Acta pharmacologica et toxicologica最新文献

The possible roles of vasodilatory prostanoids and the kallikrein-kinin system in the antihypertensive action of the angiotensin-converting enzyme (kininase II) inhibitor captopril were examined in spontaneously hypertensive rats. Captopril (20, 50 or 100 mg/kg daily orally) reduced blood pressure markedly and dose-dependently. It also increased water consumption and urine excretion, measured on the 5th day of treatment. The 24-hr urinary excretion of PGE2 was not changed, whereas that of PGF2 alpha and TxB2 tended to be enhanced. A clear increase, significant with all doses of captopril, occurred in the urinary excretion of 6-keto-PGF1 alpha. Kallikrein excretion in urine was suppressed by the two larger doses of captopril. The markedly augmented urinary excretion of 6-keto-PGF1 alpha, the stable metabolite of vasodilatory prostacyclin (PGI2), suggests that increased prostacyclin production may participate in the antihypertensive mechanism of captopril. Vasodilatory kinins can also contribute, since the captopril-induced decrease in kallikrein may reflect accumulation of kinins due to their reduced metabolism.

Four commercial radioimmunoassay (RIA) kits for digoxin varied in precision (coefficient of variation, CV within-assays 5-14%) and accuracy (up to 40%). Thus it seems that such commercial RIA-kits can reach at best a CV within-assay of 5% and a similar variation between assays. Without a good control of the performance, the variation can increase 5-6 times. We found that the precision of digoxin RIA as performed at 27 Swedish laboratories using 10 different methods varied from 0.05 to 0.61 nmol/L in between-assay SD for a pool of 2.60 nmol/L. Up to 100% deviations between the highest and lowest reported concentration of a spiked plasma pool may occasionally occur. Such deviations mostly depend on the laboratory, but there are contributions from the kit and effects of the matrix as well. Matrix effects were observed in plasma samples from patients with uremia, acute myocardial infarction and treated with spironolactone to which digoxin was added to a concentration of 2.50 nmol/L. We found 10% underestimation by one method, 10% overestimation by two methods and 5% overestimation by a fourth method, respectively, with the above described samples. For a good judgement of a found plasma concentration value, calculation of a confidence interval is useful. This can be done by computer fitting of the standard curve after duplicate runs of standards and samples in random order. One source of error in RIA appears to be the use of inaccurate standards. We found that standards provided with different RIA-kits for digoxin varied up to 30%. Various physicochemical properties of cardiac glycosides, which could influence the assays were studied. Both digitoxin and digoxin are sparsely soluble in water (5.1 and 36 mumol/L, respectively). Methanol is a much better solvent, which dissolves 6.9 mmol/L of digoxin and 20-24 mmol/L of digitoxin. Chloroform is a good solvent for digitoxin (29-34 mmol/L) but not for digoxin (0.42 mmol/L). Partition of cardenolides between chloroform and water reflected their lipophilic or hydrophilic character. Thus, digitoxin had a high affinity to the organic phase (distribution constant KD = 10(3.65)), while the hydrophilic deslanoside was preferentially found in the aqueous phase (KD = 10(-3.08). Interestingly, the sugar moiety digitoxose in the digoxin molecule turned out to be a substituent that increased lipophilicity. Adsorption of cardiac glycosides occurs to plastics and glass from aqueous solutions. To overcome losses at low concentrations, the solutions must contain plasma, albumin, alcohol or similar solubility-increasing ingredients.(ABSTRACT TRUNCATED AT 400 WORDS)