Beta 2-adrenoceptor antagonists intensify clonidine withdrawal syndrome in conscious rats

Sudden cessation of prolonged treatment with clonidine in conscious rats evokes a cardiovascular withdrawal syndrome, characterized by severe tachycardia and brief blood pressure (BP) increases, so-called "upswings." Previously, adenylate cyclase-coupled alpha 2-adrenoceptors were shown to be involved in this phenomenon. In the present study, the effect on the intensity of clonidine withdrawal symptoms of concomitant treatment with various beta-adrenoceptor antagonists during clonidine infusion (100 micrograms/kg/24 h, 7 days) was investigated. Propranolol (18 mg/kg/24 h, beta 1 and beta 2 blocker) and ICI 118.551 (12 mg/kg/24 h, beta 2 blocker) clearly aggravated the withdrawal symptoms, whereas metoprolol (18 mg/kg/24 h, beta 1 blocker) did not affect the severity of the withdrawal syndrome. Accordingly, intensification of the withdrawal syndrome appears to be mediated by beta 2- rather than by beta 1-adrenoceptors. These results point to an interaction at the level of the second-messenger adenylate cyclase (AC) system in development of clonidine withdrawal syndrome.