Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostaglandin (PG) synthesis in the kidney is localised to specific sites and is not uniformly present throughout the nephron. It is generally accepted that the regional heterogeneity of PGs, as well as the lack of vascular communications between the medulla and cortex, dictate that PGs [primarily prostacyclin (PGI2)] synthesised in the cortex (glomeruli and vasculature) regulate cortical function, while PGs (primarily PGE2) synthesised in the medulla (collecting tubule and medullary interstitial cells) regulate medullary function. Measurement of urinary unmetabolised PGs, or their stable hydration products, provides the best clinical assessment of the state of renal PG production. Under physiological circumstances, renal function is not critically dependent upon the integrity of PG synthesis, possibly because other regulatory mechanisms can compensate for PG synthesis inhibition. However, when renal PG synthesis is activated in response to altered haemodynamics (e.g. cirrhosis with ascites) or is pathologically reduced (e.g. chronic glomerular disease) then the consequences of pharmacological inhibition can become clinically apparent and measurable. In these circumstances, drugs that inhibit renal cyclo-oxygenase activity can acutely reduce glomerular filtration rate and renal blood flow by 30 to 50%. These functional changes are usually reversible upon discontinuing the drug. The long term consequences of renal PG synthesis inhibition are more difficult to assess. Theoretically, chronic inhibition of renal PG synthesis might be responsible for medullary ischaemia, possibly contributing to the picture of so-called analgesic nephropathy. Selective sparing of renal cyclo-oxygenase activity can be obtained by at least 3 mechanisms: differential 'sensitivity' of the glomerular cyclo-oxygenase; selective intra-renal inactivation of an active metabolite of the drug; differential rate of recovery of glomerular cyclo-oxygenase following irreversible acetylation by aspirin. The recent demonstration of a functional correlate of such biochemical selectivity suggests novel strategies for reducing the chronic renal toxicity of cyclo-oxygenase inhibitors.
 ...
PMID:The role of prostaglandin synthesis inhibition in the renal syndromes associated with non-narcotic analgesics. 310 92

A. No consistent changes in the urine PGE2 and PGF2 alpha related to sodium excretion could be found in hepatic cirrhosis with and without ascites. B. Intensive renal sodium retention in cirrhosis with ascites (urine Natless than 20 mEq/24 hr) is very often associated with increasing PGF/PGE ratio, whereas absolute urine PGE2 can be found low or normal. The PG shift is possibly due to a stimulation of the PGE2-9-keto-reductase. C. Application of saluretics and spironolactone in cirrhosis with ascites normalizes the PGF/PGE ratio in accordance with increasing sodium excretion. D. PG changes observed cannot be considered as a primary factor accounting for deranged renal sodium handling in cirrhosis. Anomalous PG pattern possibly reflects enchanced intrarenal vascular resistance.
Adv Prostaglandin Thromboxane Res 1980
PMID:Relationship between urinary prostaglandin (PGE2 and PGF2 alpha) and sodium excretion in various stages of chronic liver disease. 736 21

Nitric oxide (NO) and prostacyclin (PGI2) are two important modulators of renal function under normal conditions; however, little is known on their contributory role in cirrhosis with ascites. In this study, mean arterial pressure, renal hemodynamics, and sodium excretion were measured in 15 rats with cirrhosis and ascites and 16 control rats. Animals were studied in normal conditions, after inhibiting the synthesis of NO (N omega-nitro-L-arginine, 50 micrograms.kg-1.min-1) or prostaglandins (lysin acetylsalicylate, 15 mg.kg-1).min-1 and following the concomitant inhibition of both systems. Cirrhotic rats showed increased systemic pressure sensitivity and blunted renal vasoconstrictor response to nitric oxide inhibition as compared with control rats. As a consequence, the glomerular filtration rate increased in cirrhotic rats but not in control rats. In both groups of animals, NO inhibition was associated with significant increased urinary sodium and fractional sodium excretion. The only significant effect observed after prostaglandin biosynthesis inhibition was a decrease in renal plasma flow in cirrhotic rats. The concomitant inhibition of both systems reduced renal plasma flow and did not change glomerular filtration rate, with no differences between control and cirrhotic rats. Prostaglandin inhibition did not prevent the natriuretic effect of the NO inhibitor in both groups of animals. These results indicate that in experimental cirrhosis both NO and PGI2 play an important role in the maintenance of renal perfusion within normal limits.
 ...
PMID:Role of nitric oxide and prostacyclin in the control of renal perfusion in experimental cirrhosis. 765

