggregation with IC50s of 45 and 39 micrograms/ml, respectively. This suggested that venom prevented the action of prostaglandins. Pure venom was fractionated by gel filtration and at least three materials with antiplatelet activity were detected. The smallest component (factor F) was most active and was purified by additional molecular filtration and characterized by UV absorbance, thin-layer chromatography, nuclear magnetic resonance spectra, and activity to platelets. Factor F was identified as adenosine, which is known to stimulate platelet adenylate cyclase and has not been previously reported to be a component of insect venom.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1989

Serum lipoprotein and apoprotein concentrations in 4-(4-chlorophenyl)-2-hydroxytetronic acid and clofibrate-treated cholesterol and cholic acid-fed rats.

Influence of clofibrate and an aci-reductone, 4-(4-chlorophenyl)-2-hydroxytetronic acid (CHTA) on lipoproteins and apoproteins was studied in cholesterol- plus cholic acid-fed rats. CHTA (0.4 mmol/kg body wt, twice daily) significantly lowered serum total cholesterol and triglyceride concentrations at both 10 and 16 days, whereas clofibrate at the same dose did not alter serum cholesterol levels, but elevated serum triglyceride concentrations at 16 days. The abnormal cholesterol-rich very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL) and low density lipoproteins (LDL) produced by cholesterol plus cholic acid were significantly reduced in their cholesterol content by treatment with CHTA, a compound having an oxidation reduction potential. Conversely, clofibrate administration increased VLDL-cholesterol with concomitant decreases in IDL- and LDL-cholesterol concentrations. Administration of CHTA to cholesterol- plus cholic acid-fed rats significantly increased concentrations of VLDL and IDL, but had no effect on HDL protein. Both CHTA and clofibrate administration to cholesterol- plus cholic acid-fed rats significantly lowered IDL protein concentrations. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) studies of apoproteins revealed that clofibrate treatment significantly reduced apoC-III and C-II in VLDL, C-II in IDL, and apoA-IV and A-I in HDL. Rats treated with CHTA significantly raised apoC-II and C-III in HDL.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Paradoxical effects of isothiocyanate analog of tolazoline on rat aorta and human platelets.

The isothiocyanate analog (IBI) of tolazoline produced contraction of the rat aortic strip, with an ED50 value of 1.63 x 10(-5) M. The maximum contraction of the analog was nearly equal to that of tolazoline or phenylephrine. At 27 degrees C the tissue reactivity of phenylephrine and IBI was similar. When compared at equiactive concentrations, the total duration of contraction of IBI was three times longer than that of tolazoline. Thus, the longer duration of action of IBI may be attributed to the S=C=N group substitution of the molecule. IBI at 10(-6) M shifted the dose-response curve of phenylephrine to the right with reduction in maxima. Phentolamine and other alpha 1 or alpha 2 adrenoceptor blockers failed to block the responses of IBI in aorta, whereas verapamil or nifedipine blocked the response significantly. It appears that IBI is acting through calcium-channel-sensitive or calcium-receptor-related mechanism(s). In aspirin-treated platelets from human plasma, a distinct phase of aggregation induced by epinephrine can be blocked by IBI with KB of 2 x 10(-5) M. This indicates a small but selective alpha 2 related action of IBI. The aggregation induced by ADP or second component of aggregation induced by epinephrine were also blocked by IBI at concentrations comparable to that of the alpha 2-adrenoceptor-mediated response. This indicates a lack of specificity of IBI in differentiating various phases of aggregation. Therefore, as compared to tolazoline, IBI presents an interesting paradox in its interaction with various receptors or mechanisms in the vascular tissue and platelets.

Adrenergic alpha-Antagonists↗

PubMed1989

Pharmacologic effects of 4-chlorophenol in rats: comparison to clofibrate.

