This month in investigative urology: platelet activating factor: a mediator of renal pathology?
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Animals↗
Biomedical subjects
D Felsen
Publications and source records attributed to D Felsen.
Involvement of platelet activating factor and thromboxane A2 in the renal response to unilateral ureteral obstruction.
Platelet activating factor (PAF) and thromboxane A2 (TxA2) are two vasoactive mediators which can decrease renal blood flow. Both are synthesized by various intrarenal cell types or by macrophages which may infiltrate the kidney during unilateral ureteral obstruction (UUO). In several experimental systems, PAF receptor activation is accompanied by TxA2 release; pharmacological modification of TxA2 synthesis or receptor activation modulates the response to PAF. The involvement of PAF in UUO has not been studied previously, and the role of TxA2 has not been clearly defined by previous investigations. The hemodynamic response to acute UUO is characterized by decreases in renal blood flow (RBF) and glomerular filtration rate and an acute increase in ureteral pressure. In the present experiments, the involvement of either PAF or TxA2 in the acute response to UUO was studied by determining if blockade of either the TxA2 or PAF receptor would affect the renal hemodynamic response to UUO. In addition, the effect of blockade of the TxA2 receptor on the renal response to PAF was determined. Our results indicate that only a small portion of the renal response to PAF is mediated by TxA2, and that neither PAF nor TxA2 can be implicated in the acute hemodynamic response to UUO. TxA2 or PAF involvement in the chronic response to UUO still remains to be determined.
Animals↗
Cachectin/tumor necrosis factor production by fetal and newborn rat hepatic macrophages.
The capacity of fetal and newborn hepatic macrophages to produce cachectin/tumor necrosis factor (TNF) has not been previously examined. The role that TNF plays in newborn infection is also unknown. In the present report, fetal and newborn rat hepatic macrophages have been maintained in short-term tissue culture, and are shown to produce TNF in response to in-vitro endotoxin stimulation. Cells obtained are morphologically and antigenically consistent with macrophages, and are depleted of accessory cells and lymphocytes. In response to increasing doses of endotoxin, fetal and newborn hepatic macrophages produce TNF, and this production is suppressed fully by pretreatment with dexamethasone. The results demonstrate that fetal and newborn hepatic macrophages possess the capability to produce TNF in vitro. We propose that TNF may play a role in the response of the fetus and newborn to bacterial infection.
Animals↗
An in vivo evaluation of alpha adrenergic receptors in canine prostate.
The role of alpha 2 adrenergic receptors in the prostate in vivo is unknown. A model was developed to measure canine prostatic urethral pressure in vivo, and to assess the ability of various alpha adrenergic blocking agents to affect prostatic pressure. In this model, an esophogeal pressure catheter is inserted into the prostatic urethra to record prostatic urethral pressure. We investigated the effects of alpha adrenergic agonists and antagonists on prostatic pressure using this model. Dose-response curves were generated for epinephrine, and were then repeated in the presence of either prazosin (alpha 1 antagonist), yohimbine (alpha 2 antagonist) or SK&F-86466 (alpha 2 antagonist). Prazosin was the most potent of the three drugs in competitively blocking epinephrine-induced contraction of the prostate, with an inhibition constant of 0.24 micrograms./kg. calculated from the double reciprocal plot. Clonidine, an alpha 2 adrenergic agonist, caused contraction of the prostate, which was also blocked by prazosin. Furthermore, the specific alpha 2 agonist BHT-920 was totally inactive in our system. These results demonstrate that the increase in urethral pressure caused by alpha-adrenergic agonists can be blocked by alpha adrenergic antagonists. However, the specific alpha 1 antagonist, prazosin, is more potent than alpha 2 antagonists, and is also effective against an alpha 2 agonist, clonidine. This suggests that blockade of alpha 1 receptors may be a more useful strategy for causing relaxation of the prostate than blockade of alpha 2 receptors.
Adrenergic alpha-Agonists↗
Differential effect of platelet-activating factor (PAF) receptor antagonists on peptide and PAF-stimulated prostaglandin release in unilateral ureteral obstruction.
