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In summary, it is apparent that renal sodium retention in patients with advanced liver disease constitutes a fascinating constellation with numerous and diverse causes and an elusive pathophysiology. The dissociation between hyperaldosteronism and the attendant changes in renal sodium handling and the demonstration of an impairment in natriuretic hormone release despite the absence of overt signs of sodium retention underscore the complete nature of the derangement. It is likely that the development of sodium retention necessitates the participation of several hormonal and/or neural effectors, acting in concert. Additional insight into this fascinating problem must await further biochemical characterization of some of the mediators and a delineation of their pathophysiological role.

As a consequence of its ability to absorb salt in excess of water, the thick ascending limb of the mammalian kidney dilutes the urine and supplies the energy for counter current multiplication. This latter effect follows directly from the ability of the medullary thick ascending limb (mTALH) to enrich medullary osmolality. In this review, we consider certain selected aspects of mTALH function that determine its ability to dilute the urine and to contribute to overall renal concentrating power. Specifically, we shall review the mechanisms for salt absorption in the mTALH and the modulation of salt absorption in the mTALH and hence urinary concentrating power, by antidiuretic hormone (ADH), prostaglandin E2 (PGE2) and peritubular hypertonicity. Furthermore, we shall advance an explanation of how these latter three agents modulate mTALH function without affecting external salt balance.

The hypothesis that pro-inflammatory spasmogens may be generated locally in the vessels of the head by neurohumoral stimuli has been tested using an isolated extracranial vascular bed from the rabbit. No spasmogen release was detected after adenosine triphosphate, histamine, acetylcholine or noradrenaline and was seen rarely after tyramine and 5-hydroxytryptamine. Both sympathetic nerve stimulation and periods of vascular stasis released spasmogen, probably an E-type prostaglandin. The local generation of pro-inflammatory substances by excess sympathetic stimulation and/or vascular stasis might contribute to the development and maintenance of the acute migraine attack.

The role of the renal prostaglandin (PG) system in the renal effects of furosemide was assessed by using indomethacin, an inhibitor of PG synthetase, in conscious rats under conditions of vasopressin infusion (or dehydration). Urinary PGE and PGF2 alpha were measured by radioimmunoassay under conditions of furosemide-induced diuresis. The diuretic and natriuretic effects of furosemide were accompanied by a concomitant increase in the urinary excretion of PGE. In normal rats the pretreatment of indomethacin at 10 mg/kg failed to alter the diuretic effect of furosemide (5 mg/kg). In contrast, the diuretic effect of furosemide in vasopressin (2 U/kg)-infused (or dehydrated) rats was greatly inhibited by indomethacin. In regard to the natriuretic effect of furosemide, indomethacin did impair this response to furosemide both in normal and vasopressin-infused (or dehydrated) rats, but inhibited more strongly in the latter than in the former. These results suggest that the renal PGE is necessary for furosemide to produce optimal diuretic and natriuretic effects under conditions of vasopressin infusion (or dehydration).

Amlexanox markedly inhibits histamine release from rat mast cells. To clarify the mechanism of this inhibition, we investigated the effect of amlexanox on cAMP content, which, when increased, inhibits histamine release in rat peritoneal mast cells. At concentrations of 10(-8)-10(-6)M, amlexanox or isoproterenol increased the cAMP content of mast cells over that of control cells about 2-fold. When the mast cells were incubated with 10(-8), 10(-7) and 10(-6) M of amlexanox combined with 10(-7) M isoproterenol, the cAMP contents were synergistically increased 15-, 60- and 88-fold, respectively. 3-Isobutyl-1-methylxanthine (IBMX) at 10(-6)-10(-4) M increased the cAMP content 1.7-3.8-fold, and a combination of 10(-4) M IBMX and 10(-7) M isoproterenol synergistically increased the cAMP content 41-fold. A combination of amlexanox and IBMX synergistically increased the cAMP content 19-fold. The increase in cAMP content, when amlexanox and isoproterenol were combined, was transient; it peaked at 0.5 min after the drugs were administered, then decreased to 20-30% of the peak value about 2 min later. Pretreatment of mast cells with amlexanox reduced the effect of the combination of amlexanox and isoproterenol, indicating tachyphylaxis; pretreatment with IBMX had no such effect. The cAMP content of macrophages was also increased by amlexanox, but when combined with isoproterenol or PGE2, the effect was additive. Amlexanox inhibited cAMP phosphodiesterase in rat mast cells; its IC50 value was 1.4 X 10(-5) M, and its inhibitory activity was half that of IBMX.(ABSTRACT TRUNCATED AT 250 WORDS)

The intravenous administration of triple typhoid vaccine to anesthetized dogs resulted in a significant increase in renal blood flow accompanied by a modest decline in systemic blood pressure. This renal hyperemia was associated with elevated renal secretory rates of renin and prostaglandin E and F. Measurements of the intracortical distribution of radiolabeled microspheres revealed a progressive decrease in outer cortical blood flow rates and a progressive increase in inner cortical flow rates. When meclofenamate, an inhibitor of prostaglandin synthetase, was administered concomitantly with triple typhoid vaccine renal hyperemia did not develop. The renal renin secretory rate increased modestly and intracortical renal blood flow was not redistributed. The increased renal blood flow after triple typhoid vaccine administration to unanesthetized dogs was also reversed by meclofenamate. The marked increase in prostaglandin secretion by the kidney during renal hyperemia following triple typhoid vaccine administration (pyrogen), and the effect of meclofenamate, is consonant with a role for increased renal synthesis and release of prostaglandins.

