Rifampin inhibits prostaglandin E2 production and arachidonic acid release in human alveolar epithelial cells

Rifampin, a potent antimicrobial agent, is a major drug in the treatment of tuberculosis. There is evidence that rifampin also serves as an immunomodulator. Based on findings that arachidonic acid and its metabolites are involved in the pathogeneses of Mycobacterium tuberculosis infections, we investigated whether rifampin affects prostaglandin E(2) (PGE(2)) production in human alveolar epithelial cells stimulated with interleukin-1beta. Rifampin caused a dose-dependent inhibition of PGE(2) production. At doses of 100, 50, and 25 microg/ml, it inhibited PGE(2) production by 75%, 59%, and 45%, respectively (P < 0.001). Regarding the mechanism involved, rifampin caused a time- and dose-dependent inhibition of arachidonic acid release from the alveolar cells. At doses of 100, 50, 25, and 10 mug/ml, it significantly inhibited the release of arachidonic acid by 93%, 64%, 58%, and 35%, respectively (P < 0.001). Rifampin did not affect the phosphorylation of cytosolic phospholipase A(2) or the expression of cyclooxygenase-2. The inhibition of PGE(2), and presumably other arachidonic acid products, probably contributes to the efficacy of rifampin in the treatment of tuberculosis and may explain some of its adverse effects.     

Effects of blockades of alpha and beta adrenoceptors and dopamine receptors on renal nerve stimulation-induced prostaglandin E2 and renin release in anesthetized dogs

Effects of intrarenal infusions of prazosin (0.7 microgram/kg/min), yohimbine (1 microgram/kg/min), propranolol (4 micrograms/kg/min) and sulpiride (20 micrograms/kg/min) on renal prostaglandin (PG) E2 and renin release in response to renal nerve stimulation (RNS) were examined in anesthetized dogs. RNS (2.5-5 Hz, for 10 min) decreased renal blood flow and increased both PGE2 and renin secretion rates. The blood flow response was inhibited by prazosin but not by other antagonists. Prazosin and propranolol, but not yohimbine or sulpiride, attenuated the renin response. However, none of these antagonists affected the PGE2 response. The results suggest that the RNS-induced renin release is mediated by alpha adrenoceptors, which seem to be alpha-1 type, and beta adrenoceptors, but the RNS-induced PGE2 release is not mediated by these adrenoceptors. Renal dopaminergic component may play no significant role in the RNS-induced PGE2 or renin release.     

Human cytomegalovirus-induced immunosuppression. Relationship to tumor necrosis factor-dependent release of arachidonic acid and prostaglandin E2 in human monocytes.

Cytomegalovirus (CMV) has been associated with immunosuppression. Previously CMV was reported to interfere with signal transduction pathways in T cells. In this report the mechanisms underlying CMV-mediated immunosuppression were examined. Supernatants of CMV (Strains C-87, AD-169)-infected primary human monocyte (MO) cultures inhibited mitogenic T cell proliferative responses by > 95%. The inhibitory activity was observed 24 h through day 7 postinfection. The infection of MO was associated with a sustained elevation of intracellular levels of cAMP and the release of arachidonic acid (AA) and its metabolite PGE2 (activator of adenylate cyclase) in culture supernatants. The AA release was incidentally associated with TNF-alpha production. Monoclonal antibodies to TNF-alpha and pentoxyphylline (inhibitor of TNF synthesis) inhibited both AA and PGE2 release. The release of AA required protein synthesis and occurred under conditions consistent with the expression of CMV immediate early genes. Treatment of MO cultures at time of infection with 100 microM indomethacin or 1 microg of TNF-alpha mAb abolished the CMV-induced T cell inhibitory activity of the supernatants by 100%. These data suggest that TNF dependent release of AA and PGE2 contributes to CMV-induced immunosuppression.     