Unilateral ureteral obstruction (UUO) results in increased renal resistance as well as in exaggerated prostaglandin (PG) release from the obstructed hydronephrotic kidney (HNK). We have reported previously that platelet-activating factor (PAF) dose-dependently stimulates the release of PGs from both the HNK and unobstructed contralateral kidney (CLK), with CLK release being 10% that of the HNK. In the present report, we studied the interaction of PAF with its receptor by examining the effects of PAF-receptor antagonists on the release of PGs from the isolated perfused rabbit HNK and CLK stimulated by PAF; angiotensin II (AII), and bradykinin (BK) were also used as agonists. In the HNK, kadsurenone (3 microM) inhibited PAF-stimulated PGE2 and thromboxane B2 (TxB2) release by 28.2 and 62.5% respectively. CV-3988 (20 microM) and triazolam (5 microM) also preferentially diminished PAF-stimulated TxB2 release. In addition, all three drugs significantly diminished BK- and AII-stimulated TxB2 release, while CV-3988 was the only antagonist to affect peptide-stimulated PGE2 release. While effective against agonist-stimulated PG synthesis, these drugs had no direct effect on arachidonic acid metabolism to PGs. Furthermore, in the CLK, CV-3988 had no effect on BK- or AII-stimulated PGE2 release, whereas it totally inhibited PAF-stimulated release of PGE2. These results show that PAF-receptor antagonists in the HNK preferentially inhibit TxB2 release whether stimulated by PAF, AII or BK; in the CLK only PAF-stimulated PG release is affected. This biochemical difference may be of physiological significance and explain some of the functional differences between the HNK and CLK. Therefore, PAF may be an important mediator of some of the biochemical and functional changes associated with UUO.
Angiotensin II↗
Clonidine displacing substance is biologically active on smooth muscle.
A substance has been isolated from brain which potently inhibits the binding of clonidine to brain membranes (clonidine displacing substance, CDS). We sought to determine if CDS is biologically active on smooth muscle. CDS had no effect on vascular smooth muscle. In contrast, CDS potently contracted rat gastric fundus strips in a dose dependent manner. The contractile effect of CDS was not blocked by antagonists selective for biologically active substances known to contract the fundus strip. These results demonstrate that CDS has a unique and potent ability to selectively contract smooth muscle.
Animals↗
Anti-aggregatory and contractile activity of analogues of prostaglandins E1, D1 and H1.
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Fibrinolytic Agents↗
The effect of the thromboxane A2 synthesis inhibitor OKY-046 on renal function in rabbits following release of unilateral ureteral obstruction.
A marked decrease in renal blood flow (RBF) and glomerular filtration rate (GFR) was found after 24, 48 and 72 hours of total unilateral ureteral obstruction (UUO) in the rabbit. Contralateral GFR showed a modest increase consistent with compensatory hypertrophy. The urinary excretion of thromboxane B2 (TxB2), the stable metabolite of the vasoconstrictor prostaglandin, thromboxane A2 (TxA2) was significantly elevated in the urine obtained following release of the obstructed ureter when compared to the TxB2 level in the urine from the contralateral kidney. Continuous infusion of OKY-046 at 100 micrograms./kg./min. over 24 hours during UUO decreased TxB2 excretion by greater than 80 per cent. However there was no significant preservation of RBF or GFR of the obstructed kidney following ureteral release despite the selective inhibition of TxA2. Moreover the increase in contralateral GFR was also abolished. Taken together with other studies these results strongly suggest that the potent vasoconstrictor TxA2 is not responsible for the rise in renal resistance that follows acute UUO.
Acrylates↗
Effect of ureteral obstruction on renal hemodynamics.
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Angiotensin II↗
Effect of thromboxane inhibition on renal blood flow in dogs with complete unilateral ureteral obstruction.
The effect of the thromboxane synthetase inhibitor OKY-046 on renal blood flow and ureteral pressure in awake dogs during 18 hours of complete unilateral ureteral obstruction was studied. OKY-046 was infused continuously throughout the period of obstruction and post-release. Renal blood flow and ureteral pressure were constantly monitored during the study. Urinary thromboxane B2 and prostaglandin E2 excretion served as markers for inhibition of renal thromboxane A2 synthesis. The triphasic relationship between ipsilateral renal blood flow and ureteral pressure previously found following unilateral ureteral obstruction was observed despite OKY-046 infusion. Inhibition of ipsilateral urinary thromboxane B2 excretion was greater than 90% compared to control while ipsilateral urinary prostaglandin E2 excretion was not consistently decreased showing specific thromboxane inhibition. These results suggest that urinary thromboxane B2 may serve as a useful marker for determining the effects of inhibition on renal thromboxane A2 production. At the level of inhibition of thromboxane synthesis achieved we did not observe any change in the late decrease in renal blood flow which is typically seen with chronic unilateral ureteral obstruction.
Acrylates↗
The effect of sodium intake on renal prostaglandin production.