This study was designed to determine the influence of acetazolamide, a potent inhibitor of carbonic anhydrase, on the formation of gastric mucosal lesions induced by acidified aspirin (ASA) or absolute ethanol and on gastric cytoprotection induced by prostaglandin E2 (PGE2). Acetazolamide prevented dose-dependently ethanol-induced gastric lesions and this effect was accompanied by an increased biosynthesis of mucosal PGs, indicating that endogenous PGs may be involved in cytoprotection by acetazolamide. This is supported by the finding that acetazolamide failed to affect gastric ulcerations produced by acidified ASA when mucosal PG biosynthesis was almost completely suppressed. Pretreatment with acetazolamide did not influence the protective action of PGE2 on ethanol-induced mucosal lesions and only slightly inhibited the protective effect of PGE2 on ASA-induced gastric ulcerations. This study indicates that: (1) acetazolamide prevents ethanol- but not ASA-induced gastric mucosal lesions probably via stimulation of PG biosynthesis and (2) gastric alkaline secretion, mediated by carbonic anhydrase, is probably not an essential mechanism responsible for this cytoprotection induced by PGE2.

The aim of this study was to investigate whether prostaglandins (PG) are involved in the mediation of sennoside-induced colonic fluid and electrolyte secretion. Oral administration of senna pod extract dose-dependently reversed net absorption of water, sodium and chloride to net secretion, increased potassium secretion and stimulated the release of PGE2 into the colonic lumen. Inhibition of PG biosynthesis by pretreatment of the rats with indomethacin significantly inhibited the effects of senna pod extract both on net fluid transport and on PGE2 release. The inhibitory effect of indomethacin on net fluid transport induced by senna pod extract was dose-dependent. It is concluded that sennosides exert their laxative action at least partially via stimulation of colonic fluid and electrolyte secretion, and that this secretion is mediated by stimulation of endogenous PGE2 formation.

The present study evaluated whether acetaminophen can reduce sodium-taurocholate-induced damage to human gastric epithelial cells grown in monolayer culture (a preparation which excludes systemic factors). Further, the role of endogenous prostaglandin production by gastric cells in any such protection has been assessed. Results showed that (1) acetaminophen significantly protects human gastric epithelial cells against taurocholate-induced damage in vitro, in conditions independent of systemic factors, (2) protection of gastric cells by acetaminophen in vitro appears unrelated to stimulation of prostaglandin synthesis, and (3) a direct protective effect on gastric epithelial cells may play a role in protection of gastric mucosa by acetaminophen in vivo.

Sympathetic nerves innervate smooth muscle cells in the theca externa of Graafian follicles and induce contraction of the follicle wall. The interaction of prostaglandins (PGs) with the function of this neuromuscular complex has been elucidated by the use of isolated strips from the protruding part of the wall of bovine ovarian follicles. PGF2 alpha contracts the strips, and it also potentiates the contractile response to electrical field stimulation of the nerves, but it has no effect on noradrenaline-induced contractions. PGE1 and PGE2 have direct relaxatory actions on the strip preparation (previously given an active contraction by carbamylcholine) and in high doses they, therefore, reduce the contractile response induced by noradrenaline. In low doses not affecting the noradrenaline response, PGE1 and PGE2 both decrease the amount of contraction induced by electric nerve stimulation, indicating an inhibitory action of the PGEs on the transmitter release. It is suggested that the role of PGs in the process of ovulation might, at least partly, be mediated by their interactions with smooth muscle cells and their sympathetic innervation in the wall of the Graafian follicle.

The evidence is reviewed that prostaglandins of renal origin through (i) their local actions on renal blood vessels, and (ii) complex interactions with the nervous adrenergic and the endocrine vasoactive renin-angiotensin-aldosterone and kallikrein-kinin systems, may participate in the regulation of excretory functions of the kidney and thereby contribute to circulatory homeostatic mechanisms.

