benzofurans and harman

This study has used receptor autoradiography to characterize imidazoline binding sites (I-BS) in monoamine oxidase (MAO) A knockout and wild-type mice. A comparison between MAO-A and MAO-B, binding of the endogenous beta-carboline [(3)H]harmane, and I-BS, has been made using sections from brain and kidney. The loss of binding to MAO-A in the knockout animals was confirmed using the selective radioligand [(3)H]Ro41-1049, with labelling reduced to background levels. The binding of [(3)H]Ro19-6327 to MAO-B was unaffected, indicating no change in this isoform in response to the loss of MAO-A. A reduction in binding to the I(2)-BS, as labelled by both [(3)H]idazoxan and [(3)H]2-BFI (2-(2-benzofuranyl)-2-imidazoline), was seen in the MAO-A knockout animals in both brain and kidney sections, whereas binding to the I(1)-BS in kidney sections remained unchanged. The loss of I(2) binding was found to be regionally dependent and was positively correlated with the relative expression of MAO-A in specific regions in the wild-type animals. Using the MAO-A knockout mice it was also possible to demonstrate a non-MAO-A population of binding sites labelled by the putative I-BS endogenous ligand, harmane.

Topics: Animals; Autoradiography; Benzofurans; Binding Sites; Binding, Competitive; Brain; Cell Membrane; Epithelial Cells; Harmine; Idazoxan; Imidazoles; Imidazoline Receptors; Imidazolines; Iodine Radioisotopes; Kidney; Mice; Mice, Inbred C3H; Mice, Knockout; Monoamine Oxidase; Neurons; Picolinic Acids; Radioligand Assay; Receptors, Drug; Thiazoles

The beta-carboline, harmane (0.1 - 1.0 nmol) produces dose dependent hypotension when microinjected unilaterally into the rostral ventrolateral medulla (RVLM) of the anaesthetized rat. The potency of harmane on blood pressure is similar to that of the imidazoline, clonidine. The hypotensive effects of both clonidine and harmane are reversed by microinjection of the relatively I(1)-receptor selective antagonist efaroxan (20 nmol). These results are consistent with harmane acting at an I(1)-receptor in the RVLM. This is the first report of an endogenous ligand for I(1)-receptors that has central effects on blood pressure.

Topics: Adrenergic alpha-Agonists; Animals; Benzofurans; Blood Pressure; Clonidine; Harmine; Heart Rate; Hypotension; Imidazoles; Imidazoline Receptors; Male; Medulla Oblongata; Microinjections; Rats; Rats, Sprague-Dawley; Receptors, Drug