A bolus injection of methylene blue (1 mg), a guanylate cyclase inhibitor, or aspirin (3 mg) in the isolated rat lung preparation had little or no effect on resting perfusion pressure under normoxic condition. In contrast, methylene blue markedly potentiated hypoxic vasopressor response (4-fold) when injected before or during the alveolar hypoxic stimulation. Hemoglobin also potentiated the hypoxic pressor response. Similarly, methylene blue or aspirin augmented the pressor responses to angiotensin II (0.1-1 microgram). The increased hypoxic response induced by methylene blue was immediate and sustained. Methylene blue, when added during hypoxia in the presence of aspirin, further augmented the response to hypoxia compared with the enhanced hypoxic response observed with aspirin alone. Our results suggest that, in addition to the role of cyclooxygenase products, the pulmonary vascular bed may be regulated by endothelium-dependent factors that can be antagonized directly or indirectly by methylene blue.
Butyric acid is a potent antineoplastic agent with a well-documented differentiation activity on a wide variety of tumor cells. However, its clinical development is strongly limited by its very short metabolic half-life. In this study we report on the in vitro effects of new original piperazine derivatives of butyric acid on the induction of differentiation and the growth inhibition of human erythroleukemia K562 cells and myeloid leukemia HL60 cells. 1-(2-hydroxyethyl) 4-(1-oxobutyl)-piperazine (HEPB) and [1-(2-hydroxyethyl) 4-(1-oxobutyl)-piperazine] butyrate (HEPDB) were efficient in acting on the differentiation and proliferation of both cell lines, whereas 1-phenyl 4-(1-oxobutyl)-piperazine (PPB) and 1-(3,4-methylene dioxybenzyl) 4-(1-oxobutyl)-piperazine (POB) acted only on proliferation rates. Such derivatives did not induce significant toxicity in mice. These preliminary results should enable, by the development of new series of piperazine derivatives, a better understanding of the mechanisms of action of butyric acid and its analogues on the coupling of growth and differentiation of neoplastic cells.
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