CP-66,948: An antisecretory histamine H2-receptor antagonist with mucosal protective properties

CP-66,948 is a histamine H₂-receptor antagonist with gastric antisecretory activity and mucosal protective properties. The affinity of CP-66,948 for the guinea pig atria histamine H₂-receptor is 15 times greater than that of cimetidine and seven times greater than that of ranitidine.In vivo, the ED₅₀ value for inhibition of gastric acid secretion in pylorusligated rats is 2 mg/kg intraduodenally, and in histamine or pentagastrin-stimulated Heidenhain pouch dogs the antisecretory ED₅₀ values are 0.3 mg/kgper os and 1.0 mg/kgper os, respectively. CP-66,948 also inhibits ethanol-induced gastric hemorrhagic lesions in rats following either oral or systemic administration (ED₅₀ values of 12 mg/kgper os and 6 mg/kg subcutaneously). In addition, the mucosal protective activity is independent of prostaglandin synthesis. CP-66,948 inhibits gastric acid secretion in man, and its mucosal protective activity may provide additional benefits in peptic ulcer therapy.     

Inhibition of canine gastric secretion by the prostanoid Ro 22-6923

The synthetic prostanoid, Ro 22-6923, was studied for its effects on canine gastric secretion. Histamine-stimulated acid secretion was inhibited for up to 8 hr after an orally administered dose of 0.25 mg/kg Ro 22-6923. In the Amdrup (modified Pavlov) pouch model, Ro 22-6923 significantly inhibited food-stimulated acid secretion at an oral dose of 0.5 mg/kg. The effect lasted for 4 hr and was of greater intensity than that observed with 5 mg/kg cimetidine. The ED ₅₀ for Ro 22-6923 in this model was 0.25 mg/kg and 0.09 mg/kg for oral and intrapouch administration, respectively. Natural prostaglandin E ₂ was inactive up to 1 mg/kg orally, but had an ED ₅₀ of 0.08 mg/kg when administered directly into the pouch. The results indicate that Ro 22-6923 is a potent, long-acting antisecretory drug that may be useful in the therapy of peptic ulcer disease in man.     

The effects of a prostaglandin E1 analogue, misoprostol, on gastric mucosal blood volume index and haemoglobin oxygenation in humans

A double-blind placebo-controlled parallel design study was conducted in 12 healthy male volunteers to examine the effects of misoprostol, a newly synthesized prostaglandin E₁ analogue, on gastric mucosal haemodynamics in human. The indices of mucosal blood volume (expressed as ΔEr) and mucosal blood haemoglobin oxygenation (Hb-SO₂) were measured at 20 locations in the stomach prior to and after administration of misoprostol or its placebo using reflectance spectrophotometry during endoscopy. It was found that after misoprostol administration, mucosal blood volume was increased by approximately 10–25% throughout the stomach without any significant change in mucosal blood Hb-SO₂. Administration of placebo produced no significant change in these parameters. The results suggest that misoprostol has the potential to accelerate healing of gastric ulcers by increasing the gastric mucosal blood volume and oxygenation in addition to its gastric acid antisecretory activity.     

Effects of prostaglandins E2 and 552-01552-01552-01on motility of small intestine in man

Interdigestive motility of the small intestine was examined in 23 fasted healthy volunteers following luminal administration of the prostaglandins E₂ and F₂. Motility was monitored by means of water-perfused catheters measuring intraluminal pressure changes. The registration points were located 25 cm apart, in the proximal duodenum, at the angle of Treitz, and in the jejunum. Prostaglandin E₂ administered intraduodenally delayed the initiation of the subsequent activity front. The interval to the next activity front was prolonged by a dose of 1.0 mg prostaglandin E₂ from 79.5±9.5 min to 137.1±5.0 min (P<0.01) and to 158.0±14.0 min by 2.0 mg prostaglandin E₂ (P<0.05). Also, in four of seven experiments, a progressing activity front was arrested by 2.0 mg prostaglandin E₂. Prostaglandin F₂ at 2.5 or 5.0 mg given intraduodenally induced bursts of contractions with a frequency of 17.7± 0.8 contractions per minute and an amplitude of 10 to 110 mm Hg (P<0.07). In comparison, food intake produced irregular contractions at a frequency of 5.3± 1.8 contractions per minute and an amplitude of 10 to 50 mm Hg (P<0.05). It is concluded that prostaglandin E₂ delays the initiation of activity fronts in the duodenum. In contrast, prostaglandin F₂ changes the interdigestive motility pattern to one of intense contractile activity, which is different from the postprandial motility pattern.     

