Biomedical subjects

G S Marks

Publications and source records attributed to G S Marks.

At least 109 records · Page 6Linked to original sources

PubMed1988

A facile, reliable method for staining blood vessel endothelium.

A modification of the silver-based stain for outlining endothelial cell borders of rabbit aorta is described. The present method uses ammonium sulfide in place of exposure to light to develop the stain. Rabbit aortic rings were sequentially immersed in 280 mM dextrose, 15 mM silver nitrate, 280 mM dextrose, dilute ammonium sulfide, and 280 mM dextrose solutions. They were then cut open and mounted on microscope slides with glycerin jelly. The procedure is rapid, easily mastered, and suited for use in most pharmacology laboratories. The resulting preparations can be viewed under reflected or transmitted light.

Animals↗

PubMed1988

Disruption of hepatic heme biosynthesis after interaction of xenobiotics with cytochrome P-450.

Heme biosynthesis in hepatocytes is controlled by a free heme pool, which regulates delta-aminolevulinic acid synthase. Porphyrinogenic chemicals deplete the regulatory free heme pool by interacting with cytochrome P-450 thereby inhibiting heme biosynthesis and/or causing heme breakdown. Recent developments allow us to predict which groups of chemicals are likely to be porphyrinogenic. One group is exemplified by 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine. Heterocyclic compounds of this type cause mechanism-based inactivation of cytochrome P-450, leading to the formation of N-alkylporphyrins, with ferrochelatase-inhibitory activity resulting in lowering the free heme pool. Allylisopropylacetamide exemplifies a second group. Such compounds containing a terminal olefinic or acetylenic group, cause mechanism-based inactivation of cytochrome P-450. In the process, the heme moiety of cytochrome P-450 is destroyed and the free heme pool is lowered. A third group is exemplified by planar polyhalogenated or polycyclic aromatic hydrocarbons. These compounds induce specific cytochrome P-450 isozymes but are poor substrates. Active oxygen is formed, which interacts with a hepatic substrate to form a uroporphyrinogen decarboxylase inhibitor. Inhibition of this enzyme leads to depletion of the free heme pool.

Alkylation↗

PubMed1988

Patterns of isosorbide dinitrate and glyceryl trinitrate metabolites formed by selected segments of the rabbit gastrointestinal tract.

Homogenates of selected segments of the rabbit gastrointestinal tract (GIT) were studied for their ability to biotransform isosorbide dinitrate (ISDN) and glyceryl trinitrate (GTN) to their mono- and di-nitrate metabolites, respectively. In addition, preferential formation of certain metabolites was investigated by examination of the patterns of metabolites formed by the various homogenates. After a 30-min incubation of ISDN with GIT homogenates (pH 7.4, 37 degrees C), the percent disappearance of ISDN and the ratio of isosorbide-2-mononitrate (2-ISMN) to isosorbide-5-mononitrate (5-ISMN) were as follows: stomach, 32%, 0.8; duodenum, 65%, 0.1; jejunum, 59%, 0.2; ileum, 38% , 1.2; cecum, 33%, 2.7; and colon, 32%, 3.4. After a 5-min incubation of GTN with GIT homogenates, the percent disappearance of GTN and the ratio of glyceryl-1,3-dinitrate (1,3-GDN) to glyceryl-1,2-dinitrate (1,2-GDN) were as follows: duodenum, 54%, 0.65; ileum, 73%, 0.68; and colon, 61%, 0.17. Incubation of 2 x 10(-7) M ISDN with mucosal and muscularis homogenates of duodenum, jejunum, and ileum resulted in significant losses of ISDN with an equimolar formation of the mononitrate metabolites. Most of the metabolic activity for ISDN resided in the mucosal layer of each section. The ratio of 2-ISMN to 5-ISMN varied in each section (stomach to colon) and cross section (mucosal versus muscularis) of the GIT. We conclude that the metabolism of ISDN and GTN by the GIT may contribute to the high clearance of these organic nitrates, and the low oral bioavailability of ISDN. Also, multiple mechanisms appear to be involved in the biotransformation of ISDN and GTN in the rabbit GIT.

Animals↗

PubMed1988

Nitric oxide-induced vasodilation of organic nitrate-tolerant rabbit aorta.

