Cardiovascular Drugs and Therapy 1996;10:251-262. © Kluwer Academic Publishers, Boston. Printed in U.S.A. Drug Withdrawal and Rebound Hypertension: Differential Action of the Central Antihypertensive Drugs Moxonidine and Clonidine Heinz Rupp, Bernhard Maisch, and Christian G. Brilla Institute of Physiology, University of Tiibingen and Center of Internal Medicine, Division of Cardiology, Molecular Cardiology Laboratory, University of Marburg, Marburg, Germany Summary. To examine the antihypertensive action of the cen- trally acting antiadrenergic drugs moxonidine and clonidine, systolic and diastolic blood pressure as well as heart rate were monitored by radio telemetry in spontaneously hyper- tensive rats (SHR) with established high blood pressure. In- creasing 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 re- duced further, reaching values that were below those of un- treated sleeping rats. When 1.3 mg/kg/day clonidine was dis- continued, systolic as well as diastolic blood pressure increased above pretreatment values within I 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 occured also after withdrawal of 0.3 mg/kg/day clon- idine in normotensive rats, the rebound phenomenon was in- dependent 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 dem- onstrate distinct differences in the mode of action of moxo- nidine and clonidine, which can be accounted for by specific interactions of moxonidine with imidazoline Ii-receptors, whereas clonidine would interact not only with Ii-receptors but also with alpha2-adrenoceptors, and most probably also with the vagal activity. In view of our previous studies dem- onstrating a rise in blood pressure and heart rate after a hypercaloric dietary intake, the selective Ii-receptor agonist moxonidine appears particularly appropriate for treating overweight hypertension associated with an enhanced sympa- thetic 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. Cardiovasc Drugs Ther 1996;10:251-262 Key Words. rebound, hypertension, moxonidine, clonidine, imidazoline 11receptor, alpha2 receptor A crucial determinant of primary hypertension is the sympathetic outflow of the brain. In Western industri- alized societies, a number of lifestyle factors have been identified with a synergistic action on sympa- thetic outflow. Of particular relevance proved to be nutritional disorders associated with an excess caloric intake and psychosocial stress [1]. Since an excess sympathetic outflow of the brain has multiple unfavor- able actions, drugs that specifically reduce an excess sympathetic outflow could be efficient in the preven- tion of catecholamine-mediated organ damage [2-4]. However, until recently centrally acting antihyper- tensive drugs that reduce sympathetic outflow showed side effects that limited their general use [5]. Thus, clonidine, which acts on alpha2-adrenoceptors as well as imidazoline receptors, results in side effects that are mainly linked to central and peripheral alphae-adrenoceptors [6-8]. One had thus to rely on drugs that act peripherally and reduce adrenergic in- fluences by blocking adrenoceptors. In the last few years, a second generation of predominantly centrally acting antihypertensive agents, moxonidine and ril- menidine, which are selective for imidazoline recep- tors, became available [9,10]. Moxonidine has a higher selectivity for imidazoline receptors than rilmenidine [11]. The imidazoline receptors are located in the ros- tral ventrolateral medulla of the brain and are in- volved in excitatory pathways, leading to enhanced sympathetic outflow. To characterize potential differ- ences in the action of moxonidine and clonidine, we used radiotelemetry for monitoring cardiovascular pa- rameters in conscious spontaneously hypertensive (SHR) and normotensive Wistar/WU rats. Address for correspondence:Heinz Rupp, Ph.D., Center of Internal Medicine, MolecularCardiology Laboratory,Universityof Marburg, Karl-von-Frisch-Str 1, 35033Marburg, Germany. Received 7 December1995; accepted4 February 1996 251