AGE-RELATED ALTERATION OF INHIBITORY EFFE CTS OF ISRADIPINE ON ALPHA(1)-ADRENOCEPTOR MEDIATED RESPONSES

We studied age-related alteration of inhibitory effects of a Ca2+ chan nel antagonist, isradipine, on alpha(1)-adrenoceptor mediated response s in 6-, 10-, and 40-week-old rats. Age-related changes were observed in the inhibitory effects of isradipine on the norepinephrine-induced maximum contractions in the isolated thoracic aorta, the amplitude of the Ca2+-evoked increase of intracellular Ca2+ concentration and susta ined contraction in fura-2-loaded preparations and the maximum number of binding sites (B-max) of [H-3](+)-isradipine to aortic membranes. T he dissociation constant (K-D) of [H-3](+)-isradipine did not alter wi th age. In anesthetized rats, isradipine inhibited the dose-response c urves of norepinephrine on the blood pressure in 6- and 40-week-old an imals more effectively than those in 10-week-old animals. An inverse r elationship between the potency of norepinephrine in the isolated thor acic aorta, the inhibitory effects of isradipine the norepinephrine-in duced maximum contractions and the logarithm of B-max obtained in the [H-3](+)-isradipine binding experiment were found. These results sugge st that the age-related alteration of inhibitory effects of isradipine on alpha(1)-adrenoceptor mediated contractile responses and the incre ase of blood pressure are due to changes in the alpha(1)-adrenoceptor density and the population of voltage-dependent L-type Ca2+ channels, rather than changes in the affinity of drug to the alpha(1)-adrenocept or or Ca2+-sensitivity of contractile elements of aortic smooth muscle .