INHIBITION BY THE TETRAMINE DISULPHIDE, BENEXTRAMINE, OF CARDIAC CHRONOTROPIC HISTAMINE H₂‐RECEPTOR‐MEDIATED EFFECTS

Abstract

1 Benextramine (N,N'-bis[o-methoxybenzylamino)-n-hexylJcystamine), which irreversibly blocks a-adrenoceptors and does not inhibit the HI-receptor-mediated contractile effect of histamine on guinea-pig isolated ileum, also did not inhibit the Hl-receptor-mediated inotropic effect of histamine on guinea-pig isolated atrium. 2 Benextramine irreversibly inhibited the H2-receptor-mediated chronotropic effect of histamine on guinea-pig isolated atrium. 3 Since its combination with the competitive H2-receptor blocking drug cimetidine had an additive blocking effect, benextramine appears to act directly on the chronotropic H2-receptor.

Increased alpha-adrenergic receptor affinity in resistance vessels from hypertensive rats.

“…Before the second NE concentration-response curve determination, the vessels were incubated with benextramine (3 x 10~9 M; Sigma) for 15 minutes, followed by a 30-minute period in which the PSS bathing the tissue was frequently changed. Benextramine has a similar mode of action to phenoxybenzamine; it is an irreversible a-adrenergic receptor antagonist 15 -' 6 and may have an advantage over phenoxybenzamine in measurement of the agonist dissociation constant (K A ) in that it has a lower lipid and higher water solubility and is more selective for the a-adrenergic receptor. Exposure to benextramine blocks irreversibly a fraction of the a-adrenergic receptors on the vascular smooth muscle cells.…”

Phenoxybenzamine and Benextramine, but Not 4-Diphenylacetoxy-N-[2-chloroethyl]piperidine Hydrochloride, Display Irreversible Noncompetitive Antagonism at G Protein-Coupled Receptors

“…Benextramine has been known to irreversibly bind to ␣ 2 -adrenoceptors (Melchiorre, 1981;Belleau et al, 1982b;Lew and Angus, 1984;Hieble et al, 1985;Timmermans et al, 1985;Taouis et al, 1987;McKernan et al, 1988;Brink et al, 2000;Umland et al, 2001), 5-HT 1A -serotonergic receptors (Stanton and Beer, 1997), H 2 -histaminergic receptors (Belleau et al, 1982a), and neuropeptide Y receptors (Melchiorre et al, 1994). Present knowledge regarding the mechanism of action of benextramine is limited to the observations from predominantly radioligand binding studies, and it is generally assumed that benextramine irreversibly inactivates the ligand (primary or syntopic) binding sites at these receptors.…”