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PubMed1993

Higher potency of RP 67580, in the mouse and the rat compared with other nonpeptide and peptide tachykinin NK1 antagonists.

1. This study was undertaken to compare the potency and selectivity of the nonpeptide (RP 67580, (+/-)-CP-96,345 and its chloro-derivative [(+/-)-cis-3-(2-chlorobenzylamino)-2-benzhydrylquinuclidine] (CP-C1)) and peptide (GR 71,251 and spantide) neurokinin1 (NK1) antagonists in mouse and rat preparations. 2. Among the NK1 antagonists tested, RP 67580 was the most potent in inhibiting the specific binding of [125I]-Bolton Hunter substance P ([125I]-BHSP) to crude synaptosomes from the rat brain (Ki: 2.9 nM). (+/-)-CP-96,345 was about ten fold less potent (Ki: 31 nM) than RP 67580 while other compounds exhibited even less affinity. 3. All NK1 antagonists inhibit competitively the activation of phospholipase C by [Pro9]substance P ([Pro9]SP) in cultured cortical astrocytes from the newborn mouse, a preparation rich in NK1 receptors but devoid of NK2 and NK3 receptors. pA2 values for the most potent compounds, RP 67580 and (+/-)-CP-96,345, were 8.28 and 7.08 respectively. When used alone, all antagonists showed some agonist activity at 10(-5) M, except spantide which was already effective at 10(-6) M. 4. An excellent correlation was found between the potency of the NK1 antagonists in blocking the stimulation by [Pro9]SP of phosphoinositide breakdown in cortical astrocytes and in inhibiting [125I]-BHSP specific binding to rat brain synaptosomes. 5. As shown on single cells by use of the Indo-1 microfluorometric method, RP 67580 (10(-7) M) prevented reversibly the elevation of cytosolic calcium concentration induced by [Pro9]SP (10(-8) M) in cultured cortical astrocytes. 6. Several experiments indicated that the antagonists were highly selective for NK1 receptors. RP 67580 did not modify the noradrenaline-evoked activation of phospholipase C in cortical astrocytes; when used at 10-5 M all antagonists had no or only little affinity for NK2 or NK3 binding sites and did not block the NKA (10-8 M)-induced activation of phospholipase C in the hamster urinary bladder (a selectiveNK2 test).7. In conclusion, RP 67580 appears to be a potent NK1 antagonist in the mouse and the rat. Results obtained with (+/-)-CP-96,345 confirm the lower potency of this compound in these two species when compared with reported data obtained in the guinea-pig or man.

Animals↗
PubMed1994

Study of comparative antipneumococcal activities of penicillin G, RP 59500, erythromycin, sparfloxacin, ciprofloxacin, and vancomycin by using time-kill methodology.

Time-kill studies were used to examine the in vitro activities of penicillin G, RP 59500, erythromycin, ciprofloxacin, sparfloxacin, and vancomycin against 10 pneumococci expressing various degrees of susceptibility to penicillin and erythromycin. RP 59500 MICs for all strains were 0.5 to 2.0 micrograms/ml, while erythromycin MICs were 0.008 to 0.06 microgram/ml for erythromycin-susceptible strains and 32.0 to 64.0 micrograms/ml for erythromycin-resistant strains. Strains were more susceptible to sparfloxacin (0.125 to 0.5 microgram/ml) than to ciprofloxacin (0.5 to 4.0 micrograms/ml), and all were inhibited by vancomycin at MICs of 0.25 to 0.5 microgram/ml. Time-kill studies showed that antibiotic concentrations greater than the MIC were bactericidal for each strain, with the following exceptions. Erythromycin was bactericidal for one penicillin-resistant strain at 6 h, with regrowth after 12 and 24 h. Three penicillin-susceptible strains were bacteriostatically inhibited by erythromycin at concentrations greater than or equal to the MIC by 6 h. One penicillin-susceptible strain (penicillin MIC, 0.06 microgram/ml) was bacteriostatically inhibited by penicillin G at 24 h at the MIC or at one-half the MIC; a bactericidal effect was found only with penicillin G at concentrations of > or = 0.25 microgram/ml. At 10 min after inoculation a 1- to 3-log10-unit reduction (90 to 99.9%) in the original inoculum was seen for 6 of 10 strains with RP 59500 at concentrations greater than or equal to the MIC. This effect was not found with any of the other compounds tested. A bactericidal effect was found at > or = 6 h with RP 59500 at concentrations of one-half to one-quarter the MIC in 7 of 10 strains, and a bacteriostatic effect was found in 3 or 10 strains, with regrowth at 24 h. One penicillin-resistant strain was examined by the time-kill methodology at 0, 1, 2, and 3 h. RP 59500 at a concentration equal to the MIC was bactericidal within 1 h, and at a concentration of one-half the MIC it was bactericidal within 3 h. This phenomenon was not seen with the other antimicrobial agents tested. Regrowth of strains at ciprofloxacin concentrations equal to the MIC or at a one-half to one-quarter the MIC was found. For sparfloxacin, three of the four penicillin-susceptible strains and two of four penicillin-resistant strains were bacteriostatically inhibited by 6 h. Bactericidal effects were found at 6, 12, and 24 h with both intermediate-resistant, one penicillin-susceptible, and two penicillin-resistant strains. Complete killing was observed with vancomycin at concentrations greater than MIC. Of the new compounds tested, RP 59500 and sparfloxacin show promise for the treatment of infections caused by penicillin-susceptible and -resistant pneumococci. The clinical significance of rapid killing by RP 59500 remains to be determined.