8-epi-Prostaglandin (PG) F2alpha may be formed by cyclooxygenases 1 and 2 or by a free radical catalyzed process as an isoprostane. Concentrations of 8-epi-PGF2alpha in the range 1 nM to 1 microM induce a dose-dependent increase in platelet shape change, in calcium release from intracellular stores [Ca2+]iand in inositol phosphates; it also causes irreversible platelet aggregation, dependent on thromboxane generation, when incubated with subthreshold concentrations of ADP, thrombin, collagen, and arachidonic acid. Much higher concentrations of 8-epi-PGF2alpha (10-20 microM) alone induce weak, reversible aggregation. Although these effects are prevented by pharmacological thromboxane receptor antagonists, they are unlikely to be mediated by thromboxane receptors. Thus, 8-epi-PGF2alpha does not compete for binding at the stably expressed placental or endothelial isoforms of the thromboxane receptor or for binding of thromboxane ligands to human platelets. Furthermore, the response to 8-epi PGF2alpha exhibits structural specificity versus 8-epi PGF3alpha and PGF2alpha. Concentrations in the range that evoke its effects on platelets do not desensitize the aggregation response stimulated by thromboxane or PGH2 analogs. Unlike primary prostaglandins, which are rapidly metabolized to inactive products, 8-epi PGF2alpha circulates in plasma. However, the systemic concentrations found in healthy volunteers (median 48 pmol/liter) and in patients with hepatic cirrhosis (median 147 pmol/liter), a syndrome of oxidant stress in vivo, fall well below those which modulate platelet function. 8-Epi PGF2alpha may amplify the response to platelet agonists in syndromes where oxidant stress and platelet activation coincide. Despite blockade by thromboxane antagonists, 8-epi PGF2alpha does not activate either of the thromboxane receptor isoforms described in platelets. Activation of a distinct receptor would be consistent with the enzymatic formation of 8-epi PGF2alpha by cyclooxygenases. However, incidental activation of such a receptor by systemic concentrations of 8-epi PGF2alpha is unlikely to occur, even in syndromes of excessive free radical generation in vivo.
 ...
PMID:Local amplification of platelet function by 8-Epi prostaglandin F2alpha is not mediated by thromboxane receptor isoforms. 866 15

Use of non-steroidal anti-inflammatory drugs in cirrhosis has been associated with impairment of renal function based on its ability to inhibit the renal production of prostaglandins. Renal effects of dipyrone in patients with cirrhosis have not been evaluated. We aimed to assess the renal effect of therapeutic doses of dipyrone used for short periods of time in patients with cirrhosis. Twenty-nine patients with cirrhosis were included in an observer-blind clinical trial. Patients were randomized to receive three times a day oral acetaminophen (500 mg; N = 15) or dipyrone (575 mg; N = 14) for 72 hr. Serum and urine samples were obtained at baseline, 48 and 72 hr, and cystatin C, creatinine, aldosterone, 6-keto-Prostaglandin-F1 alpha and prostaglandin E2 were measured. Cystatin C and creatinine levels remained comparable in patients treated with acetaminophen and dipyrone. Urine and serum prostaglandins concentrations were significantly decreased at 72 hr in patients treated with dipyrone regardless of the status of ascites. One patient with ascites treated with dipyrone required a paracentesis and developed renal insufficiency. We conclude that dipyrone and acetaminophen did not reduce renal function when used for short periods of time (up to 72 hr) in patients with cirrhosis. However, considering that dipyrone lowered renal vasodilator prostaglandins synthesis, acetaminophen appears as the safest choice with respect to kidney function in cirrhosis.
 ...
PMID:Acute effects of dipyrone on renal function in patients with cirrhosis: a randomized controlled trial. 2515 57