It is postulated that the organic nitrate vasodilator agents, including glyceryl trinitrate (GTN) and isosorbide dinitrate (ISDN), are prodrugs, such that biotransformation to the active inorganic metabolite, nitric oxide (NO), occurs prior to the onset of vasodilation. Furthermore, it is proposed that organic nitrate tolerance in vascular tissue involves decreased formation of NO. To test this latter hypothesis, we examined vasodilation induced by NO, GTN, and ISDN in non-tolerant, GTN-tolerant, and ISDN-tolerant rabbit aortic rings (RARs). Isolated RARs were contracted submaximally with phenylephrine; the time of onset of relaxation and percent relaxation of tissue were determined in response to NO (0.3 microM), GTN (0.03 microM), and ISDN (0.12 microM) before and after a 1-h treatment with 500 microM GTN, 500 microM ISDN, or buffer only. The data demonstrated that the response to NO was not changed in GTN-tolerant and ISDN-tolerant tissues, in which there was virtually no GTN-induced or ISDN-induced relaxation. These results are consistent with the postulate that organic nitrate vasodilator drugs must undergo biotransformation to NO before vasodilation can occur and that the mechanism of organic nitrate tolerance involves decreased formation of NO.

Animals↗

PubMed1988

Mechanism of glyceryl trinitrate-induced vasodilation. I. Relationship between drug biotransformation, tissue cyclic GMP elevation and relaxation of rabbit aorta.

This study was conducted to test the hypothesis that biotransformation of glyceryl trinitrate (GTN) is involved in GTN-induced relaxation of vascular smooth muscle. The temporal relationship between GTN biotransformation, elevation of cyclic GMP content and vasodilation in rabbit aortic strips (RAS) was determined. Isolated RAS were contracted submaximally with phenylephrine, and then were incubated with 0.62 microM [3H]GTN in a 30-sec time course study. GTN-induced relaxation (inhibition of phenylephrine-induced tone) of RAS was monitored; tissue cyclic GMP content was measured by radioimmunoassay; and GTN, glyceryl-1,2-dinitrate (1,2-GDN) and glyceryl-1,3-dinitrate (1,3-GDN) concentrations in RAS were measured by thin-layer chromatography and liquid scintillation spectrometry. There was time-dependent biotransformation of GTN to GDN by the RAS and a time-dependent increase in cyclic GMP content in the RAS. Statistically significant (P less than .05) biotransformation of GTN and elevation of cyclic GMP content in the tissue occurred at 10 sec, whereas the onset of GTN-induced relaxation of RAS occurred at 12 sec. During the tissue biotransformation of GTN, there was preferential formation of 1,2-GDN compared with 1,3-GDN, with 1,2-GDN/1,3-GDN ratio of 3.0/1 at 10 sec, 5.3/1 at 20 sec and 5.8/1 at 30 sec. The results of this study are consistent with the hypothesis that GTN is a prodrug, such that biotransformation to an active metabolite is involved in GTN-induced relaxation of vascular smooth muscle. The data also indicate that the mechanisms of GTN biotransformation and GTN-induced activation of guanylate cyclase may be related intimately.

Animals↗

PubMed1988

Mechanism of glyceryl trinitrate-induced vasodilation. II. Lack of evidence for specific binding of GTN to bovine pulmonary vein.

Radioligand binding studies were conducted to test the hypothesis that specific receptor sites for glyceryl trinitrate (GTN) exist in vascular smooth muscle. The radioligand, [3H]GTN (9.98 Ci/mmol), was incubated with whole homogenate or subcellular fractions (10,000 X g pellet, 100,000 X g pellet and 100,000 X g supernatant) of bovine pulmonary vein (BPV) at 4 degrees C, 37 degrees C or room temperature. After incubation for 5, 15, 30 or 60 min, unbound and bound ligand were estimated by physical separation and liquid scintillation spectrometry. Separation of bound from free ligand was accomplished by vacuum filtration, centrifugation, equilibrium dialysis, gel filtration or precipitation. No evidence of specific binding of [3H]GTN to BPV whole homogenate or any subcellular fraction was observed. The viability of the BPV preparations was verified by demonstrating specific binding of [3H]nitrendipine to the 100,000 X g pellet. To ensure that the ligand was present throughout the incubation procedure in sufficient concentration to detect specific binding, the ability of BPV whole homogenate and subcellular fractions to biotransform GTN to glyceryl dinitrate was measured. After 60-min incubation at 37 degrees C, greater than 95% of the GTN added was unaltered; at 90 min, more than 83% of the radioactivity was associated with GTN. Our data are interpreted as not supporting the concept of a GTN receptor in BPV.