Anti-Infective Agents↗
PubMed1995

Treatment of experimental endocarditis due to erythromycin-susceptible or -resistant methicillin-resistant Staphylococcus aureus with RP 59500.

RP 59500 is a new injectable streptogramin composed of two synergistic components (quinupristin and dalfopristin) which are active against erythromycin-susceptible and -resistant gram-positive pathogens. The present experiments compared the therapeutic efficacy of RP 59500 with that of vancomycin against experimental endocarditis due to either of two erythromycin-susceptible or two constitutively erythromycin-resistant isolates of methicillin-resistant Staphylococcus aureus. RP 59500 had low MICs for the four test organisms as well as for 24 additional isolates (the MIC at which 90% of the isolates were inhibited was < 1 mg/liter) which were mostly inducibly (47%) or constitutively (39%) erythromycin resistant. Aortic endocarditis in rats was produced with catheter-induced vegetations. Three-day therapy was initiated 12 h after infection, and the drugs were delivered via a computerized pump, which permitted the mimicking of the drug kinetics produced in human serum by twice-daily intravenous injections of 7 mg of RP 59500 per kg of body weight or 1 g of vancomycin. Both antibiotics reduced vegetation bacterial titers to below detection levels in ca. 70% of animals infected with the erythromycin-susceptible isolates (P < 0.05 compared with titers in controls). Vancomycin was also effective against the constitutively resistant strains, but RP 59500 failed against these isolates. Further experiments proved that RP 59500 failures were related to the very short life span of dalfopristin in serum (< or = 2 h, compared with > or = 6 h for quinupristin), since successful treatment was restored by artificially prolonging the dalfopristin levels for 6 h. Thus, RP 59500 is a promising alternative to vancomycin against methicillin-resistant S. aureus infections, provided that pharmacokinetic parameters are adjusted to afford prolonged levels of both of its constituents in serum. This observation is also relevant to humans, in whom the life span of dalfopristin in serum is also shorter than that of quinupristin.

Animals↗
PubMed1996

Mechanism of action potential prolongation by RP 58866 and its active enantiomer, terikalant. Block of the rapidly activating delayed rectifier K+ current, IKr.

BACKGROUND: The class III antiarrhythmic agent RP 58866 and its active enantiomer, terikalant, are reported to selectively block the inward rectifier K+ current, IK1. These drugs have demonstrated efficacy in animal models of cardiac arrhythmias, suggesting that block of IK1 may be a useful antiarrhythmic mechanism. The symmetrical action potential (AP)-prolonging and bradycardic effects of these drugs, however, are inconsistent with a sole effect on IK1. METHODS AND RESULTS: We studied the effects of RP 58866 and terikalant on AP and outward K+ currents in guinea pig ventricular myocytes. RP 58866 and terikalant potently blocked the rapidly activating delayed rectifier K+ current, IKr, with IC50S of 22 and 31 nmol/L, respectively. Block of IK1 was approximately 250-fold less potent; IC50S were 8 and 6 mumol/L, respectively. No significant block of the slowly activating delayed rectifier, IK1, was observed at < or = 10 mumol/L. The phenotypical IKr currents in mouse AT-1 cells and Xenopus oocytes expressing HERG were also blocked 50% by 200 to 250 nmol/L RP 58866 or terikalant, providing further conclusive evidence for potent block of IKr. RP 58866 < or = 1 mumol/L and dofetilide increased AP duration symmetrically, consistent with selective block of IKr. Only higher concentrations (> or = 10 mumol/L) of RP 58866 slowed the rate of AP repolarization and decreased resting membrane potential, consistent with an additional but substantially less potent block of IK1. CONCLUSIONS: These data demonstrate that RP 58866 and terikalant are potent blockers of IKr and prompt a reinterpretation of previous studies that assumed specific block of IK1 by these drugs.

