Intravenous Administration Of Indomethacin Research Articles

Effects of Agmatine on Contrast-Induced Nephropathy in Rats and Rabbits.

Renal insufficiency secondary to contrast administration remains a prevalent and debilitating complication of angiographic procedures. Contrast-induced nephropathy (CIN) is a common clinical problem for which there is no effective medical treatment. However, agmatine has been shown to be effective against ischemia/reperfusion-induced acute kidney injury in rats, a similar condition to CIN. Our aim was to examine the protective effects of agmatine in a rat model of CIN and, based on those results, in a rabbit model of CIN. CIN in the rat model was induced by intravenous administration of indomethacin (10 mg/kg), Nω-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg) and iopamidol (OYPALOMIN, 7.4 g iodine/kg) at 2 weeks after a unilateral nephrectomy. CIN in the rabbit model was induced by intrarenal arterial injection of only iopamidol (BYSTAGE, 4.8 g iodine/kg). Intravenous injection of agmatine (0.1 and 0.3 mmol/kg) did not attenuate the CIN-induced renal insufficiency in the rat model. Intravenous injection of agmatine (0.3 mmol/kg) attenuated the CIN-induced renal insufficiency in the rabbit model such as increases in blood urea nitrogen and plasma creatinine levels. Renal histological damage was also improved by the agmatine administration. The difference in effects of agmatine injection between CIN rats and CIN rabbits was caused by indomethacin and L-NAME administrations. These results indicate that agmatine prevents the development of CIN-induced renal insufficiency in rabbits, and the effect is accompanied by activation of nitric oxide synthase and subsequent increase of blood flow.

Effect of the Direct Renin Inhibitor Aliskiren in the Prevention of Experimental Contrast-Induced Nephropathy in the Rat

Background: Renal vasoconstriction, activated by the renin-angiotensin system, plays a pivotal role in the pathogenesis of contrast-induced nephropathy (CIN). The purpose of this study was to evaluate the effect of aliskiren, a direct renin inhibitor, for the prophylaxis of experimental CIN in the rat. Methods: Thirty-two Wistar albino rats were divided into four groups of 8 rats each, namely the control (C), aliskiren (A), contrast media (CM) and aliskiren plus contrast media (ACM) groups. Aliskiren was given orally at a dose of 50 mg/kg/day once daily for 5 consecutive days. CIN was induced by intravenous administration of indomethacin, N-nitro-L-arginine methyl ester and high-osmolar contrast medium meglumine amidotrizoate. Renal function parameters, kidney histology and tubular expression of vascular endothelial growth factor were determined. Results: Mean serum creatinine was significantly lower (p < 0.001) and mean creatinine clearance was higher (p < 0.001) in the ACM group compared with the CM group. However, there were no differences between the ACM and CM groups in terms of tubular necrosis, proteinaceous casts, medullary congestion and vascular endothelial growth factor expression. Conclusion: Our preliminary data seem to suggest a potential role of aliskiren for the prophylaxis of CIN in an experimental rat model.

Protective Effect of the Vasopressin Agonist Terlipressin in a Rat Model of Contrast-Induced Nephropathy

Background/Aims: Contrast-induced nephropathy (CIN) remains a leading cause of iatrogenic acute renal failure. Terlipressin, a long-acting analog of vasopressin, may improve renal function. This study aimed to investigate the possible protective effect of terlipressin against the development of experimental CIN in rats. Methods: Wistar albino rats (n = 32) were allocated randomly into four equal groups of 8 each, i.e. control, terlipressin, contrast media (CM), and terlipressin plus contrast media (TCM). CIN was induced by intravenous administration of indomethacin (10 mg/kg), N-nitro L-arginine methyl ester (L-NAME, 10 mg/kg, twice at 15 and 30 min), and high-osmolar contrast media meglumine amidotrizoate 60%. Renal function parameters, kidney histology, and tubular expression of vascular endothelial growth factor (VEGF) were determined. Results: Mean serum creatinine levels were decreased (p < 0.05) and creatinine clearance (p < 0.05) increased in the TCM group compared with the CM group. Notably, rats in the TCM group displayed less tubular necrosis (p < 0.05), medullary congestion (p < 0.05), and a reduced tubular expression of VEGF (p < 0.05) compared with the CM group. Conclusion: These results demonstrate that terlipressin can inhibit the development of CIN.