Animals↗

PubMed1988

Differential inhibition of hepatic ferrochelatase by regioisomers of N-butyl-, N-pentyl-, N-hexyl-, and N-isobutylprotoporphyrin IX.

A series of analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC), viz. 4-butyl DDC, 4-pentyl DDC, and 4-hexyl DDC was administered to phenobarbital-pretreated rats. The N-alkylprotoporphyrins (N-alkylPP) isolated from the rat livers were separated into regioisomers by means of high performance liquid chromatography; the NB or NA (NB/A) regioisomers constituted 19-26% of the total regioisomers. Considerable ferrochelatase-inhibitory activity was found in the NB/A regioisomers; the NC or ND (NC/D) regioisomers had little ferrochelatase-inhibitory activity. These findings supported the idea that the ferrochelatase active site could accommodate alkyl groups larger than methyl only if they were present on the nitrogens of the A or B pyrrole rings of the N-alkylPP. The inactivity of 4-isobutyl DDC as a ferrochelatase-lowering agent was investigated. After injection of 4-isobutyl-DDC into phenobarbital-pretreated rats, N-isobutylPP was isolated from the rat livers and separated into its regioisomers; the NB/A regioisomer constituted 3.8% of the total regioisomers. The NB/A regioisomer was found to have appreciable ferrochelatase-inhibitory activity whereas the NC/D regioisomer was inactive. The inactivity of 4-isobutyl-DDC as a ferrochelatase-lowering agent was attributed to the small amount of NB/A regioisomer present in the N-isobutylPP regioisomer mixture.

Animals↗

PubMed1987

Patterns of porphyrin accumulation in response to xenobiotics. Parallels between results in chick embryo and rodents.

Our objective was to determine whether patterns of porphyrin accumulation produced by chemicals in chick embryo hepatocyte culture would indicate which enzyme of heme biosynthesis was inhibited. The ferrochelatase-inhibitory potency and porphyrin patterns produced by DDC, TTMS, and their analogues were studied. The protoporphyrin:coproporphyrin ratio observed was found to correlate with ferrochelatase-inhibitory activity. The results obtained in chick embryo with TTMS and DDC parallel those found in rodents. Griseofulvin has been shown to lower ferrochelatase activity and to cause the accumulation of protoporphyrin in rodent liver. In chick embryo liver cell culture, however, coproporphyrin, uroporphyrin, and heptacarboxylic acid porphyrin accumulate and ferrochelatase activity is not lowered. Uroporphyrin, heptacarboxylic acid porphyrin, and coproporphyrin are the major porphyrins to accumulate in response to PAHs (for example, 3,3',4,4'-TCBP in chick embryo liver cell culture). This may be explained by inhibition of UROD, which has been observed in chick embryo and rodent liver. Some chemicals, such as phenobarbital and nifedipine, cause the accumulation of these porphyrins in chick embryo liver cell culture, and this is explained by inhibition of UROD. These chemicals have not been reported to interfere with heme biosynthesis in the intact chick embryo or rodents; possibly protective mechanisms that are not available in the cell culture system are operative in the intact animal. It was concluded that porphyrin patterns may serve as a guide to which enzyme of heme biosynthesis is inhibited in chick embryo liver cell culture. The results obtained in the culture system with certain chemicals, such as DDC and TTMS analogues and PAHs, correspond with results in rodents. In other cases, such as with griseofulvin, the results do not correspond.

5-Aminolevulinate Synthetase↗

PubMed1987

The 1986 Upjohn award lecture. Interaction of chemicals with hemoproteins: implications for the mechanism of action of porphyrinogenic drugs and nitroglycerin.

