Indomethacin and cyclosporin together produce marked renal vasoconstriction in humans

OBJECTIVE: To test the hypothesis that an imbalance in intrarenal prostaglandins plays a role in cyclosporin-induced nephrotoxicity. METHODS AND RESULTS: Indomethacin was given in combination with cyclosporin to healthy volunteers. Cyclosporin alone (10 mg/kg twice a day) for 4 days had no effect on effective renal plasma flow (ERPF) and glomerular filtration rate but 4 days of therapy with cyclosporin (10 mg/kg twice a day) and indomethacin (50 mg twice a day) in combination resulted in a 37% fall in glomerular filtration rate and a 32% fall in ERPF. This suggests that autoregulatory mechanisms, possibly involving renal prostaglandins, may participate in counteracting the tendency for cyclosporin-induced renal vasoconstriction in humans. Cyclosporin increased systemic blood pressure acutely, and this was not influenced by indomethacin even though indomethacin on its own caused sodium retention. This suggests that, in contrast to the renal vasculature, the systemic vascular response to cyclosporin is neither augmented nor buffered by prostaglandins. CONCLUSION: The reduction in intrarenal prostaglandins clearly played a key role in the development of cyclosporin-induced renal vasoconstriction, but we could not demonstrate a role for prostaglandins or for sodium retention in the initiation of cyclosporin-induced hypertension.     

Prostaglandins in blood of diabetic versus non-diabetic humans

We have found a higher concentration of prostaglandins in blood from the diabetic patient under long-term indomethacin therapy as compared with blood from non-diabetics. These findings are generally (qualitatively) similar to previous reports with studies of blood serum from diabetic patients, not on indomethacin treatment, compared with non-diabetics. Certain rationale are presented in an effort to explain the reason why blood prostaglandins in the diabetic are not lowered when the patients are treated with a drug which is clearly established as a blocker of prostaglandin synthesis.     

Contribution of prostaglandins to the adenosine triphosphate-induced contraction of rabbit urinary bladder

1 Adenosine 5'-triphosphate (ATP) produced an initial rapid, phasic contraction and a later, slowly developing tonic contraction in the isolated detrusor of the rabbit but mainly a rapid, phasic response in the guinea-pig bladder. 2 Electrical field stimulation elicited only a rapid, phasic contraction in both rabbit and guinea-pig bladders. 3 Prostaglandin synthesis inhibition by means of indomethacin and suprofen abolished the tonic response to ATP in the rabbit detrusor, leaving the phasic part of the contraction almost unaffected. The ATP-induced contraction in guinea-pig bladder was not influenced by indomethacin. 4 The contractile response of rabbit urinary bladder to prostaglandins F2 alpha and E2 and to carbachol were not significantly influenced by indomethacin. The contractions induced by the prostaglandins were similar to the tonic response to ATP. 5 Tetrodotoxin, atropine, phentolamine, and theophylline did not alter the ATP-induced contraction. However, the calcium antagonists, nifedipine and nimodipine, abolished the phasic ATP response and greatly reduced the tonic part of the contraction. 6 Tachyphylaxis occurred on repeated addition of ATP; the response to field stimulation was progressively reduced only after indomethacin pretreatment. 7 ATP and prostaglandins may contribute to the non-adrenergic, non-cholinergic component of the excitation of rabbit and guinea-pig bladder.     

Adenophostin, a potent agonist of the inositol 1,4,5-trisphosphate receptor, is useful for fertilization of mouse oocytes injected with round spermatids leading to normal offspring