Kawasaki disease and hyponatremia

Sirs, We read with great interest the recent contribution by Watanabe et al. in Pediatric Nephrology [1]. They reported that hyponatremia in Kawasaki disease (KD) is a common finding, which suggests severe inflammation. They suggested that renal salt wasting due to renal involvement might underlie the development of hyponatremia in their patients with KD. They also cited that the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in KD has sometimes been reported, and cerebral vasculitis is thought to be the etiology of SIADH in KD. Nakamura et al. [2] also recently reported that hyponatremia at the patient’s first visit to hospital might be a predictor of giant coronary aneurysm (>8 mm), which was not mentioned in Watanabe et al.’s study. Nakamura et al. speculated that the relationship between hyponatremia and giant coronary aneurysms is based on the permeability of the endothelium, severity of the illness, dehydration, duration of period with fever, and so forth [2]. Although the exact mechanism for the development of hyponatremia in KD remains unknown, the relationship between interleukin (IL)-6 or IL-1 beta and ADH secretion has been suggested [3, 4]. Mastorakos et al. [3] reported that plasma ADH levels were elevated after IL-6 injection in cancer patients, suggesting that IL-6 activated the magnocellular ADH-secreting neurons and that it might be involved in SIADH. Ohta et al. [4] reported four cases with hyponatremia due to SIADH, which seems to be related to inflammation. The plasma Na concentration decreased when the patients had fever and increased plasma C-reactive protein (CRP) level. In such conditions, plasma ADH and IL-6 concentrations were increased and there was a significant correlation between them. Therefore, they performed animal experiments to investigate the role of IL in the development of SIADH. Intravenous administrations of IL-1 beta increased ADH, atrial natriuretic hormone (ANH), and adrenocorticotropic hormone (ACTH). The changes in ADH and ACTH were abolished by the pretreatment with an intravenous administration of indomethacin. Also, the intravenous administration of IL-1 beta increased the urinary sodium excretion. The pretreatment of HS142-1, an ANH antagonist, abolished the increase in urinary sodium excretion induced by IL-1 beta. Based on these findings, they speculated that IL-6 and IL-1 beta play an important role in the development of SIADH associated with inflammation. These findings suggest that natriuresis in KD might be due to not only renal involvement but also cytokines, such as IL-6 or IL-1 beta. One of our authors reported that serum IL-6 was markedly elevated in the acute stage of KD and serum IL-6 positively correlated with the serum CRP level [5]. IL-1 beta is also recognized as a mediator of endothelial damage in KD [6]. Therefore, there is a possibility that these cytokines might involve the pathogenesis of hyponatremia due to SIADH rather than cerebral vasculitis in KD, although they did not measure serum and urinary osmolarity and urinary electrolytes. Further studies are necessary to elucidate the possible relationship between these cytokines and hyponatremia due to SIADH in KD. Pediatr Nephrol (2006) 21:1490–1491 DOI 10.1007/s00467-006-0242-z

