Age-related alteration of alpha(1)-adrenoceptor mechanisms and Ca2+ inhibitory effects of isradipine.
The effects of age on alpha1-adrenoceptor and Ca2+ channel-mediated contractile mechanisms in the thoracic aorta, isolated from rats of 3, 6, 10, 18 and 40 weeks old, were studied. The potency (pD(2) value) of norepinephrine increased with age from 3 to 10 weeks, but decreased thereafter from 10 to 40 weeks. The change in pD(2) value of norepinephrine was proportional to the logarithm of the maximum number of binding sites (B(max)), obtained in the [(3)H]prazosin binding study. The inhibitory effect of a potent Ca(2)+ channel blocker, israpidine, on the norepinephrine-induced contraction decreased with age from 3 to 10 weeks, but increased in rats aged 10 to 40 weeks. An inverse relationship between the change in isradipine inhibition, the maximum reduction of isradipine on norepinephrine-induced contraction and the logarithm of B(max) was found. The inhibitory effect of a nonselective Ca2+ channel blocker, SKF96365, on the norepinephrine-induced contraction did not change with age. The amplitude of the Ca2+-induced sustained contraction, after pretreatment with isradipine (10(-7) M) in the presence of norepinephrine (10(-6) M), increased with age from 3 to 10 weeks, but decreased thereafter in rats aged 10 to 40 weeks. There was no significant difference in the slope of the regression lines between the cytosolic Ca(2)+ level ([Ca2+]i) and the tension in the presence of norepinephrine at different ages. These results suggest that the changes in alpha(1)-adrenoceptor mechanisms and the reduction by isradipine with age are due to changes in the alpha1-adrenoceptor density and the population of Ca2+ channels, but not to changes in the affinity of drugs to the alpha1-adrenoceptor or Ca2+ sensitivity of contractile elements of aortic smooth muscles.
Satoh
M
M
Department of Chemical Pharmacology, Toho University School of Pharmaceutical Sciences, Miyama, Funabashi, Chiba, Japan.
Kanai
S
S
Ashikawa
N
N
Takayanagi
I
I
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology; D017275:Isradipine / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000037:antagonists & inhibitors; D011224:Prazosin / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D002121:Calcium Channel Blockers; D007093:Imidazoles; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D002118:Calcium; D009638:Norepinephrine; D011224:Prazosin; D017275:Isradipine