Relaxin plays a major role in promoting the growth and softening of the cervix that occurs during the second half of pregnancy in the rat. There is limited evidence that prostaglandins play a role in cervical softening in mammalian species. Accordingly, this study was conducted to determine if prostaglandins mediate relaxin's effects on the rat cervix. To attain that objective, indomethacin was used to inhibit cyclooxygenase, the key enzyme in the conversion of arachidonic acid to prostaglandins. Twenty-six nonpregnant female rats were ovariectomized when they were 78 days old (day 1 of treatment). At ovariectomy (O), each rat was fitted with silicon tubing implants containing progesterone (P) and estrogen (E) in doses that provided blood levels similar to those during late pregnancy in rats. Rats were randomly assigned to three treatment groups. Group OPE controls (n = 8 rats) received 2 ml indomethacin vehicle (0.5% methyl cellulose, 0.025 Tween 80 in water) via gavage at 0900 h on days 8 and 9 and 0.5 ml relaxin vehicle (0.9% NaCl) s.c. at 6-h intervals from 1200 h on day 8 through 0600 h on day 10. Group OPER (n = 9 rats) was treated as group OPE except that 20 microg highly purified porcine relaxin was administered. Group OPERI (n = 9 rats) was treated as group OPER except that indomethacin was administered at a dose (20 mg/kg BW) that reduced cervical PGE2 levels by more than 90%. Between 0800 h and 1000 h on day 10, the cervices were removed, trimmed of fat, weighed, and placed in ice-cold Krebs-Ringer bicarbonate buffer, pH 7.5. Cervical extensibility (degree of softening) was determined within 4 h of tissue collection. Both the mean cervical wet weight and the mean cervical extensibility in the relaxin-treated group OPER rats were markedly greater (P < 0.01) than in the group OPE controls. Treatment with indomethacin did not diminish relaxin's effects on either cervical wet weight or cervical extensibility. In conclusion, this study provides evidence that relaxin's effects on cervical growth and softening in the rat are not mediated through prostaglandins.     

Modulation of glucose production by indomethacin and pentoxifylline in healthy humans

Indomethacin, an inhibitor of prostaglandin synthesis that modulates cytokine production, increases hepatic glucose output (HGO) in humans. However, prostaglandins stimulate glucose production in vitro. To investigate the mechanism of HGO stimulation by indomethacin, we compared the effect of pentoxifylline, an inhibitor of cytokine production, versus saline (study 1, n = 6) and of indomethacin versus the combination of indomethacin and pentoxifylline (study 2, n = 5) on basal HGO. HGO was measured by primed, continuous infusion of 3-3H-glucose. In study 1, pentoxifylline infusion resulted in an immediate, transient decrease of HGO of approximately 50% (from 12.9 +/- 0.4 to 6.0 +/- 1.7 micromol/kg/min after 15 minutes, P < .03 v control). There were no differences in concentrations of glucoregulatory hormones between the two experiments. In study 2, after indomethacin administration, HGO increased transiently by approximately 84% (from 9.7 +/- 0.7 at baseline to 16.7 +/- 2.4 micromol/kg/min after 135 minutes, P < .05). However, pentoxifylline did not affect the increase in HGO induced by indomethacin. There were no differences in concentrations of glucoregulatory hormones between the two experiments. Therefore, indomethacin stimulates HGO by mechanisms unrelated to glucoregulatory hormones, prostaglandins, or cytokines.     

Renal tubular transport of prostaglandins: inhibition by probenecid and indomethacin

With use of the Sperber technique in chickens, labeled prostaglandin E2 and F2alpha were infused and resulted in renal tubular excretion of the label into the urine. A labeled metabolite, 12,14-dihydro,15-keto-PGF2alpha, was infused exogenously and this label was also excreted by active tubular transport. Tubular excretion of the label from PGE2, PGF2alpha, and 13,14-dihydro,15-keto-PGF2alpha was inhibited by probenecid, indomethacin, and PAH. The PAH was 10 times weaker as an inhibitor than probenecid and indomethacin. These results indicate that the prostaglandins are actively transported across the renal tubule by the classic anionic transport system which transports PAH. Since the transport of the prostaglandins is blocked by nonsteroidal anti-inflammatory agents such as indomethacin, the anti-inflammatory action of indomethacin may be produced not only by the inhibition of prostaglandin synthesis but also by restriction of the distribution of endogenous prostaglnadins. Thin-layer chromatography of an ethyl acetate extract of urine collected during infusion of [3H]PGF2alpha revealed three discrete radioactive peaks, one of which corresponded to authentic PGF2alpha. This signified tubular excretion of PGF2alpha. One metabolite in the ethyl acetate extract was found to be of renal origin.     