Role of direct cytotoxic effects of NSAIDs in the induction of gastric lesions

A major clinical problem encountered with the use of non-steroidal anti-inflammatory drugs (NSAIDs), is gastrointestinal complications. We previously reported that NSAIDs induce both necrosis and apoptosis in vitro. We here examined the cyclooxygenase (COX) dependency of this cytotoxic effect of NSAIDs and its involvement in NSAID-induced gastric lesions. Necrosis and apoptosis by NSAIDs was observed with all selective COX-2 inhibitors except rofecoxib and was not inhibited by exogenously added prostaglandin E 2, suggesting that cytotoxicity of NSAIDs seems to be independent of the inhibition of COX. Intravenously administered indomethacin, which completely inhibited COX activity at gastric mucosa, did not produce gastric lesions. Orally administered selective COX-2 inhibitors, which did not inhibit COX at gastric mucosa, also did not produce gastric lesions. Interestingly, a combination of the oral administration of each of all selective COX-2 inhibitors except rofecoxib with the intravenous administration of indomethacin clearly produced gastric lesions. These results suggest that in addition to COX inhibition by NSAIDs, direct cytotoxicity of NSAIDs may be involved in NSAID-induced gastric lesions.

Prostanoids synthesized by cyclo‐oxygenase isoforms in rat spinal cord and their contribution to the development of neuronal hyperexcitability

1. The responses of wide dynamic range spinal dorsal horn neurones to noxious mechanical stimulation of the ankle or knee joint were tested before and after spinal administration of the non-selective cyclooxygenase (COX) inhibitors, indomethacin and meclofenamic acid. Neither of these drugs altered the responses of these neurones to noxious mechanical stimulation. 2. Wind-up of a spinal nociceptive reflex evoked by electrical stimulation of the sural nerve at C-fibre strength was dose-dependently inhibited by intravenous administration of indomethacin, a non-selective COX inhibitor, and SC58125, a selective COX-2 inhibitor. Intrathecal administration of indomethacin also reduced the wind-up of this nociceptive reflex. 3. Western blot analysis of proteins extracted from normal rat spinal cord revealed the presence of both cyclo-oxygenase (COX)-1 and COX-2 proteins. 4. Immunocytochemistry of sections of normal rat spinal cord with specific COX-1 antiserum revealed little specific COX-1-like immunoreactivity in the grey matter. With the same antiserum, intense COX-1-like immunoreactivity was observed in the cytoplasm, nuclear membrane and axonal processes of small to medium sized (< 1000 microns2) dorsal root ganglion (DRG) cell bodies. 5. Immunocytochemistry of sections of normal rat spinal cord incubated with specific COX-2 antiserum showed intense COX-2-like immunoreactivity (COX-2-li) in the superficial dorsal horn of the spinal cord (laminae I and II) and around the central canal (lamina X). COX-2-li was also observed in some neurones in deep dorsal horn and in individual motor neurones in ventral horn. COX-2-li was not observed in the cell bodies of DRG. 6. Superfusion of the lumbar spinal cord of normal rats with artificial CSF and subsequent radioimmunoassay revealed the presence of prostaglandin D2 (PGD2) < PGE2, but not PGI2 (determined by measurement of the stable metabolite, 6-keto-PGF1 alpha) or PGF2 alpha. 7. These data suggest that eicosanoids synthesized by an active COX pathway in the spinal cord of normal animals may contribute to nociceptive processing, but only when the spinal cord neurones are rendered hyperexcitable following C-fibre stimulation. Selective inhibition of one or both of the COX isoforms in normal animals may represent a novel target for spinal analgesia.

Central mechanism of indomethacin analgesia

The analgesic effect of indomethacin was investigated by using the visceral pain model in rabbits. After intravenous administration of indomethacin (2 mg/kg), the maximum increase of the visceral pain threshold was 0.42 ± 0.31 mA (P < 0.05) . The analgesic effect lasted 40 min. After intraventricular microinjection of indomethacin (50 μg), the maximum increase of the visceral pain threshold was 0.37 ± 0.43 mA . After intravenous administration of indomethacin, the content of norepinephrine in perfusates of rabbit fourth ventricle was significantly increased from 18.10 ± 8.05 to 32.16 ± 6.15 mg/40 μ l (P < 0.05) , compared with data for the control group. The content of β-endorphin in the perfusate after indomethacin administration was decreased from 5–25 min and slightly increased from 25–35 min, compared with the data for the control group, but there was no significant difference (P > 0.05). Furthermore, intraventricular microinjection of phentolamine (50 μg) could block the analgesic effect of an intravenous injection of indomethacin, while naloxone could not. The results imply that prostaglandins of the central nervous system could induce hyperalgesia. Indomethacin injected centrally and peripherally has an analgesic effect on visceral pain. This analgesic effect is mediated by α-adrenoceptors. β-Endorphin does not participate in the analgesic action of indomethacin.

