Responses Of Guinea-pig Ileum Research Articles

Anti-histaminic Activity of Desmostachya bipinnata

Desmostachya bipinnata, Gramineae (Poaceae) family, has been traditionally used in treatment of various disorders like asthma, kidney stone, diarrhoea, wound healing etc. Several extracts of Desmostachya bipinnata were prepared. Ex-vivo estimation of contractile responses of guinea pig ileum were measured for prepared extracts against histamine and compared with chlorphenirame. All the extracts were able to contract guinea pig ileum while alcoholic extract was superior among all. Such results indicated that prepared extract possess good anti-histaminic activity, which was further confirmed with histamine induced lethality test. Histamine induced lethality in guinea pigs was prevented when the extracts were administered prior to histamine injection in guinea pigs. Hence, it is concluded that the extracts possess anti-histaminic activity and may possess anti-asthmatic potential.

Holford NHG and Sheiner LB “Understanding the Dose-Effect Relationship-Clinical Application of Pharmacokinetic-Pharmacodynamic Models”, Clin Pharmacokin 6:429–453 (1981)—The Backstory

My personal interest in understanding the dose–concentration–effect relationship started during my medical student training at the University of Manchester in England. In 1967, the Department of Pharmacology introduced a 1-year Bachelor of Science degree which medical students could take between their second and third years of the medical course. Only two students applied and that is how I was accepted for an intensive, practical course in pharmacology. One of the first laboratory sessions was to study the contractions of a segment of guinea pig ileum in response to acetyl choline (Fig. 1). This taught me the difference between dose and concentration, the asymptotic nature of the concentration–effect relationship, and the often inexplicable variability of biological systems (What happened to the response at 16 ng/mL?).

Acute withdrawal induced by adenosine A1-receptor activation in isolated guinea-pig ileum: role of opioid receptors and effect of cholecystokinin

In isolated guinea-pig ileum, the mu-opioid acute withdrawal response is under control of several neuronal systems, including the kappa-opioid and the A(1)-adenosine systems, which are involved in the mu-withdrawal response inhibitory control. After mu-opioid system stimulation, indirect activation of both kappa-opioid and A(1)-adenosine systems is prevented by the peptide cholecystokinin-8 (CCk-8). Guinea-pig ileum exposed to A(1)-adenosine agonist (CPA), shows a withdrawal contracture precipitated by the A(1)-adenosine antagonist (CPT). We investigated this response. We investigated the involvement of the opioid system in the A(1)-adenosine acute withdrawal response in guinea-pig ileum, the potential induced cross-dependence between the A(1) and the opioid system and also the interaction between the CCk-8 and A(1) systems. We found that in the guinea-pig ileum preparation exposed to CPA, mu- and kappa-opioid antagonists increased the withdrawal response to CPT. Tissues exposed to CPA showed a contractile response to the opioid receptor antagonist naloxone only after complete removal of the A(1)-agonist. In the presence of CPA, the response to CCk-8 was inhibited while a significant increase in CPT response intensity was observed. In guinea-pig ileum, stimulation of the A(1) system indirectly activates both mu- and kappa-opioid systems; this indirect activation is significantly, albeit not completely, antagonised by CCk-8. Cross dependence between A(1) and opioid systems was also observed.

In Vitro Cholinomimetic Effect of Loranthus Ferrugineus in Isolated Guinea Pig Ileum

This study aimed to elucidate the mechanism(s) of the spasmogenic action of Loranthus ferrugineus in isolated guinea pig ileum. Thus the contractile responses of guinea pig ileum to graded additions of either L. ferrugineus methanol extract or its n-butanol fraction were tested in the presence and absence of various pharmacological interventions. The data showed that L. ferrugineus methanol extract and the n-butanol fraction produced a concentration-dependent spasmogenic effect in isolated guinea pig ileum segments. These effects were significantly inhibited in the presence of 1 μM atropine. In contrast, the response to the lowest concentrations of L. ferrugineus methanol extract (0.25, 0.5 and 1 mg/mL) and n-butanol fraction of L. ferrugineus (0.125, 0.25 and 0.5 mg/mL) were considerably enhanced in the presence of 0.05 μM neostigmine. Neither L. ferrugineus methanol extract nor n-butanol fraction contractile responses were affected upon the incubation of the ileal segments with 100 μM hexamethonium. The results of this study show that the spasmogenic effect of L. ferrugineus is possibly mediated through a direct action on intestinal muscarinic receptors. It is suggested that the bioactive constituents of L. ferrugineus serve as a substrate for acetylcholinesterase.

