Regional differences in the responses to prostanoids of circular muscle from guinea-pig isolated intestine

The effects of prostaglandins (PGs) D₂, E₂, F_2α, an epoxymethano analogue of PGH₂ (U-46619), prostacyclin (PGI₂), 6-keto-PGF_lα and thromboxane (Tx) B₂ were tested on spirally-cut strips of guinea-pig isolated ileum or colon. In the ileum no prostanoid exerted a marked effect on the resting tissue, but PGD₂, PGE₂ or PGI₂ 1 μg ml^?1 inhibited submaximal contraction to KC1. U-46619 1 μg ml^?1 either inhibited or increased contractions to KC1, but PGF_2α, 6-keto-PGF_1α or TxB₂ 1 μg ml^?1 had no significant effect. PGE₂ relaxed colonic strips whereas the other prostanoids caused contraction, except for TxB₂ which had no effect. The PG antagonist SC-19220 blocked colonic contractions to the prostanoids, and a residual inhibitory effect of PGD₂, U-46619 or PGI₂ was demonstrated by the reduction of submaximal contractions to acetylcholine. Our results suggest that prostanoid receptors mediating inhibitory responses of circular muscle predominate in the ileum, whereas in the colon both excitatory and inhibitory prostanoid receptors occur.     

Responses to arachidonic acid and other dilator agonists and their modification by inhibition of prostaglandin synthesis in the canine hindlimb

The influence of indomethacin, in doses that completely inhibit the response to arachidonic acid, has been examined on canine hindlimb vascular responses to intra-arterial administration of bradykinin, histamine, nitroglycerin, isoprenaline and papaverine. The hindlimb was perfused at constant flow. Dose-response curves to intra-arterial administration of arachidonic acid (12 to 200 μg kg^?1), bradykinin (0·4 to 100 ng kg^?1), histamine (1·8 to 120 ng kg^?1), nitroglycerin (15 to 100 ng kg^?1), isoprenaline (12 to 100 ng kg^?1) and papaverine (1·2 to 160 μg kg^?1) (all n = 4) were compared before and 30 min after indomethacin (5 mg kg^?1 i.v.). All the drugs produced dose-related decreases in hindlimb perfusion pressure. After indomethacin, responses for all dilator agonists except arachidonic acid, were significantly greater than control (P < 0·05), both in terms of absolute (mmHg) or percent change. Doseresponse curves after indomethacin had a left upward shift compared with control. Arachidonic acid responses were completely blocked by indomethacin. These findings suggest that indomethacin produces a non-specific increase in responsiveness of the hindlimb vascular bed to dilator substances, except arachidonic acid. The data presented do not support the hypothesis that the peripheral vasodilatation produced by bradykinin, nitroglycerin and histamine could be mediated by endogenous prostaglandin release.     

Rolipram inhibits airway microvascular leakage induced by platelet-activating factor,histamine and bradykinin in guinea-pigs

Abstract— Rolipram (0·1–1000 μg kg^?1, i.v.) reduced the increase in microvascular permeability induced by platelet-activating factor (PAF; 50 ng kg^?1, i.v.) at different sites of the guinea-pig airways. Rolipram (1–100μg kg^?1, i.v.) inhibited histamine (30μg kg^?1, i.v.)-and bradykinin (0·3 μg kg, i.v.)-induced airway microvascular leakage. These effects of rolipram were obtained at doses which inhibit histamine (7–20 μg kg^?1 min^?1)-induced bronchoconstriction (IC50 = 3 ± 1 μg kg, i.v.) without depressing arterial blood pressure in the guinea-pig. Aminophylline (50 mg kg^?1) did not change the effect of PAF. The anti-exudative effect of rolipram is of potential therapeutic value in asthma.     