Inflammation as a major cause of fluid losses in small-bowel obstruction.

The importance of inflammation for fluid losses in obstructive ileus was investigated in vivo in the rat. Inflammation was quantified by spectrophotometry of extravasated Evans blue (Eb)-albumin. Net fluid secretion in the obstructed jejunum was measured by a continuous gravimetric technique. The inflammation in the obstructed gut wall was significantly more pronounced than that in the gut distal to the obstruction and the sham-obstructed gut. The inflammation was significantly more pronounced in the serosa and external muscle layer than in the mucosa-submucosa. Acid-base balance in obstructed animals showed a significant metabolic alkalosis, whereas serum albumin and electrolytes were normal. Lumen fluid in obstructed animals showed low levels of albumin and total calcium as compared with serum, whereas fluid from the peritoneal cavity of obstructed rats showed high contents of albumin. Indomethacin and hydrocortisone given intravenously to obstructed animals significantly reduced the degree of extravasated Eb-albumin in the obstructed gut wall. Sham-operated animals showed net fluid absorption, whereas obstructed rats showed net fluid secretion. Secretion in obstructed animals was in all cases reversed into net fluid absorption after intravenous administration of indomethacin and hydrocortisone. These findings suggest that a pronounced inflammation occurs in the wall of the obstructed small intestine and that this inflammation plays an important role in the pathogenesis of the profuse fluid losses of obstructive ileus.

Indomethacin decreases jejunal fluid secretion in addition to luminal release of prostaglandin E2 in patients with acute cholera.

Human cholera is associated with an increased luminal release of prostaglandin E2 (PGE2), but whether inhibition of increased PGE2 synthesis will reduce or control intestinal secretion is uncertain. 'Steady state' perfusions (10 ml/minute) in 12 patients with acute cholera, and repeat perfusions in nine of these patients during the convalescent phase were therefore performed using the triple lumen technique. The proximal jejunum was perfused with isotonic saline containing sodium-sulphobromophthalein as a non-absorbable marker. After intravenous administration of indomethacin (1.0 mg/kg) the jejunal net transfer of fluid and the jejunal flow rate of PGE2 were determined in 30 minute periods for 120 minutes after a 120 minute control period. Indomethacin decreased net fluid secretion (2.1 (0.3-4.2) v 4.5 (2.5-8.4) ml/hour x cm; medians, Q50 ranges, p less than 0.01) and the jejunal flow rate of PGE2 (1.5 (1.2-2.7) v 2.2 (1.4-4.9) ng/minute, p less than 0.05). The results of similar perfusion studies in 22 patients with acute cholera, used to establish the spontaneous time related change in fluid secretion, showed no significant change in net fluid transfer (3.5 (2.2-6.2) to 3.5 (2.6-11.6) ml/hour x cm, p greater than 0.25) over 240 minutes. These data provide further evidence in favour of the hypothesis that prostaglandins have a role in the cholera toxin induced intestinal fluid secretion in man.