Action Potentials↗
PubMed1991

The new K+ channel opener Aprikalim (RP 52891) reduces experimental infarct size in dogs in the absence of hemodynamic changes.

The objective of the present study was to determine the effect of a novel K+ channel opener, Aprikalim (RP 52891; [trans-(-)-N-methyl-2-(3-pyridyl)-2-tetrahydrothio-pyran carbothiamide-1-oxide]), on myocardial infarct size in barbital-anesthetized dogs subjected to 90 min of left circumflex coronary artery occlusion followed by 5 hr of reperfusion. To determine if RP 52891 is mediating its effects by opening adenosine triphosphate regulated potassium channels (KATP), glibenclamide, a KATP channel antagonist was used. Dogs were pretreated with vehicle, a nonhypotensive dose of RP 52891 (10 micrograms/kg + 0.1 microgram/kg/min i.v.), glibenclamide (1 mg/kg; i.v. bolus) or RP 52891 (10 micrograms/kg and 0.1 microgram/kg/min i.v.) after pretreatment with glibenclamide (1 mg/kg i.v. bolus). At the end of reperfusion, myocardial infarct size was determined by triphenyltetrazolium staining. There were no significant differences in systemic hemodynamics, myocardial oxygen demand, collateral blood flow or ischemic bed size among groups with the exception of an increase in coronary blood flow to the ischemic area at 3 and 5 hr of reperfusion in both RP-treated groups. However, myocardial infarct size, expressed as a percentage of the area at risk, was significantly (P less than .05) reduced (38%) by RP 52891 and significantly increased (38%) by glibenclamide (vehicle, 39 +/- 4%; RP 52891, 24 +/- 2%; and glibenclamide, 54 +/- 5%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Lipolytic action of a new alpha-2 adrenergic antagonist of the piperazinopyrimidine family: RP 55462.

Recent investigations have demonstrated the in vitro lipid mobilizing effects induced by alpha-2 adrenergic antagonist administration and have focused attention on the putative therapeutic interest of such compounds in the treatment of obesity as adjuvants in caloric restriction programs. We studied the impact of RP 55462 [6-chloro-4-(isopropylamino)-5-(methyl)-2, piperazinopyrimidine], a new alpha-2 adrenergic antagonist compound of the piperazinopyrimidine family, on fat cell function. The alpha-2-blocking properties of this agent, which had been defined initially on the brain were confirmed on adipocytes. RP 55462 competed with [3H]yohimbine binding sites on human fat cell membranes and inhibited the antilipolytic action of alpha-2-agonist compounds (UK 14304, clonidine and epinephrine) in human and hamster fat cells. It was also noticed that RP 55462 alone was able to activate lipolysis in isolated fat cells from various species (man, rat, hamster and dog). Moreover, the lipolytic response induced by isoproterenol or synacthene was largely amplified in the presence of RP 55462 in rat fat cells which are the least alpha-2 adrenergic responsive tested. RP-55462-dependent stimulation of lipolysis was not affected by the presence of other alpha-2 adrenergic antagonists (idazoxan, yohimbine or phentolamine). Intravenous administration of RP 55462 in alert dogs promoted an increment in plasma nonesterified acid concentrations reflecting its lipid mobilizing action. In summary this study focuses attention on a new alpha-2-antagonist compound which exhibits an in vivo lipid mobilizing action which could be attributable to its alpha-2 adrenergic antagonist properties. Inasmuch as the lipolytic activity of RP 55462, revealed in in vitro studies, seems to be independent from its alpha-2 adrenolytic properties; further studies are required to define the mechanism of such a lipolytic effect as well as its possible involvement in in vivo conditions.

