Biomedical subjects

D R Knapp

Publications and source records attributed to D R Knapp.

77 records · Page 5Linked to original sources

PubMedDate not supplied

Protective effects of trans-13-APT, a thromboxane receptor antagonist, in endotoxemia.

The effect of the thromboxane A2/prostaglandin H2 (TxA2/PGH2) receptor antagonist trans-7[2-(p-hydroxyphenethylamino)-cyclopentyl]-heptanoic acid (trans-13-APT) on certain pathogenic sequelae of endotoxic shock and associated changes in arachidonic acid metabolism in the rat was investigated. trans-13-APT, an analog of 13-azaprostanoic acid, was synthesized and found to block human platelet aggregation induced by the thromboxane mimetic U46619. Pretreatment with trans-13-APT did not significantly alter the elevations in plasma immunoreactive (i) TxB2 or iPGE, 0.5 or 4 h after the intravenous administration of Salmonella enteritidis endotoxin. However, in the trans-13-APT-pretreated group, 4 h after administration of the endotoxin, plasma i6-keto-PGF1 alpha was significantly (p less than 0.05) reduced to 1.2 +/- 0.3 ng/ml (n = 17) compared with vehicle-treated rats (2.4 +/- 0.5 ng/ml; n = 18). The elevation in plasma i6-keto-PGF1 alpha seen 0.5 h (n = 17/group) after endotoxin infusion was not altered by trans-13-APT. trans-13-APT also significantly (p less than 0.05) attenuated the endotoxin-induced fall in platelet count (135 +/- 27 X 10(3)/mm3 vs. 350 +/- 65 X 10(3)/mm3 and hypoglycemia (73 +/- 9 vs. 97 +/- 7 mg/dl), but not the leukopenia. Since the reticuloendothelial system may be an important source of iTxB2 and i6-keto-PGF1 alpha during endotoxemia, in vitro studies were conducted with adherent peritoneal cells. High concentrations of trans-13-APT (50 and 100 microM) significantly reduced (p less than 0.05) basal but not endotoxin-induced synthesis of iTxB2 and i6-keto-PGF1 alpha by isolated adherent rat peritoneal cells.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗

PubMedDate not supplied

Rhodopsin phosphorylation in rats exposed to intense light.

The damaging effects of intense light on the rat retina are known to vary depending on the time of day of exposure. The purpose of this study was to determine if rhodopsin phosphorylation patterns, a measure of the activity of the pigment, varied in a similar manner. After 10 min in strong light (1400 lux), all six threonine and serine sites in the rat rhodopsin C-terminus were phosphorylated, with mono- to tetraphosphorylation being substantially more prominent than penta- to hexaphosphorylation. The level and multiplicity of rhodopsin phosphorylations were reduced both with the duration of light exposure and the duration of subsequent darkness. Although showing vast differences in susceptibility to light damage, rats exposed at 5 P.M. or 1 A.M. showed similar rhodopsin phosphorylation levels and patterns. These data indicate that a process controlled by circadian rhythm other than rhodopsin phosphorylation is involved either in damaging or mediating the damage evoked by intense light exposure.

Animals↗

PubMedDate not supplied

Qualitative metabolic fate of phenoxybenzamine in rat, dog, and man. Use of 15N-labeling.

Administration of an equimolar mixture of unlabeled and 15N-labeled phenoxybenzamine to rats and dogs facilitated identification of urinary metabolites by gas chromatography/chemical-ionization mass spectrometry by virtue of the the conspicuous equal-intensity ion pairs produced. By use of this technique N-benzyl-N-phenoxyisopropylamine (III), N-benzyl-N-(p-hydroxy-phenoxyisopropyl)amine (IV), and 2-benzylamino-1-propanol (VI) were identified as metabolites in rats. Phenoxyisopropylamine (V) as well as III and IV were identified in dogs. Compound IV was identified in humans under clinical treatment with phenoxybenzamine. The metabolites were screened for cardiovascular activity in rats. Compound III had weak alpha-adrenergic blocking activity and V elicited a hypertensive response.

Administration, Oral↗

PubMedDate not supplied

New ring-hydroxylated metabolites of propranolol: species differences and stereospecific 7-hydroxylation.

This study was designed to determine the structures of several unknown, potentially active, monohydroxylated metabolites of (+/-)-propranolol in rats, dogs, and man. The metabolites were isolated from urine by extraction with ethyl acetate at pH 9.6 after enzymatic hydrolysis. They were then separated as their trimethylsilyl and trifluoroacetyl derivatives and detected by flame-ionization GLC or GC/MS. Structure identification of the metabolites was based on a comparison of their GLC retention times and mass spectra with those of the seven synthetic isomeric hydroxypropranolols (HO-P's). Three metabolites not previously described, 2-HO-P, 5-HO-P, and 7-HO-P, as well as the known 4-HO-P, were identified in the rat. 2-HO-P accounted for about 1% of total monohydroxylated propranolol, 5-HO-P for 7 +/- 2% (mean +/- SE), 7-HO-P for 26 +/- 5%, and 4-HO-P for 66 +/- 5%. The separate administration of (+)- and (-)-propranolol demonstrated stereospecific 7-hydroxylation of (+)-propranolol in the rat. The formation of 5-HO-P was selective for the (-)-isomer, whereas 4-hydroxylation was not stereoselective. Also, the recovery of the dose as the monohydroxylated metabolites in urine was considerably higher after (+)-propranolol, 49 +/- 9%, than after (-)-propranolol, 32 +/- 6%. 4-HO-P was the only hydroxylation product in the dog, whereas in man small quantities of 2-HO-P, 5-HO-P, and 7-HO-P were observed in addition to 4-HO-P.

Animals↗

PubMedDate not supplied

Identification of major sulfate conjugates in the metabolism of propranolol in dog and man.

A large portion of the dose of propranolol in animals and man is unaccounted for. Using radiotracer and HPLC techniques, five previously unrecognized polar and labile metabolites were found in dog urine, together accounting for 34% of the urinary radioactivity. The two main metabolites, peak 2 (7% of the radioactivity) and peak 4 (17%) could be isolated and purified by butanol extraction and reversed phase HPLC. Direct probe MS analysis of the main peak 4 and GC/MS analysis of the same peak after trifluoroacetylation both yielded 4-hydroxypropranolol. These observations together with UV spectra before and after acid hydrolysis indicated peak 4 to be an acid- and heat-labile conjugate of 4-hydroxypropranolol with the conjugating group at the phenolic oxygen atom. Arylsulfatase from Helix pomatia and Aerobacter aerogenes completely hydrolyzed peak 4 to 4-hydroxypropranolol. Urine and plasma as well as the antioxidant sodium bisulfite, however, markedly inhibited the arylsulfatase activity. After conversion of peak 4 to its sodium salt, a fast atom bombardment-positive ion mass spectrum confirmed this metabolite to be the sulfate ester of 4-hydroxypropranolol, clearly demonstrating the quasimolecular ion (M + H)+ at m/z 378 as well as fragmentation with loss of the sulfate moiety. The second largest unknown metabolite in the dog, peak 2, was identified as the sulfate ester of 4-hydroxypropranolol glycol. The 4-hydroxypropranolol sulfate was also identified in both urine and plasma of a patient treated with propranolol, accounting for approximately 18% of the dose.

Animals↗