Acceleration by chronic treatment with clorgyline of the turnover of brain alpha 2-adrenoceptors in normotensive but not in spontaneously hypertensive rats
التفاصيل البيبلوغرافية
العنوان:
Acceleration by chronic treatment with clorgyline of the turnover of brain alpha 2-adrenoceptors in normotensive but not in spontaneously hypertensive rats
1. The aim of this study was to quantitate and compare the turnover of alpha 2-adrenoceptors in the cerebral cortex of normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats, and its modulation during chronic treatment with the monoamine oxidase (MAO) inhibitor, clorgyline. 2. In SHR, the specific binding of the agonist [3H]-UK 14304 and of the antagonist [3H]-RX 821002 was significantly reduced in the brain (Bmax 15-19% lower) as compared to that in sex- and age-matched WKY rats. In contrast, no significant changes in the Kd values for both radioligands were found between WKY and SHR rats. Therefore, SHR rats offer a genetic model with a lower density of alpha 2-adrenoceptors in the brain. 3. Chronic treatment (21-35 days) with clorgyline (1 mg kg-1, i.p.) markedly decreased the density of brain alpha 2-adrenoceptors ([3H]-UK 14304 binding) in Sprague-Dawley (Bmax reduced by 50%) and in WKY (Bmax reduced by 30%) rats without any apparent change in the affinity of the radioligand. In contrast, the density of brain alpha 2-adrenoceptors in SHR was not down-regulated by chronic clorgyline treatment. 4. The recovery of [3H]-UK 14304 binding after irreversible inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; 1.6 mg kg-1) (an alkylating agent for the alpha 2-adrenoceptor) was assessed in control and clorgyline-treated (1 mg kg-1; i.p. for 7-21 days) WKY and SHR rats to study the process of alpha 2-adrenoceptor repopulation and to calculate receptor turnover parameters. 5. The simultaneous analysis of receptor recovery curves revealed that the turnover of brain alpha2-adrenoceptors in SHR rats was accelerated (k = 0.141 day-1;t 1/2= 4.9 days; r/k =40 fmol mg-1 protein)compared to that in WKY rats (k = 0.085 day-1; tl/2= 8.1 days; r/k = 54 fmol mg-1 protein) and that the reduced density of cortical alpha2-adrenoceptors (Bmax or r/k values) in SHR was probably due to an abnormal higher receptor degradation (delta k = 66%) and not to a decreased receptor synthesis which in fact showed a slight increase (delta r = 24%).6. Treatment with clorgyline (1 mg kg-1, i.p. for 21 days) accelerated the turnover of brain alpha2-adrenoceptors in WKY rats (k = 0.328 days-1; tl/2= 2.1 days; r/k = 29 fmol mg-1 protein) and the greater increase in receptor degradation (delta k = 286%) over receptor synthesis (delta r = 109%) led to down-regulation of receptor density (r/k = 46% lower). In contrast, treatment with clorgyline did not modify significantly the turnover of brain M2-adrenoceptors in SHR (k = 0.192 days-1; t1/2 = 3.6 days;r/k = 39 fmol mg-1 protein), indicating that in this genetic model of hypertension, the desensitized alpha2-adrenoceptors cannot be further down-regulated by clorgyline treatment and that they lack the expected adaptative increase in receptor synthesis.