Adenosine Deaminase↗
PubMed1989

Apparent competition between ATP and the potassium channel opener RP 49356 on ATP-sensitive K+ channels of cardiac myocytes.

The mechanism whereby RP 49356, a novel potassium channel opener, activates ATP-sensitive K+ channels (K+-ATP channels) in isolated cardiac cells was investigated with the patch-clamp technique. When directly applied onto the inner face of an inside-out membrane patch, RP 49356 (300 microM) had no effect on K+ channels opened in an ATP-free solution. In contrast, the same concentration of the drug reactivated K+-ATP channels that had experienced spontaneous "run-down" of their activity following long recording periods. In cell-attached experiments, externally applied RP 49356 (300 microM) opened K+-ATP channels at 35 degrees in spite of the high intracellular ATP concentration, which was sufficient to prevent channel openings in the absence of the drug. In control conditions, the dose-response relation for ATP closing the channels had a Hill coefficient of 2.37 and a half-inhibition concentration of 56 microM. With 30 microM RP 49356 present in the intracellular medium, the slope factor of this relation was unchanged but the curve was shifted to the right, with a half-inhibition concentration of 515 microM. Conversely, the dose-response relation of RP 49356 activating K+-ATP channels was shifted to the right in a parallel manner under the influence of increasing concentrations of ATP. It is concluded that RP 49356 acts on cardiac K+-ATP channels by decreasing their sensitivity to ATP. Our results are consistent with an apparent competition between ATP and RP 49356.

Adenosine Triphosphate↗
PubMed1988

[3H]52770 RP, a platelet-activating factor receptor antagonist, and tritiated platelet-activating factor label a common specific binding site in human polymorphonuclear leukocytes.

In human polymorphonuclear leukocytes (PMNs), the tritiated platelet activating factor ([3H]PAF) labels in a saturable manner a single class of binding sites with a Kd of 3.5 +/- 0.5 nM (n = 7) and a maximum binding capacity (Bmax) of 206 +/- 13 fmol/2.5 X 10(6) PMNs (n = 7). 52770 RP, a nonphospholipid antagonist of PAF receptors, fully and competitively displaced the [3H]PAF from its binding sites with a Ki of 7.0 +/- 0.7 nM (n = 4). The high potency and the low solubility in cellular membranes of this compound led us to prepare [3H]52770 RP. This ligand was characterized by a binding which was rapid, reversible, confined to a single site, saturable, specific and stereoselective. Its Kd and Bmax were 4.2 +/- 0.3 nM and 181 +/- 11 fmol/2.5 X 10(6) PMNs, respectively. The stereoselectivity of the binding was suggested by the 600- and 1050-fold higher potency of the d-enantiomer with respect to l-52770 RP in displacing [3H]52770 RP or [3H]PAF, respectively. Several PAF analogs (e.g., lyso-PAF, 2-O-methyl-lyso-PAF), which are poorly active as PAF receptor agonists in functional tests, were weak displacers of [3H]PAF and [3H]52770 RP. Furthermore, for a series of 14 known PAF receptor agonists or antagonists belonging to different chemical families, there was an excellent correlation (r = 0.98) between their ability to displace [3H]PAF and [3H]52770 RP. Thus, [3H]52770 RP and [3H]PAF appear to interact with the same binding site on human PMNs which is proposed to be the PAF receptor mediating functional responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed1993

The cyclic-AMP antagonist adenosine-3',5'-cyclic monophosphosphorothioate, RP-isomer inhibits parathyroid hormone induced bone resorption, in vitro.

Stimulation of osteoclastic bone resorption is mediated via the osteoblasts. In order to investigate the second messenger events that cause the osteoblasts to initiate bone resorption we have evaluated the effect of the cyclic AMP antagonist adenosine-3'5'-cyclic monophosphosphorothioate, Rp-isomer (Rp-cAMPS) on bone resorption in vitro, by measuring the release of prelabelled 45Ca from cultured neonatal mouse calvarial bones. Forskolin (FSK, at and above 10 nM), an agent that enhances cyclic AMP-formation, stimulated bone resorption in 96 h cultures. Addition of Rp-cAMPS to the incubation media dose-dependently inhibited bone resorption induced by FSK (0.5 microM), with total inhibition obtained at 30 microM Rp-cAMPS. Bone resorption stimulated by parathyroid hormone (PTH, 0.1-10 nM, 72 h) was also inhibited by Rp-cAMPS (30 microM), while bone resorption induced by 1.25(OH)2D3 (1-10 nM, 72 h) was unaffected by Rp-cAMPS. These data demonstrate that PTH and 1,25(OH)2D3 cause bone resorption via different mechanisms and that cyclic AMP is the major second messenger in PTH-induced bone resorption.