4-Chlorophenol (4-CP) is an identified trace contaminant in commercial clofibrate preparations and the pharmacologic effects of 4-CP have not yet been widely established. We have examined the dose-dependent effects of oral 4-CP and clofibrate administration on selected hepatic parameters and on serum glucose, cholesterol, and triglyceride concentrations in male rats. 4-CP treatment (0.00125-0.08 mmol/kg, twice a day) of rats for 2 weeks increased hepatic microsomal protein (20-30%) and cytochrome P-450 (20-190%) contents without changing liver/body weight ratios. Both 4-CP (0.0025 mmol/kg body wt, twice a day) and CPIB (0.4 mmol/kg body wt, twice a day) treatment to rats for 2 weeks caused significant elevations in microsomal cytochrome P-450 content and in the maximal activities of ethylmorphine, aminopyrine, and benzphetamine N-demethylase, but not in the activity of zoxazolamine 6-hydroxylase. With the same dose of 4-CP, time-dependent increases in hepatic microsomal protein, cytochrome P-450, and the activity of benzphetamine N-demethylase were observed for a 4-week period, and the induction of hepatic microsomal benzphetamine N-demethylase activity by 4-CP was associated with an increased enzyme synthesis. 4-CP treatment produced a marked morphologic change in liver cell ultrastructure, including a proliferation of mitochondria and endoplasmic reticulum at lower 4-CP doses. A clustering of intracellular organelles (mitochondria and endoplasmic reticulum) and a foamy cytoplasm were seen at doses greater than 0.01 mmol/kg, twice a day for 2 weeks, and at 0.0025 mmol/kg, twice a day for greater than 4 weeks. The effects of 4-CP and clofibrate on fasting blood glucose and fasting serum lipid levels were also monitored throughout an 8-week period. Both 4-CP (0.005 mmol/kg body wt, twice a day) and clofibrate (0.2 mmol/kg body wt, twice a day) produced significant elevations in fasting serum glucose levels, but this dosage of 4-CP did not alter serum lipid and lipoprotein parameters, whereas clofibrate significantly reduced serum total cholesterol and high density lipoprotein cholesterol levels. These results lead us to conclude that 4-CP does not contribute to the antilipidemic effects of clofibrate.

Animals↗

PubMed1988

Characterization of the inhibition of U46619-mediated human platelet activation by the trimetoquinol isomers. Evidence for endoperoxide/thromboxane A2 receptor blockade.

Sites of inhibition for the trimetoquinol (TMQ) isomers on 15S-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid (U46619)-, 12-O-tetradecanoylphorbol 13-acetate (TPA)- and A23187-induced human platelet activation were investigated. Experiments using washed human platelets were designed to characterize relationships among functional (aggregation, secretion) and biochemical (protein phosphorylation, metabolism of inositol phospholipids and radioligand displacement analysis) processes of platelet activation by U46619 and the specificity of inhibition by the TMQ isomers. Thromboxane A2 receptor stimulation by U46619 in human platelets resulted in a time- and concentration-dependent breakdown of inositol phospholipids [phosphatidylinositol 4,5-bisphosphate (PIP2), phosphatidylinositol 4-monophosphate (PIP), and phosphatidylinositol (PI)], phosphatidic acid (PA) accumulation, phosphorylation of 20 and 45 kD proteins, aggregation and serotonin secretion. The TMQ isomers stereoselectively inhibited all U46619-mediated platelet activation processes. R(+)-TMQ was 40- and 22-fold more potent than S(-)-TMQ as an inhibitor of U46619-induced platelet aggregation and serotonin secretion respectively. In addition, R(+)-TMQ blocked U46619-induced 20 kD protein phosphorylation, 45 kD protein phosphorylation, PIP2, PIP and PI breakdown, and PA accumulation with a potency which was 8-, 13-, 45-, 37-, 33- and 33-fold greater than the S(-)-isomer respectively. In contrast to S(-)-TMQ, R(+)-TMQ produced a concentration-dependent inhibition of specific [3H]U46619 binding to endoperoxide/thromboxane A2 receptor sites in washed platelets. In other experiments, S(-)-TMQ was more potent than R(+)-TMQ as an inhibitor of TPA- and A23187-induced platelet aggregation and serotonin secretion, and of TPA-induced phosphorylation of 45 and 20 kD proteins. The inhibitory potencies of S(-)-TMQ against TPA- or A23187-induced responses were similar to those needed for antagonism of U46619-mediated platelet activation. In contrast, much higher concentrations of R(+)-TMQ were required for blockade of TPA or A23187 versus U46619-mediated responses in human platelets. Taken collectively, the data show that the TMQ isomers interfered with the endoperoxide/thromboxane A2 receptor-mediated phospholipase C-signal cascade of inositol phospholipid hydrolysis, calcium mobilization, and protein phosphorylation leading to platelet aggregation and secretion. R(+)-TMQ acted as a pharmacologically selective and highly stereospecific [R(+)-TMQ much greater than S(-)-TMQ] antagonist of endoperoxide/thromboxane A2 receptor sites in platelets.(ABSTRACT TRUNCATED AT 400 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1988

