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Biomedical subjects

J Nadler

Publications and source records attributed to J Nadler.

54 records · Page 3Linked to original sources
PubMed1989

Comparison of dopamine and fenoldopam effects on renal blood flow and prostacyclin excretion in normal and essential hypertensive subjects.

We recently reported that a low dose dopamine (DA) infusion in normal subjects increased renal blood flow (RBF) via prostacyclin (PGI2) formation without changes in PGE2 levels. The present study explores whether this mechanism is mediated by the DA1 receptor and evaluates the effect of DA on RBF and PGs in subjects with essential hypertension (EH). A low dose of DA (1 microgram/kg.min), which previously did not alter hemodynamics in normal subjects was infused into eight patient with EH to determine the role of DA stimulation in hypertensives. To assess the effect of DA1 stimulation, fenoldopam, a selective DA1 agonist, was infused (0.1 microgram/kg.min) into 10 normal and 10 hypertensive patients. Fenoldopam, unlike DA, significantly decreased diastolic blood pressure in hypertensives (96 +/- 3 to 85 +/- 2 mm Hg; P less than 0.01) along with a significant increase in pulse rate (68 +/- 2 vs. 73 +/- 2 beats/min; P less than 0.01). RBF measured by para-aminohippurate clearance increased only in normals during fenoldopam infusion from 1185 +/- 71 to 1533 +/- 84 L/min.m2 (PGI(2)01), and this was associated with an increase in PGI2 (6-keto-PGF1) excretion (149 +/- 19 vs. 214 +/- 32 ng/g creatinine; P less than 0.02). These effects of fenoldopam were similar to DA effects on RBF and PGI2 excretion in normals. In contrast, in hypertensive subjects, neither fenoldopam (867 +/- 113 vs. 1054 +/- 177 L/min.m2; P greater than 0.1) nor DA (1098 +/- 85 vs. 1061 +/- 101 L/min.m2; P greater than 0.1) increased RBF. Similarly, neither the DA nor the fenoldopam infusion stimulated PGI2 excretion in the hypertensives. The fenoldopam infusion in the hypertensives produced a significant natriuresis (22 +/- 3 to 49 +/- 9 mmol/3 h; P less than 0.05). Similar effects on Na+ excretion in this group were noted during DA infusion (17 +/- 3 to 36 +/- 3 mmol/3 h; P less than 0.05), suggesting that DA-induced natriuresis is not directly linked to DA-induced changes in RBF or PG excretion. The present study shows that in normal subjects, fenoldopam, a specific DA1 agonist, like DA, stimulates renal PGI2 release and RBF. In contrast, neither DA nor fenoldopam alters PGI2 or RBF in patients with EH, suggesting an alteration of dopaminergic tone in some hypertensives that is characterized by a defect in DA1 receptor sensitivity.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Mechanisms of blood pressure regulation by magnesium in man.

In order to determine the effect and mechanism of Mg on vascular tone, a 3-hour infusion of Mg (200 mg/h) was administered to normal subjects. The Mg infusion resulted in a drop in blood pressure (BP), a rise in renal blood flow, and an increase in urinary 6-keto-PGF1 alpha excretion. Cyclooxygenase inhibition with indomethacin and the calcium channel blocker, nifedipine, prevented these vascular effects of Mg. These data suggest that prostacyclin release via changes in Ca2+ flux may be the mechanism of Mg vasodilatory action. Since angiotensin II (AII) acts via the Ca2+ messenger system, we also studied the effects of Mg loading and dietary Mg depletion on AII responses. Mg loading blunted the rise in BP and the aldosterone-stimulating effect of AII, whereas Mg depletion significantly enhanced these AII effects. These results support the hypothesis that Mg may be an antagonist of the pressor and steroidogenic effects of AII.

Adult↗
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

Angiotensin feedback inhibition on renin is expressed via the lipoxygenase pathway.