The ferrochelatase inhibitory activity of a variety of analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) was studied in chick embryo liver cells. The ferrochelatase inhibitory activity of the 4-butyl, 4-pentyl, and 4-hexyl analogues was considered to be due to catalytic activation by cytochrome P-450 leading to heme alkylation and formation of the corresponding N-alkylporphyrins. The relative ferrochelatase inhibitory activity of the DDC analogues has implications for a postulated model of the binding of porphyrins in the ferrochelatase active site. 3-[2-(2,4,6-Trimethylphenyl)thioethyl]-4-methylsydnone (TTMS) was shown to be a potent porphyrinogenic agent and to inhibit ferrochelatase in chick embryo liver cells. A related sydnone, 3-benzyl-4-phenylsydnone did not inhibit ferrochelatase activity. These results supported the idea that the porphyrinogenicity of TTMS was due to catalytic activation by cytochrome P-450 leading to heme alkylation and formation of N-vinylprotoporphyrin which inhibits ferrochelatase. Polychlorinated biphenyls, phenobarbital, nifedipine, and a large number of structurally different chemicals which are porphyrinogenic in chick embryo liver cells inhibit uroporphyrinogen decarboxylase by an unknown mechanism. Thus drug-induced porphyrin biosynthesis in chick embryo liver cell culture appears to be caused by inhibition of either ferrochelatase or uroporphyrinogen decarboxylase. The biotransformation of nitroglycerin by human red blood cells is due to a combination of a sulfhydryl-dependent enzymatic process and an interaction with reduced hemoglobin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

A comparative study of glyceryl trinitrate biotransformation and glyceryl trinitrate induced relaxation in bovine pulmonary artery and vein.

Recent evidence supports the hypothesis that the mechanism by which glyceryl trinitrate induces relaxation of vascular smooth muscle involves the biotransformation of glyceryl trinitrate. This study was conducted to determine if there was a direct correlation between the capacity of vascular smooth muscle preparations to biotransform glyceryl trinitrate and their sensitivity to the relaxant effect of this organic nitrate. Isolated bovine pulmonary arteries and veins were contracted submaximally and cumulative dose-response relationships to glyceryl trinitrate were obtained; the vein was approximately 10 times more sensitive than the artery to glyceryl trinitrate induced relaxation. In a separate series of experiments, these vascular tissues were contracted submaximally and incubated with 0.5 microM [14C]glyceryl trinitrate for 2 min, during which glyceryl trinitrate induced relaxation was monitored. At 2 min, tissue samples were taken for determination of glyceryl trinitrate and glyceryl-1,2- and 1,3-dinitrate content by thin-layer chromatography and liquid scintillation spectrometry. Biotransformation of glyceryl trinitrate to glyceryl dinitrate occurred concomitantly with relaxation of these blood vessels. The concentration of glyceryl dinitrate in the vein was significantly less than that in the artery (p less than or equal to 0.05), even though significantly greater relaxation of the vein than the artery was observed (p less than or equal to 0.05). From these data, a simple linear relationship between glyceryl trinitrate biotransformation and relaxation is not apparent.

Animals↗

PubMed1987

Sex- and species-related differences in the biotransformation of isosorbide dinitrate by various tissues of the rabbit and rat.

The biotransformation of isosorbide dinitrate (ISDN) by various tissues of the rabbit and rat was examined. Incubation of 2 X 10(-7) M ISDN at 37 degrees C with tissue homogenates of liver, lung, kidney, intestine, skeletal muscle, aorta, and erythrocytes from the rabbit and rat resulted in a significant disappearance of ISDN after a 30-min incubation (also, 5-min incubation for liver). The disappearance of ISDN in each tissue homogenate was accompanied by an equimolar production of the mononitrate metabolites, isosorbide-2-mononitrate (2-ISMN) and isosorbide-5-mononitrate (5-ISMN), with the exception of liver homogenates where the loss of ISDN could not be accounted for by mononitrate formation. The relative rate of ISDN disappearance in various tissue homogenates was for the male rabbit, liver greater than lung approximately intestine greater than kidney greater than erythrocytes approximately skeletal muscle approximately aorta; for the female rabbit, liver greater than kidney approximately lung approximately intestine greater than erythrocytes approximately skeletal muscle approximately aorta; and for the male rat, liver greater than intestine greater than erythrocytes greater than skeletal muscle greater than lung approximately kidney. A sex difference in the percent disappearance of ISDN was observed in homogenates of lung and intestine from male and female rabbits. In addition, a sex difference in the ratio of metabolite (2-ISMN/5-ISMN) formed by denitration of ISDN was seen in homogenates of lung, skeletal muscle, and erythrocyte lysate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Isolation of an N-alkylprotoporphyrin IX from chick embryo livers following the administration of 3,5-diethoxycarbonyl-1,4-dihydro-4-ethyl-2,6-dimethylpyridine.