Evidence for prostaglandin-independent mechanisms in renin release mediated by alpha adrenoceptors during renal nerve stimulation in anesthetized dogs

We investigated alpha adrenoceptor-mediated renin release in relation to renal prostaglandin production in anesthetized dogs. The effects of intrarenally infused phentolamine (5 micrograms/kg/min) on renin and prostaglandin E2 release induced by renal nerve stimulation (RNS, 2.5-5 Hz) were studied in indomethacin (5 mg/kg i.v.)-treated and untreated dogs. In the control group, RNS reduced renal blood flow and increased both renin and prostaglandin E2 secretion rates. Phentolamine inhibited the blood flow response and attenuated the renin response; it did not affect the prostaglandin E2 response. In the indomethacin-treated group, the renal venous plasma prostaglandin E2 concentration was not changed, the renin secretion rate was increased during RNS. Phentolamine also attenuated the renin response in this prostaglandin-depleted state. These results suggest that alpha adrenoceptors participate in renin release induced by RNS and that some of the alpha adrenoceptor-mediated renin release is independent of renal prostaglandins. Prostaglandin release induced by RNS may be mediated by mechanisms other than alpha adrenoceptors.     

Effect of platelet-activating factor and serum-treated zymosan on prostaglandin E2 synthesis, arachidonic acid release, and contraction of cultured rat mesangial cells

The interaction of inflammatory cells and glomerular prostaglandins (PG) may be important during glomerulonephritis. We therefore examined the influence of platelet-activating factor (PAF), (a mediator of inflammation released from leukocytes) and of phagocytosis of zymosan on arachidonic acid metabolism and on cell contractility in rat glomerular mesangial cells in culture. PAF increased PGE2 synthesis (determined by radioimmunoassay) within minutes (threshold: 10(-10)M; maximal effect: 10(-7)M). Serum-treated zymosan also stimulated PGE2, but with a slower onset. In cells prelabeled with [14C]arachidonic acid both PAF and serum-treated zymosan released 14C from phospholipids and increased free [14C]arachidonate. The ratio of 14C-release to PGE2 was, however, different with PAF and serum-treated zymosan, indicating different phospholipid pools. Under phase-contrast microscopy, PAF caused contraction of mesangial cells with a dose-response and time-course parallel to that for PGE2 synthesis. Serum-treated zymosan caused no contraction. The PAF-induced contraction was enhanced by PG synthesis inhibition and was attenuated by addition of PGE2, indicating a feedback mechanism. The mesangial contraction by PAF may be important in favoring deposition of immune complexes, while the PGE2 synthesis stimulated by PAF and by phagocytosis of zymosan may counteract the deleterious effects of PAF during induction of glomerulonephritis.     

Resveratrol modulates arachidonic acid release, prostaglandin synthesis, and 3T6 fibroblast growth

Previous results suggested that the cyclooxygenase-2 pathway and prostaglandins might modulate 3T6 fibroblast growth. This study shows the effect of resveratrol on the main elements of arachidonic acid (AA) cascade and 3T6 fibroblast growth. The polyphenol reduced the reactive oxygen species production stimulated by fetal calf serum or platelet-derived growth factor, as well as phospholipase A(2) activity translocation and the subsequent [(3)H]AA release and prostaglandin E(2) synthesis induced by these growth factors. A Western blot analysis demonstrated that cyclooxygenase-2 induction stimulated by fetal calf serum or platelet-derived growth factor was inhibited by resveratrol. The effects of resveratrol on AA cascade were correlated with an impairment of 3T6 fibroblast proliferation and DNA synthesis. These results suggest that reactive oxygen species and AA, and/or prostaglandins such as prostaglandin E(2) might be involved in the control of 3T6 fibroblast growth by resveratrol.     

Platelet-activating factor stimulates arachidonic acid release and enhances thromboxane B2 production in intact fetal rat brain ex vivo.

The ability of brain preparations from 20-day-old rat fetuses to synthesize eicosanoids in the presence of platelet activating factor (PAF) was investigated. A rise (49%) in thromboxane B2 (TxB2; the stable thromboxane A2 metabolite) was observed after 30 min in the presence of 0.6 microM PAF. Repetitive administration of PAF did not rise TxB2 production above a certain level, suggesting desensitization. 1-O-alkyl, sn-glycero-3-phosphocholine (lyso-PAF) at 0.6 microM had no effect, whereas selective PAF antagonists, i.e., BN52021, BN50739 and BN50727, or indomethacin, a general cyclooxygenase inhibitor, blocked completely TxB2 synthesis. The calcium ionophore A23187 (10 microM) stimulated production of TxB2, prostaglandin E2 and 6-keto-prostaglandin F1 alpha eicosanoids, whereas extracellular calcium deprivation did not impair eicosanoid release. The effects of PAF and A23187 on TxB2 synthesis were not additive and were not dependent on extracellular calcium. Chelation of intracellular Ca++ by Fluo-3/AM reduced production of TxB2 and prostaglandin E2 eicosanoids. Fluo-3/AM also blocked effectively PAF-dependent TxB2 release, indicating that production of TxB2 was almost entirely dependent on free intracellular calcium levels. PAF-dependent changes in brain phospholipids, prelabeled with [3H]arachidonic acid, were examined. One hour after in vivo injection of the isotope, fetal brains were removed and incubated in vitro for 30 min with carbamyl-PAF. Radioactivity in arachidonic acid and diglyceride fractions increased (35% and 30%, respectively), whereas radioactivity in phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol decreased. BN50726 antagonist abolished the effect of PAF. The radioactivity in poly-phosphoinositides was diminished (30-40% decrease) after PAF addition.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased renal secretion of norepinephrine and prostaglandin E2 during sodium depletion in the dog.