Animals↗
PubMed1978

Clinical studies of the movement-related cortical potential (MP) and the relationship between the dentatorubrothalamic pathway and readiness potential (RP).

In order to investigate the influence of basal ganglia and cerebellar involvement on the preparatory state of the cerebral cortex for voluntary movement, the cortical potential preceding finger movement was studied in 20 patients with Parkinson's disease and 20 patients with cerebellar ataxia. Readiness potential (RP) was abnormal in 90% of the Parkinson group and in 55% of the cerebellar ataxia group. The most frequent abnormality was a depressed amplitude and earlier onset of RP in both groups. The most remarkable finding in the present study was the complete absence of RP with dyssynergia cerebellaris myoclonica (presumed Ramsay Hunt syndrome) whereas normal RP was obtained with cerebellar cortical degeneration. In addition, RP was absent or severely depressed in patients with a unilateral vascular lesion of the midbrain (Benedikt's syndrome) and in patients with Parkinson's disease who underwent unilateral intermedioventral (Vim) thalamotomy. These facts suggest a possible important role of the dentatorubrothalamic or dentatothalamic pathway in the physiogenesis of RP.

Adolescent↗
PubMed1985

Influence of RP 40749 on basal and meal-stimulated serum-gastrin, serum-pepsinogen I, and gastrin-content of the antral mucosa in duodenal ulcer patients.

Eighteen patients with active duodenal ulcer were treated with a novel antisecretory drug, RP 40749, either 100 mg or 150 mg as a daily nocturnal dose for 28 days. In these patients we evaluated the clinical course, endoscopic healing rates after 28 days, routine laboratory parameters, basal serum gastrin and pepsinogen I levels, meal-stimulated serum gastrin concentration, and the gastrin content of the antral mucosa. All nine patients receiving 150 mg RP 40749 and eight of nine patients receiving 100 mg RP 40749 healed their ulcers completely within 28 days, becoming rapidly symptom-free after an average of three days. The basal (53.8 +/- 5.2 vs 99.8 +/- 11.4 pg/ml) and meal-stimulated serum gastrin levels (109.2 +/- 12.1 vs 189.2 +/- 16.7 pg/ml) rose significantly after treatment with RP 40749, as did the gastrin content of the antral mucosa (11.3 +/- 2.1 vs 26.0 +/- 5.1 micrograms/g), suggesting increased synthesis and secretion of gastrin. Between the 100 mg and 150 mg groups, no significant differences in response were observed. Serum pepsinogen I levels (64.9 +/- 7.3 vs 147.9 +/- 17.9 ng/ml) increased after treatment; the increase after 150 mg RP 40749 was significantly greater than that after 100 mg RP 40749. The increase of serum pepsinogen levels are probably due to a spillover effect resulting from a blockade in exocrine secretion into the lumen. There were no relevant changes in routine laboratory parameters.

Adult↗
PubMed1992

Post-antibiotic effect of the new streptogramin RP 59500.

The post-antibiotic effect (PAE) of RP 59500, a new streptogramin antibiotic, was determined for Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Streptococcus pneumoniae, and Streptococcus pyogenes. A 30 min exposure of Staphylococcus aureus to 5 micrograms/ml of RP 59500 produced a PAE of 1.9-6.9 h, and a 60 min exposure of 2.5 micrograms/ml produced a PAE of 3.2-8 h. A 30 min exposure of 5 micrograms/ml of RP 59500 of coagulase-negative staphylococci produced a PAE of 2.5-7.5 h. PAEs of constitutively erythromycin-resistant staphylococcal isolates were shorter than were the PAEs of highly susceptible isolates. A 30 min exposure to 5 micrograms/ml of RP 59500 produced a PAE of 7.5-9.5 h for Streptococcus pneumoniae and a PAE of greater than 18 h for Streptococcus pyogenes. RP 59500 produced a longer PAE with Staphylococcus aureus than did vancomycin, oxacillin or erythromycin. These results suggest that RP 59500 may be administered less frequently than would be suggested by its half-life.

