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Acceleration by chronic treatment with clorgyline of the turnover of brain α 2 ‐adrenoceptors in normotensive but not in spontaneously hypertensive rats
Author(s) -
Ribas Catalina,
Miralles Antonio,
GarcíaSevilla Jesús A.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13777.x
Subject(s) - clorgyline , endocrinology , medicine , chemistry , agonist , antagonist , radioligand , monoamine oxidase , monoamine oxidase b , receptor , serotonin , enzyme , biochemistry
1 The aim of this study was to quantitate and compare the turnover of α 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 [ 3 H]‐UK 14304 and of the antagonist [ 3 H]‐RX 821002 was significantly reduced in the brain ( B max 15–19% lower) as compared to that in sex‐ and age‐matched WKY rats. In contrast, no significant changes in the K d values for both radioligands were found between WKY and SHR rats. Therefore, SHR rats offer a genetic model with a lower density of α 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 α 2 ‐adrenoceptors ([ 3 H]‐UK 14304 binding) in Sprague‐Dawley ( B max reduced by 50%) and in WKY ( B max reduced by 30%) rats without any apparent change in the affinity of the radioligand. In contrast, the density of brain α 2 ‐adrenoceptors in SHR was not down‐regulated by chronic clorgyline treatment. 4 The recovery of [ 3 H]‐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 α 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 α 2 ‐adrenoceptor repopulation and to calculate receptor turnover parameters. 5 The simultaneous analysis of receptor recovery curves revealed that the turnover of brain α 2 ‐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 ; t 1/2 = 8.1 days; r / k = 54 fmol mg −1 protein) and that the reduced density of cortical α 2 ‐adrenoceptors ( B max or r / k values) in SHR was probably due to an abnormal higher receptor degradation (Δk = 66%) and not to a decreased receptor synthesis which in fact showed a slight increase (Δ r = 24%). 6 Treatment with clorgyline (1 mg kg −1 , i.p. for 21 days) accelerated the turnover of brain α 2 ‐adrenoceptors in WKY rats ( k = 0.328 days −1 ; t 1/2 = 2.1 days; r / k = 29 fmol mg −1 protein) and the greater increase in receptor degradation (Δ k = 286%) over receptor synthesis (Δ 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 α 2 ‐adrenoceptors in SHR ( k = 0.192 days −1 ; t 1/2 = 3.6 days; r / k = 39 fmol mg −1 protein), indicating that in this genetic model of hypertension, the desensitized α 2 ‐adrenoceptors cannot be further down‐regulated by clorgyline treatment and that they lack the expected adaptative increase in receptor synthesis.