In vitro pharmacological profile of PHA-022121, a small molecule bradykinin B receptor antagonist in clinical development.

PHA-022121 is a novel small molecule bradykinin B receptor antagonist, in clinical development for the treatment and prevention of hereditary angioedema attacks. The present study describes the in vitro pharmacological characteristics of PHA-022121 and its active metabolite, PHA-022484 (M2-D). In mammalian cell lines, PHA-022121 and PHA-022484 show high affinity for the recombinant human bradykinin B receptor with K values of 0.

Pharmacological Profile of a New Small Molecule Bradykinin B Receptor Antagonist.

We here report the discovery and early characterization of Compound 3, a representative of a novel class of small molecule bradykinin (BK) B receptor antagonists, and its superior profile to the prior art B receptor antagonists Compound 1 and Compound 2. Compound 3, Compound 2, and Compound 1 are highly potent antagonists of the human recombinant B receptor (K values 0.24, 0.

The Electro-Mechanical window: a risk marker for Torsade de Pointes in a canine model of drug induced arrhythmias.

Background And Purpose: In cardiovascular pharmacology, electrical and mechanical events can be distinguished, and the phrase 'electro-mechanical window' (EMw) describes the temporal difference between these events. We studied whether changes in EMw have potential predictive value for the occurrence of arrhythmias in fentanyl/etomidate-anaesthetized beagle (FEAB) dogs.

Experimental Approach: The EMw was calculated as differences between the QT interval and QLVP(end) in FEAB dogs during atrial pacing, treatment with isoprenaline or atropine, body temperature changes and induction of Torsade de Pointes (TdP) in an LQT1 model.

Localization of extracellular superoxide dismutase in rat lung: neutrophils and macrophages as carriers of the enzyme.

Immunohistochemistry (IHC) and in situ hybridization (ISH) was used to localize extracellular superoxide dismutase (EC-SOD) and its mRNA in rat lung before and after a lipopolysaccharide (LPS)- and hyperoxia-induced inflammation. In control rats, EC-SOD mRNA was synthesized in macrophages and in cells of the arterial vessel walls and the alveolar septa. The EC-SOD protein was mainly localized in plasma and on the apical side of the epithelial cells located near bronchus-associated lymphoid tissue (BALT).

Epithelial modulation of cholinergic responses in rabbit trachea is partly due to neutral endopeptidase activity.

By the simultaneous measurement of acetylcholine release and smooth muscle contraction in rabbit tracheal segments with and without epithelium, pre- as well as postsynaptic effects of this cell layer were studied on cholinergic neurotransmission. The epithelial cell layer exerted a presynaptic inhibitory influence on acetylcholine release, induced by KCl and electrical stimulation, with a concomitant decrease in the smooth muscle contractions. The responses elicited by exogenous acetylcholine, acting postsynaptically, were also inhibited in the presence of the epithelium.

Sephadex induced granulomatous reaction in rats.

Granuloma formation in the rat lung after single or repeated i.v. injections, intratracheal instillation and intradermal implantation of Sephadex beads was studied over a time period from 3 h to 3 mo.

Effects of enantiomers of M3 antagonists on muscarinic receptors in rabbit trachea.

The effects of the enantiomers of structurally related chiral M3 antagonists (trihexyphenidyl, p-fluorohexahydrodifenidol, hexahydrodifenidol and p-fluorohexbutinol) were studied at the presynaptic M2 and postsynaptic M3 receptor level in the rabbit trachea. All isomers were M3- over M2-selective as they did not increase the release of acetylcholine (an M2 effect) at concentrations that significantly inhibited smooth muscle contraction (an M3 effect). At the smooth muscle receptor, the R-enantiomers were consistently more potent than the S-enantiomers.

Selective M3 muscarinic receptor antagonists inhibit smooth muscle contraction in rabbit trachea without increasing the release of acetylcholine.

Although five muscarinic receptor subtypes have now been cloned, only three receptor subtypes have been demonstrated pharmacologically in bronchial tissue (designated M1, M2 and M3). By using drugs that show selectivity for these receptor subtypes, in combination with a sensitive and specific high-pressure liquid chromatography method that enables the direct measurement of acetylcholine (ACh) release, the existence and function of these muscarinic receptor subtypes was investigated in rabbit trachea in vitro. Atropine and ipratropium bromide, nonselective antimuscarinic agents, dose-dependently suppressed contraction of rabbit trachea induced by transmural electrical stimulation, but at the same time enhanced the release of ACh, suggesting the presence of an autoregulatory feed-back system.

In vitro effects of tremorgenic mycotoxins.

Paxilline was isolated from Penicillium paxilli (NRRL 6110). It was studied together with penitrem B and verruculogen in the electrically stimulated guinea pig ileum. All three mycotoxins enhanced the electrically induced twitch contractions, without influencing the contractions provoked by exogenous acetylcholine.