Epithelial influence on the tracheal non‐adrenergic inhibitory response

1. The role of epithelium in the non-adrenergic non-cholinergic (NANC) inhibitory response to electrical nerve stimulation as well as to the putative neurotransmitter, vasoactive intestinal polypeptide (VIP), was evaluated in guinea-pigs anaesthetized with chloralose-urethane. 2. The tracheal pouch, an in vivo method to demonstrate the NANC inhibitory response, was used in all experiments. The relaxation response was measured as a pressure drop (cm of H2O) in the pouch. The animals were given atropine (5 mg kg-1) and propranolol (1 mg kg-1) intraperitoneally to block adrenergic and cholinergic responses in the pouch. Cervical vagi were isolated and cut craneally. The distal ends were positioned on bipolar electrodes for subsequent stimulation with 5V pulses of 2 ms duration at 15 Hz for a total of 90 s. 3. The reproducibility of NANC responses to two consecutive nerve stimulations at 20 min apart was determined in group 1. 4. In group 2 pouch relaxations to electrical nerve stimulations were determined before and after complete epithelial denudation (determined by histological and pharmacological methods) of the pouch. 5. To determine the influence of relaxant prostaglandins synthesized by the epithelial cells, the effect of indomethacin (given either intravenously or into the pouch) on the pouch relaxation due to NANC stimulation was studied in groups 3 and 4 respectively. 6. In group 5, in order to distinguish between the effects of epithelium removal and prostaglandins, the animals were pretreated with indomethacin (i.v.) 30 min before the experiment. The pouch relaxation to nerve stimulation was then determined before and after the removal of epithelium. 7. The reproducibility of the pouch relaxations to consecutive single doses of VIP 10(-9) M at 20 min apart was determined in group 6. 8. In group 7, the pouch relaxation to a single dose of VIP was determined before and after intravenous indomethacin administration, but with the pouch epithelium left intact. 9. The effect of epithelium removal on VIP-induced pouch relaxation was determined in group 8. VIP-induced response was determined before and after the epithelium removal. 10. The study showed that both epithelium removal and indomethacin administration independently had significant effects on the decrease of the pouch relaxation (NANC inhibitory response). However, epithelium removal significantly diminished pouch relaxation despite indomethacin pretreatment suggesting a second, non-arachidonic dependent, mechanism (possibly via a relaxing factor) whereby epithelium maintains airway homeostasis.(ABSTRACT TRUNCATED AT 400 WORDS)

Hormonal, Haemodynamic, and Subjective Effects of Intravenously Infused Indomethacin: No Change in the Physiological Response to Hypertonic Saline Challenge

This double-blind, placebo-controlled human study was performed to determine the endocrine responses to intravenously administered indomethacin at two dose rates (0.36 or 0.72 mg/kg bolus followed by 0.071 or 0.143 mg/kg/hr for 150 min.). A 5% hypertonic saline infusion was used for further assess the hormonal systems regulating body fluid and electrolyte balance. Plasma renin activity (PRA) and concentrations of aldosterone and vasopressin (AVP) were unaffected by indomethacin. Hypertonic saline caused a 5% increase in plasma sodium and a 4.2% increase in serum osmolality, with a concomitant two-fold rise in plasma AVP levels and significant declines in PRA and aldosterone. Indomethacin had no effects on these responses, and did not affect plasma catecholamine concentrations, but the hypertonic saline infusion doubled the noradrenaline levels in plasma. Atrial natriuretic peptide (ANP)-like immunoreactivity in plasma was not affected by indomethacin nor by hypertonic saline. The higher dose rate of indomethacin resulted in significant stimulation of growth hormone release, but plasma prolactin levels were not influenced. Thus acute intravenous administration of indomethacin proved to be devoid of significant effects on the multihormonal system regulating fluid and electrolyte balance.