Clindamycin↗
PubMed1991

Effects of RP 52028 and phenobarbital on mRNA levels of inducible and constitutive sex-specific cytochrome P450 isozymes in rat liver.

Sex-related differences in basal levels of mRNA coding for various cytochrome P450 isozymes and their inducibility by 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3- isoquinoline carboxamide (RP 52028) in comparison to phenobarbital (PB) were investigated in Sprague-Dawley rats. We observed that the inducible isozymes, namely cytochromes P450IIB1/2 and P450IIIA1/2 were barely detectable in non-induced animal livers. On the contrary, mRNAs coding for two constitutive forms of cytochrome, P450IIC7 and IIC11, were expressed at a high level in untreated rats in a sex-dependent manner. Cytochrome P450IIC11 mRNA was present in male rats only whereas P450IIC7 was expressed in both sexes but at a higher level in female rats. RP 52028 had a dose-dependent inducing effect on the P450IIB1/2 and IIIA1/2 isoforms in both sexes. After administration of a high dose (500 mg/kg), this molecule exhibited a pattern of induction similar to that of PB. Increases in the accumulation of these IIB1/2 and IIIA1/2 messengers were correlated with protein data, suggesting that RP 52028, like PB, induces these isozymes mainly through a pretranslational regulatory mechanism. On the other hand, PB and RP 52028 caused only a slight increase, less pronounced than in Wistar rats, in the mRNA level of the constitutive female-predominant P450IIC7, indicating a strain-related difference in inducibility of this isozyme. RP 52028 had no effect on P450IIC11 mRNA level in male rat liver, in contrast to the decreasing effect obtained with PB. Furthermore, the non-correlated changes in P450IIC11 mRNA level and microsomal testosterone 2 alpha-hydroxylase activity after treatment with RP suggests that this molecule modulates the expression of P450IIC11 at a posttranscriptional level only.

Animals↗
PubMed1989

Glibenclamide is a competitive antagonist of cromakalim, pinacidil and RP 49356 in guinea-pig pulmonary artery.

The relaxant effect of cromakalim (BRL 34915), pinacidil and RP 49356 (N-methyl-2-(3-pyridyl)-tetrahydro-thiopyran-2-carbothioamide-1-ox ide) on the sustained contractions induced by 20 mM KCl were compared with the effects of nicorandil. The preparation used was vascular smooth muscle of phenoxybenzamine-treated pulmonary artery rings from reserpinized guinea-pigs. Cromakalim, pinacidil, RP 49356 and nicorandil relaxed the tissues with -log EC50 values of 6.78, 6.12, 6.02 and 5.46, respectively. The inhibitory effect of cromakalim, pinacidil and RP 49356, but not of nicorandil, was competitively antagonized by glibenclamide (10(-7)-3 X 10(-6) M), yielding uniform pA2 values of 7.17-7.22 against all three relaxant drugs. The order of potency of other K+ channel blocking agents for the inhibition of vasorelaxation by cromakalim, pinacidil and RP 49356 was procaine greater than 4-aminopyridine greater than tetraethylammonium. The mainly competitive type of inhibition of the RP 49356-induced response was more comparable to that with pinacidil than with cromakalim. The relaxation caused by nicorandil was only attenuated by a high concentration of 4-aminopyridine or tetraethylammonium but was markedly antagonized by methylene blue (3 X 10(-6)-10(-5) M) and potentiated by M & B 22948 (3 X 10(-6)-10(-5) M). These results suggest that the vascular relaxation caused in guinea-pig pulmonary artery by cromakalim, pinacidil and RP 49356 is mediated through the same glibenclamide-sensitive K+ channel whereas the major mechanism for the effect of nicorandil seems to involve stimulation of guanylate cyclase.

Animals↗
PubMed1992

[3H]RP 62203, a ligand of choice to label in vivo brain 5-HT2 receptors.

