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Biomedical subjects

R Natarajan

Publications and source records attributed to R Natarajan.

At least 127 records · Page 7Linked to original sources
PubMed1989

Tumor necrosis factor and interleukin-1 are potent inhibitors of angiotensin-II-induced aldosterone synthesis.

Cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1), mediate many inflammatory and cellular responses. However, the effects of TNF and IL-1 on basal and angiotensin-II (AII)-stimulated aldosterone synthesis are not known. We studied the effect of recombinant and purified TNF and IL-1 on basal as well as AII-, ACTH-, and K+-induced aldosterone synthesis in isolated rat adrenal glomerulosa cells. Since we have previously shown that AII action is mediated by activation of the 12-lipoxygenase (12LO) pathway of arachidonic acid, we also evaluated the effects of these cytokines on the 12LO product 12-hydroxyeicosatetraenoic acid (12HETE) using a validated RIA technique. TNF at 2.5 and 5.0 ng/ml produced a dose-dependent inhibition of AII-induced aldosterone synthesis [AII, 39.0 +/- 3.3 ng/10(6) cells.h; AII plus TNF (5.0 ng/ml), 14.3 +/- 1.6; P less than 0.001 vs. AII; AII plus TNF (2.5 ng/ml), 24.7 +/- 3.2; P less than 0.01 vs. AII]. Similarly, TNF at 5.0 ng/ml also attenuated the stimulatory effect of ACTH (10(-9) M). However, K+-induced aldosterone synthesis was not altered. TNF also did not alter basal aldosterone levels. AII, as previously shown, stimulates 12HETE synthesis (basal, 608 +/- 114 pg/10(5) cells.h; versus AII, 1268 +/- 197; P less than 0.02). TNF at concentrations of 1.0-5.0 ng/ml produced a dose-dependent inhibition of AII stimulatory action on 12HETE synthesis [AII plus TNF (1.0 ng/ml), 650 +/- 26 pg, P less than 0.03 vs. AII; AII plus TNF (5.0 ng/ml), 390 +/- 46; P less than 0.01 vs. AII plus TNF (1.0 ng/ml)]. In addition, 12HETE at 10(-8) M completely restored the effects of AII during blockage by TNF. Purified human IL-1 (75% beta, 25% alpha) as well as recombinant human IL-1 beta at concentrations as low as 50 pg/ml inhibited AII-induced aldosterone synthesis. IL-1 beta did not alter ACTH- or K+-induced aldosterone synthesis and, in fact, had a tendency to potentiate ACTH effects. These results suggest that the cytokines TNF and IL-1 are potent inhibitors, particularly of AII action in the adrenal glomerulosa cell. Therefore, local or systemically produced TNF or IL-1 may be important negative modulators of aldosterone synthesis.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1989

Selective inhibition of angiotensin-II-mediated aldosterone secretion by 5-hydroxyeicosatetraenoic acid.

We have previously demonstrated that the 12-lipoxygenase (12-LO) pathway plays a key role in angiotensin-II (AII)-dependent aldosterone production. In the present study we examined the role of the 5LO pathway on AII-induced aldosterone secretion in rat glomerulosa cells in vitro. The 5LO product 5-hydroxyeicosatetraenoic acid (5HETE) and its unstable precursor 5-hydroxyperoxyeicosatetraenoic acid did not significantly alter basal aldosterone secretion in concentrations from 10(-9)-10(-7) M. In contrast, 5HETE reduced peak AII-induced aldosterone production from 59.1 +/- 9.0 to 37.96 +/- 7.2 ng/10(6) cells (P less than 0.01). This was accompanied by inhibition of the AII-stimulated rise in 12HETE production (10(-9)M AII, 160 +/- 4% of control; 10(-9) M AII plus 10(-7) M 5HETE, 90 +/- 1% of control production). However, 5HETE had no effect on the aldosterone response to potassium or ACTH, secretagogues that cause no activation of the 12LO pathway. These results suggest that the 5LO product 5HETE can selectively modulate AII-dependent aldosterone secretion. Further, the selective inhibitory effect of 5HETE on the AII effect in rat glomerulosa cells may be exerted by blockade of arachidonate metabolism via the 12LO pathway. These results suggest that the 5LO pathway may negatively modulate AII action in the adrenal zona glomerulosa.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1988

Diacylglycerol provides arachidonic acid for lipoxygenase products that mediate angiotensin II-induced aldosterone synthesis.