Possible involvement of muscarinic mechanisms in contractile response of guinea pig ileum by Erythrina velutina

Possible involvement of muscarinic mechanisms in contractile response of guinea pig ileum by Erythrina velutina

Appearance of peristaltic reflex in isolated guinea pig ileum in response to boluses of air, water, oil, and cellulose.

Distension of an isolated preparation of guinea pig ileum triggers the peristaltic reflex, a characteristic movement of the intestinal walls which generates luminal pressures and clearance of luminal contents. To determine how the reflex responds to properties of luminal contents, we compared the responses triggered by boluses of air, oil, and cellulose to boluses of Krebs' solution. We found that oil and cellulose increased pressures and contraction length and decreased outflow. Cellulose, but not oil, slowed the velocity with which the contraction propagated and increased the delay with which the end point (upstream edge) of the contraction started to propagate after the lead point (downstream edge). Air tended to produce short contraction segments and high velocity. We conclude that bolus properties such as viscosity determine the response that isolated intestinal segments generate to distension. Response patterns are reflected in contraction length, propagation velocity, and other visual parameters that define wall movements.

A Ca 2+ channel blocker-like effect of dehydrocurdione on rodent intestinal and vascular smooth muscle

Effects of dehydrocurdione, a zedoary-derived sesquiterpene, on smooth muscle were investigated by recording the mechanical activity of intestines and aorta from guinea pigs and rats. Dehydrocurdione (0.1–3 mM) induced a sustained relaxation of rat duodenum and inhibited spontaneous motility. Dehydrocurdione (0.1–1 mM) inhibited the contractile response of guinea pig ileum induced by acetylcholine (0.01–10 μM), histamine (0.03–10 μM) and substance P (0.1–30 nM) in a non-competitive manner. Acetylcholine (0.5 μM) elicited a transient contraction followed by a sustained contraction of guinea pig ileum, and dehydrocurdione pretreatment inhibited the sustained component, which depends on Ca 2+ entry from the extracellular space. The high K +-induced contraction of rat aortic ring is reported to be blocked by Ca 2+ channel blockers, while the norepinephrine-induced contraction includes a Ca 2+ channel blocker-resistant component. Dehydrocurdione (1 mM) blocked the high K + (60 mM)-induced contraction of rat aortic ring by 81%, while it inhibited the norepinephrine (1 μM)-induced contraction by only 28%. Dehydrocurdione (1 mM) significantly reduced the high K +-stimulated increase in cytosolic Ca 2+ level of Fura-2-loaded mesenteric artery from rats. These results suggest that the inhibitory effects of dehydrocurdione on intestinal and vascular smooth muscle are mediated by blockade of Ca 2+ entry from the extracellular space.

Connections between P 2 purinoceptors and capsaicin-sensitive afferents in the intestine and other tissues

