The effect of the tachykinin NK(2) receptor antagonist, nepadutant (MEN 11420 or (c(beta-D-GlcNAc)Asn-Asp-Trp-Phe-Dpr-Leuc(2beta-5beta))) was assessed on cardiovascular function (unanaesthetized rats ...and anaesthetized dogs) and gastrointestinal motor activity (fasted unanaesthetized dogs). The selective tachykinin NK(2) receptor agonist, betaAla(8)neurokinin A (4-10), up to 100 nmol/kg, i.v., did not produce changes on mean blood pressure or heart rate in unanaesthetized rats. Nepadutant did not affect blood pressure and heart rate up to 10 micromol/kg, whereas saredutant (SR 48968 or ((S)-N-methyl-N4-(4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)butyl benzamide), a nonpeptide antagonist, produced a transient reduction of mean blood pressure and heart rate. Nepadutant up to 20 micromol/kg, i.v. neither caused changes of cardiovascular and respiratory parameters in anaesthetized dogs nor induced any changes in left ventricular systolic pressure, left ventricular dP/dt or of electrocardiogram (lead II) waveforms. Intravenous administration of neurokinin A (9 nmol/kg) in unanaesthetized dogs stimulated gastrointestinal motility for 20-25 min. Nepadutant at 0.1 micromol/kg suppressed the stimulant effects of neurokinin A but, up to a dose of 10 micromol/kg, did not produce significant changes in the basal migrating motor complexes. We conclude that tachykinin NK(2) receptors do not participate in the physiologic regulation of resting cardiovascular and respiratory functions and that they do not regulate the fasted pattern of gastrointestinal motility. The cardiovascular changes induced by the nonpeptide tachykinin NK(2) receptor antagonist, saredutant, likely arise from nonspecific effects unrelated to tachykinin NK(2) receptor blockade.
Bradykinin (BK) is a vasoactive peptide reputed to play an important role in cardiovascular homeostasis. In this study, we describe the cardiovascular changes (mean blood pressure (BP) and heart rate ...(HR)) induced by the i.v. administration (left jugular vein) of two selective kinin B
2
receptor antagonist, namely icatibant (0.11 µmol/kg as a bolus) and MEN11270 (0.11 µmol/kg as a bolus or 1 µmol/kg infused in 15 or 60 min), in urethane-anaesthetized or conscious rats with an indwelling catheter implanted in the right carotid artery for BP measurements. In conscious rats, icatibant at 0.1 or 0.3 µmol/kg did not change BP but at 0.1 µmol/kg increased HR at 30 min from administration. MEN11270 at 0.1 or 0.3 µmol/kg induced a dose-related increase in BP and a concomitant bradycardia (significant at 0.3 µmol/kg) lasting for 5 or 30 min, respectively. Icatibant at 1 µmol/kg induced a slight (P < 0.05) increase in BP that resolved in 5 min and a biphasic tachycardia (peaks at 30 and 90 min from administration). MEN11270 at 1 µmol/kg induced a triphasic change in HR (tachycardia in the first 5 min, bradycardia at 30 min, and tachycardia at 90 and 120 min) and a biphasic change in BP (hypotension at 15 min and hypertension at 30 min). The i.v. infusion of MEN11270 (1 µmol/kg in 15 or 60 min) produced hypertension, whereas HR was increased only following the 15-min infusion. In urethane-anaesthetized rats, both icatibant and MEN11270 (0.1 µmol/kg as a bolus) increased BP and the onset for this effect was correlated with the time course of the antagonism of BK-induced hypotension, where the effect of MEN11270 was more rapid than that of icatibant. These results indicate that kinin B
2
receptor antagonists can induce acute cardiovascular effects, and the reason for the different haemodynamic profile between icatibant and MEN11270 could be putatively attributed to kinetic characteristics.Key words: icatibant, MEN11270, bradykinin, blood pressure, heart rate.
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DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
3HMEN 11420, a radiolabeled glycosylated peptide antagonist of the tachykinin NK2receptor, has been investigated in ligand-receptor binding assays using membranes of CHO cells transfected with the ...human tachykinin NK2receptor. 3HMEN 11420 bound to a single class of high affinity binding sites: its binding was inhibited by natural tachykinins (potency ranking: NKA ⪢ SP ≥ NKB), as well as by peptide (MEN 11420 > MEN 10376 ⪢ R 396) and nonpeptide (SR 48968 > GR 159897) selective NK2receptor antagonists. These data indicate that 3HMEN 11420 is a potent radioligand for the human tachykinin NK2receptor that may represent a useful tool for studying ligand-receptor interactions at the molecular level.