Protection against oxidative damage in cold-stored rabbit kidneys by desferrioxamine and indomethacin

The storage of rabbit kidneys in hypertonic citrate solution at 0 °C for 48–72 hr of cold ischemia resulted in oxidative damage to membranes as measured by the in vitro formation of two markers of lipid peroxidation (Schiff's base and thiobarbituric acid (TBA)-reactive material). This damage was further increased when the organs were autografted and reperfused for 60 min. The intravenous (iv) administration of desferrioxamine (a powerful iron-chelating agent) prior to the removal of the kidneys reduced the production of Schiff's bases and TBA-reactive material to low levels in the cortex of stored kidneys and decreased these measures of lipid peroxidation in the medulla by approximately 50%. Intravenous administration of indomethacin (a cyclooxygenase inhibitor) had no effect on the rate of lipid peroxidation in the renal cortex, but significantly reduced the formation of TBA-reactive material and Schiff's bases in the medulla of kidneys following storage for 72 hr. The existence of two separate pathways of lipid peroxidation (one iron-catalyzed and the other cyclooxygenase-catalyzed) in the medulla of stored kidneys was further confirmed when administration of desferrioxamine and indomethacin together resulted in significantly greater protection against lipid peroxidation than when these compounds were administered singly. The value of this combination of agents for protecting kidneys against the damage due to cold ischemia followed by reperfusion was further suggested by a trend toward improved long-term survival of the animals following replantation of the stored kidneys.

Power spectrum analysis of myometrial electromyogram and intrauterine pressure changes in the pregnant rhesus monkey in late gestation

Various methods have been used to quantify myometrial activity in the pregnant rhesus monkey during the last third of gestation. A precise definition of activity must retain the characteristics of epoch duration, amplitude, and the repetitive frequencies of active epochs. We used Fast Fourier Transform and power spectrum analysis to determine whether the patterns of myometrial contractility consist predominantly of contractions or contractures. This analysis allows quantification of activity represented by each of these patterns of activity. We applied these methods to myometrial electromyogram and intrauterine pressure recordings in pregnant rhesus monkeys to characterize the changes in myometrial activity that occur after surgery, after intravenous indomethacin administration, and when food is withdrawn for 48 hours. We conclude that changes in the frequency pattern of myometrial activity provide important information in relation to labor and delivery contractions.

Effects of dopamine on pial arteriolar diameter and CSF prostanoid levels in piglets.

We examined effects of topically applied dopamine on pial arteriolar diameter and CSF prostanoid levels in newborn pigs. Vascular responses were determined using the closed cranial window technique and intravital microscopy, and prostanoids were determined by radioimmunoassay. Topical application of dopamine did not change arteriolar diameter at 10(-7)-10(-5) M, but constricted arterioles at 10(-4) (16%) and 10(-3) M (30%). Intravenous administration of indomethacin (5 mg/kg) did not alter this constriction. In addition, CSF prostanoid levels did not increase in response to application of dopamine except for a modest increase of prostaglandin E2 at 10(-3) M. We conclude that dopamine is a constrictor at high doses of piglet pial arterioles and that this response is not modified by endogenous prostanoids.

Role of prostaglandins and kinins in the renal pressor reflex.

In previous studies we identified an afferent renal nerve-dependent pressor reflex elicited by acute unilateral renal artery stenosis (50% decrease in renal blood flow) in conscious, instrumented rats with reduced responsiveness of arterial baroreceptor reflexes and the renin-angiotensin system. The pressor reflex involves a neurogenic increase in peripheral resistance. The present study examined the nature of the intrarenal stimulus underlying this renal pressor reflex. Rats were subjected to sinoaortic denervation and, 7 to 10 days later, were chronically instrumented with Doppler flow probes on the right renal artery, superior mesenteric artery, and abdominal aorta and with an occluder on the right renal artery. Following surgical recovery and inhibition of the renin-angiotensin system (captopril), animals received intravenous isotonic saline, 6% of body weight over 60 minutes. Saline infusion did not alter baseline hemodynamics, vascular neurogenic tone, or responsiveness to tyramine, but it attenuated the reflex by 70%. A second series of experiments examined a possible role for intrarenal prostaglandins, kinins, or adenosine in the activation of renal sensory receptors during renal stenosis. Prostaglandin inhibition with intravenous administration of indomethacin and meclofenamate virtually abolished the reflex in the face of enhanced tyramine responsiveness, whereas kallikrein inhibition (aprotinin) attenuated the reflex pressor response by 33%. Adenosine inhibition with aminophylline or adenosine deaminase had no effect on the reflex; these agents and aprotinin did not affect vascular neuroeffector responsiveness (tyramine). The data suggest that the renal pressor reflex may be mediated by renal sensory nerves, possibly chemoreceptors, whose activation could depend on renal excretory function and synthesis of prostaglandins and kinins.