Prostaglandins and renin release in vitro

The present studies were undertaken to explore further the role of prostaglandins in the release of renin from the renal cortex. To provide the best assessment of renin release, renin was determined by a radioimmunoassay for the direct measurement of renin. Slices of mouse renal cortex were incubated at 37 degrees C with arachidonic acid (AA), 5,8,11,14-eicosatetraenoic acid (ETA), indomethacin, prostaglandins, and synthetic prostaglandin endoperoxide analogue (EPA). Our results showed that AA at 1.5 X 10(-8) M significantly increased renin release at 10 and 30 min of incubation. This renin increase ws abolished by either ETA or indomethacin. Prostaglandin F2 alpha (PGF2 alpha) also significantly stimulated renin release at 10 and 60 min. PGE2 and 16,16-dimethyl PGE2 (DMPGE2) showed much less renin release-stimulating activity. EPA and PGI2 on the other hand very strongly stimulated renin release. However, at higher concentrations the stimulating effect of PGI2 and EPA disappeared and even became inhibitory in the case of EPA. Other prostaglandins were found to have no effect on renin release. The results suggest that the prostaglandin system directly affects renin release from the juxtaglomerular cells independent of systemic neurogenic and hemodynamic influences.     

Laminectomy for spinal cord compression from metastatic tumor

The blood pressure response to graded infusions of angiotensin II was assessed under control conditions and following short term (16 hour) indomethacin treatment utilizing normal men equilibrated on a constant diet of normal sodium and potassium content. Although basal mean blood pressure was unchanged, the increase in blood pressure with all rates of angiotensin II infusion ranging from 200 to 1000 ng/min was significantly greater with indomethacin treatment. Pre-infusion body weight and plasma renin activity were similar under the two conditions. These results suggest that prostaglandins modulate the systemic vasoconstrictor effects of angiotensin II.     

Regulation of prostaglandin synthesis and of the selective release of lysosomal hydrolases by mouse peritoneal macrophages

Macrophages isolated from the peritoneal cavity of untreated mice and maintained in tissue culture synthesize and release prostaglandins when challenged with zymosan. These cells also selectively release lysosomal acid hydrolases under the same conditions. The major prostaglandins released into the media are found to be prostaglandins E1, E2 and 6-oxoprostaglandin F1a, whereas prostaglandin F2a is not detected. Macrophages isolated from mice that have received an intraperitoneal injection of thioglycollate broth are far less responsive to zymosan challenge. These cells require 300 microgram of zymosan to synthesize and release one-third the amount of prostaglandins released from non-stimulated macrophages exposed to 50 microgram of zymosan. In addition, thioglycollate-stimulated macrophages release less than 10% of their lysosomal acid hydrolases when exposed to 300 microgram of zymosan whereas non-stimulated cells release approximately 50% of these enzymes after treatment with 50 microgram of zymosan. The zymosan-stimulated synthesis and release of prostaglandins are completely inhibited by indomethacin, whereas the increased selective release of lysosomal acid hydrolases is not affected. Macrophages, unlike fibroblasts, do not synthesize and release prostaglandins when exposed to serum or to bradykinin.     

Release of renal prostaglandins during endotoxin-induced hypotension

The appearance of prostaglandins in dog's blood during endotoxin-induced hypotension was studied by use of the dialysis modification of the blood bathed organ technique. An increase in prostaglandins, mainly E2 and F2alpha was found in renal venous blood, whereas no such increase was seen in blood from the abdominal aorta, the inferior vena cava or the femoral vein. Three possible trigger mechanisms for this increase i.e. hypotension, reduced flow and reflexogenic sympathetic stimulation, have been investigated. It is suggested that, in addition to these three factors, circulating hormones such as noradrenaline, angiotensin or bradykinin, play a role in this release mechanism. Administration of indomethacin produced a restoration of the systemic blood pressure to its pre-endotoxin value; concomitantly a disappearance of the prostaglandins from the circulation was observed. It is concluded that prostaglandins contribute to the hypotension induced by endotoxin. Whether they are beneficial or detrimental remains to be resolved.     

Effects of indomethacin on the selective release of follicle-stimulating hormone during the period of ovulation in the rat

To determine whether indomethacin, a potent inhibitor of prostaglandins endoperoxide synthetase, affects the selective follicle-stimulating hormone (FSH) surge during the period of ovulation, the compound was administered intravenously (i.v.), concurrent with 10 IU human chorionic gonadotropin (hCG), to diestrous female rats at 16:00 hr. Indomethacin inhibited the number of ovulations in a dose-dependent manner, and treatment with 500 micrograms indomethacin reduced number of oocytes in the ampullae most effectively without enteric lesions. In the histological observation, oocytes that had began to mature were found not only in unruptured luteinized follicles but also in ovarian interstitium beneath ruptured luteinized follicle. Despite the inhibitory effects of indomethacin on ovulation, peri-ovulatory FSH and progesterone surges occurred in comparable levels and duration to vehicle-treated animals. These results indicate that indomethacin-induced inhibition of prostaglandin synthesis does not affect the selective release of FSH during the peri-ovulatory period.     