ZD9583, an Orally Effective Thromboxane A2 Synthase Inhibitor and Receptor Antagonist with a Sustained Duration of Action in Rat and Dog

The thromboxane A₂ (TXA₂) synthase inhibitory activity and the TXA₂ receptor (TP-receptor) blocking action of ZD9583 ((4Z)-6-[(2S,4S,5R)-2-(1-[2-cyano-4-methylphenoxy]-1-methylethyl)-4-(3-pyridyl)-1,3-dioxan-5-yl]hex-4-enoic acid) has been evaluated in-vitro by use of whole blood and platelets from man, and ex-vivo by use of platelets and whole blood from rats and dogs. ZD9583 caused concentration–dependent inhibition of human platelet microsomal TXA₂ production with an IC50 of 0.017 ± 0.003 μm; this inhibition was associated with an increase in prostaglandin E₂ (PGE₂) and prostaglandin F_2α (PGF_2α) formation. ZD9583 also inhibited collagen-stimulated TXA₂ synthesis in whole blood from man, rat and dog giving IC50 values of 0.027 ± 0.005, 0002 ± 0.006 and 0.013 ± 0.01 μm, respectively. The drug did not modify platelet cyclooxygenase activity as inhibition of thromboxane B₂ (TXB₂) formation was associated with a concomitant increased synthesis of prostaglandin D₂ (PGD₂), PGE₂ and PGF_2α. ZD9583 had little effect on cultured human umbilical vein endothelial cell prostacyclin synthase giving an IC50 of 24.2 ± 4.9 μm. In-vitro ZD9583 caused concentration-dependent inhibition of U46619-induced aggregation responses of platelets from man, rat and dog, yielding apparent log A₂ values of 8.7 ± 0.12, 8.8 ± 0.2 and 9.3 ± 0.2, respectively. The drug was selective; at concentrations up to 100 μm it did not affect 5-hydroxytryptamine or the primary phases of adenosine diphosphate and adrenaline-induced aggregation. ZD9583 (100 μm) did not, furthermore, modify the platelet inhibitory effects of PGD₂, prostaglandin E₁ (PGE₁) and prostacyclin. Oral administration of ZD9583 (3–10 mg kg^?1) to both rats and dogs caused dose-dependant inhibition of collagen-stimulated TXA₂ production ex-vivo which persisted for up to 12 h. The drug also caused profound TXA₂ receptor blockade in both species for in excess of 12-h after an oral dose of 3 mg kg^?1. ZD9583 (3 mg kg^?1, p.o.), when administered to dogs over a five-day period at 12 h intervals, did not cause either tachyphylaxis or an accumulation of effect. We conclude that ZD9583 is a potent, selective, orally active thromboxane synthase inhibitor and TXA₂ receptor antagonist.     

An α-adrenoceptor-mediated mechanism of hypoactivity induced by β-amyrin palmitate

Abstract— Inhibitory effects of β-amyrin palmitate in locomotor activity of mice were studied by combining this compound with α-adrenergic agonists or antagonists and a dopaminergic agonist. β-Amyrin palmitate (2·5, 5·0 and 10·0 mg kg^?1, i.p.) decreased locomotor activity of mice in a dose-dependent manner. It enhanced hypoactivity of mice treated with clonidine (0·025 mg kg^?1, i.p.) and antagonized hyperactivity produced by phenylephrine (40 μg, i.c.v.). The inhibitory action of β-amyrin palmitate was not affected by yohimbine (1·5 mg kg^?1, i.p.), but was potentiated by prazosin (0·75 mg kg^?1, i.p.). When combined with a dopaminergic agonist, apomorphine (2·0 mg kg^?1, i.p.), β-amyrin palmitate (5·0 and 10·0 mg kg^?1, i.p.) did not affect locomotor stimulation produced by apomorphine. These results suggest that β-amyrin palmitate might inhibit α₁-adrenoceptors.     

Dual Inhibition of Platelet-activating Factor and Arachidonic Acid Metabolism by Ajmaline and Effect on Carrageenan-induced Rat Paw Oedema

Abstract— The effects of ajmaline on human platelet aggregation, arachidonate metabolism and platelet activating factor (PAF)-induced lethality in rabbits were examined. Platelet aggregation induced by several stimuli (ADP, collagen, and PAF) was inhibited by increasing concentrations of ajmaline. The potency of ajmaline was higher when PAF was employed as stimulating agent in comparison with other agonists (IC50 70, 270 and 380 μm for PAF, ADP and collagen, respectively) whereas ajmaline had no effect against arachidonic acid-induced aggregation. In contrast however, ajmaline inhibited arachidonate metabolism by platelet homogenates. The formation of both thromboxane A₂ and 12-hydroxy-eicosatetraenoic acid was inhibited by ajmaline with comparable potencies. Pretreatment of rabbits with ajmaline (50 mg kg^?1) completely abolished the lethal effects of PAF (11 μg kg^?1) given intravenously (P < 0·001). In addition, ajmaline at doses ranging from 50 to 100 mg kg^?1 inhibited carrageenan-induced rat paw oedema (P < 0·001). In this test ajmaline was three times more potent than aspirin. In the light of these results we conclude that ajmaline, a known anti-arrhythmic agent is a PAF antagonist and a dual inhibitor of platelet cyclo-oxygenase and lipoxygenase enzymes with anti-inflammatory properties.     