The lipoxygenase products of arachidonic acid metabolism have been shown to be important mediators of stimulus secretion coupling in various endocrine tissues. We have recently shown that the 12-lipoxygenase product, 12-hydroxyeicosatetraenoic acid plays a key role as a new specific mediator of angiotensin II-induced aldosterone secretion in the adrenal. In view of the several pathways by which cellular arachidonate can be generated and the important role of diacylglycerol in angiotensin II-responses, we studied the role of diacylglycerol as the source of arachidonic acid for 12-hydroxyeicosatetraenoic formation. Treatment of normal human adrenal glomerulosa cells with the selective diacylglycerol-lipase inhibitor, RHC 80267, resulted in a dose-dependent inhibition of angiotensin II-induced aldosterone as well as 12-hydroxyeicosatetraenoic formation. These results suggest that AA derived from diacylglycerol is the precursor of 12-hydroxyeicosatetraenoic involved in angiotensin II-induced aldosterone secretion. These results reveal a new second messenger role for diacylglycerol in addition to activation of protein kinase C.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1988

Role of the lipoxygenase pathway in angiotensin II-mediated aldosterone biosynthesis in human adrenal glomerulosa cells.

We studied the role of the lipoxygenase pathway of arachidonic acid metabolism in angiotensin II (AII)-stimulated aldosterone secretion in normal and adenomatous human adrenal glomerulosa tissue. In freshly isolated normal adrenal glomerulosa cells, the AII-mediated stimulation of aldosterone secretion was not altered by cyclooxygenase blockade with ibuprofen. In contrast, BW755c (10(-5) mol/L), a nonselective lipoxygenase inhibitor, and baicalein (10(-6) mol/L), a more selective 12-lipoxygenase blocker, inhibited AII-mediated aldosterone secretion, but did not alter basal aldosterone secretion. The glomerulosa cells produced the lipoxygenase products 12- and 15-hydroxyeicosatetraenoic acid (HETE) in the basal state, as measured by high pressure liquid chromatography and RIA. However, AII selectively stimulated only 12-HETE production [basal, 1329 +/- 207 (+/- SE) pg (3.99 +/- 0.62 pmol)/10(5) cells.h; AII, 2365 +/- 333 (7.09 +/- 1.0); n = 9; P less than 0.02], suggesting that 12-lipoxygenase activation may be involved in AII-mediated aldosterone secretion by normal cells. In addition, the lipoxygenase inhibitors that blocked AII-mediated aldosterone secretion also prevented AII-mediated 12-HETE formation. In contrast, neither ACTH nor K+ stimulated 12-HETE formation, suggesting that 12-lipoxygenase activation is primarily involved in AII action in normal glomerulosa cells. BW755c caused a marked dose-dependent inhibition of basal aldosterone secretion in freshly isolated cells from aldosterone-producing adenomas [APA; basal, 66 +/- 3 ng (182 +/- 8 pmol)/10(6) cells.h; 10(-5) mol/L BW755c, 49 +/- 2 (136 +/- 6); 10(-4) mol/L BW755c, 30 +/- 2 (83 +/- 6)]. In contrast, the cyclooxygenase inhibitor indomethacin and the selective 5-lipoxygenase inhibitor U60257 did not alter basal aldosterone secretion by these cells. The APA cells produced 12- and 15-HETE, and BW755c at the same dose that inhibited aldosterone secretion also inhibited the production of both 12- and 15-HETE. In the cultured APA cells, AII-stimulated aldosterone secretion was inhibited by BW755c [basal, 26 +/- 8 pg/mL (72.0 +/- 22.1 pmol/L); AII, 336 +/- 79 (930 +/- 218); AII plus BW755c, 92 +/- 38 (255 +/- 105) n = 13; P less than 0.01]. The lipoxygenase products 12- and 15-HETE restored the stimulatory effect of AII during inhibition by BW755c, indicating a role for these lipoxygenase pathways in AII-mediated aldosterone secretion in APA cells. These results suggest that the stimulatory effects of AII on aldosterone secretion are mediated by stimulation of the lipoxygenase pathway in human zona glomerulosa cells.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1987

Specific action of the lipoxygenase pathway in mediating angiotensin II-induced aldosterone synthesis in isolated adrenal glomerulosa cells.