To determine whether vasoactive renal hormones modulate renal blood flow during alterations of sodium balance, simultaneous measurements of arterial and renal venous concentrations of norepinephrine and prostaglandin E2 (PGE2) and of plasma renin activity, as well as renal blood flow and systemic hemodynamics were carried out in 24 sodium-depleted and 28 sodium-replete anesthetized dogs. The mean arterial blood pressure of the sodium depleted dogs was not significantly different from that of the animals fed a normal sodium diet, but cardiac output was significantly lower (3.07 +/- 0.18 vs. 3.77 +/- 0.17 liters/min, mean +/- SEM; P < 0.01). Despite the higher total peripheral vascular resistance in the sodium-depleted dogs (46.1 +/- 2.9 vs. 37.0 +/- 2.1 arbitrary resistance U; P < 0.02), the renal blood flow and renal vascular resistance were not significantly different in the two groups. The arterial plasma renin activity and concentration of norepinephrine were higher in the sodium-depleted animals than in the controls; the arterial concentration of PGE2 was equal in both groups. The renal venous plasma renin activity was higher in the sodium-depleted dogs. Similarly, the renal venous norepinephrine concentration was higher in the sodium-depleted dogs than in the controls (457 +/- 44 vs. 196 +/- 25 pg/ml; P < 0.01); renal venous PGE2 concentration was also higher in the sodium depleted dogs (92 +/- 22 vs. 48 +/- 11 pg/ml; P < 0.01). Administration of indomethacin to five sodium-replete dogs had no effect on renal blood flow. In five sodium-depleted dogs indomethacin lowered renal blood flow from 243 +/- 19 to 189 +/- 30 ml/min (P < 0.05) and PGE2 in renal venous blood from 71 +/- 14 to 15 +/- 2 pg/ml (P < 0.02). The results indicate that moderate chronic sodium depletion, in addition to enhancing the activity of the renin-angiotensin system, also increases the activity of the renal adrenergic nervous system and increases renal PGE2 synthesis. In sodium-depleted dogs, inhibition of prostaglandin synthesis was associated with a significant decrease in renal blood flow. The results suggest that the renal blood flow is maintained during moderate sodium depletion by an effect of the prostaglandins to oppose the vasoconstrictor effects of angiotensin II and the renal sympathetic nervous system.     

Prostaglandin E2 and [14C]arachidonic acid release by carbachol in the isolated canine parietal cell

Parietal cells have the capacity to synthesize prostaglandins (PGs) and these PGs have a significant effect on parietal cell acid secretion. We examined the stimuli responsible for the control of PG production by parietal cells. Two approaches were utilized. One consisted of measuring PGE2 concentration in the incubation media containing dispersed canine parietal cells stimulated with increasing concentrations of carbachol, histamine plus a phosphodiesterase inhibitor and pentagastrin. PGE2 was measured by radioimmunoassay. The other consisted of measuring the release of radioactive arachidonic acid by parietal cells prelabeled with [4C]arachidonic acid to increasing concentrations of the secretagogues. Both techniques gave very similar results. Only carbachol stimulated the release of PGE2 as well as [14C]arachidonic acid into the incubation media. The increase in PGE2 release was from a base line of 44.3 +/- 10.8 pg/ml to 51.0 +/- 11.7, 55.2 +/- 11.1 and 69.3 +/- 14.3 pg/ml at carbachol concentrations of 10(-6), 10(-5) and 10(-4) M, respectively. In prelabeled cells, carbachol stimulated 1072 +/- 141 and 1264 +/- 155 cpm/ml above basal at concentrations of 10(-5) and 10(-4) M, respectively. Neither histamine nor pentagastrin stimulated PGE2 or [14C]arachidonic acid release significantly at any concentration. The effect of carbachol on the release of [14C]arachidonic acid was blocked by atropine and the exclusion of calcium from the incubation media. Our data suggest that the cholinergic tone to the stomach with subsequent interaction of acetylcholine with muscarinic receptors determines the amount of PG production by the parietal cells. Prostaglandins may then modulate acid secretion by limiting the combined, potentiated effects of the secretagogues.     

