Cardiovascular Effects of Withdrawal of Some Centrally Acting Antihypertensive Drugs in the Rat

We have studied on the cardiovascular effects appearing after termination of 12 day continuous infusions with clonidine (500 μg/kg/day), guanfacine (10 mg/kg/day), azeoexole (B‐HT 933, 10 and 60 mg/kg/day) and α‐methyldopa (200 mg/kg/day) in conscious spontaneously hypertensive rats. The infusions of the four drugs reduced the mean arterial pressure to approximately the same extent. Following withdrawal of clonidine, a marked overshoot of heart rate and a period of blood pressure lability appeared, together with an elevation of the plasma noradrenaline concentration. The severities of the withdrawal responses after cessation of infusion with clonidine and azepexole were comparable, whereas those observed after guanfacine and α‐methyldopa were of an insignificant degree. Precipitation of the discontinuation symptoms by i.p. injection of yohimbine (3 and 10 mg/kg) at day 12 of the infusions resulted in equally severe responses in clonidine‐ and guanfacine‐treated animals, whereas those observed in α‐methyldopa treated rats were absent or much less severe. Morphine and oxymetazoline suppress the appearance of blood pressure upswings after clonidine withdrawal when applied intracerebroventricularly (10 and 30 μg/kg, respectively). The withdrawal tachycardia is abolished by i.p. injection of 30 μg oxymetazoline/kg, but not by morphine (up to 10 mg/kg). 7 These results indicate, that cessation of prolonged α 2 ‐adrenoceptor stimulation by imidazolines or azepexole leads to a cardiovascular withdrawal syndrome. Central as well as peripheral factors play a role in this phenomenon.