Effects of aging on α₁-adrenoceptor mechanisms and the inhibitory effect of diltiazem on noradrenaline maximum response in isolated rat aortic preparation

Abstract

The effects of aging on alpha 1-adrenoceptor mechanisms in aortic preparations isolated from 3-, 6-, 10-, 18-, and 40-week-old rats were studied and compared with serotonin receptor mechanisms in the same preparations. The potency (pD2 value) of noradrenaline increased with age from 3 to 10 weeks, but decreased thereafter with age from 10 to 40 weeks. The affinity (pKA value) of noradrenaline and of prazosin (pA2 value) did not alter with aging. The change in potency or the pD2 value of noradrenaline was proportional to receptor reserve (pD2-pKA value) for noradrenaline, suggesting that the change of potency of noradrenaline with age was due to a change of receptor reserve, but not to change of drug affinity to alpha 1-adrenoceptors. The potency (pD2 value) and affinity (pKA value) of serotonin, and the affinity (pA2 value) of ketanserin, did not alter with aging, suggesting that serotonin receptor mechanisms in rat aorta did not change with age. The inhibitory effect of diltiazem on noradrenaline maximum response decreased with age from 3 to 10 weeks, but increased with age from 10 to 40 weeks. An inverse relationship between changes of diltiazem inhibition and receptor reserve of noradrenaline was found. Diltiazem's inhibitory effect on serotonin maximum response did not alter with aging.

Effects of aging on .ALPHA.1-adrenoceptor mechanisms in the isolated mouse aortic preparation

“…However, age-related change in the potency of noradrenaline was not a unidirectional increment or decrement but was biphasic in its characteristic; the noradrenaline potency increased significantly from 5-to 10-weeks whereas it decreased thereafter from 10-to 40-weeks. This biphasic feature of age-related change in the noradrenaline potency is well consistent with the findings in rat thoracic aorta (Takayanagi et al, 1989) and rat vas deferens (Takayanagi et al, 1987), the noradrenaline-induced contractions of which are mediated primarily through α1-AR. These findings in the mouse and the rat suggest that α1-AR-mediated contractile process in thoracic aorta changes with aging.…”

“…This view is strongly supported by several lines of evidence obtained in the studies employing vascular beds from the rat (Docherty, 1988;Hyland et al, 1987;McAdams and Waterfall, 1986;Takayanagi et al, 1989) and the rabbit (Hayashi and Toda, 1978). In this regard, Takayanagi et al provided evidence showing that potency of noradrenaline in eliciting aortic contraction exhibits biphasic changes depending on weekly-age in the rat; pD2 value (an index of agonistic potency) of noradrenaline increases from 3-to 10-weeks whereas it decreases from 10-to 40-weeks (see Table 1) (Takayanagi et al, 1989). Based on the investigations into the changes in the affinities of noradrenaline (pKA value) and prazosin (pA2 value), the biphasic changes in noradrenaline potency with weekly aging was indicated to be ascribed to a drug affinity-unrelated ingredient (an alteration in receptor reserve).…”

“…However, this possibility may be ruled out since pA2 value of prazosin vs. noradrenaline did not change with aging. In this regard, Takayanagi et al (Takayanagi et al, 1989) also reported that the pA2 value of prazosin vs. noradrenaline was practically the same from 3-to 40-weeks, precluding the possible variations in drug affinity to α1-ARs. They also showed that pKA value (minus logarithm of dissociation constant) of noradrenaline, an index of the affinity of noradrenaline vs. α1-ARs, was consistent from 3-to 40-weeks, strongly supporting the view that drug affinity to α1-ARs remains invariable without being affected by aging (Takayanagi et al, 1989).…”

“…In this regard, Takayanagi et al (Takayanagi et al, 1989) also reported that the pA2 value of prazosin vs. noradrenaline was practically the same from 3-to 40-weeks, precluding the possible variations in drug affinity to α1-ARs. They also showed that pKA value (minus logarithm of dissociation constant) of noradrenaline, an index of the affinity of noradrenaline vs. α1-ARs, was consistent from 3-to 40-weeks, strongly supporting the view that drug affinity to α1-ARs remains invariable without being affected by aging (Takayanagi et al, 1989). On the other hand, pD2 values of noradrenaline in different aged rat were found to be proportional to the differences between pD2 and pKA values (pD2 -pKA values) (Takayanagi et al, 1989).…”

“…J. Pharmacol. 67: 1398-1402(1989. subdivided into α1A, α1B, and α1D, the cloned counterparts of which correspond to α1a, α1b, and α1d (Muramatsu et al, 1995;Muramatsu et al, 1990;Shibano et al, 2002).…”