Gastric antisecretory effects of E prostaglandins in rhesus monkeys

The gastric antisecretory actions of prostaglandin E₁ methyl ester (PGE₁ME) and prostaglandin E₂ (PGE₂) were evaluated in unanesthetized gastric fistula rhesus monkeys. Basal and stimulated gastric secretory studies were conducted. Multiple subcutaneous injections of either histamine or pentagastrin were given hourly for four consecutive hours. When a constant plateau of gastric secretion was reached, the PGs were administered as a single intravenous bolus at doses of 10–100 g/kg. PGE₁ME inhibited basal, histamine-, and pentagastrin-stimulated gastric secretion. PGE₂ was found to inhibit the histamine-stimulated gastric secretion. The PGs showed greater sensitivity to the inhibition of acid concentration rather than the volume of secretion. The PGs significantly altered gastric juice concentration of hydrogen and sodium ion inversely, while potassium and chloride concentration were not altered. These experiments suggest that the rhesus monkey is a useful species for studying the gastric antisecretory effects of E prostaglandins.     

Effects of FK506, an immunosuppressive agent,on genesis of water-immersion stress-induced gastric lesions in rats

We examined the effects of FK506, an immunosuppressive agent, on the genesis of water immersion stress-induced gastric lesions in rats. Using high-performance liquid chromatography, four kinds of prostaglandins, ie, 6-keto-prostaglandin F₁, prostaglandin F₂, prostaglandin E₂, and prostaglandin D₂, were detected, and no leukotrienes were detected in gastric mucosa in rats without stress. After 6 hr of stress, gastric lesions developed with decreases in all prostaglandin contents, and the emergence of peptide leukotrienes was observed. Intramuscular administration of FK506 (0.1, 0.25, 0.5, 1.0, and 2.0 mg/kg) reduced lesion index dose-dependently. Administration of FK506 at doses over 0.25 mg/kg decreased all prostaglandin contents, but did not affect the increase in leukotriene contents. Pretreatment with famotidine or omeprazole reduced lesion index, and the protective effects were equivalent to those of 1.0 mg/kg of FK506, although FK506 did not affect gastric secretion during water-immersion stress. Water-immersion stress did not change the activities of xanthine oxidase in either stomach or serum. Polyoxyethylenemodified superoxide dismutase did not prevent gastric lesions. Water-immersion stress significantly increased myeloperoxidase activity in gastric mucosa, and FK506 reduced the increase in myeloperoxidase activity induced by stress. From our results, other factors besides gastric acid secretion and tissue eicosanoid contents, such as chemoattractant factor, might also be involved in the genesis of water-immersion stress-induced gastric lesions in rats.     

Effects of a proton pump inhibitor,omeprazole, on gastric secretion and gastric and duodenal ulcers or erosions in rats

