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The collagen-like syndrome was induced in rats by hydralazine application during 5 months. Prolongation of hyperglycemia following oral glucose appeared in rats. This was accompanied by lowered levels in serum zinc, although the serum insulin levels were unchanged.

Hydralazine (1-hydrazinophthalazine) was administered in drinking water as a 0.0312% solution to randomly bred Swiss mice for life beginning at 5 weeks of age. The treatments gave rise to statistically significant incidences of lung tumors: 55% in females and 43% in males. A decreased copper concentration and superoxide dismutase activity in the lung of mice were observed. The role of copper and superoxide dismutase in the malignant process is briefly discussed.

LE-positive collagen-like syndrome was produced in rats with chronic hydralazine treatment. An increase in histamine level in total blood and serum was found in the hydralazine-treated animals.

In this study, we sought to determine the role of neutral proteases in cartilage matrix proteoglycan degradation, which occurs during the experimental hydralazine-induced collagen-like syndrome (c-l-s) in rats. The digestion of endogenous proteoglycans by neutral proteases in homogenates of cartilage from rats with c-l-s has been measured and compared with that of normal age-matched controls. Cartilage specimens from the tibial plateau were analysed for DNA and proteoglycan content, and neutral proteoglycan-degrading activity, No significant difference in cartilage DNA concentration was observed among the rats with c-l-s and the controls. Total neutral proteoglycan-degrading metallo-enzyme activity, determined by direct tissue assay, was significantly higher in c-l-s cartilage than that in control cartilage. Serine protease activity on proteoglycans was much lower than that of metalloprotease. The results of this study are consistent with the hypothesis that the neutral metalloproteases of cartilage are involved in the degradation of proteoglycans in c-l-s.

Collagen-like syndrome was induced in rats by oral hydralazine administration during 5 months. After 4 months, a subgroup of rats was shifted from the standard diet to the diet supplemented with copper (II) (60 micrograms of copper per g of pellet) as copper sulphate. A decreased serum copper concentration was noted, LE cells were observed in the blood of 75% of rats fed with standard diet. In the subgroup of copper supplemented rats, the LE cells were observed in 40% of rats only. The activity of superoxide dismutase, the antioxidative copper-dependent enzyme, was significantly lower in erythrocytes of rats fed with standard diet, than the activity in rats fed with copper supplemented diet. These results are briefly discussed.

Collagen was obtained from liver tissue of rats with hydralazine-induced collagen-like syndrome. Bacterial collagenase was used to solubilize the collagen, and the aldehyde content of this material was measured using N-methyl benzothiazolone hydrazone. The aldehyde content was decreased in the in the collagen from livers of rats with collagen-like syndrome. The changes in hepatic collagen may be analogous to the effect of aging on collagen, wherein collagen cross-linking is strengthened although qualitative changes in cross-linking may lower the measurable aldehydes.

Alkaline elution has been used to examine the integrity of DNA isolated from liver and kidney from rats treated with hydralazine (1-hydrazinophthalazine). Hydralazine was administered intragastrically at daily doses of 5, 10 and 25 mg per kg body weight to randomly bred female Wistar rats during 3 weeks. The relative strand scission, expressed as rad equivalents increased with increasing drug dose. The incidence of strand scission gives further support to the suggestion that hydralazine can be metabolically activated generating DNA-reactive species.