Use of [3H]trimetoquinol as a radioligand in human platelets: interaction with putative endoperoxide/thromboxane A2 receptor sites.

We have recently shown that trimetoquinol [1-(3,4,5-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4- tetrahydroisoquinoline; TMQ] is a potent and stereoselective [R(+)-isomer greater than S(-)-isomer] antagonist of aggregation induced by thromboxane A2 and stable epoxymethano PGH2 analogues (U46619; U44069) in human platelets. The present study was undertaken to characterize the pharmacological specificity of binding sites for racemic- [3H]TMQ in washed human platelets. Specific binding of [3H]TMQ, determined by addition of 100 microM R(+)-TMQ, accounted for 12-26% of the total binding at 1.0 microM. Saturation data suggested two binding sites with apparent dissociation constants of 2.8 nM and 1.4 microM for the high and low affinity binding sites, respectively. Maximal binding densities (pmol/mg protein) were 2.3 and 42.9 for the respective high and low affinity sites. The optical isomers of TMQ, cis and trans-isomers of 13-azaprostanoic acid (13-APA), and U46619 inhibited [3H]TMQ specific binding to the low affinity site. R(+)-TMQ was 32-fold more potent than S(-)-TMQ at inhibiting [3H]TMQ binding, and the stereoselective potency difference and concentrations needed to inhibit binding were similar to those required for inhibition of U46619-induced platelet aggregation and serotonin secretion. Similarly, trans-13-APA was 90-fold more potent than cis-13-APA as a competitor of [3H]TMQ binding. U46619 also inhibited TMQ binding at concentrations (IC50 = 0.4 microM) similar to those required for aggregation (EC50 = 0.16 microM) and secretion (EC50 = 0.23 microM). At 1 mM, arachidonic acid inhibited [3H] TMQ binding by only 25%. Our studies indicate that [3H]TMQ interacts with specific binding sites with characteristics indicative of putative endoperoxide/thromboxane A2 receptors in human platelets.

Blood Platelets↗

PubMed1988

Synthetic aci-reductones: 3,4-dihydroxy-2H-1-benzopyran-2-ones and their cis- and trans-4a,5,6,7,8,8a-hexahydro diastereomers. Antiaggregatory, antilipidemic, and redox properties compared to those of the 4-substituted 2-hydroxytetronic acids.

Synthetic procedures for the elaboration of aci-reductones belonging to the 6- or 7-mono- or bis-substituted-3,4-dihydroxy-2H-1-benzopyran-2-ones (6-10) and their cis- and trans-4a,5,6,7,8,8a-hexahydro diastereomers (11, 12) are described. hexahydrobenzopyranone aci-reductones were conveniently prepared by using Meldrum's synthon (2,2-dimethyl-1,3-dioxane-4,6-dione, 49). Certain of these substances were evaluated for antilipidemic activity in the cholesterol-fed rat model, and all analogues were studied for their ability to inhibit aggregation of human platelets. Results are compared to aci-reductones belonging to the 4-aryl- and 4-spiroalkyl-2-hydroxytetronic acid systems (4,5a,b). Redox potentials for all aci-reductones were determined with cyclic voltammetry. It would appear that the 4-aryl-2-hydroxytetronic acids represent leads for further study as antiatherosclerotic drugs owing to their favorable antilipidemic and antiaggregatory properties whereas the benzopyranones are of most interest as probes for platelet antiaggregatory mechanism studies.

Adenosine Diphosphate↗