Precipitation by yohimbine of the withdrawal syndromes of clonidine, guanfacine, and methyldopa in the spontaneously hypertensive rat.
In conscious spontaneously hypertensive (SH) rats, continuously infused with clonidine (500 micrograms/kg/day s.c.) for 12 days, yohimbine (3 or 10 mg/kg i.p.) dose dependently precipitated an overshoot of heart rate and other withdrawal symptoms, such as blood pressure upswings, diarrhea, ptosis, body shivering, jumping, and wet-dog shakes. Naloxone (3 or 30 mg/kg i.p.) or prazosin (1 mg/kg i.p.) did not evoke withdrawal signs in clonidine-treated SH rats. In SH rats treated for 12 days with guanfacine (10 mg/kg/day s.c.), the administration of yohimbine elicited a withdrawal pattern similar in severity and appearance to that observed in clonidine-treated rats. In methyldopa-treated (200 mg/kg/day) SH rats, the yohimbine-precipitated withdrawal symptoms were much less pronounced than those observed in the clonidine- and guanfacine-treated animals, despite the equipotency of the infusions in reducing mean arterial pressure. These results indicate that the clonidine-withdrawal syndrome can be precipitated by acute alpha 2-adrenoceptor blockade. The previously observed minor severity of the guanfacine-discontinuation syndrome in the rat should be attributed to the longer half-life of this drug as compared to clonidine. On the other hand, alpha-methylnoradrenaline much less intensively triggers the mechanisms underlying withdrawal symptoms than clonidine or guanfacine.
D000818:Animals; D000959:Antihypertensive Agents / Q000009:adverse effects*; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000009:adverse effects*; D016316:Guanfacine; D006146:Guanidines / Q000009:adverse effects*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D008750:Methyldopa / Q000009:adverse effects*; D010648:Phenylacetates / Q000009:adverse effects*; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D013375:Substance Withdrawal Syndrome; D015016:Yohimbine / Q000494:pharmacology*
D000959:Antihypertensive Agents; D006146:Guanidines; D010648:Phenylacetates; D011942:Receptors, Adrenergic, alpha; D015016:Yohimbine; D016316:Guanfacine; D008750:Methyldopa; D003000:Clonidine; D011224:Prazosin