Lysophosphatidic acids (LPA) with a C18 fatty acyl group accelerated thymidine incorporation into cultured rat aortic vascular smooth muscle cells and stimulated their cell division. LPA acted synergistically with epidermal growth factor and fibroblast growth factor but additively with platelet-derived growth factor. The stimulatory actions of LPA were suggested to be rather specific from the following findings: 1) their stimulation of DNA synthesis increased with an increase in their acyl moiety; 2) lysophosphatidylcholine, a neutral lysophospholipid, had no mitogenic action but was cytotoxic at high concentrations; and 3) LPA induced a rapid external Ca(2+)-independent increase in intracellular Ca2+ concentration ([Ca2+]i) in single fura 2-loaded cells that resembled the receptor-mediated increases in [Ca2+]i triggered by different agonists, whereas lysophosphatidylcholine provoked a slow sustained increase in [Ca2+]i in an external Ca(2+)-dependent manner. These results are discussed in relation to the possible pathophysiological role of LPA.
Abstract-We have investigated the effect of a newly synthesized compound NZ 107, 4-bromo-5-(3-ethoxy-4 methoxybenzylamino)-3(2H)-pyridazinone, on bron choconstriction induced by slow reacting substance of anaphylaxis (SRS-A) in the guinea pig. Orally administered NZ-107 (10 mg/kg, 2 hr) inhibited antigen induced SRS-A-mediated bronchoconstriction in sensitized guinea pigs. NZ-107 (2 mg/kg, i.v., 1 min) prevented the antigen-induced response about as well as the SRS-A antagonist FPL-5571 2 and rapidly reversed it. This rapid reversal by NZ 107 but not FPL-55712 also appeared with the leukotriene (LT) D4-induced con traction of the isolated trachea. NZ-107 more selectively inhibited the LTD4 response than those of histamine, acetylcholine and KCI. Compared to FPL-5571 2, NZ-107 was one-fifteenth less potent in inhibiting the LTD4 response, but two-fold more potent in inhibiting the LTC4 response. NZ-107 inhibited the LTD4 response of the trachea 10-fold more potently than that of the ileum (-log IC50: trachea 5.61, ileum 4.56). The combination of NZ-107 (1 fM) with the (3-agonist iso proterenol had no synergistic effect on the LTD4 response, but those of theophylline and papaverine had large effects. From these results, NZ-1 07 is a selective inhibitor of the SRS-A response and may be useful in the therapy of bronchial asthma and other diseases in which the LTs are thought to be involved.
Abstract-The effects of propranolol on lipid metabolism were studied in spon taneously hypertensive rats (SHR).Male SHR and corresponding Wistar Kyoto rats (WKY) were used at 5 weeks of age. The SHR were given 10 mg/kg/day of dl-propranolol•HCI by gavage for 10 weeks. Body weight gain in untreated SHR and propranolol-treated SHR (SHR-P) groups were low, as compared with those of the WKY group.Total cholesterol, phospholipid and total lipid of the serum and liver in the SHR-P group were higher than in the SHR group.In the early weeks of treatment, serum triglyceride and non-esterified fatty acid levels in the SHR-P group were slightly lower than those in the SHR group.Aortic lipid levels in the SHR-P group were lower than those in the SHR group.During the later weeks of treatment, blood glucose level in the SHR-P group was higher than in the SHR group.The serum immunoreactive insulin value in the SHR-P group was slightly lower than in the SHR group.These results may suggest that propranolol inhibits hormone-sensitive lipase activity in the early weeks of treatment and influences cholesterol biosynthesis and/or catabolism.
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