The effects of omeprazole, a proton pump inhibitor, on gastric secretion and gastric or duodenal ulcers or erosions in rats were studied. Omeprazole, given intraduodenally, dose-dependently inhibited the gastric secretion (volume, acid and pepsin output) of pylorus-ligated rats. The antisecretory activity of omeprazole at 100 mg/kg persisted for 14 hr after treatment. Acutely induced gastric ulcers or erosions such as Shay ulcers, water-immersion stress-, indomethacin-, aspirin-, or prednisolone-induced erosions were all markedly inhibited by oral or intraduodenal administration of 10–100 mg/kg of omeprazole. The development of duodenal ulcers and gastric erosions caused by mepirizole was also potently inhibited by omeprazole at 3–10 mg/kg given orally. Repeated administration of omeprazole, 200 mg/kg/day in two divided doses for 14 days, significantly accelerated the spontaneous healing of acetic acid-induced gastric ulcers. The mechanism by which omeprazole inhibits the development of acute ulcers and accelerates healing of preexisting ulcers appears to be mainly due to its potent and longlasting antisecretory activity. The antisecretory and antiulcer activities of omeprazole are equal to or exceed those of cimetidine, both in the maximum inhibitory response and ED₅₀ values.     

Role of prostaglandins in the early phases of experimental gastric carcinogenesis in the rat

Summary The study was initiated to evaluate the effect of N-methyl-N-nitro-N-nitrosoguanidine (NG) on gastric intraluminal prostaglandin release during a 30-day treatment period and to investigate the effect of a stable prostaglandin E¹ analogue (misoprostol) on NG-induced gastric mucosal damage during the same time period. Samples of gastric juice (1 h) were obtained from 40 male Sprague-Dawley rats with chronic gastric fistulas, in basal conditions and after 5, 15 and 30 days of continuous oral administration of NG (120 mg/l) or tap water. Aliquots of gastric juice were titrated with 0.1 M NaOH. Other aliquots were extracted with ethyl acetate and subjected to specific radioimmunoassay for prostaglandin E₂. The severity of gastric mucosal lesions was evaluated in 60 rats after 5 days and 30 days of continuous oral administration of NG (120 mg/l) or NG plus misoprostol (200 g/kg^-1/day^-1) or tap water, and a histological study was carried out. Administration of NG induced a significant decrease of gastric intraluminal prostaglandin E₂ concentration at 15 and 30 days. Oral administration of misoprostol, at non-antisecretory doses, protected the rats against NG-induced gastric mucosal damage. Prostaglandins may be involved in the early phases of experimental gastric carcinogenesis.This work was supported by grants from the Ministry of Education (MPI)     

Effects of NC-1300-B,A new benzimidazole derivative,on hog gastric H+, K+-ATPase,gastric acid secretion and HCl-ethanol-induced gastric lesions in rats

This study was designed to determine the effect of a newly synthesized benzimidazole derivative NC-1300-B on H⁺,K⁺ -ATPase (proton pump) in the hog gastric mucosa and on the basal gastric acid secretion and necrotizing agent-induced gastric lesions in rats. NC-1300-B inhibited the proton pump in a concentration-dependent manner and concentrations which inhibited the enzyme activity by 50% were 4.4×10^–6 M at pH 6.0 and 3.1 ×10^–5 M at pH 7.4. NC-1300-B administered orally or intraperitoneally 0.5 hr before ligating the pylorus inhibited the gastric acid secretion in a dose-dependent manner. The ED₅₀ values (doses which inhibit acid output or lesion formation by 50%) for acid secretion were 11.5 and 11.0 mg/kg with oral and intraperitoneal administration, respectively. The antisecretory effect in a dose of 100 mg/kg persisted for up to 72 hr. NC-1300-B administered orally or intraperitoneally 0.5 hr before HCl-ethanol administration protected against damage of the gastric mucosa in a dose-dependent manner. The ED₅₀ values for lesion formation were 13.3 and 23.0 mg/kg with oral and intraperitoneal administration, respectively. This protection with an oral dose of 100 mg/kg persisted for up to 72 hr. While pretreatment with 5 mg/kg of indomethacin given subcutaneously did not appreciably reverse the NC-1300-B protection, the pretreatment with 10 mg/kg of N-ethylmaleimide given subcutaneously potently reversed the NC-1300-B protection. NC-1300-B administered intragastrically at 30 mg/kg significantly inhibited the amplitude of gastric contraction for 50 min after intragastric administration. These effects of NC-1300-B on gastric secretion and lesion formation are much the same as those of the established proton pump inhibitor omeprazole, except for the short duration of the action of omeprazole (<24 hr).     

