Adrenergic and Nonadrenergic Effects of Imidazoline and Related Antihypertensive Drugs in the Brain and Periphery

In radioligand binding studies the alpha 2-adrenoceptor antagonist ligand [3H]yohimbine binds exclusively to adrenergic sites. However, in addition to binding to alpha 2-adrenoceptor sites, two other ligands, [3H]clonidine and [3H]idazoxan, also bind at nonadrenergic imidazoline sites. Many of the compounds with a high affinity for these imidazoline sites are centrally acting antihypertensive drugs and there is some evidence that these sites are involved in blood pressure regulation. With chronic treatment of rabbits with guanabenz, clonidine, and rilmenidine, down regulation of alpha 2 but not imidazoline sites occurred in forebrain and hindbrain with guanabenz treatment, and in hindbrain with clonidine treatment. However, no change in either imidazoline or alpha 2-adrenoceptor binding site number occurred in animals given chronic rilmenidine treatment. This rank order of effect, guanabenz greater than clonidine greater than rilmenidine, is consistent with the alpha 2-adrenoceptor activation by the three drugs in the periphery. In contrast, chronic treatment with guanabenz, clonidine, and rilmenidine had similar effects on blood pressure, heart rate, and responses to intracisternal clonidine. We suggest that stimulation of alpha 2-adrenoceptors cannot account for all the changes in cardiovascular responses observed on chronic treatment and that activation of nonadrenergic imidazoline-preferring sites may contribute to the antihypertensive properties of imidazoline and related compounds.