Burn injury enhances brain prostaglandin E2 production through induction of cyclooxygenase-2 and microsomal prostaglandin E synthase in cerebral vascular endothelial cells in rats

OBJECTIVES: To examine whether peripheral burn injury in rats elevates prostaglandin E2 in the central nervous system and to determine where in the central nervous system enzymes responsible for prostaglandin E2 synthesis are expressed. DESIGN: Prospective controlled animal study. SETTING: University research laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: Rats received either approximately 25% full-thickness burn injury or sham treatment. At 36 hrs after the injury, the cerebrospinal fluid was sampled to measure prostaglandin E2, and the brain and the spinal cord were sampled for immunohistochemical detection of cyclooxygenase-2 and microsomal-type prostaglandin E2 synthase, enzymes that are responsible for prostaglandin E2 production. MEASUREMENTS AND MAIN RESULTS: The prostaglandin E2 concentration in the cerebrospinal fluid was significantly elevated in the injured rats, and this elevation was suppressed by a cyclooxygenase-2-specific inhibitor, NS398. Only in the injured rats, cyclooxygenase-2 and microsomal-type prostaglandin E synthase proteins were detected in vascular endothelial cells throughout the central nervous system with no regional difference. A double-immunofluorescence study revealed that cyclooxygenase-2 and microsomal-type prostaglandin E synthase were coexpressed in the perinuclear region of the endothelial cells. CONCLUSIONS: These results indicate that peripheral burn injury induces cyclooxygenase-2 and microsomal-type prostaglandin E synthase in endothelial cells of the central nervous system. These enzymes likely elevate the cerebrospinal fluid concentration of prostaglandin E2, a prostanoid that, in turn, activates prostaglandin E2 receptors on the central nervous system neurons involved in the general symptoms following burn injury.     

前列腺素E2(PGE2)在烧伤后大鼠血管内皮细胞分泌的机制研究

目的 明确外周烧伤是否可引起中枢神经系统血管内皮细胞前列腺素E2增加及其发生机制.方法 试验大鼠(SD大鼠)接受约25%的全层(Ⅲ度)烧伤,并进行相关治疗,在36小时后,对大鼠脑脊液进行采样,测量其中的前列腺素E2(PGE2)含量,同时对大鼠脑和脊椎组织进行免疫组化研究,对其中与前列腺素合成有关的2种重要酶,环氧化酶2(COX-2)和微粒体前列腺E2合成酶(mPGES)进行分析.结果 在烧伤后的大鼠脑脊液中,前列腺素E2的含量明显增加,但可以被环氧化酶2的选择性抑制剂NS398所抑制.在烧伤后,对大鼠中枢神经系统血管内皮细胞的免疫组化研究可以发现COX-2和mPGES.双重免疫荧光法发现这2种酶主要集中在内皮细胞的核周.结论 外周的烧伤主要通过诱导中枢神经内皮细胞产生COX-2和mPGES.这些酶可以提高脑脊液中的前列腺素E2浓度,从而激活中枢神经系统前列腺素E2的受体,产生烧伤后的全身症状.适当的应用COX-2抑制剂,使烧伤患者的PGE2水平处在对机体有利的合适范围内,不仅可以减少患者的临床的不适症状,以减轻烧伤早期损害和第二次打击时机体失控的炎症反应,而且可以减少患者感染的发生率.     