Gastroprotective Effects of DA-6034, a New Flavonoid Derivative, in Various Gastric Mucosal Damage Models

This study evaluated the gastroprotective activity of DA-6034 against various ulcerogens including ethanol, aspirin, indomethacin, stress, and acetic acid. The basic mechanisms of DA-6034 as a defensive factor such as mucus secretion and endogenous prostaglandin E₂ synthesis were determined. Rats with gastric lesions induced by ethanol-HCl, aspirin, indomethacin, and stress that had been pretreated with DA-6034 orally showed a statistically significant decrease or decreasing tendency of the gastric lesion. In acetic acid-induced gastric lesions, repeated oral administration of DA-6034 exhibited a U-shape activity in ulcer healing, with the maximum and minimum inhibition being observed at 30 and 10 mg/kg/day, respectively. DA-6034 also increased the mucus content in the gel layer as well as endogenous prostaglandin E₂ synthesis. These results suggest that DA-6034 prevents gastric mucosal injury, and these gastroprotective activities appear to be due to the increase in the gastric defensive systems.     

Effect of 15(R), 15-methyl prostaglandin E2 and indomethacin on pancreatic secretion in man

In addition to gastric mucosal cytoprotective and antisecretory effects, prostaglandin E₂ has a beneficial effect on experimental pancreatitis in some animal models, while prostaglandin synthesis inhibitors such as indomethacin and salicylates may induce pancreatitis at maximal doses. However, their effect on human pancreas is unclear. For this reason we considered it necessary to delineate their actions on human pancreatic secretion. Six healthy volunteers were studied on six separate days. On day 1, against a background of 1 pmol/kg/hr secretin, increasing doses of CCK were infused intravenously. On day 2, increasing doses of an amino acid mixture were infused intraduodenally and both studies were repeated on two occasions, following 100 g 15(R), 15-methyl prostaglandin E₂ per os on one and following indomethacin 50 mg orally 12 and 1 hr prior to the study on the other. Both indomethacin and PGE₂ had no significant effect on pancreatic secretion in response to graded doses of CCK. 15(R), 15-Methyl prostaglandin E₂ and indomethacin caused a reduction of amylase output in response to the higher doses of intraduodenal amino acids. The prostaglandin E₂ derivative also elicited a significant increase in basal bicarbonate output. In conclusion: the acute effects of 15(R), 15-methyl prostaglandin E₂ and indomethacin on human pancreatic secretion do not seem to offer an explanation for the mechanisms of protection against experimental acute pancreatitis or an association with pancreatitis, respectively.     

Gastrointestinal Protection by Low-Dose Oral Prostaglandin E2 in Rheumatic Diseases

In a previous study oral prostaglandin E₂ (PGE₂) was shown to protect against indomethacin-induced gastrointestinal bleeding in patients with rheumatic diseases. This study examined whether a lower oral dose of PGE₂, without acid antisecretory effect, is protective. Its methylated analogue 15(R)15 Me PGE₂, which has effect on the acid secretion given orally, was also tested. Indomethacin, 50 mg three times daily, induced an increase in gastrointestinal bleeding measured by the ⁵¹Cr technique. PGE₂, 0.33 mg three times daily, taken concomitantly significantly reduced fecal blood loss. 15(R)15 Me PGE₂, 40 μg three times daily, was also effective. The prostaglandins did not increase joint symptoms and had no significant side effects. It is suggested that the combination of nonsteroidal anti-inflammatory drugs with a low oral dose of E₂ prostaglandins could be used clinically, especially in patients with rheumatic diseases.     