A study on the clinical equivalence and patient preference of fluticasone propionate 250 microg twice daily via the Diskus/Accuhaler inhaler or the Diskhaler inhaler in adult asthmatic patients

Bovine respiratory syncytial virus (BRSV) depressed the proliferative reactivity of normal ovine peripheral blood lymphocytes to phytohaemagglutinin (PHA). This BRSV-induced reduction in proliferative reactivity was not reversed or ameliorated by the addition of (1) indomethacin or flunixin meglumine, substances known to inhibit the production of prostaglandins, or (2) the cytokines, interleukin-1 (IL-1) and interleukin-2 (IL-2), or (3) rat growth factor. The results suggest that the suppression of ovine lymphocyte reactivity to PHA associated with BRSV was not caused by the release of cyclooxygenase products such as prostaglandins, or the production of inhibitors of IL-1 or IL-2.     

Role of prostaglandins in the mediation of systemic tachyphylaxis to angiotensin II

Angiotensin-induced prostaglandin release has been implicated in the deveolpment of tachyphylaxis to angiotensin in vitro. Based on these findings and evidence that prostaglandins modulate the angiotensin reposne locally, experiments were done to investigate the role of prostaglandins in the systemic tachyphylaxis to angiotensin. Rats were given intravenous infusions of 1-asparaginyl-5-valyl and 1-aspartyl-5-isoleucyl andiotensin II at two different doses. Using systemic blood pressure as a parameter, varying degrees of tachyphylaxis were produced and the aspartyl analog was found to be more tachyphylactic. When rats were given indomethacin, a prostaglading synthesis inhibitors, the response to intravenous infusion of aspartyl angiotensin was not significantly altered.     

Effect of n-3 fatty acids on VLDL production by hepatocytes is mediated through prostaglandins

The mechanism of the hypolipidemic effect of n-3 fatty acids was studied using isolated rat hepatocytes maintained in culture. EPA and DHA caused a significant reduction in the incorporation of 3[H]-leucine into apoB associated with the VLDL produced by hepatocytes in culture when compared to that in presence of palmitic acid. Presence of indomethacin, an inhibitor of cyclo-oxygenase reversed the effect of EPA on VLDL synthesis while diethyl carbamazine an inhibitor of lipoxygenase did not show any effect suggesting that the effect of EPA may be mediated through prostaglandins. This was further tested by invivo experiments where animals were fed fish oil containing diet with and without aspirin, which inhibits formation of prostaglandins. The incorporation of 3[H]-leucine into apo B and 14[C]-acetate into cholesterol of VLDL produced by hepatocytes from aspirin treated animals were significantly high. The reversal of the effect of n-3 fatty acids by agents which inhibit the formation of prostaglandin suggests that the n-3 fatty acids may exert their effect on VLDL production by liver cells through prostaglandins.     

A point mutation in the cytb gene of cardiac mtDNA associated with complex III deficiency in ischemic cardiomyopathy

Involvement of prostaglandins (PGs) and histamine in the hypothalamus and hippocampus in the clonidine-induced pituitary-adrenocortical response was investigated in conscious rats. The hypothalamic-pituitary adrenocortical (HPA) activity was assessed indirectly by measuring corticosterone secretion. Clonidine, an alpha 2-adrenergic agonist, given intracerebroventricularly (10 micrograms icv), considerably increased the serum corticosterone and hypothalamic histamine levels and markedly elevated the hippocampal histamine levels. Systemic or icv pretreatment with indomethacin (2 mg/kg or 10 micrograms), an inhibitor of prostaglandin synthesis, significantly reduced the clonidine-induced corticosterone response and abolished the increase in the hypothalamic and hippocampal histamine levels elicited by clonidine. Indomethacin in the doses used did not substantially change the resting serum corticosterone or hypothalamic and hippocampal histamine levels. These results indicate that prostaglandins and hypothalamic histamine are considerably involved in the HPA response to alpha 2-adrenergic receptor stimulation. They also suggest involvement of prostaglandins and histamine of the hippocampus in the clonidine-induced HPA response.     