We used membranes from Chinese hamster ovary cells stably transfected with the human tachykinin NK(2) receptor, either wild-type or mutated, at four aromatic residues (His(198), Tyr(266), Phe(270), ...Tyr(289)) located in transmembrane segments V to VII, to assess the role of these residues in the binding of natural tachykinins and peptide and nonpeptide antagonists. Three radioligands, the agonist (125)Ineurokinin A (NKA), the peptide antagonist (3)HMEN 11420, and the nonpeptide antagonist (3)HSR 48968 bound to the wild-type receptor with high affinity (K(d) = 2.4 nM, 0.3 nM, and 4.0 nM, respectively). Four of the six mutant receptors tested retained high affinity for at least one of the radioligands. H(198)A mutation abrogated the binding of NKA but not that of MEN 11420 or SR 48968 (K(d) = 4.8 and 11.5 nM, respectively); Y(266)F mutation abrogated the binding of MEN 11420 but not that of NKA or SR 48968 (K(d) = 2.8 nM and 1.2 nM, respectively); F(270)A mutation abrogated the binding of both NKA and MEN 11420 but not that of SR 48968 (K(d) = 1.6 nM); Y(289)F mutation abrogated the binding of SR 48968 but not that of NKA and MEN 11420 (K(d) = 2.0 and 2.9 nM, respectively). Y(266)A and Y(289)A mutations abrogated the binding of all radioligands. Among the unlabeled antagonists, the affinity of the nonpeptide GR 159897, at variance with SR 48968, resulted heavily compromised by H(198)A and Y(266)F mutations; the peptide antagonists R396 and MEN 10376 essentially followed the binding profile of NKA, but R396 showed markedly increased affinity for the Y(289)F mutant receptor. Taken together, these results indicate that different, partially overlapping sets of sites may be involved in the binding of agonists and diverse antagonists to the human tachykinin NK(2) receptor.
super(3)HMEN 11420, a radiolabeled glycosylated peptide antagonist of the tachykinin NK sub(2) receptor, has been investigated in ligand-receptor binding assays using membranes of CHO cells ...transfected with the human tachykinin NK sub(2) receptor. super(3)HMEN 11420 bound to a single class of high affinity binding sites: its binding was inhibited by natural tachykinins (potency ranking: NKA Gt SP greater than or equal to NKB), as well as by peptide (MEN 11420 > MEN 10376 Gt R 396) and nonpeptide (SR 48968 > GR 159897) selective NK sub(2) receptor antagonists. These data indicate that super(3)HMEN 11420 is a potent radioligand for the human tachykinin NK sub(2) receptor that may represent a useful tool for studying ligand-receptor interactions at the molecular level.
The objective of our study was to evaluate the effects of the apolipoprotein E (ApoE) phenotype and gender on the response to tacrine treatment in Alzheimer's disease (AD). ApoE phenotyping was ...performed on 76 patients treated with tacrine for AD. This group comprised 33 ApoE epsilon4 allele carriers (epsilon4+) and 43 non-epsilon4 carriers (epsilon4-). Patients were treated blindly in relation to the ApoE phenotype, with incremental tacrine dosages ranging from 40 mg/day up to the highest dosage (160 mg) tolerated without side-effects. At least 6 weeks elapsed between each increase. Changes in the scores for the Alzheimer Disease Assessment Scale-Cognitive Component (ADAS-Cog) between baseline and each increment in dosage were assessed in the epsilon4- and epsilon4+ groups. The cut-off point for being considered as responsive to tacrine treatment was a 4-point decrease in the ADAS-Cog score. There was no tendency for the epsilon4- carriers to respond better than the epsilon4+ carriers. When patients were stratified by gender, no differences were found between the effects of the treatment on men and women. Consequently, these results do not support the hypothesis that the ApoE phenotype and gender are predictors of the response to tacrine in AD patients.
Caerulein (C)-induced delay in gastric emptying (GE), due to pylorospasm, was used as an experimental model for a quantitative test of the activity of some spasmolytic drugs in conscious rats. ...Rociverine at doses of 10 and 15 mg kg-1 i.p., though not at higher doses, considerably reduced this delay. Of the other drugs tested only papaverine had this effect and to a lesser degree. Atropine, N-butylscopolammonium bromide and dicyclomine proved to be inactive or further reduced GE. The effect of spasmolytics on C pylorospasm seems to be the outcome of two actions possessed by the drugs in varying degree: on the one hand a pyloric sphincter relaxant action, which increases GE, and on the other a relaxant action on the smooth musculature of the stomach, which tends to reduce GE. The model used highlights the activity of the spasmolytics that act on pylorospasm at doses which per se do not cause a marked delay in GE.
![Characterization of [3H]MEN...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0006-291X/small "Characterization of [3H]MEN 11420, a Novel Glycosylated Peptide Antagonist Radioligand of the Tachykinin NK2Receptor")
