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Biomedical subjects

P T Murray

Publications and source records attributed to P T Murray.

8 recordsLinked to original sources
PubMed2002

Fenoldopam mesylate blocks reductions in renal plasma flow after radiocontrast dye infusion: a pilot trial in the prevention of contrast nephropathy.

BACKGROUND: Radiocontrast nephropathy (RCN) is a common source of acute renal failure in hospitalized patients and is associated with increased morbidity and mortality rates. Fenoldopam mesylate is a dopamine A1 receptor agonist that augments renal plasma flow (RPF) in patients with normotensive and hypertensive conditions. To determine whether fenoldopam mesylate attenuates reductions in RPF after contrast infusion, we conducted a double-blind, randomized, placebo-controlled pilot trial of fenoldopam mesylate in patients who underwent contrast angiography. METHODS: Fifty-one patients with chronic renal insufficiency (creatinine level, 2.0-5.0 mg/dL) who were undergoing contrast angiography were screened, and 45 patients were randomized to receive normal saline solution (1/2 NS) or 1/2 NS plus fenoldopam mesylate at 0.1 microg/kg/min at lease 1 hour before infusion with contrast dye. Serum creatinine level was measured at baseline and at 24, 48, and 72 hours after angiography. The primary endpoint was change in RPF 1 hour after contrast infusion. The secondary endpoint was incidence of RCN, defined as a 0.5 mg/dL or a 25% rise in serum creatinine level at 48 hours. RESULTS: RPF at 1 hour after angiography was 15.8% above baseline in the fenoldopam mesylate group compared with 33.2% below baseline in the 1/2 NS group (P <.05). The incidence rate of RCN at 48 hours was 41.0% in the 1/2 NS group versus 21% in the fenoldopam mesylate group (P =.148). Among patients with diabetes, the incidence rate of RCN tended to be higher in the 1/2 NS group compared with the fenoldopam mesylate group (64% vs 33%; P =.14). The peak serum creatinine level at 72 hours after contrast infusion was significantly higher at in the 1/2 NS group (creatinine level, 3.6 +/- 1.0 mg/dL) compared with the fenoldopam mesylate group (creatinine level, 2.8 +/- 0.35 mg/dL; P <.05). RPF was significantly (P <.0001) reduced in patients with RCN compared with patients in whom RCN did not develop. CONCLUSION: The results of this pilot trial suggest that fenoldopam mesylate is a promising prophylactic agent for RCN and that larger multicenter trials should be conducted to prove its efficacy.

Acute Kidney Injury↗
PubMed2001

Design and rationale of CONTRAST--a prospective, randomized, placebo-controlled trial of fenoldopam mesylate for the prevention of radiocontrast nephropathy.

Radiocontrast-induced nephropathy develops in approximately 10% to 20% of patients following administration of iodine-based dye and is one of the most prognostically detrimental complications that invasive cardiologists and radiologists encounter. Preexisting renal dysfunction and diabetes mellitus are two of the most powerful predictors of the likelihood of developing acute renal insufficiency after contrast delivery. To date, only adequate preprocedural hydration and postprocedural hydration to offset dehydration from contrast-induced diuresis have been shown to be effective in preventing this condition. Fenoldopam mesylate, a systemic vasodilator currently FDA-approved for short-term, in-hospital management of severe hypertension, has been shown to increase renal plasma flow in patients with and without chronic renal insufficiency. As a selective agonist of the dopamine-1 receptor, fenoldopam may preserve outer medullary renal blood flow and thereby attenuate radiocontrast-induced nephropathy. Small studies with fenoldopam prior to iodine-based dye administration have demonstrated low rates of radiocontrast nephropathy, and a larger, randomized trial has found that renal blood flow 1 hour after angiography rose in the fenoldopam group compared to a decline in the placebo group. The CONTRAST study has been designed to determine whether fenoldopam is indeed effective in diminishing the occurrence of radiocontrast-induced nephropathy.

Acute Kidney Injury↗
PubMed1998

Endotoxin impairs agonist-induced calcium mobilization in bovine aortic myocytes by a nitric oxide-independent mechanism.

