Drug withdrawal and rebound hypertension: differential action of the central antihypertensive drugs moxonidine and clonidine.
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.
Rupp
H
H
Institute of Physiology, University of Tubingen, Germany.
Maisch
B
B
Brilla
C G
CG
D000818:Animals; D000959:Antihypertensive Agents / Q000009:adverse effects* / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000009:adverse effects* / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced* / Q000188:drug therapy*; D007093:Imidazoles / Q000009:adverse effects* / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000209:etiology*; D013686:Telemetry / Q000379:methods
D000959:Antihypertensive Agents; D007093:Imidazoles; C043482:moxonidine; D003000:Clonidine