There are only a few ligands available for labelling brain receptors simply because in vivo binding requires more severe experimental conditions than in vitro binding. We now describe the in vivo binding properties of [3H]RP 62203, a new potent and selective 5-HT2 antagonist. After intravenous injection into rats, [3H]RP 62203 accumulated predominantly in brain regions containing 5-HT2 receptors, with a frontal cortex/cerebellum ratio of 6 to 7. A good correlation was obtained between the regional distribution of [3H]RP 62203 in the brain and the density of 5-HT2 receptors measured in vitro. In vivo binding of [3H] RP 62203 was saturable in the frontal cortex but not in the cerebellum. The Bmax in the frontal cortex was equal to 42.5 fmol/mg, thus in the same range as was found in vitro. The 5-HT2 selectivity was ascertained by displacement (prevention) experiments; 5-HT2 antagonists or the agonist 2,5-dimethoxy- 4-iodophenylisopropylamine could prevent specific labelling of [3H]RP 62203 only in brain regions containing 5-HT2 receptors. Interestingly, the radioactivity remaining in various brain regions after displacement with pipamperone corresponded exactly to that measured in the cerebellum, with or without pipamperone. In conclusion, [3H]RP 62203 possesses striking properties of in vivo binding which make it a suitable candidate for examining 5-HT2 receptors in human brain by positron emission tomography scanning.

Amphetamines↗
PubMed1992

RP-30A: new tracer for detection of changes in testicular blood flow in rat torsion model.

RP-30A is a radioactive tracer being evaluated for the detection of regional myocardial blood flow. This study compares RP-30A to technetium 99m pertechnetate as radioactive tracers for the detection of testicular blood flow changes in early testicular torsion. The left testis of adult male Sprague-Dawley rats was subjected to either thirty or sixty minutes of 720 degrees torsion. Injections of RP-30A or 99mTc-pertechnetate followed by sacrifice and scintillation counting of the testes was performed. No significant difference was detected between the torted testes and the right control testes in both groups receiving 99mTc-pertechnetate and the thirty-minute group receiving RP-30A. The torted testes of the sixty-minute group receiving RP-30A revealed a significant difference (decrease) in uptake indicating that RP-30A may be a more sensitive tracer in detecting testicular blood flow changes in early testicular torsion.

Animals↗
PubMed1988

Immunopotentiating activities of a low molecular weight lipopeptide, RP 56 142--studies in infectious models.

RP 56 142, N2-[N-(N-lauroyl-L-alanyl)-gamma-D glutamyl] L,L-2,6-diaminopimelamic acid belongs to a family of immunomodulating lipopeptides. Its structure is directly derived from that of lauroyltetrapeptide RP 40 639 which is a mixture of two stereoisomers, one of which (with D,D-2,6 diaminopimelamic acid) is totally devoid of in vivo activity. RP 56 142 displayed potent protective activities against bacterial infections such as K. pneumoniae, L. monocytogenes or S. typhimurium (at doses ranging between 0.03 and 100 mg/kg s.c., i.p., i.v.). In combined treatment protocols, suboptimal doses of RP 56 142 given preventively (day-1) or curatively (day 0 + 4h) significantly protected mice receiving antibiotics at doses which were ineffective when administered by themselves. Given s.c. 1 or 2 days before infectious challenge, RP 56 142 was able to normalize and even enhance significantly the resistance of mice previously immunocompromised by lomustine, 5-fluorouracile or hydrocortisone. These results correlated with the stimulation of the clearance of a virulent Salmonella typhimurium strain and with an important production of colony-stimulating factor in RP 56 142-treated mice.

Adjuvants, Immunologic↗
PubMed1991

Mechanical, biochemical and electrophysiological studies of RP 49356 and cromakalim in guinea-pig and bovine trachealis muscle.

Experiments have been performed using guinea-pig and bovine trachealis in order to determine whether cromakalim and RP 49356 share the same relaxant action and to analyse the mechanisms underlying this action. RP 49356 was approximately 3 times less potent than cromakalim in suppressing the spontaneous tone of guinea-pig trachea and, like cromakalim, was antagonised by glibenclamide and by phentolamine. Biochemical studies showed that relaxant concentrations of cromakalim and RP 49356 did not alter the cAMP or cGMP content of guinea-pig trachealis muscle and did not inhibit cAMP or cGMP hydrolysis by tracheal homogenates. Like cromakalim, RP 49356 caused marked hyperpolarisation of guinea-pig trachealis cells. Patch clamp recording using inside-out membrane patches from bovine trachealis showed that cromakalim, RP 49356, glibenclamide and phentolamine were each without effect on the open state probability (Popen) of large conductance, Ca(2+)-activated K(+)-channels. We conclude that cromakalim and RP 49356 share a similar action in opening K(+)-channels in the trachealis cell membrane. This action probably does not involve the intracellular accumulation of cyclic nucleotides and the channel involved is not the large conductance, Ca(2+)-dependent K(+)-channel.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