Influence of Vasoactive Substances on Early Toxic Acute Renal Failure in the Dog

The influence of different vasoactive substances on the evolution of HgCl2-induced acute renal failure (ARF) was evaluated in the dog. HgCl2 alone caused a progressive fall in both glomerular filtration (GFR) and renal blood flow (RBF) during the first 3 h of the mercury administration (delta after 3 h: -44% and -39%) and provoked a concomitant stimulation of the renin-angiotensin (RAS) and thromboxane systems. The administration of the thromboxane inhibitor dazoxiben (2 mg/kg i.v. every 2 h) adequately inhibited the activation of the thromboxane system after HgCl2, but could not prevent the fall in GFR and RBF. The continuous intrarenal administration of the Ca2+ entry blocker verapamil (0.005 mg/kg per min) into the left kidney resulted in the prevention of the postmercurial fall in GFR and RBF at the perfusion site. This beneficial effect was immediately lost when the verapamil administration was stopped. Finally, the administration of the converting enzyme inhibitor captopril (300 micrograms/kg every 2 h) resulted in an effective inhibition of the renin-angiotensin system, the prevention of the postmercurial fall in RBF, and the partial attenuation of the fall in GFR. This beneficial effect was immediately lost after the intravenous administration of indomethacin (2 mg/kg). These results indicate that the fall in GFR after HgCl2 can be prevented by vasoactive agents such as captopril and verapamil and point at least in part to a pathophysiological role of the renin-angiotensin system or of an alteration in the equilibrium between renin-angiotensin and prostaglandins. The thromboxane system is seemingly of no major importance.

Effects of indomethacin on cardiac output distribution in normal and asphyxiated piglets

We determined the effect of breathing 9% CO 2/10% O 2/81% N 2 (asphyxia) on cardiac output distribution (microspheres) in 4–5 day old unanesthetized, chronically instrumented piglets prior to and following intravenous indomethacin administration. Thirty minutes of asphyxia caused Pa CO 2 to increase from 35 ± 2 mmHg to 66 ± 2 mmHg, Pa O 2 to decrease form 73 ± 4 mmHg to 41 ± 1 mmHg, and pH to decrease from 7.52 ± 0.05 to 7.21 ± 0.07. Arterial pressure was increased slightly but cardiac output was not changed significantly. Asphyxia caused blood flow to the brain, diaphragm, liver, heart, and adrenal glands to increase while causing decreases in blood flow to the skin, small intestine, and colon. Blood flows to the stomach and kidneys tended to decrease, but the changes were not significant. Treatment with indomethacin during asphyxia did not alter arterial pressure or cardiac output but decreased cerebral blood flow to the preasphyxiated level and decreased adrenal blood flow about 20%. Indomethacin did not alter blood flow to any other systemic organ. At this time the piglet was allowed to breathe air for 2.5 hr undisturbed. Two and a half hours after indomethacin administration, blood flows to all organs returned to the preasphyxia control levels with the exception of cerebral blood flow which was reduced (93 ± 13 to 65 ± 5 ml/100 g·min. Three hours after indomethacin administration, the cerebral hyperemia caused by asphyxia was less (134 ± 17 b ml/100 g·min) than prior to indomethacin (221 ± 15 ml/100 g·min. Indomethacin did not alter the asphyxia-induced changes to any other systemic organ. We conclude that in newborn pigs, systemic treatment with indomethacin decreases cerebral blood flow and cerebral hyperemia in response to asphyxia, without affecting blood flow to any other systemic organ.