Angiotensin II (AII) action on adrenal and smooth muscle cells is mediated via mechanisms that include changes in calcium flux and phosphoinositide hydrolysis. Phosphoinositide metabolism results in the release of arachidonic acid, a precursor of both the cyclooxygenase (CO) and lipoxygenase (LO) pathway. The effects of both LO and CO inhibitors on AII action were studied using both static incubations and perifusions of rat renal cortical slices. 12-Hydroperoxyeicosatetraenoic acid and its stable metabolite 12-hydroxyacid mimicked the inhibitory actions of AII on renin. A specific CO blocker did not alter AII inhibition of renin and a 5-LO blocker U60,257 was also ineffective, whereas the LO blockers BW755c, phenidone, and baicalein all eliminated or interfered with the action of AII on renin. All inhibition in the presence of a LO blocker was restored by adding nanomolar concentrations of 12-hydroperoxyeicosatetraenoic acid. LO inhibitors were specific for blocking AII, as they did not interfere with potassium (K+)-induced renin inhibition. These results imply that 12 and/or 15 products of the LO pathway are involved in AII action.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1988

The renal vasodilating effect of dopamine is mediated by calcium flux and prostacyclin release in man.

A low dose of dopamine (DA; 1 microgram/kg.min for 3 h) was infused into 10 normal subjects to determine whether vasodilator prostaglandins might be involved in the vascular action of this vasoactive hormone. Although this DA dose did not alter blood pressure, pulse, or cardiac index, it significantly increased renal blood flow (RBF), as estimated by para-amino-hippurate clearance [1.40 +/- 0.10 (+/- SE) to 1.93 +/- 0.18 L/min.1.73 m2; P less than 0.02]. This increase was due to DA receptor action since it was blocked by metoclopramide, a DA antagonist, and was not altered by prazosin, an alpha-adrenergic antagonist. DA simultaneously increased the urinary excretion rate of 6-keto-PGF1 alpha, a stable metabolite of prostacyclin [PGI2; 79 +/- 16 to 154 +/- 32 ng/g creatinine (2 +/- 0.40 to 3.88 +/- 0.78 pmol/mumol creatinine); P less than 0.02], but there was no change in PGE2 excretion. This dose of DA increased urinary Na+ and K+ excretion and slightly increased creatinine clearance from 0.12 +/- 0.01 to 0.16 +/- 0.02 L/min.1.73 m2 (P less than 0.05). Metoclopramide also blocked the increase in PGI2 excretion, indicating that this increase was due to DA. The relationship between RBF and PGI2 was supported by studies in which either indomethacin or ibuprofen, both cyclooxygenase inhibitors, blocked the increase in both RBF and PGI2 excretion rate. Since some DA actions may be mediated through calcium flux, we also administered nifedipine, a calcium channel-blocking drug, and found that the DA effect on RBF and PGI2 was significantly reduced. These studies suggest that the DA effect on RBF is mediated by calcium flux, which probably activates renal vascular phospholipase, leading to release of arachidonic acid and synthesis of PGI2, a potent vasodilator.

Adult↗
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↗
PubMed1986

Efficacy of pneumococcal vaccine in high-risk patients. Results of a Veterans Administration Cooperative Study.

We conducted a randomized, double-blind, placebo-controlled trial to test the efficacy of the 14-valent pneumococcal capsular polysaccharide vaccine in 2295 high-risk patients (patients with one or more of the following: age above 55 years and the presence of chronic cardiac, pulmonary, renal, or hepatic disease, alcoholism, or diabetes mellitus). Seventy-one episodes of proved or probable pneumococcal pneumonia or bronchitis occurred among 63 of the patients (27 placebo recipients and 36 vaccine recipients). Vaccine-serotype Streptococcus pneumoniae strains were recovered in association with 11 infections in the placebo group and 14 infections in the vaccine group. Pneumococcal infections occurred most frequently among patients with chronic pulmonary, cardiac, or renal diseases. Among vaccine recipients who subsequently had vaccine-type pneumonia or bronchitis, the majority did not make or sustain serum antibodies against their infecting organism in concentrations that were twice as high as the base-line values, or more than 400 ng of antibody nitrogen per milliliter, although their base-line levels were higher than those in subjects in whom infection did not develop. We were unable to demonstrate any efficacy of the pneumococcal vaccine in preventing pneumonia or bronchitis in this population. Our data suggest that chronically ill patients, who are most susceptible to infection, may have an impaired immune response to the pneumococcal vaccine.

