The vasodilator, hypotensive, and antihypertensive effects of hydralazine and its known and putative metabolites were compared in vitro, in the isolated, perfused mesenteric arterial bed of the rat, and in vivo, in the urethane-anesthetized normotensive rat (NR) and in the conscious renal hypertensive rat (RHR). In the mesenteric bed, hydralazine produced inhibition of noradrenaline (NA)-induced vasoconstriction (IC50-NA = 0.4 micrograms/ml). All the metabolites were five to greater than 250 times less potent than the parent compound. Hydralazine inhibited potassium-induced vasoconstriction at concentrations (IC50-K+ = 700 micrograms/ml) above those required to inhibit NA. Two metabolites, 9-hydroxy-3-methyl-s-triazolo-(3.4-a)phthalazine and the acetone hydrazone (HP-AH), were more potent (five- and 10-fold, respectively) than hydralazine in inhibiting potassium-induced vasoconstriction. The other metabolites produced less than 50% inhibition at the highest concentration tested. In in vivo studies, blood pressure in NR or RHR was reduced by hydralazine, following doses of 0.1 or 0.25 mg/kg i.v. and above. HP-AH was sixfold less active than hydralazine in NR and 10-fold less active in RHR, while the pyruvic acid hydrazone was 33- and 14-fold 1 s active, respectively. The other metabolites tested were practically inactive in concentrations up to the limits of solubility. Although several hydralazine metabolites show some vasodilator and blood pressure-lowering activity, it seems unlikely that the formation of metabolites is a major factor in the antihypertensive effect of hydralazine or is responsible for its long duration of action.

Animals↗

PubMedDate not supplied

The content and distribution of glycosaminoglycans in the ejaculates of normal and vasectomized men.

The glycosaminoglycans (GAGs) of sperm and seminal plasma of normal men and seminal plasma of vasectomized individuals have been identified and quantified by two dimensional (2D) electrophoresis. The sperm contains predominantly CSC and HS as well as significant amounts of DS which achieves a high level in the sperm of the youngest man, while HA and LSC are either undetectable or present in small quantities. In normal seminal plasma, characteristically, DS is essentially lacking whereas CSC is the major GAG and HA and LSC account for relatively high percentages. Interestingly, in the ejaculates of vasectomized men the DS content is relatively prominent and the HA concentration varies widely. The oversulfated chondroitin sulfates CSD/CSE were detected in 7 of the 37 specimens. Their presence in a normal human body fluid is reported for the first time and the previous observation of the youthful DS/CSC switch is expanded to this study.

Adult↗

PubMedDate not supplied

P-glycoprotein and MRP1 expression in axillary lymph node metastases of breast cancer patients.

BACKGROUND: Only little information on the expression of P-glycoprotein (P-gp) and MRP1 in metastases of breast carcinomas is currently available. The aim of the present study was to investigate the expression of these two proteins in axillary lymph node metastases of breast cancer patients. MATERIALS AND METHODS: We determined the expression of P-gp and MRP1 in axillary lymph node metastases of 63 breast cancer patients and, in 32 patients, compared this expression to the expression of corresponding primary tumors. P-gp was detected by means of C219 and Ab-2 monoclonal antibodies, and MRP1 by means of the MRPr1 monoclonal antibody. RESULTS: In lymph node metastases, P-gp expression was positive, usually at low levels, in 28 (44%) specimens whilst MRP1 expression was positive in all specimens with low, intermediate and high levels in 3 (5%), 46 (73%) and 14 (22%) specimens, respectively. The percentage of P-gp expression was slightly lower in lymph nodes than in primary tumors while MRP1 expression showed a higher staining intensity in lymph nodes than in their corresponding primary tumors. CONCLUSION: These data indicate that both P-gp and MRP1 are frequently expressed in lymph node metastases of breast cancer patients and that MRP1 expression is more pronounced in lymph node metastases than in corresponding primary tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Pharmacokinetics and tissue distribution of the renin inhibitor N-(2-(R)-benzyl-3-tert-butyl-sulfonyl-propionyl)-His-ChacVal-n-butylami ne in marmosets.

The fate of CGP 38 560 [N-(2-(R)-benzyl-3-tert-butyl-sulfonyl-propionyl)-His-ChacVal-n-bu tylamine], a potent renin inhibitor, has been studied in marmosets. [3H]CGP 38 560 is rapidly cleared from the plasma. The elimination process is biphasic, with a t1/2 of 4.8 +/- 1.0 min (mean +/- SD) in the first phase and 26.6 +/- 8.4 min (mean +/- SD) in the second. The kinetics of elimination from plasma are similar when measured both in a radio-inhibitor binding assay and radiometrically using 3H-labeled substance. The drug is mainly eliminated in the bile, almost 73.8% of the i.v. administered dose being excreted within the first 60 min. It is detectable in bile in both unchanged (8.6%) and metabolized form. HPLC analysis of bile extracts showed at least five tritiated peaks representing constituents capable of binding human renin (A, B, C, D, and E). These fractions were isolated, purified, and analyzed by mass spectrometry. Peak E corresponded to unchanged CGP 38 560. Metabolites A, B, C, and D are more polar than the parent compound, as indicated by their retention times upon HPLC analysis. The metabolic pathways inferable from the respective molecular weights are hydroxylation, oxygenation, and, in one case, cleavage of the n-butylamino group located at the COOH-terminal. From comparisons of the pharmacokinetic parameters after iv (0.1 mg/kg) and oral (10 mg/kg) administration, it can be estimated that the bioavailability of CGP 38 560 in the marmoset is 0.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

[The polymorphic forms of alpha 1-acid glycoprotein of mentally retarded patients].

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Electrophoresis↗