The Adenosine Agonist NECA Inhibits Intestinal Secretion and Peristalsis

Abstract— This study aimed to determine whether the antidiarrhoeal effect of the mixed A₁/A₂ adenosine agonist NECA (5′-N-ethylcarboxamido adenosine) is due to inhibition of intestinal fluid transport or to contractility. Intestinal secretion was stimulated in anaesthetized rats by intra-arterial infusions of PGE₂ (4 μg min^?1) or vasoactive intestinal peptide (0·8 μg min^?1). NECA reversed PGE₂-induced secretion in the jejunum (ED50 16 μg kg^?1) and ileum (ED50 21 μg kg^?1, i.v.) and inhibited VIP-induced secretion in the jejunum (ED50 21·5 μg kg^?1). NECA inhibited twitch responses (0·1 Hz, 1 ms, IC50 11·2Nm ) but not tetanic contractions at 10 Hz of the transmurally stimulated guinea-pig ileum. Likewise, NECA (10 μm ) did not inhibit frequency-related contractions over the range of 2·5 to 40 Hz of rat jejunum or ileum. However, NECA was shown to be a potent inhibitor (30 Nm ) of the peristaltic reflex in the rat ileum. The results indicate that adenosine receptors are involved in modulating peristalsis as well as the secretory activity of the mucosa in the rat small intestine.     

Constipation Evoked by 5-HT3-Receptor Antagonism: Evidence for Heterogeneous Efficacy among Different Antagonists in Guinea-pigs

Abstract— The abilities of selective 5-HT₃-receptor antagonists to evoke constipation were examined in conscious guinea-pigs and in preparations of guinea-pig isolated colon. Compared with vehicle-treated guinea-pigs, acute doses of granisetron (0·1, 1 and 10 mg kg^?1, i.p.) and tropisetron (10 mg kg^?1, i.p., but not 1 and 0.1 mg kg^?1, i.p.) significantly (P < 0·05) reduced the total number of faecal pellets excreted during a 12-h observation period. By contrast, BRL 46470 (0·1–10 mg kg^?1, i.p.) had no significant effect on the incidence of defecation. Mid-to-distal lengths of guinea-pig isolated colon spontaneously expelled faecal pellets. Granisetron (0·1 and 1 μm ) and tropisetron (1 μm ) reduced or prevented the rate at which they were spontaneously expelled. Morphine (0·1 μm ) and clonidine (10 nm ) also slowed faecal pellet transit time. Naloxone (0·1 μm ) had no effects alone, but reversed the actions of granisetron, morphine and clonidine. BRL 46470 (1 μm ) had no significant effect on the transit of faecal pellets in guinea-pig isolated colon. In segments of guinea-pig isolated colon which did not contain faecal pellets, granisetron, tropisetron and BRL 46470 antagonized the ability of 5-HT to evoke cholinergically-mediated contractions of the longitudinal muscle. The respective pA₂ values and slopes of the Schild plots were 8·5 ± 0·05, slope 1·06 ± 0·03; 8·5 ± 0·1, slope 0·91 ± 0·04; and 7·9 ± 0·1, slope 0·93 ± 0·05. Our experiments suggest that not all 5-HT₃-receptor antagonists are the same. In particular, BRL 46470 does not prevent defecation or faecal pellet expulsion in guinea-pig colon, even though this compound is an effective 5-HT₃-receptor antagonist in the same tissue. For the 5-HT₃-receptor antagonists which did cause constipation, the effects can be at least partly attributed to an indirect opioid-dependent action within the colonic enteric nervous system.     