Endothelium-dependent and independent responses to prostaglandin H2 and arachidonic acid in isolated dog cerebral arteries

The addition of prostaglandin (PG) H2 produced a transient contraction followed by a relaxation in helical strips of dog cerebral arteries partially contracted with PGF2 alpha or K+. The contraction was abolished by removal of endothelium, and the relaxation was potentiated. Relaxation induced by PGI2 was not influenced by endothelium denudation. The PGH2-induced contraction in strips with intact endothelium was not influenced by OKY-046, a thromboxane A2 synthesis inhibitor, but was abolished by treatment with ONO3708, an antagonist of vasoconstrictor PGs, whereas the relaxation was inhibited by tranylcypromine or diphloretin phosphate, a nonselective PG antagonist. Contraction induced by arachidonic acid (AA) was reversed to relaxation by removal of endothelium or treatment with ONO3708. Treatment with indomethacin attenuated the AA-induced contraction in the intact strips and also the relaxation in the strips treated with ONO3708 or denuded of endothelium. It may be concluded that vasoconstrictor PGs are synthesized from PGH2 or AA mainly in endothelium, and the production of PGI2 from PGH2 is not dependent on endothelium. Thromboxane A2 in concentrations sufficient to elicit significant contractions does not appear to be liberated from the cerebroarterial wall stimulated by PGH2.     

Positive inotropic effect and phosphoinositide breakdown mediated by arachidonic acid and prostaglandin F2 alpha

We investigated the mechanism of arachidonate- and prostaglandin-induced alteration of cardiac contractile activity in isolated rat left ventricular papillary muscles. Superfusion with 10(-6) to 10(-4) M arachidonic acid resulted in a slow developing positive inotropic effect (PIE) in a concentration-dependent manner. The PIE was abolished by pretreatment with 10(-5) M indomethacin. Prostaglandin (PG) F2 alpha also produced a significant PIE in a concentration-dependent manner, but the EC50 value was approximately 2 orders of magnitude lower and the maximum contractile response was 2-fold higher than those of arachidonate. PGE2 and PGI2 were without an effect on contractile force at concentrations ranging from 10(-9) to 10(-6) M. Both arachidonate and PGF2 alpha provoked slow responses in the partially depolarized muscles in a time course similar to that of development in the PIE. Neither arachidonate nor PGF2 alpha affected tissue levels of cyclic AMP and cyclic GMP, but these molecules increased accumulations of [3H]inositol phosphates (IPs) in a concentration-dependent manner similar to that observed for their PIE. The enhanced accumulation of [3H]IPs induced by arachidonate was abolished by pretreatment with 10(-5) M indomethacin. Although an increase in [3H]IP level was relatively rapid in PGF2 alpha-treated tissues, maximum accumulations of [3H]IPs were identical between arachidonate- and PGF2 alpha-treated tissues. Thus, for comparable increases in [3H]IPs, there was a greater PIE with PGF2 alpha than with arachidonate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Selective renal vasodilation and active renal artery perfusion improve renal function in dogs with acute heart failure

Renal failure is common in heart failure due to renovascular constriction and hypotension. We tested whether selective pharmacological renal artery vasodilation and active renal artery perfusion (ARP) could improve renal function without adverse effects on systemic blood pressure in a canine model of acute heart failure (AHF). AHF was induced by coronary microembolization in 16 adult mongrel dogs. In five dogs, selective intrarenal (IR) papaverine (1, 2, and 4 mg/min) was administered into the left renal artery. In six dogs, ARP was performed in the left renal artery to normalize mean renal arterial pressure followed by administration of IR papaverine (2 mg/min). In five dogs, ARP plus intravenous furosemide was tested. Urine output (UO) and cortical renal blood flow decreased during AHF and were restored by 2 mg/min IR papaverine (UO: baseline 4.2 +/- 0.6, AHF 1.6 +/- 1.3, IR papaverine 5.8 +/- 1.1 ml/15 min; cortical blood flow: baseline 4.3 +/- 0.2, AHF 2.4 +/- 0.6, IR papaverine 4.2 +/- 1.2 ml/min/g) with no significant change in aortic pressure. ARP also increased urine output and cortical renal blood flow (UO: baseline 5.0 +/- 1.1, AHF 0.5 +/- 0.4, ARP 3.8 +/- 3.1 ml/15 min; cortical blood flow: baseline 4.0 +/- 0.5, AHF 2.0 +/- 0.8, ARP 3.52 +/- 1.1 ml/min/g). A combination of these methods in AHF further increased urine output to twice the normal baseline (10.5 +/- 7.5 ml/15 min). Addition of furosemide synergistically increased UO above that achieved with ARP alone (5.5 +/- 2.6 versus 40.3 +/- 24.7 ml/15 min, p = 0.03). In conclusion, ARP and selective renal vasodilation may effectively promote salt and water excretion in the setting of heart failure, particularly when systemic blood pressure is low.     

