Search

1. 3H-prazosin binds to brain alpha 1-adrenoceptors with high affinity (K(D) 25 degrees C approximately or equal to 1 nM). The number of binding sites in different regions of the brain varied from 44-114 fmoles/mg of protein: striatum = medulla oblongata less than hypothalamus less than cortex. 2. 3H-p-aminoclonidine labels brain alpha 1-adrenoceptors. Its binding capacity (66-209 fmoles/mg prot). is higher in the hypothalamus greater than cortex greater than striatum greater than or equal to medulla oblongata. Its affinity varies from one region to another (0.85 mM in cortex, 3.0 nM in hypothalamus). 3. S 3341 in a potent inhibitor of 3H-p-aminoclonidine like clonidine and a weak inhibitor of 3H-prazosin. 4. Comparison of the inhibitory effect of S 3341 and clonidine on the binding of 3H-prazosin and 3H-aminoclonidine indicates that S 3341 is 2-3 times more specific for alpha 2-adrenoceptors than clonidine. 5. Inhibition constants of S 3341 and clonidine (K1) are not identical in various brain regions but clonidine and S 3341 constants vary in parallel.

1. The radioreceptor assay for S 3341, an alpha 2-adrenergic agonist, is based on the ability of the S 3341 to compete with the specific binding of [3H] clonidine to alpha-receptors of rat cerebral cortex membranes. The technique described was used for S 3341 plasma determination. 2. S 3341 levels in plasma and blood pressure were measured in hypertensive subjects 1, 3, 5, 8, 12, 24 and 48 hours after ingestion of the drug. 3. The s 3341 plasma level rose to a maximum between the first and the third hours after ingestion and then declined, with a mean half-life of 14 hours. There were substantial inter-individual variations, ranging from 3 to 24 hours. 4. The fall in blood pressure mirrored the increase in the s 3341 plasma level during the three hours following the ingestion of the drug.

Several studies have suggested that clonidine, guanfacine and rilmenidine decrease systemic blood pressure by stimulating central alpha 2-adrenergic receptors. However, we have shown that these molecules interact not only with alpha 2-adrenergic but also a new type of "non catecholamine" receptor in rabbit and human renal proximal tubules. This receptor, which we have called the imidazoline-guanidium receptor site (IGRS) seems to be pharmacologically, biochemically and fractionally distinct from alpha 2-adrenergic receptors. In order to determine the relative affinity of rilmenidine for these two types of receptor, we studied its capacity to inhibit the liaison of (H3)-idazoxan, a ligand with a high affinity for the IGRS, and of (H3)-rauwolscine, a ligand selective for alpha 2-adrenergic receptors in the rabbit kidney. The results based on the apparent constants of inhibition (Ki) of the two radioligands [231 +/- 34 nM for (H3)-idazoxan and 2440 +/- 322 nM for (H3)-rauwolscine] showed that the selectivity of rilmenidine was 10 times greater for IGRS than for alpha 2-adrenergic receptors. This preferential activity on IGRS was confirmed by studies of the influx of Na22 into isolated renal proximal tubule cells of the rabbit. They showed that rilmenidine, in contrast to catecholamines, inhibited the transport of Na22 into the renal cells. In conclusion, the data from our studies shows that rilmenidine interacts with renal IGRS and inhibits cellular transport of sodium by a mechanism other than the stimulation of alpha 2-adrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Imidazolines have been proposed as highly selective drugs for alpha 2-adrenergic receptors. However, we have recently showed that the imidazoline ligand 3H-RX 781094 (idazoxan) binds to both alpha 2-receptors and imidazoline guanidinium receptive substance (IGRS) in rabbit renal proximal tubule. Binding of 3H-RX 781094 to the purified basolateral membranes (15-fold enriched in Na-KATPase activity) was rapid (t 1/2 = 5 mn.) reversible (t 1/2) = 4 mn.), saturable and of high affinity. Scatchard analysis of equilibrium binding data showed that 3H-RX 781094 labels 566 +/- 118 fmol/mg of proteins of binding sites with an apparent dissociation constant (Kd) of 1.45 +/- 0.14 nM. On the other hand, the non imidazoline ligand 3H-rauwolscine binds only to the alpha 2-adrenergic receptors with a maximal density of 155 +/- 28 fmol/mg of protein and a Kd of 11.5 +/- 1.5 nM. In order to define the relative affinity of the alpha-2-agonists, clonidine, rilmenidine and guanfacine for the two classes of receptors, we performed competition studies of the alpha 2-antagonists 3H-RX 781094 (imidazoline) and 3H-rauwolscine (non imidazoline) binding to basolateral membranes from rabbit proximal tubule. The order of potency for inhibition of the two radioligand binding was rilmenidine greater than clonidine greater than guanfacine for 3H-RX 781094 and clonidine greater than guanfacine greater than rilmenidine for 3H-rauwolscine. Therefore, rilmenidine displayed a higher affinity for IGRS than for alpha 2 adrenergic receptors; on the other hand, clonidine and guanfacine preferentially interact with alpha 2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)