Relations between P 2 purinoceptors and capsaicin-sensitive sensory neurons include an excitatory action of P 2 purinoceptor agonists on spinal afferent neurons, as well as release of ATP from afferents at their central and peripheral endings, and a possible participation of ATP in nociception and/or in `local efferent' responses mediated by sensory nerves at the periphery. The present paper briefly summarizes available evidence on these interrelations. Ample evidence shows that ATP and other P 2 purinoceptor agonists can activate primary afferent neurons, through P2X 3 receptors and probably other purinoceptors as well, but evidence for an involvement of P 2 purinoceptors in nociception or in `local efferent' responses due to activation of primary afferents is, at best, circumstantial. The possibility is also dealt with that P 2 purinoceptor activation may cause small intestinal contraction with the mediation of capsaicin-sensitive sensory neurons and that the motor response to capsaicin in this tissue may involve the release of a P 2 purinoceptor stimulant from sensory nerves. Our data show that cholinergic contractions of the guinea-pig ileum in response to the P 2 purinoceptor agonist α,β-methylene ATP (α,β-meATP) are blocked by atropine, but not by in vitro capsaicin pretreatment (which completely blocks the contractile action of capsaicin). Cholinergic ileum contractions due to capsaicin (2 μM) are insensitive to suramin (a P 2 purinoceptor antagonist; 100 μM). In the presence of antagonists acting at tachykinin NK 1 and NK 2 receptors, however, suramin (100 μM) causes a significant inhibition of the capsaicin-evoked contraction. These data indicate that capsaicin-sensitive nerves are not involved in the excitatory effect of α,β-methylene ATP on myenteric neurons. On the other hand, ATP is probably involved in the `non-tachykininergic' component of the capsaicin-induced excitatory response of the small intestine. ATP may originate from sensory neurons and probably acts as activator of myenteric nerves.

Pharmacological heterogeneity of neurotensin receptors: an in vitro study.

Neurotensin (NT), a linear tridecapeptide, has been shown to exert a variety of biological effects in the periphery and in the central nervous system. The aim of the present study was to characterize the NT receptors mediating the contractions of two isolated organs, the rat stomach strip and the guinea pig ileum. More than 20 compounds, peptides, nonpeptides, or pseudopeptides, were tested for their agonistic and antagonistic effects against NT and a series of potent analogs or fragments. Receptors were characterized using the two classical criteria suggested by Schild, the order of potency of agonists and the affinity of antagonists. The results shown in this study indicate that the contractions of the guinea pig ileum in response to NT are mediated by acetylcholine and prostaglandins because they are blocked by atropine and indomethacin. The contractions induced by NT in the rat stomach are not influenced by atropine, indomethacin, methysergide, and diphenhydramine and may result from the direct activation of smooth muscle receptors. Differences in the order of potency of agonists were also found between the two preparations: in the rat stomach strip, the order of potency was AcNT(8-13) > Arg-NT(8-13) > Lys-NT(8-13) > NT = NT(8-13) and in the guinea pig ileum was Arg-NT(8-13) > AcNT(8-13) > NT = NT(8-13) > Lys-NT(8-13). The nonpeptide antagonist SR 48692 was shown to possess higher apparent affinity for the rat stomach functional sites (pA2 8.0) than for those of the guinea pig ileum (pA2 6.45). The results presented in this paper suggest that two different pharmacological entities may subserve the myotropic effect of NT and some analogs and fragments in the gastrointestinal tract of the guinea pig and the rat.

Pharmacological studies on antidiarrheal effects of Hange-shashin-to.

We attempted to characterize the antidiarrheal action of Hange-shashin-to (TJ-14), a kampo medicine, by comparing its action with that of loperamide. The oral administration of TJ-14 caused the dose-dependent suppression of castor oil-induced diarrhea at 250 to 1000 mg/kg. No significant repression was noted by TJ-14 even at 1000 mg/kg, p.o. for diarrhea induced by pilocarpine, serotonin or barium chloride. Oral treatment with loperamide at 5 mg/kg markedly suppressed diarrhea induced by castor oil and barium chloride. Contractions of isolated guinea pig ileum in response to acetylcholine (1 x 10(-7) g/ml), histamine (1 x 10(-7) g/ml) or barium chloride (3 x 10(-4) g/ml) were little affected by TJ-14 at 10(-4) g/ml. The responses elicited by the three contractive drugs were dose-dependently suppressed by loperamide. TJ-14 did not affect the small intestinal transit even at an oral dose of 1000 mg/kg. On the other hand, the small intestinal transit was significantly suppressed by loperamide (5 mg/kg, p.o.). These results indicate that TJ-14 can effectively control castor oil-induced diarrhea, and that its antidiarrheal action was not based on the suppression of intestinal motility.

