ABSTRACT
Lipoxygenase inhibitors reduce blood pressure in hypertensive rats. The vasodepressor effect of lipoxygenase inhibitors may be related to increased production of prostaglandin (PG) I2 since lipoxygenase-derived fatty acid hydroperoxides inhibit PGI2 synthase. This hypothesis was examined in rats made hypertensive by infusion of angiotensin II (200 ng/min i.p.) for 12 to 14 days. In hypertensive but not in normotensive rats, the lipoxygenase inhibitor baicalein (60 mg/kg s.c.) increased (P<.05) the conversion of exogenous PGH2 to PGI2 by aortic segments, the release of 6-keto-PGF1alpha by aortic rings, the concentration of 6-keto-PGF1alpha in blood, and the renal excretion of 6-keto-PGF1alpha. Treatment with baicalein did not affect the blood pressure of normotensive rats but decreased the blood pressure of hypertensive rats from 177+/-8 to 133+/-9 mm Hg after 120 minutes (P<.05). Also, the lipoxygenase inhibitor cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (8 mg/kg s.c.) was without effect on the blood pressure of normotensive rats but decreased the blood pressure of hypertensive rats from 182+/-4 to 139+/-8 mm Hg (P<.05). However, the blood pressure of hypertensive rats pretreated with indomethacin (5 mg/kg i.v.) was affected by neither baicalein nor cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate. Moreover, in hypertensive rats in which baicalein had decreased blood pressure to 148+/-6 mm Hg, the administration of rabbit serum containing antibodies against 5,6-dihydro-PGI2 (0.3 mL i.v.) partially reversed the response to baicalein, increasing blood pressure to 179+/-7 mm Hg within 20 minutes (P<.05). The antibodies also were shown to block the vasodepressor effect of PGI2 but not of PGE2. Collectively, these data suggest contribution of PGI2 to the acute antihypertensive effect of baicalein in rats with angiotensin II-induced hypertension.
Subject(s)
Blood Pressure/drug effects , Enzyme Inhibitors/pharmacology , Epoprostenol/physiology , Flavanones , Flavonoids/pharmacology , Hypertension/metabolism , Lipoxygenase Inhibitors , Angiotensin II , Animals , Arachidonate 12-Lipoxygenase/metabolism , Epoprostenol/blood , Hypertension/chemically induced , Hypertension/enzymology , Hypertension/physiopathology , Male , Rats , Rats, Sprague-Dawley , Vasoconstrictor AgentsABSTRACT
BACKGROUND: The contribution of TNF receptor (TNF-R) expression was investigated with respect to TNF sensitivity or insensitivity for androgen-dependent and androgen-independent human prostate cancer (PCA) cell lines, respectively. METHODS: Flow cytometric analyses using monoclonal antibodies against the 55-kDa receptor (TNF-R1) and the 75-kDa receptor (TNF-R2) indicated that both receptors were expressed on all three cell lines. RESULTS: Moreover, expression of TNF-R1 was greater than expression of TNF-R2 in these PCA cells. All three PCA cell lines produced IL-6. However, IL-6 production was enhanced when TNF-insensitive JCA-1 and PC-3 cells, but not TNF-sensitive LNCaP cells, were treated with rTNF (10(-9) M). CONCLUSIONS: These data suggest that the lack of an antiproliferative effect of rTNF on the androgen-independent PCA cell lines PC-3 and JCA-1 is not due to the failure of these cells to express TNF-R, but may be related to the differences in TNF-mediated IL-6 expression by these PCA cell lines.
Subject(s)
Drug Resistance, Neoplasm , Prostatic Neoplasms/drug therapy , Receptors, Tumor Necrosis Factor/physiology , Tumor Necrosis Factor-alpha/pharmacology , Androgens/pharmacology , Antibodies, Monoclonal/pharmacology , Binding Sites , Cell Division , Flow Cytometry , Gene Expression , Humans , Interferon-gamma/pharmacology , Interleukin-6/biosynthesis , Male , Prostatic Neoplasms/pathology , RNA, Messenger/metabolism , Receptors, Tumor Necrosis Factor/genetics , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Recombinant Proteins/pharmacology , Tumor Cells, Cultured , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Cell volume regulation in LLC-PK1 cells was evaluated by measuring 86Rb efflux (rate constant), used as an indicator of K+ efflux. Hypotonic shock induced a transient increase in the rate constant which returned to baseline values after 15 min. ETYA, an arachidonic acid-competitive antagonist as well as the cytochrome P450 inhibitors SKF 525-A, clotrimazole and 7-ethoxyresorufin, inhibited the hypotonic shock-induced increment in the rate constant. Arachidonic acid did not change hypotonic shock-induced increments in K+ efflux. LLC-PK1 cells were unable to metabolize 14C-arachidonic acid. We concluded that although arachidonic acid inhibitors block the hypotonic shock-induced increment in K+ efflux, this effect cannot be related to inhibition of arachidonic acid metabolism.
Subject(s)
Cytochrome P-450 Enzyme System/metabolism , LLC-PK1 Cells/drug effects , Potassium/metabolism , Animals , Arachidonic Acid/pharmacology , Cells, Cultured , Chromatography, High Pressure Liquid , Osmotic Pressure , Rubidium/metabolism , SwineABSTRACT
Evidence that angiotensin(1-7) (Ang(1-7)) is biologically active and can be synthesized by the kidney prompted us to examine its actions in the rat, isolated kidney. Ang(1-7) had three major effects producing, (1) a substantial natriuresis and diuresis, (2) an increase in urinary sodium concentration associated with a fall in potassium concentration and (3) an increase in glomerular filtration rate without affecting renal vascular resistance. Thus, Ang(1-7) may participate in the renal effects of the renin-angiotensin system.