Antipyretic effect of indomethacin suppository in rabbits.

We have designed a thermistor rectal probe thermometer for measuring the antipyretic activity of suppositories. Using this thermistor probe, we tested the antipyretic effect of an indomethacin suppository in comparison with oral and intravenous administrations in rabbits (male, 2.5-2.9 kg). The rectal temperature of normal rabbits remained unchanged after rectal and intravenous administration of indomethacin, 25 mg/body and 10 mg/kg, respectively. The antipyretic effect was tested in febrile rabbits injected with bacterial pyrogen, lipopolysaccharide (LPS) 0.2 microgram/kg (i.v.). The dose-dependent antipyretic activities were observed in febrile rabbits administered with indomethacin by rectal (6.3-23.7 mg/body), intravenous (2.5-10 mg/kg) and oral (2.5-20 mg/kg) routes. When indomethacin was administered simultaneously or 1 h after LPS, the most potent antipyretic effect was observed in the case of rectal administration and the weakest effect was observed in that of oral administration. These data indicate that the rectal administration of drugs can produce a potent antipyretic activity, not inferior to that of the intravenous injection.

Indomethacin does not potentiate renovascular constriction during hypercapnia in unanesthetized rabbits

The role of prostanoids in regulation of the renal circulation during hypercapnia was examined in unanesthetized rabbits. Renal blood flow (RBF) was determined with 15 μm radioactive microspheres during normocapnia (PaCO 2 ≅ 30 mmHg) and hypercapnia ( PaCO 2 ≅ 60 mmHg), before and after intravenous administration of indomethacin (10 mg/kg) or vehicle (n=6 for each group). Arterial blood pressure was not different among the 4 conditions in each group. RBF was 438±61 and 326 ± 69 (P<0.05) ml/min per 100 g during normocapnia and hypercapnia, respectively, before indomethacin, and following administration of indomethacin, RBF was 426 ± 59 ml/min per 100 g during normocapnia and 295 ± 60 ml/min per 100 g during hypercapnia (P<0.05). In the vehicle group, RBF was 409±74 and 226±45(P<0.05) ml/min per 100 g during normocapnia and hypercapnia, respectively, before vehicle; and following administration of vehicle, RBF was 371±46 ml/min per 100 g during normocapnia and 219 ± 50 (P<0.05) per 100 g during hypercapnia. RBF during normocapnia was not affected by administration of indomethacin or vehicle. The successive responses to hypercapnia were not different within the indomethacin and vehicle groups, and the second responses to hypercapnia were not different between the two groups. These findings suggest that prostanoids do not contribute significantly to regulation of the renal circulation during normocapnia and hypercapnia in unanesthetized rabbits.

Histamine-induced spasm not significantly modulated by prostanoids in a swine model of coronary artery spasm

The role of prostanoids in a swine model of coronary artery spasm was examined. Eighteen miniature pigs underwent endothelial denudation of the left coronary artery (left circumflex branch in 14 pigs and left anterior descending branch in 4 pigs) followed by high cholesterol feeding. Three months after the denudation, when coronary artery spasm was repeatedly provoked along the denuded portion of the coronary artery by histamine, the vasoconstrictive effect of thromboxane A2 and the preventive effects of indomethacin and prostacyclin against histamine-induced coronary artery spasm were examined. Intracoronary administration of thiothromboxane A2, 200 micrograms, a stable thromboxane A2 analog, failed to provoke coronary artery spasm (seven of seven cases) but nonselectively constricted the coronary artery by 33%. Intravenous administration of indomethacin, 2 mg/kg, or continuous intravenous infusion of prostacyclin, 50 ng/kg per min, failed to prevent histamine-induced coronary artery spasm (four of four and eight of eight cases, respectively), yet the spasm was all but prevented by intravenous pretreatment with diphenhydramine at a dose of 1 mg/kg. Thus, in this swine model, prostanoids may not play a primary role in the occurrence of coronary artery spasm.