The release of renal prostaglandins during saline infusion in normal and hypertensive subjects.

1. Renal venous prostaglandin concentrations (PGA, PGE and PGF) were determined, together with renal plasma flow, urinary output and blood pressure changes, before and after infusion of sodium chloride solution (saline) in four normotensive and three hypertensive subjects. 2. No changes in blood pressure and in glomerular filtration rate were observed. 3. Saline infusion induced a significant increase in renal venous PGA and PGE, and also in total and non-cortical renal plasma flow and urinary output. There was an insignificant increase in renal venous PGF. 4. These findings show that prostaglandin release after saline infusion is associated with changes in renal blood flow and suggest that the natriuretic and diuretic effect of saline could be the result of prostaglandin release.     

Effects of prophylactic fenoldopam infusion on renal blood flow and renal tubular function during acute hypovolemia in anesthetized dogs

OBJECTIVE: It was hypothesized that fenoldopam mesylate, a selective dopamine agonist, may preserve renal perfusion and decrease tubular oxygen consumption during states of hypoperfusion, such as hypovolemic shock. The objective of this study was to quantify the effects of fenoldopam (0.1 microg x kg(-1) x min(-1)) on renal blood flow, urine output, creatinine clearance, and sodium clearance in pentobarbital anesthetized dogs that had undergone partial exsanguination to acutely decrease cardiac output. DESIGN: Prospective, randomized, controlled experiment. SETTING: University-based animal laboratory and research unit. SUBJECTS: Eight female beagle dogs. INTERVENTIONS: Arterial blood pressure, heart rate, cardiac output, renal blood flow, urine output, creatinine clearance, and fractional excretion of sodium were measured and calculated at four times: a) before infusion of fenoldopam or normal saline; b) during infusion of fenoldopam or normal saline (1 hr); c) during a 90-min period of hypovolemia (induced by acute partial exsanguination), with concurrent infusion of fenoldopam or normal saline; and d) during a 1-hr period after retransfusing the dogs. MEASUREMENTS AND MAIN RESULTS: Administration of fenoldopam (0.1 microg x kg(-1) x min(-1)) was not associated with hemodynamic instability. Renal blood flow and urine output decreased significantly from baseline (p <.01) during the hypovolemic period in the placebo group (72 +/- 20 to 47 +/- 6 mL/min and 0.26 +/- 0.15 to 0.08 +/- 0.05 mL/min, respectively) but not in the fenoldopam group (75 +/- 14 to 73 +/- 17 mL/min and 0.3 +/- 0.19 to 0.14 +/- 0.05 mL/min, respectively). Creatinine clearance and fractional excretion of sodium decreased significantly from baseline (p <.01) in the placebo group during the hypovolemic period (3.0 +/- 0.4 to 1.8 +/- 0.8 mL x kg(-1) x min(-1) and 1.7% +/- 0.9% to 0.4% +/- 0.2%, respectively) but not in the dogs that received fenoldopam (3.0 +/- 1.0 to 2.9 +/- 0.5 mL x kg(-1) x min(-1) and 1.9% +/- 1.1% to 1.7% +/- 2.7%, respectively). CONCLUSIONS: Fenoldopam ablated the tubular prerenal response to profound hypovolemia and maintained renal blood flow, glomerular filtration rate, and natriuresis without causing hypotension. This suggests that fenoldopam may have a renoprotective effect in acute ischemic injury.     

Role of the renal nerves in modulating renin release during pressure reduction at the feline kidney