Role of eicosanoids, nitric oxide, and afferent neurons in antacid induced protection in the rat stomach

The mechanism underlying the mucosal protective effect of antacids is still unclear. This study shows that in rats the aluminum containing antacid, hydrotalcit, induces dose dependent protection against gastric mucosal damage caused by ethanol or indomethacin which is considerably enhanced by acidification. Hydrotalcit did not increase gastric mucosal formation or the intraluminal release of prostaglandins, and did not prevent the increase in mucosal leukotriene C4 formation in response to ethanol. Pretreatment with indomethacin did not attenuate the protective effect of unmodified or acidified hydrotalcit. Furthermore, hydrotalcit significantly reduced the gastric damage caused by indomethacin even when it was administered up to 2 hours after the ulcerogen. In indomethacin treated rats, simultaneous administration of hydrotalcit did not affect the concentrations of indomethacin in serum or inflammatory exudates nor did it attenuate the inhibition of prostaglandin release into the exudates. In hydrotalcit treated rats there was no attenuation of the increase in sulphidopeptide leukotriene release or decrease in leukocyte influx into inflammatory exudates elicited by indomethacin administration. Functional ablation of afferent neurons and inhibition of endogenous nitric oxide partially antagonised the protective effect of unmodified, but not of acidified, hydrotalcit. It is concluded that (i) the protective effect of unmodified and acidified hydrotalcit is independent of the eicosanoid system; (ii) protection against indomethacin induced gastric lesions does not require treatment before dosing of the ulcerogen and does not interfere with absorption and anti-inflammatory actions of indomethacin; (iii) endogenous nitric oxide and afferent neurons contribute partly to the effect of unmodified, but not of acidified, hydrotalcit suggesting that different mechanisms mediate their mucosal protective activity.     

Spectrum of serum thyroglobulin elevation in congenital thyroid disorders

The effect of the prostaglandin synthetase inhibitor, indomethacin on urodynamic values measured by radionuclide imaging was studied in 17 men in a double-blind placebo controlled randomized trial. Measurements were made of voiding time, time for 50% emptying, average flow rate, ejection fraction, post-void residual urine volume, voided volume, and total bladder volume. Statistical analyses indicated no placebo-indomethacin differences between the two groups. Although prostaglandins are thought to contribute to the act of micturition by maintenance of bladder tone and contractility, our studies indicate that a standard dose of the prostaglandin inhibitor, indomethacin, did not affect the voiding component of bladder function. Patients need not discontinue prostaglandin inhibitors and other non-steroidal anti-inflammatory drugs with such effects prior to urodynamic testing.     

The effect of indomethacin on renal function in pentobarbital-anesthetized dogs

The effects of indomethacin, an inhibitor of prostaglandin synthesis, on renal blood flow, glomerular filtration rate, urine flow and excretion of sodium and potassium were studied in the anesthetized dog. Indomethacin, 2.5 mg/kg i.v., decreased renal blood flow but increased aortic pressure and calculated renal vascular resistance. Glomerular filtration rate was not influenced by the synthetase inhibitor. Sodium excretion was decreased and para-aminohippurate extraction was increased after administration of indomethacin. Transient decreases in urine flow and potassium excretion were observed; however, both parameters returned to control value 75 minutes after administration of indomethacin. The early decrease in urine flow rate correlated closely with the decrease in sodium excretion. These data suggest that in the anesthetized dog, endogenous prostaglandins may serve to maintain renal blood flow but not glomerular filtration rate. Under the conditions of the present experiments, sodium excretion and to a lesser extent potassium excretion have been suggested as being dependent on prostaglandin synthesis.     

Severe hyperchloriduria-hyperkaliuria: a new congenital renal tubular abnormality?

A female infant, aged 5 weeks, had metabolic alkalosis associated with severe electrolyte disturbances. In addition to findings typically seen in patients with Bartter syndrome or hyperprostaglandin E syndrome, she had massive urinary excretion of prostaglandins E2 and E-M, normal calcium metabolism, hyperphosphaturia, and severe hyperchloriduria and hyperkaliuria with limited response to indomethacin. These findings may represent a new congenital renal tubular abnormality.     

Coronary arterial smooth muscle contraction by a substance released from platelets: evidence that it is thromboxane A2

When human platelets are aggregated by thrombin, material is released that rapidly contracts strips of spirally cut porcine coronary artery. Prevention of the contraction by indomethacin suggested mediation by a prostaglandin. The contraction produced by aggregating platelets was unlike those produced by prostaglandins E2, F2alpha, G2, or H2, but resembled that evoked by thromboxane A2, which is formed by platelets during aggregation.