Antibodies, Bacterial↗
PubMed1986

Antibiotic-resistant isolates of Streptococcus pneumoniae from clinical specimens: a cluster of serotype 19A organisms in Brooklyn, New York.

Ten of 294 isolates of Streptococcus pneumoniae from patients enrolled in a Veterans Administration Cooperative Studies Program trial of pneumococcal vaccine efficacy were moderately resistant or resistant to penicillin. Nine of these organisms were serotype 19A isolated from patients at the Brooklyn (New York) V.A. Medical Center over an 18-month period (March 1983-November 1984). The minimal inhibitory concentration of penicillin for these pneumococci ranged from 1.0 to 2.0 micrograms/ml by the agar dilution technique and from 4.0 to 8.0 micrograms/ml by tube dilution. These organisms were resistant also to other beta-lactam antibiotics and to tetracycline, chloramphenicol, and trimethoprim-sulfamethoxazole. They were sensitive to erythromycin, clindamycin, vancomycin, and rifampin. The epidemiological source of these isolates was not discovered. However, it is possible that a focus of multiple antibiotic-resistant serotype 19A S. pneumoniae is present in Brooklyn.

Drug Resistance, Microbial↗
PubMed1985

HTLV-III infection among health care workers. Association with needle-stick injuries.

Health care workers are caring for an increasing number of persons infected with human T-cell lymphotropic virus type III (HTLV-III), the primary etiologic agent of the acquired immunodeficiency syndrome (AIDS). We studied 361 health care and clinical laboratory personnel from institutions in several metropolitan areas with both high and moderate levels of HTLV-III infection among high-risk group members to evaluate routes of exposure to and seropositivity for HTLV-III. Protection of the privacy of subjects and prospective determination of risk factors were integral components of the study design. Six (26%) of 23 health care workers with recognized risk factors for AIDS had HTLV-III antibodies. Thirty-nine (14%) of 278 workers at one institution as well as a total of five workers from other institutions reported possible percutaneous exposure to HTLV-III, usually injuries with needles that had been used on AIDS patients. There were three HTLV-III seropositive subjects who reported possible parenteral exposure to HTLV-III but no recognized AIDS risk factors. One was a symptomatic female, subject A, and her apparent sources of HTLV-III exposure were two puncture wounds, without injection of blood, made with needles used on AIDS patients. Human T-cell lymphotropic virus type III was cultured from her asymptomatic, seronegative long-term sexual partner, apparently representing female-to-male transmission. For the two other seropositive workers (subjects B and C) with nosocomial parenteral exposure, we could not rule out heterosexual transmission as a possible source of HTLV-III exposure. These latter two cases as well as the identification of seropositive health care providers from known risk groups point to the need for thorough case investigation to identify routes of exposure in health care workers. The risk of nosocomial HTLV-III transmission appears to be low and related to percutaneous exposure. Medical personnel should be trained systematically in the proper techniques and handling of instruments for phlebotomy and similar procedures to decrease occupational exposure to HTLV-III.

Acquired Immunodeficiency Syndrome↗
PubMed1983

The effect of adrenergic stimulation on urinary prostaglandin E2 and 6 keto PGF1 alpha in man.

To evaluate the details of the adrenergic stimulation of urinary prostaglandins in man, ten normal volunteers were given various agonists and antagonists. The effect of 4 hour IV infusions of norepinephrine (NE), NE + phentolamine (PHT), NE + phenoxybenzamine (PHB), NE + prazosin (PZ), isoproterenol (ISO), and PHT alone on urinary PGE2 and PGI2 (6 keto PGF1 alpha) were determined. PGE2 and 6 keto PGF1 alpha were measured by radioimmunoassay from 4 hour urine samples. NE stimulated both PGE2 (196 +/- 40 to 370 +/- 84 ng/4 hrs/g creatinine and 6 keto PGF1 alpha (184 +/- 30 to 326 +/- 36), both p less than 0.01. In contrast, ISO had no effect on either PGE2 or 6 keto PGF1 alpha excretion. Alpha blockade with PHT. PHB, or PZ inhibited the NE induced systemic pressor effect. However, the effect of the alpha blockers on the NE induced stimulation of PGE2 and 6 keto PGF1 alpha varied. PHT did not alter the NE stimulated PGE2 or 6 keto PGF1 alpha release (370 +/- 84 vs. 381 +/- 80) PGE2 and (326 +/- 50 vs. 315 +/- 40) 6 keto PGF1 alpha both p greater than 0.2). PHT alone stimulated only 6 keto PGF1 alpha. PHB and the specific alpha 1 antagonist PZ similarly eliminated the NE induced prostaglandin release. These results suggest that adrenergically mediated urinary prostaglandin release in man is via an alpha receptor with alpha 1 characteristics.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Stimulation of renal prostaglandins by pressor hormones in man: comparison of prostaglandin E2 and prostacyclin (6 keto prostaglandin F1 alpha).