The ferrochelatase-lowering activity of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) analogues in chick embryo hepatocyte culture has been assumed to be due to the formation of an N-alkylprotoporphyrin IX. This assumption required confirmation. For this reason the 4-ethyl analogue of DDC was administered to phenobarbital-pretreated 19-day-old chick embryos. This resulted in hepatic accumulation of a green pigment with ferrochelatase-inhibitory activity. The green pigment was identified as an N-alkylprotoporphyrin IX by comparison of the electronic absorption spectra of its dimethyl ester and Zn complex with the corresponding spectra obtained from synthetic N-ethylprotoporphyrin IX.

Animals↗

PubMed1986

Porphyrinogenic activity and ferrochelatase-inhibitory activity of sydnones in chick embryo liver cells.

3-[2-(2,4,6-Trimethylphenyl)thioethyl]-4-methylsydnone was shown to be a potent porphyrinogenic agent in chick embryo liver cells. The accumulation of protoporphyrin IX was consistent with the finding that ferrochelatase activity was inhibited. 3-Benzyl-4-phenylsydnone did not inhibit ferrochelatase activity and protoporphyrin IX was found to constitute only a minor fraction of the prophyrins. These results support the idea that the porphyrinogenicity of 3-[2-(2,4,6-trimethylphenyl)thioethyl]-4-methylsydnone is due to its catalytic activation by cytochrome P-450 leading to heme alkylation and formation of N-vinylprotoprophyrin IX which inhibits ferrochelatase.

Animals↗

PubMed1986

Properties of 17- to 19-day-old chick embryo liver microsomes. Induction of cytochrome P-450, effect of storage at low temperature, and resistance to lipid peroxidation.

Maximal hepatic cytochrome P-450 levels were induced in the 17-day-old chick embryo (four to five times control) with a dose of sodium phenobarbital of 6 mg/egg/day for 2 days. Similar levels of hepatic cytochrome P-450 were induced with a dose of propylisopropylacetamide of 4 mg/egg/day for 1 day. Chick embryo hepatic microsomes from phenobarbital-pretreated or from untreated chick embryos could be stored for periods of 14 days at -70 degrees C without a decrease in cytochrome P-450 levels. Moreover, no significant differences was discerned between the degree of suicidal inactivation of chick embryo hepatic cytochrome P-450 by 3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine in fresh and stored microsomes. Unlike rat hepatic microsomes, chick embryo hepatic microsomes do not undergo lipid peroxidative loss of cytochrome P-450 and heme when incubated in the presence of NADPH.

Animals↗

PubMed1986

The effects of dihydropyridine calcium antagonists on heme biosynthesis in chick embryo liver cell culture.

A variety of 1,4-dihydropyridine calcium antagonists were tested for porphyrinogenic activity in chick embryo liver cell culture. 3,5-Dimethoxycarbonyl-1,4-dihydro-2, 6-dimethyl-4-(ortho-nitrophenyl)pyridine (nifedipine) was shown to be a potent porphyrinogenic agent. This activity was shared by a number of related analogues, viz., the 4-phenyl, 4-(meta-nitrophenyl), 4-(para-nitrophenyl), 4-(ortho-methoxyphenyl), 4-(meta-trifluoromethylphenyl), and 4-(para-trifluoromethylphenyl) analogues and nitrendipine; nicardipine exhibited very weak activity. The porphyrinogenic potency of the 1,4-dihydropyridines did not parallel their calcium antagonist activity. Nifedipine did not exhibit ferrochelatase-lowering activity in chick embryo liver cell culture and uroporphyrin and heptacarboxylic acid porphyrin were the major porphyrins to accumulate. Nifedipine did not cause suicidal destruction of cytochrome P-450 in chick embryo hepatic microsomes. Because nifedipine possesses comparable porphyrinogenic activity to sodium secobarbital in chick embryo liver cell culture, caution is required if nifedipine or related drugs are administered to patients with hereditary hepatic porphyria.