Antagonism by SB 204070 of 5-HT-evoked Contractions in the Dog Stomach: an In-vivo Model of 5-HT4 Receptor Function

The ability of 5-hydroxytryptamine (5-HT) to evoke contractile activity in the gastric Heidenhain pouch was measured in conscious dogs using a method in which 5-HT₄ receptor-antagonist activity can be measured in-vivo. At doses of 5-HT which evoked short-lived measurable responses (5 or 10 μg kg^?1, i.v.), it was found that this activity was greatly reduced by atropine (100 μg kg^?1, i.v.), but was unaffected by methysergide, methiothepin, ketanserin (each at 100 μg kg^?1, i.v.) or granisetron (10 or 100 μg kg^?1, i.v.). At best SDZ 205–557 2-diethylaminoethyl-[2-methoxy-4-amino-5-chloro] benzoate; 100 μg kg^?1, i.v.) reduced the action of 5-HT in 4/5 animals and increased it in the other but its effects were variable in magnitude and not consistently maintained. However, the more potent and selective 5-HT₄-receptor antagonist SB 204070 (1-butyl-4-piperidinylmethyl 8-amino-7-chloro-1,4-benzodioxan-5-carboxylate hydrochloride) dose-dependently antagonized the 5-HT-evoked contractions in all dogs tested. This action was reversible, but long-lasting with an effective half-life of 18·0 h when administered at 1 μg kg^?1. The estimated ID50 value was 0·55 μg kg^?1.     

Granisetron and Ondansetron: Effects on the Ileal Brake Mechanism in the Rat

Abstract— Studies were carried out on 20 male adult rats to investigate how the action of the selective 5-HT₃-receptor antagonists, granisetron and ondansetron, influence gastrointestinal transit under control conditions and when stomach-to-caecum transit was delayed by ileal infusion of lipid. Stomach-to-caecum transit time (SCTT) was measured using environmental hydrogen analysis. Subcutaneous administration of granisetron (BRL 43694,40, 80 or 150 μg kg^?1) significantly delayed the passage of the head of the baked bean meal through the stomach and the small intestine under control conditions (P < 0·05). Similarly, subcutaneous administration of ondansetron (GR 38032F, 80 or 150 μg kg^?1) delayed control SCTT of the head of the meal but this did not reach statistical significance. In contrast, granisetron significantly reversed the delay in SCTT induced by ileal infusion of lipid at 40 (P < 0·001), 80 (P < 0·01) and 150 μg kg^?1 (P < 0·05). Ondansetron also reversed the lipid-induced delay at 40 (P < 0·01), 80 (P < 0·001) and 150 μg kg^?1 (P < 0·001). These apparently conflicting results may be rationalized by postulating the presence of 5-HT₃ receptors on afferent nerves which, when inhibited by the specific antagonists, initiate reflexes that both accelerate and delay transit.     

Interactions of opioids with caffeine: evaluation by ambulatory activity in mice

Abstract— Morphine (up to 10 mg kg^?1), buprenorphine (up to 0·1 mg kg^?1), pentazocine (30 mg kg^?1) and caffeine (up to 10 mg kg^?1), significantly increased mouse ambulation. The combination of morphine, buprenorphine and pentazocine with caffeine generally enhanced the effect. Dopamine D₁- and D₂-receptor bockade, depletion of stored dopamine, and inhibition of dopamine synthesis could reduce the ambulation increased by single administration of morphine, buprenorphine and caffeine, and by combined administration of morphine and buprenorphine with caffeine. Although naloxone (0·1–3 mg kg^?1) itself did not change mouse ambulation, at 3 mg kg^?1, it reduced the effect of caffeine. The repeated administration of morphine (10 mg kg^?1) induced a sensitization to the ambulation-increasing effect, and was inhibited by the combination of caffeine (10 mg kg^?1) in the repeated administration schedule. The repeated administration of caffeine (10 mg kg^?1) with buprenorphine (0·3 mg kg^?1) resulted in a decrease in the effect to the level of caffeine alone. The development of cross-sensitization to morphine (10 mg kg^?1) by the repeated treatment with buprenorphine (0·3 mg kg^?1) was inhibited by caffeine (10 mg kg^?1). Our results suggest that the dopaminergic systems are involved in the enhanced interaction of opioids having agonistic action on μ- or σ-receptors with caffeine. However, it is also considered that, following the repeated administration, caffeine acts to reduce the sensitivity to the ambulation-increasing effect of opioids, probably inducing up-regulation of adenosinergic systems.     