The effect of chronic alterations in dietary sodium intake on renal arachidonic acid (AA) metabolism was studied in male Wistar rats who were maintained for 14 days on a diet consisting of sodium-deficient food and either deionized water (low salt intake, LSI), 1% saline (normal salt intake, NSI), or 2% saline (high salt intake, HSI). 24 h Urinary Sodium (UNaV) and plasma renin activity (PRA) measurements were shown to validate the dietary protocol. Microsomal preparations from the cortices and medullae were incubated with radiolabeled exogenous AA, and endogenous urinary prostaglandin (PG) levels were assayed by RIA to quantify renal PG synthesis. Cortical PGF2 alpha and PGE2 synthesis was found to be the greatest following LSI. In contrast, medullary PGF2 alpha was shown to be the least following LSI and to increase with increased sodium intake. Likewise, urinary PGF2 alpha levels significantly increased with increasing sodium intake. Changes in urinary PGE2 levels showed the same trend as PGF2 alpha but did not achieve statistical significance. These data show that dietary sodium differentially affects renal cortical and medullary PG synthesis and may reflect physiological differences in the regulation of cyclooxygenase in these zones. These data further suggest that the major source of urinary PGs is the renal medulla since the relationship of urinary levels to sodium intake mimics that described for the synthesis of PGs by the medullary tissue.
Animals↗
Platelet-activating factor is a potent stimulus for renal prostaglandin synthesis: possible significance in unilateral ureteral obstruction.
Platelet-activating factor (PAF), a lipid with potent platelet-stimulating and hypotensive properties, has been shown to stimulate the release of prostaglandins (PGs) from a number of cell types. It is produced by a variety of inflammatory cells and the renal medulla. However, no studies to date have examined the effect of PAF on the intact kidney. We, therefore, studied the effect of bolus injections of PAF on the isolated perfused rabbit kidney subjected to aseptic ureteral ligation for 72 hr. Intrarenal resistance and release of PGs by both the hydronephrotic (HNK) and contralateral kidney (CLK) were quantified. Intrarenal administration of PAF causes a dose-dependent stimulation of the release of PGE2, thromboxane B2 (TxB2) and the PGI2 metabolite, 6-keto-PGF1 alpha from the HNK and CLK. The magnitude of the release from the HNK is much greater than that for the CLK. A 100-ng bolus injection of PAF into the HNK results in the release of 1561.0 +/- 312.0 and 117.7 +/- 38.2 ng of PGE2 and TxB2, respectively, whereas administration of this dose to the CLK causes 291.0 +/- 35.0 ng of PGE2 and 19.0 +/- 4.2 ng of TxB2 to be released. Renal vascular resistance (RVR) is increased by PAF in the HNK. Product identity was confirmed using selective inhibitors and bioassay. These data show that PAF is a potent stimulus for renal PG release and that this release may have vascular consequences.
Animals↗
Indications and contraindications for the use of nonsteroidal antiinflammatory drugs in urology.
Prostaglandins are ubiquitous biologically active compounds that are involved in inflammatory reactions, hemostasis, and, under certain circumstances, the maintenance of renal function. NSAIDs, which inhibit PG synthesis, are used therapeutically most often as antiinflammatory agents in conditions of inflammation and pain, mostly of a nonurologic nature. However, since NSAIDs inhibit systemic PG synthesis, administration of NSAIDs can lead to adverse side effects. For example, the gastrointestinal irritation caused by NSAIDs probably reflects removal of a cytoprotective effect of gastrointestinal PGs. Similarly, the kidney may be especially susceptible to adverse effects of NSAIDs. In diseases such as peptic ulcers, diabetes, hypertension, congestive heart failure, liver disease with ascites, and renal insufficiency, PGs seem to play a protective role in the kidney. This protective role, which results from increased synthesis of vasodilator PGs in the face of elevated vasoconstrictors, is diminished in the presence of NSAIDs. Other side effects include the antagonism by NSAIDs of the action of diuretics, such that the dose of the diuretic must be adjusted accordingly. The diuretic triamterene should not be used in conjunction with indomethacin due to several reported cases of toxicity. Another drug interaction involves the salicylates, which have been shown to diminish the uricosuric effects of probenecid and sulfinpyrazone. Likewise, since corticosteroids increase the renal clearance of salicylates, it is important to monitor the patient carefully following termination of steroid treatment in patients receiving large doses of salicylates, since this change in elimination can precipitate toxicity. In addition, the NSAIDs bind to plasma proteins and, as such, can displace or be displaced by other drugs that bind in the same manner and can result in either decreased efficacy or toxicity. Despite the fact that the kidney may not be the target of NSAID therapy, renal function may be adversely affected by NSAID treatment. It has therefore been proposed that a renal-sparing NSAID would be a very useful therapeutic agent. Sulindac (Clinoril) has been suggested to be such an agent, eg, able to inhibit systemic PG synthesis (usually monitored by measuring serum thromboxane synthesis) without an apparent effect on renal PG synthesis (monitored by measurement of urinary PGs). However, recent data have suggested that Sulindac does inhibit renal PG synthesis and does not exhibit selectivity. The reasons for the discrepancy are not clear, but may relate to the doses or time intervals examined.(ABSTRACT TRUNCATED AT 400 WORDS)
Acute Kidney Injury↗