Angiotensin II (AII) in adrenal glomerulosa cells activates phospholipase C resulting in the formation of inositol phosphates and diacylglycerol rich in arachidonic acid (AA). Although glomerulosa cells can metabolize AA via cyclooxygenase (CO), this pathway plays little role in aldosterone synthesis. Recent evidence suggests that the lipoxygenase (LO) pathway may be important for hormonal secretion in endocrine tissues such as the islet of Langerhans. However, the capacity of the glomerulosa cell to synthesize LO products and their role in aldosterone secretion is not known. To study this, the effect of nonselective and selective LO inhibitors on AII, ACTH, and potassium-induced aldosterone secretion and LO product formation was evaluated in isolated rat glomerulosa cells. BW755c, a nonselective LO inhibitor dose dependently reduced the AII-stimulated level of aldosterone without altering AII binding (91 +/- 6 to 36 +/- 4 ng/10(6) cells/h 10(-4) M, P less than 0.001). The same effect was observed with another nonselective LO blocker, phenidone, and a more selective 12-LO inhibitor, Baicalein. In contrast U-60257, a selective 5-LO inhibitor did not change the AII-stimulated levels of aldosterone (208 +/- 11% control, AII 10(-9) M vs. 222 +/- 38%, AII + U-60257). The LO blockers action was specific for AII since neither BW755c nor phenidone altered ACTH or K+-induced aldosterone secretion. AII stimulated the formation of the 12-LO product 12-hydroxyeicosatetraenoic acid (12-HETE) as measured by ultraviolet detection and HPLC in AA loaded cells and by a specific RIA in unlabeled cells (501 +/- 50 to 990 +/- 10 pg/10(5) cells, P less than 0.02). BW755c prevented the AII-mediated rise in 12-HETE formation. In contrast, neither ACTH nor K+ increased 12-HETE levels. The addition of 12-HETE or its unstable precursor 12-HPETE (10(-9) or 10(-8) M) completely restored AII action during LO blockade. AII also produced an increase in 15-HETE formation, but the 15-LO products had no effect on aldosterone secretion. These studies suggest that the 12-LO pathway plays a key role as a new specific mediator of AII-induced aldosterone secretion.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1984

Vitamin B6 status in patients with cancer of the uterine cervix.

The activities of aspartate aminotransferase and alanine aminotransferase in erythrocytes with and without the addition of pyridoxal phosphate were determined in healthy controls and in Indian women with cancer of the uterine cervix. The percent stimulation of the erythrocyte transferases as a result of the addition of pyridoxal phosphate was negligible in the case of normal subjects (less than 5% stimulation). In the patients with cervical cancer, a 23-35% stimulation was observed, indicating a deficiency of vitamin B6. It is not yet known whether the deficiency is the cause of the disease or due to the tumor.

Alanine Transaminase↗
PubMed1982

Collagen film for burn wound dressings reconstituted from animal intestines.

Collagen was isolated and purified from sheep intestines and cast into a film. The collagen film was cross-linked with ultraviolet light and reinforced by imbedding a nylon mesh. The collagen membrane was evaluated as a wound dressing for second- and third-degree burns in rats. Histopathological studies of the burns with and without the collagen dressings were made. The study showed the burn wounds dressed with collagen membrane exhibited rapid epithelialization with little inflammatory change and dense fibrous tissue ingrowth in the subdermal layers.

Amino Acids↗
PubMed1981

Effect of pH on the micellar properties of amphiphilic drugs in aqueous solution.

The influence of pH on the micellar properties of several amphiphilic drugs under conditions of constant ionic strength has been investigated. No significant effect of pH on the critical micelle concentration or micellar size of chlorpromazine hydrochloride was noted over a pH range well below the pKa. The micellar properties of opipramol, thiopropazate, flupenthixol, clopenthixol, and trifluoperazine, which contain a piperazine moiety showed considerable pH dependence. The concentration dependence of the pKa in these micellar systems was taken into consideration in the selection of pH values representative of complete protonation of either one or both of the piperazine N atoms. A lower aggregation number and higher critical micelle concentration was observed at a low pH corresponding to complete protonation of both charge centres. Mepyramine maleate exhibited a non-micellar mode of association at pH 5.5 which could be described by a stepwise association model in which association constants, KN, increased sequentially with aggregation number. N, according to the relationship, KN = K(N - 1)/N where K = 31.3 dm3mol-1. No significant association could be detected at pH 2 when the pyridine ring N was fully protonated.

Chlorpromazine↗
PubMed1980

Micellar properties and surface activity of some bolaform drugs in aqueous solution.

The micellar properties of a series of dicationic drugs with structures resembling those of the bolaform electrolytes have been examined using light scattering, surface tension and conductivity techniques. The compounds investigated included, demecarium bromide, ambenonium chloride, dequalinium acetate, distigmine bromide and chlorhexidine acetate. Demecarium and dequalinium formed micelles at critical concentrations of 9 x 10(-3) and 4 x 10(-3) mol kg-1 respectively. No significant association of chlorhexidine acetate could be detected, contrary to previous reports.

Ambenonium Chloride↗