Pharmacokinetics and Cardiovascular Effects of YM-21095, a Novel Renin Inhibitor,in Dogs and Monkeys

Abstract— The pharmacokinetics and cardiovascular effects of YM-21095 ((2 RS), (3S)-3-[N^α-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)-butyl]-l-histidylamino]-4-cyclohexyl-1-[(1-methyl-5-tetrazolyl)thio]-2-butanol), a potent renin inhibitor, have been studied in beagle dogs and squirrel monkeys. Plasma levels of YM-21095 after 3 mg kg^?1 intravenous dosing to dogs declined biphasically and fitted a two-compartment model. Kinetics were as follows: t½α = 4·9±0·2 min, t½β = 2·76±0·79 h, Vd_ss = 3·86±1·04 L kg^?1, plasma clearance = 2·22 ± 0·39 L kg^?1, and AUC= 1445 ± 266 ng h mL^?1. After 30 mg kg^?1 oral dose, maximum plasma concentration, t_max and AUC of YM-21095 were 28·8 ± 9·6 ng mL^?1, 0·25 h and 23·6 ± 7·7 ng h mL^?1, respectively. Systemic bioavailability as determined on the basis of the ratio of AUC after intravenous and oral dose was 0·16 ± 0·04%. In conscious, sodium-depleted monkeys, YM-21095 at an oral dose of 30 mg kg^?1 lowered systolic blood pressure and inhibited plasma renin activity without affecting heart rate and plasma aldosterone concentration. Maximum plasma concentration of YM-21095 after 30 mg kg^?1 oral dose to monkeys was 71·8 ± 41·5 ng mL^?1, which was reached 0·5 h after the dose. At equihypotensive doses, captopril and nicardipine increased plasma renin activity markedly and slightly, respectively. These results suggest that oral absorption of YM-21095 is low in dogs and monkeys, and YM-21095 shows a blood pressure lowering effect by inhibiting plasma renin activity in sodium-depleted monkeys.     

Amelioration of Cisplatin Nephrotoxicity with Glycine: Dose Dependency in Rats

The effects of glycine (0·1-1·0 g μg kg^?1, i.v.) on the acute changes in renal haemodynamics and nephrotoxicity produced by cisplatin (6·0 mg g kg^?1, i.v.) were investigated in the rat. Cisplatin produced decreases of 50% in the clearance of [³H] inulin (C_IN) and renal blood flow (RBF), 110 min following its injection. Glycine at a dose of 0·1 g kg^?1 produced no attenuation of the cisplatin-induced decrease in C_IN or RBF. Furthermore, this dose of glycine provided no significant protection of renal function over a 7-day period following cisplatin injection. By contrast, glycine at a dose of either 0·5 or 1·0 g kg^?1 markedly attenuated cisplatin-induced falls in C_IN and RBF, with the highest dose completely preventing any falls in these indices during the course of the experiment. Treatment with these higher doses of glycine produced prominent protection from the nephrotoxic actions of cisplatin, as evidenced by improvements in a range of indices of renal function which included plasma urea and creatinine concentrations, urine output, sodium excretion, C_IN and the clearance of [¹⁴C]P-aminohippurate. The results of experiments with an intermediate dose of 0·25 g kg^?1 glycine revealed some degree of amelioration of acute renal haemodynamic effects of cisplatin, particularly with regard to C_IN; whilst in the nephrotoxicity study, 0·25 g kg^?1 glycine produced a modest but significant reduction in cisplatin-induced acute renal dysfunction. The results have revealed a clear association between the acute renal haemodynamic effects produced by glycine in cisplatin-injected rats with the longer-term renal protective effects of glycine in cisplatin nephrotoxicity. The findings indicate that glycine's ability to prevent the falls in RBF and glomerular filtration rate produced by cisplatin plays an important role in the protective effect of glycine in cisplatin-induced nephrotoxicity.     

Catecholamine uptake blockade in anaesthetized dogs: influence on cardiovascular responses

The effects of differential and combined catecholamine uptake antagonism on cardiovascular responses of anaesthetized dogs to isoprenaline, noradrenaline, and electrical stimulation of the left ansa subclavia nerve have been studied. Uptake 1 inhibition by cocaine HCl (5 mg kg^?1 and 1 mg kg^?1 every 45 min) enhanced responses to noradrenaline (0·1 to 2·0 μg kg^?1 i.v.) and sympathetic nerve stimulation (1 to 20 Hz), but did not affect those to isoprenaline. Uptake 2 inhibition by metanephrine (40 μg kg^?1 min^?1) enhanced cardiac responses to isoprenaline (0·05 to 1·0 μg kg^?1 i.v.), but did not significantly alter those to noradrenaline or nerve stimulation. Responses to all agonist interventions were increased by the combined administration of cocaine and metanephrine. Cocaine preferentially enhanced the positive chronotropic cardiac response to noradrenaline, but metanephrine did not differentiate between heart rate and contractility. These results have been discussed in the light of the mechanism of drug action involved.     

