In vivo and in vitro effects of hydralazine on cellular growth, differentiation, and chromatin structure

The effects of hydralazine (1-hydrazinophthalazine), an antihypertensive drug, on mammalian cell growth, viability, and differentiation were assessed using Friend leukemia cells, Chinese hamster ovary cells, human lymphocytes, and rat lymphocytes, testicular germ cells, and epididymal sperm. Cultured cells in exponential phase growth were more susceptible to hydralazine cytotoxicity than stationary phase (G0) cells. Growth inhibition was associated with a dose-related slowdown of cell progression through S phase and was observed prior to a decrease of cell viability. At high drug concentrations, progression in all phases of the cell cycle was partially or totally inhibited. Hydralazine did not have an effect on the proliferation and differentiation of testicular germ cells in spontaneously hypertensive rats receiving 0-90 mg/kg/day (up to 20 times the dose used in humans) of hydralazine for a 12-week period. Hydralazine-exposed, histone-containing somatic cells and protamine-containing sperm cells failed to show any alterations in stainability with a DNA-intercalating dye nor in the susceptibility of nuclear DNA to undergo acid-induced denaturation in situ. The data suggest that hydralazine causes a dose-related suppression of mammalian cell growth with S phase appearing to be the most susceptible to hydralazine cytotoxicity. Furthermore, the interaction of hydralazine with chromatin at concentrations leading to antigenicity did not inhibit DNA staining with the intercalating dye acridine orange, suggesting that the drug does not competitively intercalate at a detectable level. Association of hydralazine with chromatin did not cause a detectable level of stabilization or destabilization of the DNA to denaturation in situ.