New bioactive monoterpene glycosides from Paeoniae Radix.

Bioassay-guided separation of MeOH extract of Japanese Paeoniae Radix inhibiting contractile responses of guinea pig ileum stimulated with electric field disclosed a new monoterpene glycoside, 6-O-beta-D-glucopyranosyl-lactinolide (1), as an active constituent together with two new monoterpene glycosides (3 and 4) and two new monoterpenes (2 and 5). Furthermore, 1-O-beta-D-glucopyranosyl-paeonisuffrone (2) was found to inhibit histamine release from rat peritoneal exudate cells induced by antigen-antibody reaction.

Competitive and selective antagonistic action of NPC 17731 on bradykinin-induced relaxant and contractile responses of the guinea pig isolated ileum

1. 1. The aim of the present study was to evaluate, by means of functional studies, the effect of the newly developed bradykinin (BK) receptor antagonist NPC 17731, D-Arg 0, Arg 1-Pro 2-Hyp 3-Gly 4-Phe 5-Ser 6-[DHype (transpropyl) 7]-Oic 8-Arg 9, against BK-mediated biphasic response in the guinea pig ileum “in vitro” (circular and longitudinal layers). 2. 2. In the circular muscle, NPC 17731 (0.1–1000 nM) dose dependently and reversibly antagonized, with similar potency, both the contractile and relaxant responses caused by BK, as well as BK-induced contraction in longitudinal smooth muscle with IC 50 of 23, 29 and 37 nM, respectively. 3. 3. NPC 17731 (10–300 nM) also caused a concentration-dependent displacement to the right of BK-induced contraction and relaxant responses in the circular smooth muscle of guinea pig ileum, without changing BK maximal response. Schild plot analyses were linear (correlation close to 1), yielding pKb values of 8.89 ± 0.19 and 8.73 ± 0.18, respectively, and slopes not significantly different from unity, providing evidence that NPC 17731 acts as a pure B 2 competitive receptor antagonist against both BK responses. 4. 4. Similarly, NPC 17731 (3-100 nM) antagonized, in a graded and competitive manner, BK-induced contraction in longitudinal muscle from guinea pig ileum with a slope not different from unity, yielding a pKb value of 8.62 ± 0.13. 5. 5. These results indicate that the new B 2 BK receptor antagonist NPC 17731 antagonizes, with high affinity and with similar potency through simple competitive and selective mechanisms, BK receptor-mediating contraction or relaxant responses in circular and longitudinal smooth muscles from guinea pig ileum. In addition, these results also suggest that although BK-induced contraction or relaxation responses in guinea pig ileum are coupled to distinct second messengers, NPC 17731 interacts with a homogeneous population of B 2 receptors in both guinea pig ileum preparations.

Multiple mechanisms of bradykinin-induced contraction in rat and guinea pig smooth muscles in vitro

Bradykinin caused graded contraction in the guinea pig ileum, trachea and urinary bladder and rat uterus and vas deferens in vitro. The order of potency (EC 50, nM) was: ileum (3) > uterus (5) > trachea (15) > vas deferens (41) > urinary bladder (52) and the maximal responses (percentage to 80 mM KCl) were: 152 ± 8 (ileum), 122 ± 6 (uterus), 97 ± 3 (urinary bladder), 75 ± 5 (trachea) and 33 ± 3 (vas deferens). Responses to bradykinin in guinea pig ileum and urinary bladder and rat vas deferens and uterus were markedly attenuated in Ca 2+-free medium with or without EGTA or by nicardipine, whereas those in guinea pig trachea depended almost exclusively on intracellular Ca 2+ sources which were sensitive to ryanodine. Treatment of the animals with pertussis toxin only inhibited bradykinin-induced contraction of the rat uterus. Furthermore, the protein kinase C inhibitors, H 7 (5-isoquinolinysulfonyl-2-methyl-piperazine) and staurosporine, antagonized in a graded manner bradykinin responses in guinea pig ileum and trachea and rat vas deferens, indicating the possible dependence on activation of protein kinase C mechanisms, while responses of the rat uterus rely on coupling by a pertussis toxin-sensitive G protein. Thus, bradykinin acting at B 2 receptors may induce contractions in several smooth muscles from rat and guinea pig through activation of multiple second messenger pathways.