Influence of intravenous infusion of ethanol on regional blood flow in conscious rats

Abstract— The effects of intravenous infusions of ethanol and saline (0·9% NaCl) on mean arterial pressure (MAP), heart rate (HR), total peripheral resistance (TPR), cardiac contractility (dP/dt_max) and systemic haemodynamics were studied in conscious, unrestrained rats by the radioactive microsphere technique. Saline (0·03 and 0·06 mL min^?1 kg^?1 for 12 min each dose) in the time-control group did not affect MAP, HR, TPR, dP/dt_max or vascular conductances in any organs or beds. While the low dose ethanol (2·4 mg min^?1 kg^?1) did not alter MAP, HR, TPR, systemic haemodynamics or dP/dt_max, the high dose (4·8 mg min^?1 kg^?1) slightly reduced MAP and TPR but did not affect HR, cardiac output or dP/dt_max. Both doses of ethanol vasodilated the intestine and spleen, but vasoconstricted the skin. The high dose caused additional vasodilatation in the heart and testes and the low dose also constricted the skeletal muscle bed. Our results show that ethanol, at non-hypotensive or slightly hypotensive doses, has marked vasodilator effects in the heart, intestine, spleen and testes.     

Dopamine Antagonists Can Inhibit Methamphetamine Sensitization,But Not Cocaine Sensitization,When Assessed by Ambulatory Activity in Mice

Abstract— The repeated subcutaneous administration of methamphetamine (2 mg kg^?1) and cocaine (10 mg kg^?1) at 3–4 day intervals induced sensitization to their ambulation-increasing effects in mice. Subcutaneous administration of SCH 23390 (R-(+)-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0·003–0·03 mg kg^?1) and YM-09151–2 (cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide; 0·003–0·03 mg kg^?1), the selective dopamine D₁ and D₂ antagonists, respectively, reduced dose-dependently the acute ambulation-increasing effect of methamphetamine. The development of methamphetamine sensitization was inhibited when it was administered in combination with either SCH 23390 or YM-09151–2 in the repeated administration schedule. Although SCH 23390 (0·01–0·1 mg kg^?1) and YM-09151–2 (0·01–0·1 mg kg^?1) also reduced the ambulation-increasing effect of cocaine (10 mg kg^?1), neither drug inhibited the cocaine sensitization. Mice given cocaine with SCH 23390 (0·03 mg kg^?1) or YM-09151–2 (0·03 and 0·1 mg kg^?1) showed higher sensitivity than those given cocaine alone. The present results suggest that, although both the dopamine D₁ and D₂ antagonists reduce the acute stimulant effects of both methamphetamine and cocaine, they are only effective for inhibition of the methamphetamine sensitization. Mechanisms other than the dopaminergic system appear to be involved in the cocaine sensitization.     

The character of the antagonism by polyphloretin phosphate of contractions to prostaglandins E1 and F2α in guinea-pig ileum

Polyphloretin phosphate (PPP) produced a dose-dependent decrease in the tone and reduction of the spontaneous phasic contractions of the longitudinal muscle of guinea-pig isolated ileum. PPP (100 μg ml^?1) after a 2 min contact with the ileum decreased the contractile effects of PGE₁ 0·1 μM by 40·6 ± 7·4%, of PGE₁ 0·01 μM by 86·7 ± 3·3% and of PGF_2α 0·1 μM by 62·2 ± 8·6%. After 10 min contact of PPP the contractile effect of PGE₁ 0·1 μM was decreased by 47·7 ± 4·7% and that of PGF_2α0·1 μM by 89·6 ± 1·7%. When the contact was longer, PPP showed a pronounced after-effect in respect to the effects of PGE₁ and particularly of PGF_2α. PPP significantly reduced contractions to 5-HT and BaCl₂, but not to acetylcholine, histamine or substance P. The type of antagonism of PGE₁ by PPP was examined using cumulative concentration-effect curves for PGE₁ in the presence of increasing concentrations of PPP. We conclude that on guinea-pig ileum PPP acts as a non-competitive antagonist of PGE₁ and PGF_2α.     