Experiments were undertaken in pentobarbitone-anaesthetized cats to determine how reflex activation of the renal nerves altered the responsiveness of the kidney to release renin during reductions in renal perfusion pressure. Reflex activation of the renal nerves was achieved by reducing carotid sinus perfusion pressure by 30 mmHg, which increased systemic blood pressure. During this period renal perfusion pressure was regulated at control levels and neither renal blood flow nor glomerular filtration rate changed, but there was a significant decrease in sodium excretion and increase in renin secretion. Renal denervation abolished both these latter responses. Renal perfusion pressure reduction, by 25-30 mmHg, had no effect on renal blood flow or glomerular filtration rate but significantly decreased sodium excretion and increased renin secretion. Simultaneous reduction of carotid sinus and renal perfusion pressures had no effect on renal blood flow or glomerular filtration rate, decreased sodium excretion, and the magnitude of the increase in renin secretion was significantly greater than that obtained with reduction in renal perfusion pressure alone. Renal denervation abolished the increase in renin secretion during these manoeuvres. During atenolol administration, renal haemodynamics and sodium excretion responses to renal pressure reduction were similar to those obtained in the absence of the drug. Renin secretion was increased, but significantly less than in the absence of atenolol. Simultaneous carotid sinus and renal pressure reductions during atenolol administration had no effect on renal haemodynamics, reduced sodium excretion and increased renin secretion, the magnitude of which was significantly greater than that recorded with only renal pressure reduction in the presence of atenolol. Direct electrical stimulation of the renal nerves, at frequencies which caused a 5-10% reduction in renal blood flow, did not change glomerular filtration rate, decreased sodium excretion by 30% and increased the rate of renin secretion twofold. In the presence of atenolol, such renal nerve stimulation reduced renal blood flow to the same degree, did not change filtration rate, decreased sodium excretion by 37% but did not change renin secretion. These results show that the magnitude of the release of renin in response to renal pressure reduction is dependent on activity within the renal nerves, being blunted after denervation, and enhanced during reflex activation of the renal nerves.     

Effects of halothane on pulmonary inactivation of noradrenaline and prostaglandin E2 in anaesthetized dogs.

1. The inactivation of noradrenaline and prostaglandin E2 was studied in the pulmonary circulation of anaesthetized dogs. 2. Under chloralose anaesthesia and ventilation with air, the inactivation of noradrenaline was 20% and that of prostaglandin E2 was 91%. These values are in agreement with results from previous work. 3. When the dogs were ventilated with halothane-air mixtures, the inactivation of prostaglandin E2 was unaffected but that of noradrenaline was significantly reduced. 4. This effect of halothane is probably due to an interaction with the transport system for noradrenaline associated with cell membranes. 5. Analogous changes in pulmonary noradrenaline inactivation could occur in patients anaesthetized with halothane.     

白细胞介素18和前列腺素E2与骨关节炎

目的：回顾近年来国内外有关白细胞介素18和前列腺素E2在骨关节炎发病机制中作用的研究，分析白细胞介素18和前列腺素E2在骨关节炎发病机制中的作用进展。 资料来源：应用计算机检索Medline 1995—01／2005—02相关白细胞介素18和前列腺素E2与骨关节炎的文献，检索词“Interleukin-18，prostaglandin E2，cytokines，Osteoarthritis”，并限定文献语言种类为English．同时计算机检索清华同方中国医院1995—01／2005—02相关自细胞介素18和前列腺素E2与骨关节炎，部分为细胞因子与骨关节炎的文献，检索词为“白细胞介素18，前列腺素E2，细胞因子，骨关节炎”。 资料选择：对资料进行初选，选取包含白细胞介素18、前列腺素E2、细胞因子与骨关节炎的文献，开始查找摘要与全文。纳入标准：①自细胞介素18与骨关节炎。②前列腺素E2与骨关节炎。③细胞因子与骨关节炎。④白细胞介素18，前列腺素E2与骨关节炎。排除标准：①细胞因子，炎症介质与类风湿性、风湿性关节炎。②骨关节炎的治疗。③重复的综述文献与研究．Meta分析类文章。 资料提炼：共收集了有关白细胞介素18和前列腺素E2与骨关节炎，部分为细胞因子与骨关节炎的文献212篇，纳入65篇。其中2篇阐述了白细胞介素18和前列腺素E2在骨关节炎中的共同作用。将文献进行综合评价。 资料综合：骨关节炎是人体活动关节中最常见的一种疼痛和退行性变疾病，其发病机制尚未完全阐明。其中细胞因子和炎症介质起着重要作用。新发现致炎因子自细胞介素18是骨关节炎发病机制中重要的一种炎症前因子，能诱导炎症介质前列腺素E2的产生。从免疫、病理、动物试验进行研究，揭示白细胞介素18，前列腺素E2在骨关节炎发病机制中的作用。结论：自细胞介素18与前列腺素E2参与了骨关节炎的发病机制，自细胞介素18的增高可能引起前列腺素E2含量的增高，从而在骨关节炎的发病机制中发挥重要作用。