Opioid effects of short enkephalin fragments containing the Gly-Phe sequence on contractile responses of guinea pig ileum

1. Effects of the fragments H-Gly-Phe-OH, H-Gly-Phe-NH 2 or H-Gly-Phe-OMe on the electrically stimulated cholinergic contractions of the longitudinal layer in isolated guinea pig ileum and on the Morphine-, Met-enkephalin- or Leu-enkephalin-induced inhibition of these contractions were analyzed for opioid activity in respect to Gly-Phe sequence. 2. H-Gly-Phe-OH or H-Gly-Phe-NH 2 exerted no effects, while H-Gly-Phe-OMe applied cumulatively (1 pM-1 mM), concentration-dependently reduced the contractions to electrical stimulation, the IC 50 value being 1.96 ± 0.06 μM. Naloxone (1–5 μM) did not reverse the H-Gly-Phe-OMe effects. 3. H-Gly-Phe-OMe at single concentrations (1–10 μM) significantly decreased the maximum inhibition produced by cumulatively added (0.1 nM-100 μM) morphine, Met-enkephalin or Leu-enkephalin. The regression lines for the opioids were shifted to the right but not always in a parallel fashion; the IC 50 values were higher as compared to the controls and lower as compared to the IC 50 values after naloxone. 4. The p A 2 value for H-Gly-Phe-OMe with respect to morphine (6.43 ± 0.14) did not differ from that to Met-enkephalin (6.68 ± 0.35) or Leu-enkephalin (9.06 ± 0.98); the slope of the p A 2 plot to morphine was near unity. 5. These data indicated that H-Gly-Phe-OMe exerted predominantly a potent non-competitive opioid antagonistic effect suggesting that short enkephalin fragments containing the Gly-Phe sequence might possess an opioid activity.

Characterization of endothelin receptors mediating the effects of the endothelin/sarafotoxin peptides on autonomic neurotransmission in the rat vas deferens and guinea-pig ileum.

1. To characterize the receptors mediating the effects of the endothelin/sarafotoxin family of peptides on the responses to electrical stimulation of the rat vas deferens (RVD) and guinea-pig ileum (GPI) we have used endothelin-1 (ET-1), ET-3, sarafotoxin 6b (SX6b) and SX6c as agonists and the endothelin-receptor antagonists BQ-123 (ETA receptor selective) and PD 142893 (non-selective). 2. In the RVD, ET-1 and SX6b increased the twitches induced by field stimulation starting at a threshold concentration of 10(-10) M while the threshold concentration for ET-3 was 3 x 10(-9) M. SX6c (up to 3 x 10(-8) M) did not potentiate the twitches. SX6b produced significantly (P < 0.05) greater potentiations than ET-1 at concentrations of 3 x 10(-9) M and higher, and 10(-7) M ET-3 also produced a significantly greater effect than ET-1 at the same concentration. Thus, at threshold the rank order of peptides was ET-1 = SX6b > ET-3 >>> SX6c, and at concentrations of 3 x 10(-8) M and higher, SX6b > ET-3 > ET-1 >>> SX6c. 3. In the presence of BQ-123 or PD 142893 (10(-5) M) the threshold concentrations for ET-1 to augment the twitches were increased 30 fold. In the same conditions neither SX6b nor ET-3 potentiated the responses. The relative activities of the endothelin/sarafotoxin peptides and the effectiveness of the endothelin receptor antagonists are consistent with postjunctional ETA receptors mediating these effects. 4. In the transmurally stimulated GPI the endothelin/sarafotoxin peptides produced two effects; an increase in the basal tension of the tissues and an inhibition of the twitch responses. To increase the basal tension the peptides had the order of potency ET-1 > SX6b>> ET-3 = SX6c. These direct effects of ET-1 or SX6b were strongly antagonized (100 fold) by either BQ-123 (10-5M) or PD 142893(10-5 M). Thus, ETA receptors mediate contractions of the GPI induced by these peptides.5. The endothelin/sarafotoxin peptides were approximately equipotent at depressing twitches of the GPI in response to transmural stimulation (EC50s, 4 x 10-11 to 1.5 x 10-10 M). The depressions induced byET-1 were unaffected by either BQ-123 (10-5 M) or PD 142893 (10-5 M). BQ-123 produced a small(three fold) antagonism of the inhibitory effects of ET-3 or SX6c. These results indicate that a receptor of the ETB type mediates the inhibitory effects of the endothelin/sarafotoxin peptides on neurotransmission in the GPI.6. Thus, both ETA receptors and ETB receptors mediate the effects of the endothelin/sarafotoxinpeptides on neurotransmission.

