CHARACTERIZATION OF THE ALPHA-ADRENOCEPTOR-MEDIATED EFFECTS AND ANTIHYPERTENSIVE ACTIVITY OF ICI-106270 - COMPARISON WITH CLONIDINE

  • 1 January 1984
    • journal article
    • research article
    • Vol. 229  (1) , 58-66
Abstract
Clonidine and ICI 106270 are centrally acting antihypertensive agents which act through stimulation of medullary .alpha.2 adrenoceptors. Both compounds are equipotent agonists at .alpha.2 adrenoceptors as assessed in functional studied in isolated organs and in radioligand binding studies. Clonidine and ICI 106270 possess the same degree of selectivity for .alpha.2 adrenoceptors over .alpha.1 adrenoceptors. Clonidine and ICI 106270 are equipotent antihypertensive agents after intracisternal administration to spontaneously hypertensive rats, consistent with the observations made in vitro that both compounds are equipotent .alpha.2 adrenoceptor agonists. Both compounds were less potent in lowering blood pressure i.v. administration than that intracisternal administration, thus confirming a central mechanism of action. Clonidine was a more potent antihypertensive agent than ICI 106270 after i.v. administration, which, in view of the equal potencies observed after intracisternal administration, suggests that diffusion of ICI 106270 into the CNS is selectively retarded, relative to clonidine, by the blood-brain barrier. The differences observed in the rate of penetration of the blood-brain barrier are consistent with the higher pKa and corresponding higher extent of ionization (at physiological pH) and lower lipophilicity of ICI 102670 relative to clonidine. A relatively large difference between the i.v. and p.o. [oral] antihypertensive potencies was observed for ICI 106270 which indicates poor p.o. absorption of ICI 106270 relative to clanidine, again likely resulting from the greater proportion of ICI 106270 existing in the ionized species. The potency difference between clonidine and ICI 106270 for p.o. antihypertensive efficacy is similar to the potency difference observed for sedative activity after p.o. administration to spontaneously hypertensive rats, suggesting that ICI 106270 had a similar propensity as clonidine to produce sedation at therapeutic doses.