Cardiovasc Drugs Ther 1996 Jun;10 Suppl 1:251-62

Drug withdrawal and rebound hypertension: differential action of the central antihypertensive drugs moxonidine and clonidine.

Rupp H, Maisch B, Brilla CG

Institute of Physiology, University of Tubingen, Germany.

To examine the antihypertensive action of the centrally acting antiadrenergic
drugs moxonidine and clonidine, systolic and diastolic blood pressure as well
as heart rate were monitored by radio telemetry in spontaneously hypertensive
rats (SHR) with established high blood pressure. Increasing doses were
administered with regular rat chow for 6-8 day periods. Moxonidine reduced (p <
0.05) diastolic blood pressure at a dose of 8 mg/kg/day and systolic blood
pressure at 13 mg/kg/day. Heart rate was reduced during high activity of rats
corresponding to an antitachycardiac action. After withdrawal of 18 mg/kg
administered for only 1 day, blood pressure returned to pretreatment values
within 8 days. Clonidine reduced systolic and diastolic blood pressure at 0.3
mg/kg/day. At 0.8 and 1.3 mg/kg/day, systolic blood pressure reduction was less
pronounced, although heart rate was reduced further, reaching values that were
below those of untreated sleeping rats. When 1.3 mg/kg/day clonidine was
discontinued, systolic as well as diastolic blood pressure increased above
pretreatment values within 1 day. A rebound was also observed in heart rate,
which increased by 150 beats/ min. A comparable rebound in blood pressure was
observed after withdrawal of 0.3 mg/kg/day. Since a blood pressure rebound
occurred also after withdrawal of 0.3 mg/kg/day clonidine in normotensive rats,
the rebound phenomenon was independent of the presence of high blood pressure.
No blood pressure rebound was observed when moxonidine (8 mg/kg/ day) was
administered (chow or gavage) in normotensive rats. These findings in
unanesthetized undisturbed rats demonstrate distinct differences in the mode of
action of moxonidine and clonidine, which can be accounted for by specific
interactions of moxonidine with imidazoline I1-receptors, whereas clonidine
would interact not only with I1-receptors but also with alpha2-adrenoceptors,
and most probably also with the vagal activity. In view of our previous studies
demonstrating a rise in blood pressure and heart rate after a hypercaloric
dietary intake, the selective I1-receptor agonist moxonidine appears
particularly appropriate for treating overweight hypertension associated with
an enhanced sympathetic outflow of the brain. Of importance in this respect is
that a moxonidine-induced reduction in sympathetic outflow was not associated
with a gain in body weight but resulted in reduced caloric intake.