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 reninangiotensin system.
This study was designed to examine the contribution of lipoxygenase products to mechanisms of vascular contraction and elevated blood pressure in rats with aortic coarctation-induced hypertension. In cytosolic fractions of aortae taken from hypertensive rats, 12-lipoxygenase protein was increased as compared to normotensive controls. Aortic rings from hypertensive, but not from normotensive rats, exhibited a basal tone which was reduced 74+/-12 and 71+/-22%, respectively, by the lipoxygenase inhibitors cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (CDC, 10(-5) mol/L) and 5,8,11-eicosatriynoic acid (ETI, 10(-5) mol/L). CDC (8 mg/kg s.c.) did not affect the blood pressure of normotensive rats but decreased that of hypertensive rats from 182+/-6 to 151+/-10 mm Hg. The blood pressure lowering effect of CDC was blunted in hypertensive rats pretreated with indomethacin or antibodies against 5,6-dihydro-prostaglandin I2. These data suggest contribution of lipoxygenase-derived products to mechanisms underlying aortic smooth muscle basal tone and elevated blood pressure in rats with aortic coarctation-induced hypertension. The vasodepressor effect of CDC depends on a mechanism involving vasodilatory prostaglandins.
Human recombinant tumor necrosis factor-alpha (rTNF-alpha, 10(-12)-10(-8) M) inhibited the proliferation of androgen-dependent LNCaP cells by 32-56%. In contrast, proliferation of androgen-independent PC-3 and JCA-1 cells was only slightly inhibited, or not inhibited at all, respectively. Human recombinant interferon-gamma (rIFN-gamma, 500 U/ml) decreased proliferation of PC-3 and JCA-1 cells by 35% and 53%, respectively, but had no effect on LNCaP cells. Interestingly, the combination of rIFN-gamma and TNF-alpha had greater antiproliferative effects on JCA-1 cells than treatment with either cytokine alone. However, the antiproliferative effects of this combination were similar to those observed for PC-3 or LNCaP cells treated with rIFN-gamma or TNF-alpha alone, respectively. These data suggest that some forms of androgen-independent prostate cancer may benefit from a combination therapy of IFN-gamma and TNF-alpha, while the use of IFN-gamma alone may be more efficacious in others.
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. © 1996 Wiley‐Liss, Inc.
Abstract-Lipoxygenase inhibitors reduce blood pressure in hypertensive rats. The vasodepressor effect of lipoxygenase inhibitors may be related to increased production of prostaglandin (PG) I 2 since lipoxygenase-derived fatty acid hydroperoxides inhibit PGI 2 synthase. This hypothesis was examined in rats made hypertensive by infusion of angiotensin II (200 ng/min IP) for 12 to 14 days. In hypertensive but not in normotensive rats, the lipoxygenase inhibitor baicalein (60 mg/kg SC) increased (PϽ.05) the conversion of exogenous PGH 2 to PGI 2 by aortic segments, the release of 6-keto-PGF 1␣ by aortic rings, the concentration of 6-keto-PGF 1␣ in blood, and the renal excretion of 6-keto-PGF 1␣ . Treatment with baicalein did not affect the blood pressure of normotensive rats but decreased the blood pressure of hypertensive rats from 177Ϯ8 to 133Ϯ9 mm Hg after 120 minutes (PϽ.05). Also, the lipoxygenase inhibitor cinnamyl-3,4-dihydroxy-␣-cyanocinnamate (8 mg/kg SC) was without effect on the blood pressure of normotensive rats but decreased the blood pressure of hypertensive rats from 182Ϯ4 to 139Ϯ8 mm Hg (PϽ.05). However, the blood pressure of hypertensive rats pretreated with indomethacin (5 mg/kg IV) was affected by neither baicalein nor cinnamyl-3,4-dihydroxy-␣-cyanocinnamate. Moreover, in hypertensive rats in which baicalein had decreased blood pressure to 148Ϯ6 mm Hg, the administration of rabbit serum containing antibodies against 5,6-dihydro-PGI 2 (0.3 mL IV) partially reversed the response to baicalein, increasing blood pressure to 179Ϯ7 mm Hg within 20 minutes (PϽ.05). The antibodies also were shown to block the vasodepressor effect of PGI 2 but not of PGE 2 . Collectively, these data suggest contribution of PGI 2 to the acute antihypertensive effect of baicalein in rats with angiotensin II-induced hypertension.
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