Prospective evaluation of gastric acid secretion and cobalamin absorption following gastric bypass for clinically severe obesity

The pathophysiologic mechanism(s) responsible for cobalamin deficiency after Roux-en-Y gastric bypass for clinically severe obesity remains unexplained. Inadequate secretion of intrinsic factor has been postulated, but decreased gastric acid secretion resulting in maldigestion and inadequate liberation of free cobalamin from its native protein-bound form is also possible. The aim of this study was to determine prospectively secretion of gastric acid and absorption of crystalline (free) and protein-bound cobalamin before and after gastric bypass. Eight patients (two men, six women) underwent orogastric intubation of the intact stomach preoperatively and the proximal gastric pouch postoperatively. Gastric acid secretion in the basal and stimulated (pentagastrin, 6 µg/kg) states was determined by a perfused, nonabsorbable marker technique to quantitate recovery of gastric secretion. Absorption of radiolabeled (⁵⁷Co) crystalline and protein-bound cobalamin was assessed on separate days by 24-hr urinary excretion. After gastric bypass, acid secretion (juvysem) was markedly reduced in basal (9.1±3.6 vs 0.005±0.003 meq/hr;P=0.04) and stimulated (12.8±1.8 vs 0.008±0.003 meq/30 min;P=0.002) states. Absorption of crystalline cobalamin was decreased (15.8±2.5 vs 9.4±1.4%;P=0.08) to a lesser extent than was protein-bound cobalamin (5.9±1.0 vs 1.1±0.3%;P=0.004). In summary, gastric acid secretion from the gastric pouch is negligible after gastric bypass, and food-bound cobalamin is maldigested and subsequently malabsorbed presumably due to pouch achlorhydria. Decreased absorption of free cobalamin suggests decreased cobalamin-intrinsic factor complex formation. This study suggests that cobalamin deficiency after Roux-en-Y gastric bypass results both from inadequate digestion of food-bound cobalamin and from insufficient secretion of intrinsic factor.This work was supported in part by a grant (DK39337) from the National Institutes of Health, the Ethicon Corporation, and the Mayo Foundation.     

Prostaglandin deficiency by itself is not the cause of mepirizole-induced duodenal ulcers in rats

The purpose of these studies was to determine the role played by endogenous prostaglandins in the development of gastric ulcers produced by indomethacin, and of duodenal ulcers produced by mepirizole in rats. Indomethacin (10 mg/kg subcutaneously) produced gastric ulcers, whereas mepirizole (100 mg/kg subcutaneously) produced exclusively duodenal ulcers. Both drugs, given at ulcerogenic doses, reduced the gastric and duodenal generation of PGE₂, PGF₂, 6-keto-PGF₁, and thromboxane B₂. In this regard, the extent of reduction was more pronounced after indomethacin than after mepirizole. Despite this greater inhibition of prostaglandin synthesis by indomethacin, this drug did not produce duodenal ulcers, whereas mepirizole was duodenoulcerogenic. In addition, mepirizole increased gastric acid secretion by 74%, whereas indomethacin had no effect on acid secretion. Oral administration of 16,16-dimethyl PGE₂, given at nonantisecretory doses (0.5–5 g/kg), prevented formation of indomethacin-induced gastric ulcers, whereas antisecretory doses were required to prevent formation of mepirizole-induced duodenal ulcers. We conclude that a reduction of prostaglandin formation in the duodenal mucosa is not by itself sufficient to induce duodenal ulcers. We hypothesize that three changes, produced by mepirizole, must be present for duodenal ulcers to develop: increased gastric acid secretion, decreased duodenal bicarbonate secretion (as demonstrated earlier), and decreased duodenal content of prostaglandins. The decreased prostaglandin formation, although not causing duodenal ulcers, may lower the resistance of duodenal mucosa to the hyperacidity induced by mepirizole. On the other hand, in the case of gastric ulcers following administration of indomethacin, a decrease in gastric mucosal levels of prostaglandins may play a more important role than changes in gastric acidity.These investigations were supported in part by a grant from the U.S.P.H.S. (AM RO1 37050)     