Comparison of the effects of (±) CP 96,345 and L-668,169 on neurokinin receptor mediated responses in rat and guinea-pig isolated tissues

The effects of (±) CP 96,345 and L-668,169 on NK 1-, NK 2- and NK 3-receptor mediated contractile responses were compared in guinea-pig and rat isolated smooth muscle tissues. Both (±) CP 96,345 and L-668,169 inhibited NK 1-mediated responses in guinea-pig ileum (pA 2 = 9.3 and 6.4 respectively) but not in rat bladder (pK B = < 6 and < 5.5 respectively) consistent with species differences in NK 1-receptor pharmacology. Both compounds showed some selectivity in inhibiting NK 1-receptor evoked responses in guinea-pig ileum compared to their inhibitory effects on NK 2-receptor mediated responses in guinea-pig bladder and rat ileum and NK 3-mediated responses in guinea-pig ileum and rat portal vein.

Pharmacological studies of jumper ant ( Myrmecia pilosula) venom: Evidence for the presence of histamine, and haemolytic and eicosanoid-releasing factors

Jumper ant venom was prepared by extraction of venom sacs in distilled water and centrifugation to remove insoluble material. Jumper ant venom (2 μg/ml) produced a biphasic response on isolated guinea-pig ileum, i.e. an initial rapid contraction followed by a slower prolonged contraction. The histamine antagonist mepyramine (0.1 μM) inhibited the first phase of this response by > 90%. In the isolated rat stomach fundus strip (which is insensitive to histamine), jumper ant venom (6 μg/ml) produced only a single contraction. No tachyphylaxis was observed to repeated doses of jumper ant venom in guinea-pig ileum or rat fundus strip. Responses to jumper ant venom of the egg-albumin-sensitised guinea-pig ileum were not significantly different before and after an in vitro anaphylactic response induced by egg albumin (0.5 mg/ml). Fluorometric assay revealed a mean value of 0.9 ± 0.2% of the dry weight as histamine in jumper ant venom. Both the lipoxygenase/cyclo-oxygenase inhibitor BW755C and the cyclo-oxygenase inhibitor indomethacin significantly inhibited the second phase response to jumper ant venom of the guinea-pig ileum, and the response of the rat fundus strip. The muscarinic receptor antagonist atropine (0.1 μM), the bradykinin antagonist [Thi 5,8,D-Phe 7]-bradykinin (10 μM) and the angiotensin converting enzyme inhibitor captopril (20 μM) did not affect either phase of the venom response in guinea-pig ileum. Jumper ant venom caused haemolysis of guinea-pig blood. The degree of haemolysis was significantly reduced when boiled venom was used. These results suggest that jumper ant venom contains histamine and may cause the release of cyclo-oxygenase products. It also contains a heat-sensitive haemolytic factor.

Contractile response of guinea pig ileum by repetitive application of morphine

1. 1. The repetitive application of morphine gradually induced a contracture in the isolated guinea pig ileum. 2. 2. The optimum conditions for induction of the contracture were as follows: the concentration, incubation time and washout time of morphine were 1 or 10 μM, 2 and 3 min, respectively. 3. 3. Preincubation with naloxone or TTX blocked this morphine-induced contracture. 4. 4. Among twitch-inhibiting drugs, only clonidine induced a contracture similar to that induced by morphine, while tetrodotoxin (TTX) and adenosine did not. 5. 5. The contracture was also observed in the longitudinal muscle-myenteric plexus preparations. 6. 6. These findings indicate that morphine has a dual inhibitory and excitatory action on the guinea pig ileum and that its repetitive application preferentially diminish the inhibitory one.