We hypothesized that endotoxin (LPS) would impair vasoconstrictor-agonist-induced calcium (Ca2+) mobilization by a nitric oxide (NO)-dependent mechanism. We incubated bovine aortic myocytes (passages 16 to 23) for 22 to 24 hours with 0 to 1.0 mg/ml Escherichia coli lipopolysaccharide (LPS). Medium (Dulbecco's modified Eagle's medium (DMEM) + 10% fetal bovine serum (FBS)) was assayed for nitrite (chemiluminescence), and myocytes were loaded with fura-2 acetoxymethyl ester (fura-2AM), after which we assessed basal and thrombin (10 U/ml)-induced peak Ca2+ mobilization by microspectrofluorimetry. LPS (0.01 to 1.0 mg/ml) led to dose-dependent nitrite accumulation, which was blocked by coincubation with N(omega)-nitro-L-arginine methyl ester (L-NAME, 1 mmol/L). LPS also impaired Ca2+ responses in a dose-dependent manner (from -13% at 0.1 mg/ml to -47% at 1.0 mg/ml, n = 8 to 43/dose). However, coincubation with L-NAME did not ameliorate the Ca2+ mobilization defect (peak Ca2+ increments: control = 419 +/-30 nmol/L, vs LPS (1 mg/ml) = 206+/-18 nmol/L (mean+/-SE), n = 15; p < 0.001; control/L-NAME: 417+/-31 nmol/L vs LPS/L-NAME: 212+/-19 nmol/L; n = 17 p < 0.001), despite inhibition of associated nitrite accumulation in the medium (control vs LPS: p < 0.001; control/L-NAME vs LPS/L-NAME: p > 0.05; LPS vs LPS/L-NAME: p < 0.001). Supplemental L-arginine augmented LPS-induced nitrite generation without affecting Ca2+ mobilization. Indomethacin failed to prevent the LPS-induced decrement in thrombin response, but did inhibit LPS-induced myocyte nitrite production, suggesting "crosstalk" between the NO-synthase and cyclo-oxygenase (COX) systems. These experiments suggest that LPS-induced vascular contractile impairment is at least partly mediated by an NO-independent impairment of agonist-induced myocyte Ca2+ mobilization. This further suggests that any important contribution of NO synthesis to LPS-induced contractile dysfunction must depend on impairment of the Ca2+ sensitivity of the contractile apparatus (i.e., pharmacomechanical coupling).

Animals↗
PubMed1998

Selectivity of endotoxin-induced defect in endothelial calcium mobilization.

BACKGROUND: We hypothesized that endotoxin (LPS) would impair bradykinin (BK)-induced calcium (Ca2+) mobilization in aortic endothelial cells, perhaps due to cytotoxicity or via stimulation of nitric oxide (NO) synthesis. As well, we sought to define contributions of LPS-stimulated Ca2+ mobilization to these effects. METHODS: LPS- or BK-induced increments of intracellular Ca2+ were assessed by microspectrofluorimetry with fura-2 in passaged bovine aortic endothelial cells. Time- and dose-dependent effects of LPS exposure (+/- inhibitors of NO or prostaglandin synthesis) on subsequent BK-induced Ca2+ mobilization and on attached cell counts were determined. RESULTS: LPS (0.1 to 1.0 mg/ml) led to rapid increments of Ca2+, while Ca2+ responses were delayed following LPS (1 to 10 microg/ml) and lower doses were without effect. By contrast, LPS more potently (1.0 pg to 1.0 microg/ml) led to dose- and time-dependent impairment of subsequent BK-induced Ca2+ mobilization, with peak effect at four to six hours, persisting for at least 18 hours. This delayed effect on BK-response was unaltered by inhibition of either NO synthase or cyclooxygenase. The effect of LPS on BK-responsivity depended importantly on cell confluence, as it was not observed in subconfluent cells. By contrast, LPS-induced cell detachment, which was observed only at doses > or = 1.0 microg/ml, did not depend on confluence. CONCLUSIONS: Different mechanisms lead to endothelial cytotoxicity and to impaired BK-response following LPS. Only the former effect, occurring at higher doses, might depend on initial LPS-induced Ca2+ mobilization.

Animals↗
PubMed1997

Endotoxin impairs agonist-induced calcium mobilization in rat mesangial cells.

We hypothesized that endotoxin would impair agonist-induced calcium (Ca2+) mobilization in rat mesangial cells, owing to the induction of nitric oxide synthase (NOS) and augmented nitric oxide (NO) synthesis. We measured basal and bradykinin-induced peak free cytosolic Ca2+ concentrations through microspectrofluorimetry with fura-2 in confluent mesangial cells, and assayed conditioned medium for nitrite accumulation. Prior to measurement, cells were incubated overnight in serum-supplemented medium, with or without endotoxin, 1-arginine, indomethacin, meclofenamate, or N omega-nitro-L-arginine methyl ester (L-NAME). Endotoxin (1 mg/ml) decreased bradykinin-induced peak Ca2+ responses by 35 to 60% (p < 0.0001) and increased nitrite accumulation > 6-fold (p < 0.01). Arginine supplementation further (> 9-fold, p < 0.0001) increased nitrite accumulation without changing the effect on Ca2+. Inhibition of NOS abolished increments in nitrite concentration but had no effect on impaired Ca2+ responses. Cyclooxygenase (COX) inhibitors, present during incubation with endotoxin, but not afterward, normalized bradykinin-stimulated calcium responses. Thrombin-stimulated Ca2+ responses were similarly affected. We conclude that neither NO nor prostaglandins act directly to impair agonist-induced Ca2+ mobilization following endotoxin exposure; however, this effect may be an indirect effect of COX products, including reactive oxygen intermediates.

Animals↗