Animals↗

PubMed1986

Comparison of the effects of 3-ethoxycarbonyl-1,4-dihydro-2,4-dimethylpyridine and 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine on ferrochelatase activity and heme biosynthesis in chick embryo liver cells in culture.

3-Ethoxycarbonyl-1,4-dihydro-2,4-dimethylpyridine (EDP) was shown to lack the ferrochelatase-lowering activity of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) in chick embryo liver cells in culture. This was attributed to the inability of EDP to cause destruction of the heme moiety of cytochrome P-450 with concomitant formation of N-methylprotoporphyrin IX. EDP was less potent as a porphyrinogenic agent than DDC and caused the accumulation of uroporphyrin, heptacarboxylic porphyrin, and coproporphyrin in contrast with DDC which caused primarily protoporphyrin to accumulate. The inactivity of EDP as a ferrochelatase-lowering agent and its low porphyrinogenic potency was explained, at least in part, by its rapid transformation in aqueous solution to other nondihydropyridine products. The two ethoxycarbonyl substituents of DDC are therefore essential for N-methylprotoporphyrin formation, ferrochelatase-lowering activity, and optimal porphyrin-inducing activity.

Animals↗

PubMed1986

Endothelium-dependent relaxation of rabbit aorta by acetylcholine requires ethylenediaminetetraacetic acid.

Experiments were conducted to determine if ethylenediaminetetraacetic acid (EDTA) was essential for the acetylcholine (ACh)-induced relaxation of blood vessels. Isolated rabbit aortic rings were prepared for recording isometric tension. They were maintained in Krebs bicarbonate solution with various concentrations of EDTA. With EDTA concentrations of 0 or 0.003 mM, no ACh-induced relaxation was observed; only the contractile effect of ACh was seen. With 0.03 and 0.30 mM EDTA, ACh induced relaxation with EC50 values of 0.11 and 0.098 microM, respectively. Under the experimental conditions used, EDTA was essential for demonstration of ACh-induced relaxation.

Acetylcholine↗

PubMed1986

Biotransformation of glyceryl trinitrate occurs concurrently with relaxation of rabbit aorta.

This study was conducted to test the hypothesis that biotransformation of glyceryl trinitrate (GTN) is involved in GTN-induced relaxation of vascular smooth muscle. Isolated rabbit aortic strips (RAS) were contracted submaximally with phenylephrine (PE) and then were incubated with 0.5 microM [14C]GTN in a time course study. GTN-induced relaxation (inhibition of PE-induced tone) of RAS was monitored and tissue GTN and glyceryl-1,2- and 1,3-dinitrate (GDN) concentrations were measured by thin-layer chromatography and liquid scintillation spectrometry at 0.5, 1, 2 and 20 min after incubation. Biotransformation of GTN to GDN occurred during GTN-induced relaxation of RAS. The tissue GDN concentration was dependent on the time duration of incubation with GTN and was related to the magnitude of GTN-induced tissue relaxation. At the 20-min interval, the GDN concentration in the incubation medium indicated appreciable efflux of GDN metabolites from the RAS. In the biotransformation of GTN by RAS, there was about 4-fold preferential formation of 1,2-GDN compared with 1,3-GDN. RAS were made tolerant to GTN in vitro by incubation with 500 microM GTN for 1 hr. After washing, GTN-tolerant and nontolerant (incubation with vehicle for 1 hr) RAS were contracted submaximally with PE, and then were incubated with 0.5 microM [14C]GTN for 2 min. GTN-induced relaxation of RAS and tissue GDN concentration were significantly less for GTN-tolerant tissue compared with nontolerant tissue. Tissue GTN concentration was similar for both GTN-tolerant and nontolerant RAS, which indicated that the tissue uptake of GTN was similar and that GTN biotransformation was diminished in tolerant tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