Effect of prostaglandin E2 on gastric mucosal bleeding caused by aspirin

The effect of prostaglandin E₂ on gastric mucosal bleeding caused by aspirin was studied. Blood in serial gastric washings was measured chemically for 30 min. Normal blood loss was equivalent to 0.05 ml/day. Aspirin, 600 mg four times daily, increased gastric bleeding on day 1; bleeding was further increased on day 2. On day 2, ingestion of 0.5 mg of prostaglandin E₂ 15 min before 600 mg of aspirin reduced the gastric microbleeding caused by aspirin. Prostaglandin E₂, 0.5 mg four times daily, did not change the normal blood loss. No consistent changes in gastric emptying or in secretion of chloride were detected.This work was supported in part by a grant from The Upjohn Company, Kalamazoo, Michigan.     

Effects of nonsteroidal antiinflammatory drugs on ulcerogenesis and gastric secretion in pylorus-ligated rat

The effects of nonsteroidal antiinflammatory drugs on ulcerogenesis and gastric secretion were evaluated in a pylorus-ligated rat model. Oral administration of salicylate (50 mg/kg), aspirin (50 mg/kg), and indomethacin (3.5 mg/kg) significantly increased ulcerogenesis over the basal value by six- to sevenfold, but ibuprofen's (10 mg/kg) fourfold increase was not significant. Aspirin in conjunction with histamine (0.5 mg/kg subcutaneously) significantly increased ulcerogenesis by 2.7-fold compared to histamine alone. Basal acid secretion was increased significantly by 156% after indomethacin, but not by other nonsteroidal antiinflammatory drugs. In contrast, all nonsteroidal antiinflammatory drugs, except indomethacin, significantly decreased histamine-stimulated acid secretion. Nonsteroidal antiinflammatory drugs had no effect on pepsinogen secretion. Ranitidine pretreatment (25 mg/kg intraperitoneally) significantly decreased basal acid and pepsinogen secretion in all treatment groups by >85% and >40%, respectively, and ulcerations induced by salicylate, aspirin, and indomethacin were also inhibited by 90%, 60%, and 60%, respectively. The observed inhibition of prostaglandin E₂ generation by nonsteroidal antiinflammatory drugs under basal secretory conditions appeared to correlate with the extent of ulcerogenesis. Our data support the concept that acid, in addition to inhibition of prostaglandin E₂ synthesis, plays an important role in the pathogenesis of nonsteroidal antiinflammatory drug-induced gastropathy.     

Oral administration of loxiglumide (CCK antagonist) inhibits postprandial gallbladder contraction without affecting gastric emptying

The effect of a single oral dose of loxiglumide, a cholecystokinin antagonist, on postprandial gallbladder contraction and on gastric emptying was evaluated in humans. Following a 12-hr fasting period, two tablets of loxiglumide (400 mg each) or placebo was administered on different days, in random order and in a double-blind fashion to 10 healthy volunteers 15 min before the ingestion of a 1050-kcal standard meal. Gallbladder and antral volumes were measured by real-time ultrasonography in basal conditions and at fixed time intervals after the meal. Oral loxiglumide administration was followed by a total inhibition of the gallbladder contraction for 60 min after the end of the meal ingestion. Thereafter, up to the end of the study period, gallbladder volume was larger than that of the placebo study (at 300 min after the meal 2.7±1.6 ml after placebo and 8.2±3.5 ml after loxiglumide; P<0.008). No difference between placebo and loxiglumide was found in the antral volumes at any time interval (postprandial 63.5±16.5 ml after placebo and 59.4±24 ml after loxiglumide; at 300 min after the meal 20.8±13.3 ml after placebo and 18.9±9.5 ml after loxiglumide). In conclusion, a single oral dose of loxiglumide at the dose of 800 mg can inhibit postprandial gallbladder contraction without affecting gastric emptying. It would therefore appear that in man endogenous CCK, released after a solid-liquid, caloric, nutrient-balanced meal, plays a major role in the contraction of the gallbladder but does not affect gastric emptying.     

