Characterization of the alpha adrenoceptor-mediated effects and antihypertensive activity of ICI 106270: comparison with clonidine.

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 studies in isolated organs and in radioligand binding studies. In addition, 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 after i.v. administration than after intracisternal administration, thus confirming a central mechanism of action. Interestingly, 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 central nervous system 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 106270 relative to clonidine. A relatively large difference between the i.v. and p.o. antihypertensive potencies was observed for ICI 106270 which indicates poor p.o. absorption of ICI 106270 relative to clonidine, again likely resulting from the greater proportion of ICI 106270 existing in the ionized species.(ABSTRACT TRUNCATED AT 250 WORDS)