Alpha 1-adrenoceptor subtype affinities of drugs for the treatment of prostatic hypertrophy. Evidence for heterogeneity of chloroethylclonidine-resistant rat renal alpha 1-adrenoceptor.

Abstract

We have used radioligand binding and inositol phosphate accumulation studies to determine the affinity at mixed alpha 1A- and alpha 1B-adrenoceptors (rat cerebral cortex and kidney), alpha 1A-adrenoceptors (rat cerebral cortex and kidney following inactivation of alpha 1B-adrenoceptors by chloroethylclonidine treatment) and alpha 1B-adrenoceptors (rat spleen) for drugs currently under investigation for the treatment of benign prostatic hypertrophy, alfuzosin, naftopidil and (-)- and (+)-tamsulosin. Alfuzosin and naftopidil had similar affinities in all model systems (approximately 10 nM and 130 nM, respectively) and lacked relevant selectivity for alpha 1-adrenoceptor subtypes. Their potency to inhibit noradrenaline-stimulated inositol phosphate formation in cerebral cortex matched their affinities as determined in the binding studies. Tamsulosin had higher affinity at alpha 1A- than at alpha 1B-adrenoceptors, and was slightly more potent than alfuzosin and naftopidil at alpha 1B- and considerably more potent at alpha 1A-adrenoceptors. However, the interaction of the tamsulosin isomers with chloroethylclonidine-insensitive (alpha 1A-like) adrenoceptors was complex. A detailed analysis of the tamsulosin data and those obtained with other drugs, most notably noradrenaline and oxymetazoline, suggested that chloroethylclonidine-insensitive alpha 1-adrenoceptors may be heterogeneous and that this heterogeneity may differ between cerebral cortex and kidney of the rat.

• Authors: M C Michel, R Büscher, J Kerker, H Kraneis, W Erdbrügger, O E Brodde
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 348 Issue 4 Pg. 385-95 (Oct 1993) ISSN: 0028-1298 [Print] Germany
• PMID: 7506392 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Alkylating Agents
• Inositol Phosphates
• Receptors, Adrenergic, alpha-1
• chlorethylclonidine
• Clonidine

Topics

• Alkylating Agents (pharmacology)
• Animals
• Centrifugation, Density Gradient
• Cerebral Cortex (drug effects, metabolism)
• Clonidine (analogs & derivatives, pharmacology)
• Drug Resistance
• In Vitro Techniques
• Inositol Phosphates (metabolism)
• Kidney (drug effects, metabolism)
• Liver (drug effects, metabolism)
• Male
• Membranes (drug effects, metabolism)
• Prostatic Hyperplasia (drug therapy)
• Radioligand Assay
• Rats
• Rats, Wistar
• Receptors, Adrenergic, alpha-1 (drug effects, metabolism)