The influence of low-sodium dialysate (126 mmol/l) on plasma levels of prostaglandin E2 (PGE2) and PGF2 alpha, plasma renin activity (PRA) and arterial blood pressure was investigated in 16 patients on maintenance hemodialysis. PGE2 rose more than tenfold and there was a significant increase in PGF2 alpha and PRA. Mean arterial pressure dropped by 30 mm Hg causing discomfort in several patients. By contrast, conventional hemodialysis against 140 mmol/l of sodium was followed by less pronounced changes in plasma prostaglandins, and reduction of blood pressure was moderate (13 mm Hg). It is suggested that vasodilating prostaglandins may contribute to dialysis hypotension. Their origin may not be confined to the kidneys but rather extend to the lungs and circulating blood cells. The in vitro generation of prostaglandins was demonstrated when donor blood was circulated in an extracorporeal dialysis system.

The effect of in vitro addition of indomethacin, an inhibitor of the cyclooxygenase pathway, and of prostaglandin E1 and E2 on the proliferative capacity of phytohemagglutinin- and concanavalin A-stimulated spleen lymphocytes from young and old, long-lived (C3H X C57BL/10 RIII)F1 mice was investigated. Mitogen-activated splenocytes from old mice showed a different sensitivity to these drugs than splenocytes from young animals. Additionally, our data indicate that drugs can act either as inhibitors or as stimulators of mitogenesis, depending on the mitogen used, the dose of the drug, the age of the cell donor and the length of time in culture. It is suggested that prostaglandins of the E series may play a role in the pathogenesis of age-associated immune impairment.

The effects of chronic gentamicin administration on renal function was studied in dogs receiving 4 mg/kg i.m. of gentamicin b.i.d. for 28 days. Administration of gentamicin resulted in a bimodal change in renal function. A decrease in urine osmolality was first noted on day 6 and declined progressively throughout the study. This decrease in urinary concentrating ability was preceded by a steady rise in urinary prostaglandin E2 (PGE) excretion and followed by a rise in plasma renin activity (PRA). Prior to an increase in azotemia, urinary PGE decreased precipitously while PRA continued to rise throughout the remainder of the study. The precipitous decrease in GFR was accompanied by a significant increase in FENa to seven times control. These studies suggest a dual effect of chronic gentamicin administration on renal function: (1) an early effect manifested by stimulation of urinary prostaglandin production with a concomitant loss of urinary concentrating ability and mild prerenal azotemia, and (2) a late effect, preceded by a decrease in urinary prostaglandin excretion while PRA continues to increase, and manifested by increase fractional excretion of sodium and progressive azotemia.

Studies were undertaken to further elucidate the role of endogenous prostaglandins in normal renal function in the awake dog. Meclofenamate (2 mg/kg and 2 mg/kg/h, i.v.) was administered after control measurements. Parallel time control experiments were also performed. Inhibition of renal prostaglandin synthesis was documented by significant reduction in urinary prostaglandin E2 excretion rate. Urine flow and sodium excretion were reduced by meclofenamate infusion. In addition, fractional excretion of sodium was reduced, implying enhanced sodium reabsorption during prostaglandin synthesis inhibition. Renal hemodynamics, glomerular filtration and systemic hemodynamics were unaffected. It is concluded that endogenous prostaglandin release is important in influencing sodium and water excretion in the conscious dog.

Tumor necrosis factor alpha is increasingly being recognized as an important macrophage-derived cytokine that possesses pleomorphic effects in both physiologic and immunologic systems. Current evidence has demonstrated that tumor necrosis factor may stimulate a plethora of cellular responses in vitro and induce multiple physiologic derangements when given in vivo. While the biologic activity of tumor necrosis factor elaborated by macrophages and macrophage cell lines in response to bacterial and protozoal cell products have been well documented, the endogenous factors that regulate the production of this monokine are not as clearly delineated. This chapter focuses on the cellular and molecular mechanisms that endogenously regulate the production of tumor necrosis factor.

The relationships between the renal kallikrein-kinin (K-K) and prostaglandin (PG) systems under conditions of furosemide-induced diuresis were studied in normal rats. Urinary PGE and PGF2 alpha were measured by radioimmunoassay, and urinary kallikrein by enzymatic activity. The diuretic and natriuretic effects of furosemide were accompanied by a concomitant increase in the urinary excretion of kallikrein and PGE. The urinary excretion of kallikrein and PGE was closely related to the urinary excretion of sodium, potassium and chloride. The urinary excretion of kallikrein also showed a highly significant correlation with the urinary excretion of PGE. Pretreatment of the animal with indomethacin or aprotinin inhibited furosemide-induced diuresis and natriuresis. Aprotinin inhibited the urinary excretion of PGE, while indomethacin did not exert any inhibitory action on the urinary excretion of kallikrein. Although the urinary excretion of kallikrein was closely related to the urinary excretion of potassium, both indomethacin and aprotinin had no effect on the urinary excretion of potassium. The results indicate that the potassium-sodium exchange caused by furosemide in the distal nephron might stimulate the renal K-K system to result in increasing synthesis of PGE, which would, at least in part, participate in the diuretic and natriuretic effects of furosemide.