Ex-vivo and In-vivo Antithrombotic Effect of Triflavin,an RGD-containing Peptide

Abstract— Triflavin, an Arg-Gly-Asp-containing snake venom peptide, inhibits platelet aggregation through the blockade of fibrinogen binding to the activated platelets. It binds to fibrinogen receptors associated with the glycoprotein IIb/IIIa complex with a K_d value of 7 × 10^?8 m. In this study, we found that ¹²⁵I-triflavin reached the maximal binding to human platelets within 5 min at 25°C. In addition, when triflavin was intravenously administered at 1·0 mg kg^?1 to rabbits, it reversibly impaired the platelet aggregation of platelet-rich plasma caused by ADP (20 μm) ex-vivo over 30 min. The platelet counts of the experimental rabbits remained unchanged. Triflavin was effective in reducing the mortality of ADP-induced acute pulmonary thromboembolism in mice when administered intravenously at a dose of 2 μg g^?1. Therefore, triflavin was proven to be an effective antithrombotic agent in preventing ADP-induced acute pulmonary thromboembolism in mice and impairing reversibly the platelet function of rabbits when given intravenously.     

DAU 6215, a novel 5-HT3-receptor antagonist,selectively antagonizes scopolamine-induced deficit in a passive-avoidance task,but not scopolamine-induced hypermotility in rats

Abstract— This study examined the effects of DAU 6215, a selective 5-HT₃-receptor antagonist, on either impairment of a passive-avoidance task or hypermotility, both caused by scopolamine in rats. In the first experiment, scopolamine (0·75 mg kg^?1, i.p.) disrupted acquisition of a one-trial ‘step through’ passive-avoidance response. Pretreatment with DAU 6215 (1, 10, 30 and 100 μg kg^?1, i.p.) antagonized this deficit induced by scopolamine, with a bell-shaped dose-response curve. Scopolamine (0·75 mg kg^?1, i.p.) produced a significant increase in locomotor activity which was unaffected by pretreatment with DAU 6215 (10 and 30 μg kg^?1, i.p.). The present results further support the suggestion that 5-HT₃-receptor antagonists may prevent the memory disturbance caused by a reduction in central cholinergic function in the rat. The inefficacy shown by DAU 6215 on hyperactivity induced by scopolamine appears to rule out the possibility of a pharmacokinetic interference between DAU 6215 and scopolamine.     

The Protective Effect of Glycine in Cisplatin Nephrotoxicity: Inhibition with NG-Nitro-l-arginine Methyl Ester

Abstract— The effect of glycine on the acute changes in renal haemodynamics and nephrotoxicity produced by cisplatin was investigated in the rat. Cisplatin (6·0 mg kg^?1, i.v.) injection in anaesthetized rats produced, over a period of 2 h, falls of approximately 50% in renal blood flow (RBF) and the clearance of [³H]inulin (CL_IN), effects which were prevented by co-administration of glycine (1·0 g kg^?1). Infusion of the nitric oxide (NO) synthase-inhibitor N^G-nitro-l -arginine methyl ester, l -NAME (10 μg min^?1 kg^?1, i.v.), abolished glycine's ability to maintain RBF in cisplatin-injected rats whilst partially inhibiting the ability of glycine to preserve CL_IN. Treatment of cisplatin-injected rats with glycine (1·0 g kg^?1, i.v.) significantly ameliorated the nephrotoxic effects of cisplatin (6·0 mg kg^?1) as judged by improvements in a range of indices of renal function which included plasma urea and creatinine concentrations, urine output, sodium excretion, CL_IN and the clearance of [¹⁴C]p-aminohippurate. Administration of l -NAME (1·0 mg kg^?1, i.v.) to rats which received cisplatin and glycine significantly inhibited the reno-protective effect of glycine. However, l -NAME administration to rats which were treated only with cisplatin did not result in any potentiation of cisplatin nephrotoxicity. The findings of this study suggest that glycine can block the acute falls in RBF and C_IN produced by cisplatin by a mechanism which involves the production of NO. Furthermore, the results indicate that these renal haemodynamic actions of glycine are responsible, at least in part, for the ability of this amino acid to ameliorate cisplatin nephrotoxicity.