Effects of a New Histamine H2-Receptor Antagonist, Z-300, on Gastric Secretion and Gastro-Duodenal Lesions in Rats: Comparison with Roxatidine.

We examined the effects of a new compound, N-[3-[3-(piperidinomethyl)phenoxy]-propyl]-2-(2-hydroxyethyl-1- thio)acetamido.2-(4-hydroxy benzoyl)benzoate (Z-300), on the histamine H2-receptor, gastric secretion in rats and dogs, and acute gastro-duodenal lesions or chronic gastric ulcers in rats. Roxatidine acetate hydrochloride (roxatidine), a known histamine H2-receptor antagonist, was used as a reference compound. The pA2 values for Z-300 and roxatidine for the isolated guinea pig atrium were 6.8 and 7.0, respectively. These agents at less than 10(-5) M did not affect the contraction of guinea pig ileum in response to carbachol. Z-300, administered either orally or parenterally, significantly inhibited the basal and histamine-stimulated gastric acid secretion in rats. Gastric acid secretion stimulated by histamine, pentagastrin or carbachol in Heidenhain pouch dogs was also significantly inhibited by the compound. The effect persisted for greater than 7 hr in the case of histamine-stimulation. Oral Z-300 significantly protected the gastric mucosa from water-immersion stress-, indomethacin-, aspirin- and HCl.ethanol-induced lesions and protected the duodenal mucosa against mepirizole- and cysteamine-induced ulcers. These effects on gastric secretion and lesion formation were, as a whole, stronger than those observed with roxatidine. Z-300, but not roxatidine, significantly accelerated the spontaneous healing of acetic acid ulcers induced in rats and prevented the delay in ulcer healing caused by indomethacin. The mechanism of action of Z-300 on acute lesions and chronic ulcers appears to be mostly related to its potent antisecretory and mucosal-protective activities.

Effects of a New Histamine H2-Receptor Antagonist, Z-300, on Gastric Secretion and Gastro-Duodenal Lesions in Rats: Comparison with Roxatidine

We examined the effects of a new compound, N-[3-[3-(piperidinomethyl)phenoxy]-propyl]-2-(2-hydroxyethyl-1-thio)acetamido-2-(4-hydroxy benzoyl)benzoate (Z-300), on the histamine H2-receptor, gastric secretion in rats and dogs, and acute gastro-duodenal lesions or chronic gastric ulcers in rats. Roxatidine acetate hydrochloride (roxatidine), a known histamine H2-receptor antagonist, was used as a reference compound. The pA2 values for Z-300 and roxatidine for the isolated guinea pig atrium were 6.8 and 7.0, respectively. These agents at <10−5 M did not affect the contraction of guinea pig ileum in response to carbachol. Z-300, administered either orally or parenterally, significantly inhibited the basal and histamine-stimulated gastric acid secretion in rats. Gastric acid secretion stimulated by histamine, pentagastrin or carbachol in Heidenhain pouch dogs was also significantly inhibited by the compound. The effect persisted for >7 hr in the case of histamine-stimulation. Oral Z-300 significantly protected the gastric mucosa from water-immersion stress-, indomethacin-, aspirin- and HCl* ethanol-induced lesions and protected the duodenal mucosa against mepirizole- and cysteamine-induced ulcers. These effects on gastric secretion and lesion formation were, as a whole, stronger than those observed with roxatidine. Z-300, but not roxatidine, significantly accelerated the spontaneous healing of acetic acid ulcers induced in rats and prevented the delay in ulcer healing caused by indomethacin. The mechanism of action of Z-300 on acute lesions and chronic ulcers appears to be mostly related to its potent antisecretory and mucosal-protective activities.