The effect of vasoconstrictive agonists and their nonpressor analogs on renal prostaglandin production was investigated in normal subjects maintained on constant diets. Arginine vasopressin (AVP), 10 U, desamino-d arginine vasopressin (dDAVP), 4 micrograms, angiotensin II (AII), 5 ng/kg . min, des-Asp angiotensin II (AIII), 5 ng/kg . min, norepinephrine (NE), 0.1 microgram/kg . min, and NE plus phenoxybenzamine (PHB), 0.8 mg/kg, were administered on separate days. Prostaglandin E2 (PGE2) and the stable prostacyclin metabolite, 6 keto prostaglandin F1 alpha were measured in 4-h urine collections by procedures with high resolution chromatography and RIA using highly specific antisera. AVP and dDAVP similarly reduced urine volume and increased urine osmolality. AII, AIII, NE, and NE + PHB did not alter basal urine volume, osmolality, creatinine, or electrolyte excretion. Blood pressure was similarly increased by AII and NE infusions (23 +/- 3 vs. 19 +/- 2 (SE) mm Hg). AVP and AII increased only PGE2 excretion (61 +/- 8 to 151 +/- 34 ng/4 h for AVP, and 38.7 +/- 7 to 75 +/- 19 ng/4 h for AII, P less than 0.05). The nonpressor analogs, dDAVP and AIII, had no effect on urinary prostaglandin excretion. In contrast, NE increased both PGE2 (from 38.7 +/- 7 to 74.5 +/- 12 ng/4 h, P less than 0.02) and 6 keto prostaglandin F1 alpha (from 34.6 +/- 8 to 56.1 +/- 9 ng/4 h, P less than 0.02). alpha-Blockade with PHB totally abolished the NE-induced systemic pressor and prostaglandin stimulatory effect. These data suggest that renal PGE2 and prostacyclin are not altered in parallel by vasoactive stimuli. PGE2 appears to be released in response to agents that induce renal vasoconstriction and reduced renal blood flow whereas renal prostacyclin excretion is stimulated by an adrenergic agonist via alpha-receptor activation and not vasoconstriction per se.

6-Ketoprostaglandin F1 alpha↗
PubMedDate not supplied

Women and HIV: when to test?

The devastating effects of HIV infection in women can be altered dramatically with new therapies. Certain clinical syndromes, including oral thrush, diffuse lymphadenopathy, wasting, unexplained fevers, or oral hairy leukoplakia, clearly indicate a need for HIV testing. This article reviews other clinical syndromes, both gender-specific and non-gender-specific, that may prompt the practitioner to consider HIV testing.

Adult↗
PubMedDate not supplied

Determination of red blood cell intracellular free magnesium by nuclear magnetic resonance as an assessment of magnesium depletion.

Red blood (RBC) ionized magnesium (Mg2+) was determined by nuclear magnetic resonance (NMR) in order to assess the usefulness of this technique as an index of magnesium depletion. Twenty-four normal subjects underwent a 3-week low-Mg diet. The RBC Mg2+ fell from 209 +/- 9.8 microM before diet to 162 +/- 9.3 microM at the end of the 3 weeks (p < 0.001). In patient populations, 22 hypomagnesemic hospitalized patients had a significantly lower RBC Mg than normal (146 +/- 7.1 microM, p < 0.002), and 37 outpatients with diabetes mellitus had a mean RBC Mg2+ of 172 +/- 7.1 microM which was also significantly lower than normal (p < 0.001). These data suggest that determination of RBC Mg2+ may be used to reflect intracellular Mg status.

Diabetes Mellitus↗