Antisecretory and antigastrin effects of rioprostil in gastric fistula dogs

This investigation examined the effect of rioprostil, a primary alcohol prostaglandin E₁ analog, on betazole-stimulated gastric acid secretion and on basal and food-stimulated (postprandial) serum gastrin levels in gastric fistula dogs. Rioprostil inhibited betazolestimulated gastric acid secretion with an ED₅₀ of 16 (10–24) g/kg, intragastrically. A near-maximal gastric antisecretory dose (100 g/kg, intragastrically) had no effect on basal serum gastrin levels but significantly attenuated the rapid rise in serum gastrin which follows feeding, a result different from that reported for other prostaglandin E₁ analogs. A nonantisecretory dose of rioprostil (1.0 g/kg, intragastrically) also attenuated the rise in postprandial serum gastrin. An antigastrin effect using a nonantisecretory dose of an antiulcer agent has not been reported previously and may indicate that rioprostil has a direct inhibitory effect on secretion of gastrin. The ability of rioprostil to inhibit gastric acid secretion and decrease postprandial peak serum gastrin levels, coupled with previously established cytoprotective efficacy, makes it an attractive clinical candidate for the treatment and prevention of peptic ulcer disease.Rioprostil is being jointly developed by Bayer A.G., Cilag A.G., Miles Laboratories, Inc., and Ortho Pharmaceutical Corporation.     

Acetazolamide Interferes with the Protective Effect of Prostaglandin E2 in the Rat Gastric Mucosa

Oral prostaglandin E₂ protected the gastric mucosa against the damage induced by intraperitoneal indomethacin in the rat. Blocking of the gastric alkaline secretion by subcutaneous acetazolamide potentiated the ulcerogenic action of indomethacin and reduced or abolished the protective effect of a submaximal dose prostaglandin E₂. The results are compatible with the hypothesis that stimulation of the alkaline secretion is one of the mechanisms by which prostaglandin E₂ protects the gastric mucosa.     

Comparison of the effect of prostaglandin E1, prostacycline and adenosine on peripheral vascular resistance

Prostacycline, prostaglandin E₁, and adenosine are highly effective vasodilators. These three drugs are widely used in the treatment of peripheral arterial occlusive disease. The aim of the study was to compare the vasodilatory potency of these substances in the isolated perfused guinea pig hind limb. After equilibration with Tyrode's solution and precontraction with noradrenaline 3µM, prostaglandin E₁ and adenosine were administered at dosages of 0.1, 0.3, and 1µM, whereas prostacycline was administered at a dosage of 0.01, 0.03 and 0.1µM. 0.01µM prostacycline, 0.1 µM prostaglandin E₁, and 0.1µM adenosine were the lowest dosages at which a significant vasodilation could be reached for each substance. The reduction of peripheral vascular resistance at comparable dosages of 0.1µM was 11.0 ± 2.6% (x ± SEM, n=5) for adenosine, 12.0 ± 1.0% (n=5) for prostaglandin E₁, but 28.0 ± 9.3% (n=5) for prostacycline (p<0.05 versus adenosine and prostaglandin E₁). Even at a dosage of 0.01 µM prostacycline, a comparable reduction in peripheral vascular resistance (16.0 ± 2.8%) could be reached, compared to a ten-fold higher dosage of prostaglandin E₁ and adenosine. At the highest concentration of 1 µM, the vasodilatory effect of adenosine was significantly less expressed, compared to that of prostaglandin E₁ (18.0 ± 3.4% versus 33.0 ± 4.7%). In summary, prostacycline, at a ten-fold lower concentration, showed comparable vasodilatory effects to adenosine and prostaglandin E₁. The rank order at the vasodilatory potency is prostacycline > prostaglandin E₁ > adenosine.